LYMPHOMAS

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LYMPHOMAS 2021
ESMO POCKET GUIDELINES
LYMPHOMAS
2021
GUIDELINES COMMITTEE
Chair: Giuseppe Curigliano; Deputy Chair: Cristiana Sessa; Steering Committee Members: Christian Buske,
Paolo G. Casali, Nathan Cherny, Nicoletta Colombo, Silke Gillessen, Karin Jordan, Sibylle Loibl, Jean-Pascal
Machiels, Matthias Preusser, Rolf A. Stahel, Arndt Vogel; Subject Editors: Paolo Ascierto, Eric Baudin, Alfredo
Berruti, Andrew Davies, Michel Ducreux, Caroline Even, Karim Fizazi, Francesca Gay, Nicolas Girard, Nadia
Harbeck, Mats Jerkeman, Karin Jordan, James Larkin, Jonathan Ledermann, Natasha Leighl, Erika Martinelli,
Olivier Michielin, Ana Oaknin, Shani Paluch-Shimon, Thomas Powles, Martin Reck, Carla Ripamonti, Daniele
Santini, Florian Scotté, Elizabeth Smyth, Silvia Stacchiotti, Michael Weller; International Coordinator of
Guidelines Adaptation in Asia Pacific: Takayuki Yoshino; Staff: Claire Bramley, Sarah Escuin, Catherine Evans,
Louise Green, Lone Kristoffersen, Svetlana Jezdic, Jennifer Lamarre, Richard Lutz, Keith McGregor, Teodora
Pavlova, George Pentheroudakis, Francesco Rho.
ESMO CLINICAL PRACTICE GUIDELINES

Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Eichenauer DA, Aleman BMP, André M, Federico M, Hutchings M, Illidge T, Engert A and Ladetto M, on behalf
of the ESMO Guidelines Committee
Ann Oncol 2018;29(Suppl 4):iv19–29
https://www.annalsofoncology.org/article/S0923-7534(19)31690-4/fulltext
Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, Walewski J, André M, Johnson
PW, Pfreundschuh M and Ladetto M, on behalf of the ESMO Guidelines Committee
Ann Oncol 2015;26(Suppl 5):v116–25
Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
Dreyling M, Campo E, Hermine O, Jerkeman M, Le Gouill S, Rule S, Shpilberg O, Walewski J and Ladetto M,
on behalf of the ESMO Guidelines Committee
Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis,
Kastritis E, Leblond V, Dimopoulos MA, Kimby E, Staber P, Kersten MJ, Tedeschi A and Buske C, on behalf
of the ESMO Guidelines Committee
Distributed with support from F. Hoffmann-La Roche Ltd.

F. Hoffmann-La Roche Ltd has not influenced the content of this publication.
2
Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis,
Willemze R, Hodak E, Zinzani PL, Specht L and Ladetto M, on behalf of the ESMO Guidelines Committee
https://www.annalsofoncology.org/article/S0923-7534(19)31693-X/fulltext
Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis,
d’Amore F, Gaulard P, Trümper L, Corradini P, Kim W-S, Specht L, Bjerregaard Pedersen M and Ladetto M,
on behalf of the ESMO Guidelines Committee
Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma:
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Vitolo U, Seymour JF, Martelli M, Illerhaus G, Illidge T, Zucca E, Campo E and Ladetto M, on behalf of the ESMO
Guidelines Committee
Hairy cell leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Robak T, Matutes E, Catovsky D, Zinzani PL and Buske C, on behalf of the ESMO Guidelines Committee
Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis,
Zucca E, Arcaini L, Buske C, Johnson PW, Ponzoni M, Raderer M, Ricardi U, Salar A, Stamatopoulos K,
Thieblemont C, Wotherspoon A and Ladetto M, on behalf of the ESMO Guidelines Committee
Ann Oncol 2020;31(1):17–29
Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up
Dreyling M, Ghielmini M, Rule S, Salles G, Ladetto M, Tonino SH, Herfarth K, Seymour JF and Jerkeman M, on
behalf of the ESMO Guidelines Committee
Ann Oncol 2021:32(3):298-308
3
Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up
Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann CU, Kater AP, Gregor M, Cymbalista F, Buske C, Hillmen P,
Hallek M and Mey U, on behalf of the ESMO Guidelines Committee
Ann Oncol 2021:32(1):23-33
4
ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE
FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.
This quick reference booklet provides you with the most important content
of the ESMO Clinical Practice Guidelines (CPGs) on the management of
lymphomas (Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell
lymphoma, follicular lymphoma, Waldenström’s macroglobulinaemia, marginal
zone lymphoma, primary cutaneous lymphomas, peripheral T-cell lymphomas,
extranodal diffuse large B-cell lymphoma and primary mediastinal B-cell
lymphoma, chronic lymphocytic leukaemia and hairy cell leukaemia). Key content
includes diagnostic criteria, staging of disease, treatment plans and follow-
up. The ESMO CPGs on lymphomas are intended to provide you with a set of
recommendations for the best standards of care for lymphoma, using evidence-
based medicine. Implementation of ESMO CPGs facilitates knowledge uptake and
helps you to deliver an appropriate quality of focused care to your patients.
Please note that this document is not exhaustive and it may be important to refer
to the full CPGs for critical clinical decision-making.
The approval and licensed indication of drugs mentioned in this pocket guideline
may vary in different countries. Please consult your local prescribing information.
This booklet can be used as a quick reference guide to access key content on
evidence-based management of lymphomas.
Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the

full guidelines.
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12-28
HODGKIN LYMPHOMA (HL)
DIAGNOSIS.............................................................................................................12
STAGING AND RISK ASSESSMENT........................................................................12
TREATMENT OF CLASSICAL HL.............................................................................14
Limited-stage disease.............................................................................................14
Intermediate-stage disease.....................................................................................16
Advanced-stage disease..........................................................................................18
Relapsed disease....................................................................................................20
TREATMENT OF NODULAR LYMPHOCYTE-PREDOMINANT HL (NLPHL)...............21
Stage IA without risk factors...................................................................................21
Other stages............................................................................................................21
Relapsed NLPHL.....................................................................................................22
RESPONSE EVALUATION........................................................................................22
PROGNOSIS...........................................................................................................22
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP..........................22
SUMMARY RECOMMENDATIONS FOR HL.............................................. 24
28-41
DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
DIAGNOSIS.............................................................................................................28
TREATMENT...........................................................................................................31
Young low-risk patients (aaIPI = 0) without bulky disease......................................33
Young low-intermediate-risk patients (aaIPI = 1) or IPI low-risk
(aaIPI = 0) patients with bulky disease....................................................................33
Young high-risk and high-intermediate-risk patients (aaIPI ≥ 2).............................33
Patients aged 60-80 years.......................................................................................34
Patients aged > 80 years.........................................................................................34
Central nervous system prophylaxis.......................................................................34
Special considerations for some DLBCLs...............................................................35
Response evaluation...............................................................................................35
FOLLOW-UP............................................................................................................36
6
Relapsed and refractory DLBCL..............................................................................36
PERSONALISED MEDICINE....................................................................................37
SUMMARY RECOMMENDATIONS FOR DLBCL......................................... 38
42-60
NEWLY DIAGNOSED AND RELAPSED MANTLE CELL LYMPHOMA (MCL)

DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY..........................................42
Leukaemic non-nodal subtype of MCL....................................................................45
TREATMENT...........................................................................................................46
First-line: Stages I-II...............................................................................................46
First-line: Stages III-IV............................................................................................47
Elderly patients.......................................................................................................47
Younger patients.....................................................................................................49
SUMMARY RECOMMENDATIONS FOR NEWLY DIAGNOSED AND
RELAPSED MCL............................................................................ 57
61-72
WALDENSTRÖM'S MACROGLOBULINAEMIA (WM)

DIAGNOSIS.............................................................................................................61
MANAGEMENT.......................................................................................................64
Asymptomatic patients...........................................................................................64
First-line therapy.....................................................................................................64
SUMMARY RECOMMENDATIONS FOR WM............................................ 70
7
73-87
PRIMARY CUTANEOUS LYMPHOMAS (PCLs)

DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY..........................................73
TREATMENT...........................................................................................................76
Mycosis fungoides and variants..............................................................................76
Sézary syndrome....................................................................................................78
Primary cutaneous CD30+ lymphoproliferative disorders.......................................79
Subcutaneous panniculitis-like T-cell lymphomas...................................................81
Primary cutaneous extranodal NK/T-cell lymphoma, nasal type..............................81
Primary cutaneous peripheral T-cell lymphoma-not otherwise specified................82
Cutaneous B-cell lymphoma...................................................................................82
SUMMARY RECOMMENDATIONS FOR PCLs........................................... 85
88-99
PERIPHERAL T-CELL LYMPHOMA (PTCL)
DIAGNOSIS.............................................................................................................88
Prognostic indices..................................................................................................89
TREATMENT...........................................................................................................89
Nodal PTCLs (PTCL-NOS, AITL, ALCL ALK+/-).......................................................91
Enteropathy-associated T-cell lymphoma................................................................92
Extranodal natural killer/T-cell lymphoma...............................................................93
Hepatosplenic T-cell lymphoma..............................................................................94
Radiotherapy...........................................................................................................94
Stem cell transplantation........................................................................................95
RESPONSE EVALUATION AND FOLLOW-UP...........................................................95
SUMMARY RECOMMENDATIONS FOR PTCL........................................... 96
8
100-129
EXTRANODAL DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AND
PRIMARY MEDIASTINAL B-CELL LYMPHOMA
DIAGNOSIS...........................................................................................................100
Primary mediastinal large B-cell lymphoma (PMBCL)..........................................100
Primary testicular lymphoma (PTL)......................................................................101
Primary central nervous system lymphoma (PCNSL)...........................................101
Primary diffuse large B-cell lymphoma of the breast (PBL)..................................102
Primary diffuse large B-cell lymphoma of the bone (PBoL)..................................102
STAGING AND RISK ASSESSMENT......................................................................103
PMBCL..................................................................................................................105
PTL.......................................................................................................................105
PCNSL..................................................................................................................105
PBL.......................................................................................................................106
PBoL.....................................................................................................................107
TREATMENT.........................................................................................................108
PMBCL..................................................................................................................109
PTL.......................................................................................................................110
PCNSL..................................................................................................................111
PBL.......................................................................................................................113
PBoL.....................................................................................................................114
PERSONALISED MEDICINE..................................................................................115
FOLLOW-UP..........................................................................................................116
SUMMARY RECOMMENDATIONS FOR EXTRANODAL DLBCL AND PMBCL......117
130-144
HAIRY CELL LEUKAEMIA (HCL)
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY........................................130
STAGING AND RISK STRATIFICATION..................................................................131
TREATMENT.........................................................................................................132
First-line................................................................................................................132
Response evaluation.............................................................................................134
Treatment of relapsed patients and patients refractory to purine analogues.........135
Splenectomy.........................................................................................................137
Allogeneic stem cell transplantation......................................................................137
Treatment during pregnancy.................................................................................137
Supportive treatment............................................................................................138
9
Treatment of HCL variant......................................................................................138
FOLLOW-UP AND LONG-TERM IMPLICATIONS...................................................140
SUMMARY RECOMMENDATIONS FOR HCL...........................................141
145-164
MARGINAL ZONE LYMPHOMAS

Clonal B-cell lymphocytosis of marginal zone origin.............................................146
Extranodal marginal zone lymphoma (EMZL).......................................................146
Splenic marginal zone lymphoma (SMZL)............................................................146
Nodal marginal zone lymphoma (NMZL)..............................................................146
Initial work-up.......................................................................................................146
Main prognostic factors and prognostic indices...................................................150
TREATMENT.........................................................................................................151
EMZL....................................................................................................................151
SMZL....................................................................................................................155
NMZL....................................................................................................................155
Marginal zone lymphoma patients with recurrent disease....................................155
RESPONSE EVALUATION AND FOLLOW-UP.........................................................156
General considerations.........................................................................................156
Gastric marginal zone lymphoma..........................................................................156
SMZL....................................................................................................................158
SUMMARY RECOMMENDATIONS FOR MARGINAL ZONE LYMPHOMAS..........160
165-183
NEWLY DIAGNOSED AND RELAPSED FOLLICULAR LYMPHOMA (FL)
TREATMENT OF LOCALISED FL (STAGES I-II)......................................................168
TREATMENT OF ADVANCED FL (STAGES III-IV)...................................................168
10
First-line treatment................................................................................................168
Relapsed disease..................................................................................................172
Innovative approaches..........................................................................................174
Response evaluation.............................................................................................177
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP........................177
SUMMARY RECOMMENDATIONS FOR NEWLY DIAGNOSED AND
RELAPSED FL..............................................................................180
184-203
CHRONIC LYMPHOCYTIC LEUKAEMIA

Early, asymptomatic stage....................................................................................185
Advanced or symptomatic stage...........................................................................187
Prognostication.....................................................................................................188
Goals of therapy....................................................................................................189
MANAGEMENT OF EARLY DISEASE......................................................................189
Binet stage A and B without active disease;
Rai 0, I and II without active disease.....................................................................189
MANAGEMENT OF ADVANCED DISEASE..............................................................189
Binet stage A and B with active disease or Binet stage C;
Rai 0-II with active disease or Rai III-IV................................................................189
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP........................197
Richter’s transformation.......................................................................................197
SUMMARY RECOMMENDATIONS FOR CHRONIC LYMPHOCYTIC LEUKAEMIA....198
204-208
GLOSSARY
11
HODGKIN LYMPHOMA
DIAGNOSIS
• Pathological diagnosis should be made according to the World Health
Organization (WHO) classification on tissue from excisional lymph node biopsy
or surgical specimen
• Hodgkin and Reed–Sternberg cells, which have consistently positive staining for
cluster of differentiation (CD)15 and CD30, define classical Hodgkin lymphoma (cHL)
• Lymphocyte predominant (LP) cells, which are CD20- and CD45-positive but
lack CD15 and CD30, are required for the diagnosis of nodular lymphocyte-
predominant Hodgkin lymphoma (NLPHL)
STAGING AND RISK ASSESSMENT
• The diagnostic work-up is shown in the table below
DIAGNOSTIC WORK-UP IN HODGKIN LYMPHOMA
Lymph node biopsy (or a biopsy from another organ with suspected
Diagnosis
affection)
Medical history and physical examination
X-ray of the chest
Contrast-enhanced CT scan of the neck, chest and abdomen
Staging and risk stratification
PET
Full blood cell count and blood chemistry, ESR
HBV, HCV and HIV screening
ECG
Echocardiography
Pulmonary function test
Pre-treatment examinations Reproductive counselling (in patients of reproductive age)
Serum pregnancy test (in female patients of reproductive age)
Consultation of an ear, nose and throat specialist including a fibreoptic
nasolaryngoscopy (if PET-CT scan is not available at initial staging)
CT, computed tomography; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis
C virus; HIV, human immunodeficiency virus; PET, positron emission tomography
• A medical history, including presence of B symptoms (fever, drenching night

sweats, unexplained weight loss > 10% over 6 months) and other disease-related
symptoms, such as fatigue, pruritus and alcohol-induced pain, is required
together with a physical examination
• Chest X-ray and a contrast-enhanced computed tomography (CT) scan of the
neck, chest and abdomen are mandatory
12
• Whole-body positron emission tomography (PET) should be carried out at
baseline, if available
• Bone marrow (BM) biopsy is required if PET-CT is not available
• Full blood count, erythrocyte sedimentation rate (ESR) testing and blood
chemistry analysis (including C-reactive protein, alkaline phosphatase, lactate
dehydrogenase, liver enzymes and albumin), together with screening for
hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV),
are mandatory
• Disease is staged as limited, intermediate or advanced, according to the
Ann Arbor classification
Definitions of disease stage according to the European Organisation for Research
and Treatment of Cancer/Lymphoma Study Association and the German Hodgkin
Study Group are shown in the table below
Pre-treatment cardiac and pulmonary function tests are required and
reproductive counselling should be offered to patients of reproductive age
DEFINITION OF HODGKIN LYMPHOMA RISK GROUPS ACCORDING
TO THE EORTC/LYSA AND THE GHSG
EORTC/LYSA GHSG
Treatment group
Limited stages CS I-II without risk factors CS I-II without risk factors
(supradiaphragmatic)
Intermediate stages CS I-II with ≥ 1 risk factors CS I, CS IIA with ≥ 1 risk factors
(supradiaphragmatic) CS IIB with risk factors C and/or
D, but not A/B
Advanced stages CS III-IV CS IIB with risk factors A
and/or B
CS III/IV
Risk factors
A: Large mediastinal mass* A: Large mediastinal mass*
B: Age ≥ 50 years B: Extranodal disease
C: Elevated ESR† C: Elevated ESR†
D: ≥ 4 nodal areas‡ D: ≥ 3 nodal areas‡
*Large mediastinal mass: Mediastinum-to-thorax ratio ≥ 0.35 (EORTC/LYSA); mediastinal mass larger than one third of the
maximum thoracic width (GHSG)
†
Elevated ESR: > 50 mm/h without B symptoms; > 30 mm/h with B symptoms (B symptoms: Fever, night sweat, unexplained
weight loss > 10% over 6 months)
‡
Nodal areas: Involvement of ≥ 4 out of 5 supradiaphragmatic nodal areas (EORTC/LYSA); involvement of ≥ 3 out of 11 nodal
areas on both sides of the diaphragm (GHSG)
CS, clinical stage; EORTC, European Organisation for Research and Treatment of Cancer; ESR, erythrocyte sedimentation rate;
GHSG, German Hodgkin Study Group; LYSA, Lymphoma Study Association
13
TREATMENT OF cHL
Limited-stage disease
• Treatment recommendations for limited-stage disease are shown in the figure below
THERAPEUTIC ALGORITHM FOR NEWLY DIAGNOSED, LIMITED-STAGE HODGKIN
LYMPHOMA IN PATIENTS ≤ 60 YEARS
Diagnosis of limited-stage HL*
2 cycles of ABVD 2 cycles of ABVD
20-Gy ISRT PET-CT scan
PET-positive PET-negative
2 cycles of BEACOPPesc 1 cycle of ABVD
30-Gy ISRT 20-Gy ISRT
*Except for stage IA NLPHL without risk factors (treated with ISRT alone)
The figure includes one approach not guided by interim PET based on the GHSG HD10 study (left) and one PET-guided approach
based on the EORTC/LYSA/FIL H10 study (right)
ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; BEACOPPesc, bleomycin/etoposide/doxorubicin/cyclophosphamide/
vincristine/procarbazine/prednisolone in escalated dose; CT, computed tomography; EORTC, European Organisation for Research
and Treatment of Cancer; FIL, Fondazione Italiana Linfomi; GHSG, German Hodgkin Study Group; HL, Hodgkin lymphoma;
ISRT, involved-site radiotherapy; LYSA, Lymphoma Study Association; NLPHL, nodular lymphocyte-predominant Hodgkin
lymphoma; PET, positron emission tomography
14
• Combined modality treatment, comprising brief chemotherapy (ChT) followed by
radiotherapy (RT), provides superior tumour control to RT alone
• 2 or 3 cycles of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD),
as shown in the table below, followed by conventionally fractionated RT is the
standard of care
THE ABVD REGIMEN
DOSE (mg/m2) ADMINISTRATION DAYS
Doxorubicin 25 IV 1 + 15
Bleomycin 10 IV 1 + 15
Vinblastine 6 IV 1 + 15
Dacarbazine 375 IV 1 + 15
Recycle: Day 29
ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; IV, intravenous
• 2 cycles of ABVD and 20-Gy involved-field RT (IFRT) is as effective as, and less
toxic than, 4 cycles of ABVD and 30-Gy IFRT
• International Lymphoma Radiation Oncology Group (ILROG) RT guidelines
recommend involved-site RT (ISRT), rather than IFRT, after ChT, although there is
no prospective, randomised study evidence
• A patient group that can be safety treated with ChT alone has not yet been defined
but this approach may be used when the late risk of delivering RT outweighs the
short-term improved disease-control benefit
• Early treatment intensification with 2 cycles of bleomycin/etoposide/doxorubicin/
cyclophosphamide/vincristine/procarbazine/prednisolone in escalated dose
(BEACOPPescalated) before ISRT, as shown in the table on the next page, may
improve the prognosis of patients with a positive interim PET after 2 cycles of
ABVD, and is recommended in this setting
15
THE BEACOPPescalated REGIMEN
DOSE (mg/m2) ADMINISTRATION DAYS
Bleomycin 10 IV 8
Etoposide 200 IV 1-3
Doxorubicin 35 IV 1
Cyclophosphamide 1250 IV 1
Vincristine 1.4* IV 8
Procarbazine 100 PO 1-7
Prednisolone 40 PO 1-14
G-CSF SC From day 8
*The maximum absolute dose of vincristine is 2 mg

Recycle: Day 22
BEACOPPescalated, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisolone in escalated
dose; G-CSF, granulocyte colony-stimulating factor; IV, intravenous; PO, oral; SC, subcutaneous
Intermediate-stage disease
• Intermediate-stage Hodgkin lymphoma (HL) is usually treated with combined
modality approaches, as shown in the figure on the next page
16
THERAPEUTIC ALGORITHM FOR NEWLY DIAGNOSED, INTERMEDIATE-STAGE HL
IN PATIENTS ≤ 60 YEARS
Diagnosis of intermediate-stage HL
2 cycles of BEACOPPesc + 2 cycles of ABVD

2 cycles of ABVD
or
4 cycles of ABVD
PET-CT scan
30-Gy ISRT
PET-positive PET-negative
2 cycles of BEACOPPesc 2 cycles of ABVD
30-Gy ISRT 30-Gy ISRT
The figure includes one approach not guided by interim PET, based on the GHSG HD14 study (left) and one PET-guided approach
based on the EORTC/LYSA/FIL H10 study (right)
ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; BEACOPPesc, bleomycin/etoposide/doxorubicin/cyclophosphamide/
vincristine/procarbazine/prednisolone in escalated dose; CT, computed tomography; EORTC, European Organisation for Research
and Treatment of Cancer; FIL, Fondazione Italiana Linfomi; GHSG, German Hodgkin Study Group; HL, Hodgkin lymphoma;
ISRT, involved-site radiotherapy; LYSA, Lymphoma Study Association; PET, positron emission tomography
• Four cycles of ABVD followed by conventionally fractionated RT at 30 Gy is

considered to be the standard of care
• In patients ≤ 60 years who are eligible for a more intensive treatment, 2 cycles of
BEACOPPescalated followed by 2 cycles of ABVD and RT at 30 Gy may improve
freedom from treatment failure, compared with 4 cycles of ABVD plus RT, but
does not improve overall survival
17
• ISRT and IFRT have not been compared in a randomised study and the ILROG
guidelines recommend ISRT after ChT
• Non-inferiority of ChT compared with combined modality treatment in patients
with a negative interim PET (Deauville score ≤ 2) was not demonstrated in a
randomised trial
• ChT alone may be offered when the late risk of delivering RT outweighs the
• Early treatment intensification with 2 cycles of BEACOPPescalated before ISRT
may improve the prognosis of patients with a positive interim PET after 2 cycles
of ABVD, and is recommended in this setting
• In patients > 60 years, bleomycin should be discontinued after the second ChT
cycle to avoid the bleomycin-induced toxicity associated with the use of
> 2 cycles of ABVD in older individuals
Advanced-stage disease
• ChT alone is the usual treatment approach for advanced-stage HL, with RT being
confined to patients with residual disease after ChT, as shown in the figure on the
next page
18
THERAPEUTIC ALGORITHM FOR NEWLY DIAGNOSED, ADVANCED-STAGE HL IN
PATIENTS ≤ 60 YEARS
Diagnosis of advanced-stage HL
6 cycles of 2 cycles of BEACOPPesc 2 cycles of ABVD

BEACOPPesc
or
6 cycles of ABVD
PET-CT scan PET-CT scan
Localised RT
to residual
lymphoma PET-positive PET-negative PET-positive PET-negative
≥ 2.5 cm
4 cycles of 2 cycles of 4 cycles of 4 cycles of

BEACOPPesc BEACOPPesc BEACOPPesc AVD
or
4 cycles of
ABVD
PET-CT scan PET-CT scan
PET-positive PET-negative PET-positive PET-negative
Localised RT Observation Localised RT Observation

to residual to residual
lymphoma lymphoma
≥ 2.5 cm ≥ 2.5 cm
The figure includes one approach not guided by interim PET (left) and two PET-guided approaches based on the GHSG HD18
study (middle) and the RATHL study (right)
ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; AVD, doxorubicin/vinblastine/dacarbazine; BEACOPPesc, bleomycin/
etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisolone in escalated dose; CT, computed tomography;
GHSG, German Hodgkin Study Group; HL, Hodgkin lymphoma; PET, positron emission tomography; RT, radiotherapy
1919
• In patients ≤ 60 years, 6 cycles of ABVD or 4-6 cycles of BEACOPPescalated are
recommended, optionally followed by localised RT
• In patients receiving ABVD who have a negative interim PET (Deauville score ≤ 3
in RATHL) after 2 cycles, omission of bleomycin in cycles 3-6 [i.e. doxorubicin/
vinblastine/dacarbazine (AVD)] should be considered, particularly in elderly
patients and those at an increased risk for lung toxicity, although a 3-year
progression-free survival (PFS) difference > 5% could not be excluded in a
multicentre study
• Whether omission of consolidating RT is safe in patients with a negative PET after
2 cycles of ABVD or at the end of ChT has not been answered definitively
• In patients receiving ABVD, those with a positive interim PET (Deauville score ≥ 4
in RATHL and SWOG S0816 and ≥ 3 in HD0801) after 2 cycles of ABVD may have
a better prognosis if they switch to intensified protocols rather than continuing
on ABVD, although this has not been investigated in a randomised trial
• 6 cycles of brentuximab vedotin (BV) plus AVD may improve modified 2-year
PFS but has an increased rate of neuropathy and haematological toxicity; longer
follow-up is required to confirm its role in this setting
• In patients receiving BEACOPPescalated
Those with a negative interim PET (Deauville score ≤ 2 in HD18) can receive
4 cycles of therapy compared with 6 for PET-positive patients
In addition, RT can be restricted to patients with PET-positive (Deauville score
≥ 3 in HD15 and most of HD18 or ≥ 4 in part of HD18) residual lymphoma
≥ 2.5 cm after 4 and 6 cycles of BEACOPPescalated, respectively
• Randomised trials have demonstrated superior tumour control with
BEACOPPescalated compared with ABVD and a network meta-analysis showed
a significant 5-year survival benefit of 10%, but the associated acute toxicity
demands appropriate surveillance and provision of supportive care
• The BEACOPP regimen is associated with an increased treatment mortality rate in
patients > 60 years and ABVD is the standard of care for older patients fit enough
for multi-agent ChT, with discontinuation of bleomycin after the second cycle of
ChT
Relapsed disease
• High-dose ChT (HDCT) followed by autologous stem cell transplantation (ASCT)
is the treatment of choice for most patients with refractory or relapsed HL
• High-risk patients may benefit from tandem ASCT
• Consolidation with BV after HDCT and ASCT has been shown to improve
tumour control in patients with ≥ 1 risk factors: Primary disease progression,
20
early disease recurrence < 12 months after the end of first-line treatment and
extranodal disease at relapse
• Salvage regimens, e.g. dexamethasone/high-dose cytarabine/cisplatin (DHAP),
ifosfamide/gemcitabine/vinorelbine (IGEV) or ifosfamide/carboplatin/etoposide
(ICE), reduce tumour burden and mobilise stem cells before HDCT and ASCT
• In some patients, single-agent BV leads to a negative PET and is therefore a
sufficient salvage therapy before HDCT and ASCT
• A negative PET is the goal of salvage therapy because a complete metabolic
response prior to HDCT and ASCT is associated with improved clinical outcome
• The role of RT before HDCT and ASCT has not been defined but its use can be
considered in patients with single PET-positive lymph nodes after salvage therapy
• BV is an option for patients failing ASCT and has demonstrated a long-term
(> 5 years) remission rate of 9%
• Anti-programmed cell death protein 1 (PD-1) antibodies are approved for use in
patients with disease recurrence after HDCT followed by ASCT and BV and show
high response rates and durable remissions
• Allogeneic stem cell transplantation (alloSCT) is a potentially curative option
for patients failing HDCT and ASCT and should be considered for young,
chemosensitive patients in good general condition, after evaluation of the
risk–benefit ratio
• Patients with multiple relapses should be enrolled in clinical trials evaluating
novel agents whenever possible, otherwise gemcitabine-based palliative ChT
and/or regional RT can lead to acceptable remission rates and quality of life and
improved survival in these patients
TREATMENT OF NLPHL
Stage IA without risk factors
• The standard treatment for stage IA disease without risk factors is ISRT 30 Gy,
recommended by the ILROG guidelines
• The ISRT fields for single-modality RT are larger than those for combined-
modality RT in order to include potential microscopic regional disease
Other stages
• Except for stage IA without risk factors, NLPHL is treated identically to cHL
• Addition of an anti-CD20 antibody may improve treatment efficacy, and promising
results have been demonstrated with rituximab/cyclophosphamide/doxorubicin/
vincristine/prednisolone (R-CHOP), but prospective data are not available
21
Relapsed NLPHL
• A renewed biopsy should be obtained in patients with suspected NLPHL
before initiation of salvage therapy to exclude transformation into aggressive
non-Hodgkin lymphoma
• Transformation rates appear to be higher than previously reported
• Localised NLPHL relapses can be effectively treated with single-agent anti-CD20
antibodies, such as rituximab or ofatumumab
• More aggressive ChT, possibly combined with an anti-CD20 antibody, may be
required for patients with more disseminated disease at relapse and additional
poor-risk features
• Salvage therapy should be tailored to the individual and based on factors
including time to relapse, disease extent at relapse and prior treatment
• BV is not a treatment option because malignant LP cells in NLPHL lack CD30
RESPONSE EVALUATION
• If no PET-guided treatment is intended, interim response evaluation by contrast-
enhanced CT should be carried out before RT in limited- and intermediate-stage
disease and after 4 cycles of ChT as well as before RT in advanced stages
• In interim-PET-guided treatment, patients receiving ABVD should undergo an
interim PET-CT scan after 2 cycles of ChT and patients with advanced disease
should also have a PET-CT scan after the end of ChT
• In patients with advanced HL receiving BEACOPPescalated, interim PET-CT scans
should be carried out after 2 cycles of ChT and after the end of ChT
• Final staging should be carried out after the completion of treatment
• Physical examination, laboratory analyses and contrast-enhanced CT are mandatory
• If available, PET-CT should replace CT at final staging
PROGNOSIS
• With modern treatment strategies, 80-90% of HL patients achieve permanent
remission and can be considered cured
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
• History, physical examination and laboratory analysis, including full blood cell
count, ESR testing and blood chemistry, should be carried out every 3 months
for the first half-year, every 6 months until the fourth year and once a year
thereafter
22
• CT scans and previously pathological radiographic tests must be conducted
once to confirm remission status; thereafter, clinical follow-up is sufficient and
surveillance scans are not indicated unless clinical symptoms occur
• Thyroid function (thyroid-stimulating hormone) should be evaluated annually in
patients in whom the neck has been irradiated
• Testosterone and oestrogen levels should be monitored, particularly in younger
patients who underwent intensive ChT
• Patients should be asked about symptoms indicating long-term toxicity,
especially those affecting the heart and lungs
• Cancer screening should be conducted regularly, particularly breast cancer
screening in female patients who were < 40 years old at the time of chest or
axillary irradiation; annual mammography should commence 8-10 years after RT
and those ≤ 30 years at the time of chest irradiation should also receive breast
magnetic resonance imaging (MRI)
23
DIAGNOSIS
Pathological diagnosis is made according to the WHO classification on tissue from
excisional lymph node biopsy or surgical specimen
Hodgkin and Reed–Sternberg cells define cHL and NLPHL is characterised by
LP cells
A medical history, including presence of B symptoms (fever, drenching night
sweats, unexplained weight loss > 10% over 6 months) and disease-related
symptoms, is required together with a physical examination
Chest X-ray and a contrast-enhanced CT scan of the neck, chest and abdomen
are mandatory
Whole-body PET should be performed, if available
BM biopsy is required if PET-CT is not available
Full blood count, ESR testing and blood chemistry analysis, together with
screening for HBV, HCV and HIV, are mandatory
Disease is staged as limited, intermediate or advanced, according to the Ann Arbor
classification
Pre-treatment cardiac and pulmonary function tests are required and reproductive
counselling should be offered to patients of reproductive age
TREATMENT OF cHL
Limited-stage disease
• Combined modality treatment with 2 cycles of ABVD and 20-Gy IFRT is the
standard of care
• ISRT is recommended over IFRT after ChT
• ChT alone can be considered when the late risk of delivering RT outweighs the
• The use of 2 cycles of BEACOPPescalated before ISRT is recommended for
patients with a positive interim PET following 2 cycles of ABVD
Intermediate-stage disease
• 4 cycles of ABVD followed by conventionally fractionated RT at 30 Gy is the
standard of care
• Patients ≤ 60 years, who are eligible for a more intensive treatment, may benefit
from 2 cycles of BEACOPPescalated followed by 2 cycles of ABVD and RT at 30 Gy
24
• ISRT is recommended over IFRT after ChT
• ChT alone can be considered when the late risk of delivering RT outweighs the
• The use of 2 cycles of BEACOPPescalated before ISRT is recommended for
patients with a positive interim PET following 2 cycles of ABVD
• In patients > 60 years, bleomycin should be discontinued after the second ChT
cycle
Advanced-stage disease
• ChT alone is the usual treatment approach, with RT being confined to patients
with residual disease after ChT
• In patients ≤ 60 years, 6 cycles of ABVD or 4-6 cycles of BEACOPPescalated are
recommended, optionally followed by localised RT
• In patients with a negative interim PET after 2 cycles of ABVD, omission of
bleomycin in cycles 3-6 should be considered, particularly in elderly patients and
those at an increased risk for lung toxicity
• In patients with a positive interim PET after 2 cycles of ABVD, switching from
ABVD to intensified protocols can be considered
• 6 cycles of BV plus AVD may improve PFS but has an increased rate of
neuropathy and haematological toxicity
• Patients with a negative interim PET on BEACOPPescalated can receive 4 cycles
of therapy compared with 6 for PET-positive patients, and RT can be restricted
to patients with PET-positive (Deauville score ≥ 3 in HD15 and most of HD18
or ≥ 4 in part of HD18) residual lymphoma ≥ 2.5 cm after 4 and 6 cycles of
BEACOPPescalated, respectively
• BEACOPPescalated-associated acute toxicity demands appropriate surveillance
and provision of supportive care
• ABVD is the standard of care for older patients fit enough for multi-agent ChT, with
discontinuation of bleomycin after the second cycle of ChT
Relapsed disease
• HDCT followed by ASCT is the treatment of choice for most patients with
refractory or relapsed HL
• High-risk patients may benefit from tandem ASCT
• Consolidation with BV after HDCT and ASCT may improve tumour control
in patients with ≥ 1 risk factors: Primary disease progression, early disease
recurrence < 12 months after the end of first-line treatment and extranodal
disease at relapse
25
• The goal of salvage therapy, with regimens including DHAP, IGEV or ICE, is a
negative PET prior to HDCT and ASCT
• In some patients, single-agent BV is a sufficient salvage therapy before HDCT and
ASCT
• In patients with single PET-positive lymph nodes after salvage therapy, RT before
HDCT and ASCT can be considered
• BV is an option for patients failing ASCT
• Anti-PD-1 antibodies are approved for use in patients with disease recurrence
after HDCT followed by ASCT and BV
• AlloSCT is a potentially curative option for patients failing HDCT and ASCT
and should be considered for young, chemosensitive patients in good general
condition
• Patients with multiple relapses should be enrolled in clinical trials whenever possible,
otherwise gemcitabine-based palliative ChT and/or regional RT can lead to acceptable
remission rates and quality of life and improved survival in these patients
TREATMENT OF NLPHL
Stage IA without risk factors
• The standard treatment for stage IA disease without risk factors is ISRT 30 Gy
• The ISRT fields for single-modality RT are larger than those for combined-
modality RT
Other stages
• Except for stage IA without risk factors, NLPHL is treated identically to cHL
• Addition of an anti-CD20 antibody (e.g. R-CHOP) may improve treatment efficacy
Relapsed NLPHL
• A renewed biopsy should be obtained in patients with suspected NLPHL
before initiation of salvage therapy to exclude transformation into aggressive
non-Hodgkin lymphoma
• Localised NLPHL relapses can be effectively treated with single-agent anti-CD20
antibodies, such as rituximab or ofatumumab
• More aggressive ChT, possibly combined with an anti-CD20 antibody, may be
required for patients with more disseminated disease at relapse and additional
poor-risk features
26
• Salvage therapy should be tailored to the individual and based on factors
including time to relapse, disease extent at relapse and prior treatment
• BV is not a treatment option
RESPONSE EVALUATION
If no PET-guided treatment is intended, interim response evaluation by contrast-
enhanced CT should be carried out before RT in limited- and intermediate-stage
disease, and after 4 cycles of ChT as well as before RT in advanced stages
In interim-PET-guided treatment, patients receiving ABVD should undergo an
interim PET-CT scan after 2 cycles of ChT and patients with advanced disease
should also have a PET-CT scan after the end of ChT
In patients with advanced HL receiving BEACOPPescalated, interim PET-CT scans
should be carried out after 2 cycles of ChT and after the end of ChT
Final staging should be carried out after the completion of treatment
Physical examination, laboratory analyses and contrast-enhanced CT are
mandatory
If available, PET-CT should replace CT at final staging
PROGNOSIS
With modern treatment strategies, 80-90% of HL patients can be considered cured
History, physical examination and laboratory analysis, including full blood cell
count, ESR testing and blood chemistry, should be carried out every 3 months for
the first half-year, every 6 months until the fourth year and annually thereafter
CT scans and previously pathological radiographic tests are required once to
confirm remission status; thereafter, clinical follow-up is sufficient and surveillance
scans are not indicated unless clinical symptoms occur
Thyroid function should be evaluated annually in patients undergoing neck irradiation
Testosterone and oestrogen levels should be monitored, particularly in younger
patients who underwent intensive ChT
Patients should be asked about symptoms indicating long-term toxicity, especially
those affecting the heart and lungs
Regular cancer screening is required; female patients < 40 years old at the time of
chest or axillary irradiation should have an annual mammogram, commencing 8-10
years after RT, and those ≤ 30 years old at the time should also undergo breast
MRI
27
DIAGNOSIS
• The diagnosis of diffuse large B-cell lymphoma (DLBCL) should be performed
in a reference haematopathology laboratory with expertise in morphological
interpretation and the facilities to carry out the full range of phenotypic and
molecular investigations required
• A surgical excision biopsy, which allows assessment of nodal architecture and
adequate material for phenotypic and molecular analysis, remains the
optimal method of diagnosis
• Unfixed samples, which allow flow cytometry and high-quality DNA/RNA
extraction, are preferred
• Needle-core and endoscopic biopsies should be used only when surgery
is impractical or would entail excessive risk
• A fine-needle aspirate should not be the sole basis for a diagnosis
• Morphological diagnosis should be confirmed by immunophenotypic
investigations, either immunohistochemistry (IHC), flow cytometry
or a combination of both
• Panels used should be able to confirm B-cell lineage and be sufficiently
comprehensive to distinguish between possible variant forms and
alternative diagnoses
• Diagnosis should be made according to the current World Health Organization
(WHO) classification
28 28
• Physical examination, performance status (PS), assessment of B symptoms,
complete blood count (CBC), routine blood chemistry [including lactate
dehydrogenase (LDH) and uric acid] and screening tests for human
immunodeficiency virus (HIV), hepatitis B virus [HBV; hepatitis B surface (HBs)
antigen, anti-HBs and anti-hepatitis B core (HBc) antibodies] and hepatitis C virus
(HCV) are required
• Protein electrophoresis is recommended
• [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography
(PET)-computed tomography (CT) is the gold standard for staging DLBCL
• When contrast-enhanced CT is not routinely performed prior to PET-CT, a full
diagnostic high-dose contrast-enhanced CT should be carried out when necessary,
in combination with PET-CT and after the PET scan
• Baseline contrast-enhanced CT can determine if the low-dose, non-enhanced CT
part of the PET-CT scan will be sufficient for restaging
• Biopsy is not required when bone or marrow involvement indicating advanced-
stage disease is demonstrated by PET-CT, but it is appropriate when PET is
negative and biopsy results would change prognosis and treatment, particularly
when a reduced number of immunochemotherapy cycles is proposed
• Magnetic resonance imaging (MRI) is the modality of choice when central
nervous system (CNS) lymphoma is suspected
• A diagnostic lumbar puncture should be considered for high-risk patients and
flow cytometry enhances the detection of lymphoma cells
• Cardiac function, with left ventricular ejection fraction (LVEF), should be assessed
before treatment
• Staging should be conducted according to the Ann Arbor classification system,
as shown in the table on the next page
29
ANN ARBOR STAGING CLASSIFICATION
STAGE
Involvement of a single lymphatic region (I) or localised involvement of single
I
extralymphatic organ or site (IE)
Involvement of two or more lymphatic regions on the same side of the diaphragm (II)
II or localised involvement of a single extralymphatic organ or site and of one or more
lymphatic regions on the same side of the diaphragm (IIE)
III Involvement of lymphatic regions on both sides of the diaphragm
Diffuse or disseminated involvement of one or more extralymphatic organs with

IV
or without lymphatic involvement
• The International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) should be
used to calculate prognosis, as shown on the next page
• Other factors potentially affecting prognosis and treatment, such as the
maximum disease bulk, should also be assessed
30
INTERNATIONAL PROGNOSTIC INDEX

IPI ESTIMATED 3-YEAR OVERALL
SURVIVAL % (95% CI)
Age > 60 years
Serum LDH > normal

Risk factors Stage III-IV
PS 2-4
Extranodal sites > 1
Low 0-1 91 (89-94)

Low-intermediate 2 81 (73-86)
Risk categories
High-intermediate 3 65 (58-73)
High 4-5 59 (49-69)

aaIPI IN PATIENTS ≤ 60 YEARS
Risk factors Serum LDH > normal
Stage III-IV
PS 2-4
Low 0 98 (96-100)
Low-intermediate 1 92 (87-95)
Risk categories
High-intermediate 2
75 (66-82)
High 3
aaIPI, age-adjusted International Prognostic Index; CI, confidence interval; IPI, International Prognostic Index; LDH, lactate
dehydrogenase; PS, performance status

TREATMENT
• Treatment strategies should be stratified according to age, IPI and feasibility
of dose-intensified approaches, as shown on the next pages
31
RECOMMENDED TREATMENT STRATEGIES
PATIENTS ≤ 60 YEARS
IPI low-risk (aaIPI = 0) and IPI low-risk (aaIPI = 0) with bulk IPI high-intermediate-risk or
no bulk or IPI low-intermediate-risk
(aaIPI = 1) IPI high-risk (aaIPI ≥ 2)
R-CHOP21 x 6-8
OR
R-CHOP14 x 6 with 8 R
R-ACVBP and sequential
consolidation Consider more intensive
R-CHOP21 x 6 regimens in selected patients:
OR
R-CHOP21 x 6 IFRT on bulk R-CHOEP14 x 6
OR
R-CHOP or R-ACVBP plus HDCT
with ASCT
Consider CNS prophylaxis in patients at risk for CNS progression
ELDERLY (> 60 YEARS)

> 80 years without cardiac Unfit or frail or > 60 years
Fit, 60-80 years
dysfunction with cardiac dysfunction
Doxorubicin substitution
R-CHOP21 x 6-8 with gemcitabine, etoposide,
(R-CHOP21 x 6 for IPI low-risk) Attenuated regimens: liposomal doxorubicin or others:
OR R-miniCHOP21 x 6 R-C(X)OP21 x 6
R-CHOP14 x 6 with 8 R OR
Palliative care
Consider CNS prophylaxis in patients at risk
FIRST RELAPSE/PROGRESSION
Eligible for transplant Not eligible for transplant
Platinum-based ChT regimens (i.e. R-DHAP, R-ICE, Platinum- and/or gemcitabine-based regimens
R-GDP) as salvage treatment
For chemosensitive patients: R-HDCT with ASCT Clinical trials with novel drugs
as remission consolidation
Consider alloSCT in patients relapsed after

R-HDCT with ASCT or in patients with poor
risk factors at relapse
32
> 2 RELAPSES/PROGRESSIONS
Eligible for transplant Not eligible for transplant
AlloSCT Clinical trials with novel drugs
Clinical trials with novel drugs Palliative care
aaIPI, age-adjusted IPI; ACVBP, doxorubicin/vindesine/cyclophosphamide/bleomycin/prednisolone; alloSCT, allogeneic stem

cell transplantation; ASCT, autologous stem cell transplantation; CHOEP, cyclophosphamide/doxorubicin/vincristine/etoposide/
prednisolone; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ChT, chemotherapy; CNS, central
nervous system; DHAP, cisplatin/high-dose cytarabine/dexamethasone; GDP, cisplatin/gemcitabine/dexamethasone;
HDCT, high-dose chemotherapy; ICE, ifosfamide/carboplatin/etoposide; IFRT, involved-field radiotherapy; IPI, International
Prognostic Index; R, rituximab; R-C(X)OP, R-CHOP with substitution of doxorubicin with another agent; R-miniCHOP21, attenuated
immunochemotherapy regimen every 21 days
• Inclusion in a clinical trial is recommended whenever possible

• When tumour load is high, precautions, such as several days’ prephase
administration of oral prednisolone to avoid tumour lysis syndrome, are advised
• Dose reductions due to haematological toxicity should be avoided
• Febrile neutropaenia justifies prophylactic use of haematopoietic growth factors in
patients treated with curative intent and those > 60 years of age
Young low-risk patients (aaIPI = 0) without bulky disease
• The current standard is 6 cycles of cyclophosphamide/doxorubicin/vincristine/
prednisolone (CHOP) combined with six doses of rituximab (R), every 21 days
(R-CHOP21)
• Consolidation by radiotherapy (RT) to initial non-bulky sites has no proven benefit,
with or without R
Young low-intermediate-risk patients (aaIPI = 1) or IPI low-risk (aaIPI = 0) patients
with bulky disease
• R-CHOP21 × 6 with RT to sites of previous bulky disease is effective
• The intensified regimen of R/doxorubicin/vindesine/cyclophosphamide/bleomycin/
prednisolone (R-ACVBP) given every 2 weeks followed by sequential consolidation,
is an effective alternative, and has been shown to improve survival compared with
8 cycles of R-CHOP, although RT was omitted in both arms
Young high-risk and high-intermediate-risk patients (aaIPI ≥ 2)
• There is no current standard for these patients and enrolment in clinical trials is a
priority
• 6-8 cycles of CHOP combined with eight doses of R given every 21 days are
commonly used
• Intensive treatments can be considered in selected patients
33
Dose-dense R-CHOP, given every 14 days (R-CHOP14), has no survival benefit
over standard R-CHOP21
Direct comparisons with R-CHOP of the frequently used intensive R-ACVBP
or R/cyclophosphamide/doxorubicin/vincristine/etoposide/prednisolone
(R-CHOEP) regimens have not been performed
• The use of high-dose chemotherapy (HDCT) with autologous stem cell
transplantation (ASCT) following R-chemotherapy (ChT) has not shown
consistent improvements in outcome compared with R-ChT alone and remains
experimental
This approach may be used for selected high-risk patients
• The role of RT consolidation to initial sites of bulky disease is unknown
• The use of interim PET to select patients who may benefit from consolidative
ASCT or from RT is under evaluation
Patients aged 60-80 years
• The current standard is 6-8 cycles of CHOP plus eight doses of R given every
21 days
• R-CHOP14 has not shown a survival advantage over R-CHOP21
If used, 6 cycles of CHOP with 8 cycles of R are sufficient
• In localised disease, consolidation RT showed no benefit prior to the introduction
of R, but it may improve outcome in patients with bulky disease
• Extended R treatment has been shown to improve outcome in poor prognosis
patients without increasing toxicity
A comprehensive geriatric assessment, to ascertain comorbidities and functional
decline, is recommended to guide treatment choices in these patients
• R-CHOP can generally be used up to the age of 80 years in fit patients but
modulation of treatment according to geriatric assessment is recommended
Patients aged > 80 years
• R with attenuated ChT (R-miniCHOP) can induce complete remission and prolong
survival in fit patients
• Substitution of doxorubicin with gemcitabine, etoposide or liposomal
doxorubicin, or even its omission, can be considered from the outset or after
a few cycles in patients with cardiac dysfunction or who are frail or unfit
CNS prophylaxis
• CNS prophylaxis is recommended for patients with high-intermediate-risk and
high-risk IPI, particularly those with more than one extranodal site or elevated
LDH, or patients with testicular, renal or adrenal involvement
34
• MYC rearrangement is also associated with a high risk of CNS relapse
• Intrathecal methotrexate administration may not be an optimal method but
intravenous (IV) high-dose methotrexate is related to efficient disease control and
is under clinical investigation
Special considerations for some DLBCLs
• Patients with HIV infection should receive the same treatment as HIV-negative
patients, but with antiviral therapy
• Patients previously exposed to HBV (HBs antigen-negative, anti-HBc-positive)
are at risk of reactivation during R-CHOP treatment; antiviral prophylaxis or
periodic HBV DNA monitoring, with antiviral treatment if reactivation occurs,
are recommended
Response evaluation
Post-treatment evaluation
• FDG–PET-CT is the recommended standard for post-treatment assessment
• The Lugano classification based on the visual Deauville criteria (five-point scale)
has proposed different ‘metabolic response’ categories, as shown below
PET FIVE-POINT SCALE (DEAUVILLE CRITERIA)

1 No uptake
2 Uptake ≤ mediastinum
3 Uptake > mediastinum but ≤ liver
4 Moderately increased uptake compared to liver
5 Markedly increased uptake to liver and/or new lesions

PET, positron emission tomography

• Complete metabolic response is indicated by Deauville scores 1-3, with scores
4 and 5 indicating residual disease
• A biopsy is recommended when there is residual metabolically active tissue and
salvage treatment is being considered
Interim evaluation
• Imaging with CT or PET-CT after 3-4 cycles can be used to rule out progression
• Changing treatment solely on PET-CT is discouraged unless there is clear
evidence of progression
• Early PET imaging, after 1-2 cycles, may be predictive of outcome but is currently
limited to the clinical trial setting
35
FOLLOW-UP
• A history and physical examination should be conducted every 3 months for
1 year, every 6 months for an additional 2 years and then annually, with a focus
on the development of secondary tumours or other long-term side effects
of ChT
• Blood counts should be performed at 3, 6, 12 and 24 months and then only as
needed for evaluation of suspicious symptoms or clinical findings in patients
suitable for further therapy
• CT scanning at 6, 12 and 24 months after treatment is common but routine
imaging of patients in complete remission does not provide any outcome benefits
and may increase the incidence of secondary malignancies
• Routine PET scan surveillance is not recommended
• High-risk patients with curative options may require more frequent evaluation
Relapsed and refractory DLBCL
Diagnosis, staging and risk assessment
• Suspected relapse on imaging should be confirmed by a needle-core biopsy
before proceeding to second-line treatment
• Patients amenable to curative therapy should undergo the same staging and risk
assessments performed at first diagnosis
Treatment, response evaluation and follow-up
• Recommendations are based on the assumption that patients received adequate
R and anthracycline first-line therapy
• In patients < 65-70 years of age with good PS and no major organ dysfunction,
salvage regimens with R and ChT followed, in responsive patients, by HDCT and
ASCT, are recommended
• R/cisplatin/high-dose cytarabine/dexamethasone (R-DHAP) and R/ifosfamide/
carboplatin/etoposide (R-ICE) give similar outcomes
• Rituximab/cisplatin/gemcitabine/dexamethasone (R-GDP) has similar efficacy
but less toxicity than R-DHAP
• The potential benefits of R-DHAP in germinal centre (GC) B-cell sub-types
require confirmation
• Carmustine/etoposide/cytarabine/melphalan (BEAM) is the most commonly used
high-dose regimen
• Involved-field RT (IFRT) or iceberg RT may be useful in limited-stage disease
but have not been evaluated in controlled trials
36
• R maintenance therapy is not recommended
• Allogeneic stem cell transplantation (alloSCT) may be considered in patients with
refractory disease, early relapse or relapse after ASCT
• When high-dose therapy is not suitable, salvage regimens, including rituximab/
gemcitabine/oxaliplatin (R-GEMOX), can be used
• Pixantrone, a new anthracycline-like drug with reduced cardiotoxicity, has shown
efficacy in heavily treated patients
• Patients should preferably be enrolled in clinical trials investigating novel agents
• First-line treatment response evaluation criteria should be used after 3-4 cycles of
salvage therapy and after the end of all therapy
• Follow-up is the same as for first response
PERSONALISED MEDICINE
• Currently, no molecularly targeted agents are appropriate for routine use in
clinical practice
• Agents under investigation in activated B-cell DLBCL include bortezomib and
lenalidomide, which target the nuclear factor kappa light chain enhancer of activated
B cells (NFkB) pathway, and the Bruton's tyrosine kinase inhibitor ibrutinib
37
DIAGNOSIS
The diagnosis of DLBCL should be performed in a reference haematopathology
laboratory with expertise in morphological interpretation and the facilities to carry
out the full range of phenotypic and molecular investigations required
A surgical excision biopsy remains the optimal method of diagnosis
Needle-core and endoscopic biopsies should be used only when surgery
is impractical or would entail excessive risk
A fine-needle aspirate should not be the sole basis for a diagnosis
Morphological diagnosis should be confirmed by immunophenotypic
investigations, either IHC, flow cytometry or a combination of both
Diagnosis should be made according to the current WHO classification
Physical examination, PS, assessment of B symptoms, CBC, routine blood
chemistry (including LDH and uric acid) and screening tests for HIV, HBV and HCV
are required
Protein electrophoresis is recommended
FDG–PET-CT imaging is the gold standard for staging DLBCL
When contrast-enhanced CT is not routinely performed prior to PET-CT, a full
diagnostic high-dose contrast-enhanced CT should be carried out when necessary,
in combination with PET-CT
Biopsy is not required when bone or marrow involvement indicating advanced-
stage disease is demonstrated by PET-CT, but it is appropriate when PET is
negative and biopsy results would change prognosis and treatment, particularly
when a reduced number of immunochemotherapy cycles is proposed
MRI is the modality of choice when CNS lymphoma is suspected
A diagnostic lumbar puncture should be considered for high-risk patients
Cardiac function, with LVEF, should be assessed before treatment
Staging should be conducted according to the Ann Arbor classification system
The IPI and aaIPI should be used to calculate prognosis
TREATMENT
Treatment should be stratified according to age, IPI and feasibility of
dose-intensified approaches
Inclusion in a clinical trial is recommended whenever possible
38
When tumour load is high, precautions to avoid tumour lysis syndrome are advised
Dose reductions due to haematological toxicity should be avoided
Febrile neutropaenia justifies prophylactic use of haematopoietic growth factors in
patients treated with curative intent and those > 60 years of age
Young low-risk patients (aaIPI = 0) without bulky disease
• R-CHOP21 × 6 is the current standard
• RT consolidation to initial non-bulky sites has no proven benefit, with or
without R
Young low-intermediate-risk patients (aaIPI = 1) or IPI low-risk (aaIPI = 0)
patients with bulky disease
• R-CHOP21 × 6, with RT to sites of previous bulky disease, or R-ACVBP given
every 2 weeks can be recommended
Young high-risk and high-intermediate-risk patients (aaIPI ≥ 2)
• There is no current standard of treatment and enrolment in clinical trials
is a priority
• 6-8 cycles of CHOP combined with eight doses of R given every 21 days are
commonly used
• Intensive R-CHOP14, R-ACVBP or R-CHOEP can be considered in selected
patients
• HDCT with ASCT following R-ChT remains experimental or can be used for
selected high-risk patients
• The role of RT consolidation to initial sites of bulky disease is unknown
Patients aged 60-80 years
• The current standard is 6-8 cycles of CHOP plus eight doses of R given every
21 days
• R-CHOP14 has no survival advantage over R-CHOP21, but if used, 6 cycles
of CHOP with 8 cycles of R are sufficient
• Consolidation RT may improve outcome in patients with bulky disease
• A comprehensive geriatric assessment, to ascertain comorbidities and
functional decline, is recommended to guide treatment choices in elderly,
poor-prognosis patients
• R-CHOP can generally be used up to the age of 80 years in fit patients but
modulation of treatment according to geriatric assessment is recommended
Patients aged > 80 years
• R-miniCHOP can induce complete remission and prolonged survival
in fit patients
39
• Substitution of doxorubicin with gemcitabine, etoposide or liposomal
doxorubicin, or even its omission, can be considered from the outset or
after a few cycles in patients with cardiac dysfunction or who are frail or unfit
CNS prophylaxis
• CNS prophylaxis is recommended for patients with high-intermediate-risk and
high-risk IPI disease, particularly those with more than one extranodal site or
elevated LDH, or patients with testicular, renal or adrenal involvement
• High-dose IV methotrexate is related to efficient disease control
Special considerations for some DLBCLs
• Patients with HIV infection should receive the same treatment as HIV-negative
patients, but with antiviral therapy
• Antiviral prophylaxis or periodic HBV DNA monitoring, with antiviral treatment
as necessary, are recommended for patients at risk of HBV reactivation during
R-CHOP treatment
Response evaluation
• FDG–PET-CT is the recommended standard for post-treatment assessment
• A biopsy is recommended when there is residual metabolically active tissue
and salvage treatment is being considered
Interim evaluation
• Imaging with CT or PET-CT after 3-4 cycles can be used to rule out progression
• Changing treatment solely on PET-CT is discouraged, unless there is clear
evidence of progression
FOLLOW-UP
A history and physical examination should be conducted every 3 months
for 1 year, every 6 months for an additional 2 years and then annually,
with a focus on the development of secondary tumours or other long-term
side effects of ChT
Blood counts should be performed at 3, 6, 12 and 24 months and then only as
needed for evaluation of suspicious symptoms or clinical findings in patients
suitable for further therapy
CT scanning at 6, 12 and 24 months after the end of treatment is common practice,
but routine imaging of patients in complete remission does not provide outcome
40
benefits and may increase the incidence of secondary malignancies
Routine PET scan surveillance is not recommended
High-risk patients with curative options may require more frequent evaluation
Relapsed and refractory DLBCL
Diagnosis, staging and risk assessment
• Suspected relapse on imaging should be confirmed by a needle-core biopsy
before proceeding to second-line treatment
• Patients amenable to curative therapy should undergo the same staging and risk
assessments performed at first diagnosis
Treatment, response evaluation and follow-up
• In patients < 65-70 years of age with good PS and no major organ dysfunction,
salvage regimens with R and ChT followed, in responsive patients, by HDCT and
ASCT, are recommended
• R-DHAP, R-ICE and R-GDP give similar outcomes
• BEAM is the most commonly used high-dose regimen
• IFRT may be useful in limited-stage disease
• R maintenance therapy is not recommended
• AlloSCT may be considered in patients with refractory disease, early relapse
or relapse after ASCT
• Salvage regimens, including R-GEMOX, can be used when HDCT/ASCT
is not feasible
• Patients should preferably be enrolled in clinical trials investigating novel agents
• First-line treatment response evaluation criteria should be used after 3-4 cycles of
salvage therapy and after the end of all therapy
• Follow-up is the same as for first response
Currently, no molecularly targeted agents are appropriate for routine use
in clinical practice
41
NEWLY DIAGNOSED AND RELAPSED MANTLE
CELL LYMPHOMA
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY
• Diagnosis of mantle cell lymphoma (MCL) should be based on a surgical
specimen, preferably a lymph node biopsy
• Core biopsies should only be carried out in patients without easily accessible
lymph nodes (e.g. retroperitoneal bulk), giving consideration to the heterogeneity
of MCL
• With leukaemic manifestation only, a bone marrow (BM) biopsy may be
sufficient if additional diagnostic measures are also applied: Immunophenotype
[cluster of differentiation (CD)5+,CD19/20+], detection of t(11;14)(q13;q32) and
overexpression of cyclin D1
• Fine-needle aspirations are not recommended for a reliable evaluation of
additional risk factors (cytology, cell proliferation)
• Diagnosis should be according to the World Health Organization (WHO)
classification and Ki-67, which is the most established histomorphological
risk factor
• Tumours have a classic morphology of small-medium sized cells with irregular
nuclei but malignant lymphocytes may present with a spectrum of morphological
variants and as only a few cases are correctly diagnosed using classical histology
alone, review by an expert haematopathologist is advised
• Immunohistochemistry for detection of cyclin D1-overexpression is mandatory
• In cyclin D1-negative cases, detection of SOX11 may help to establish the
diagnosis
• Additional biopsy material should be stored freshly frozen to allow additional
molecular analyses
• Thorough initial staging is recommended, as shown in the table on the next page,
particularly in rare non-bulky stages I and II disease
42
LUGANO CLASSIFICATION
STAGE AREA OF INVOLVEMENT
I (IE) One lymph node region or extranodal site (IE)
Two or more lymph node regions or localised extranodal sites (IIE) on the same side of
II (IIE)
the diaphragm
Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer’s ring) on both sides
III
of the diaphragm
IV Diffuse or disseminated extralymphatic organ involvement
Cheson BD et al. J Clin Oncol 2014;32:3059–68 Reprinted with permission.
• As shown in the table below, the initial work-up should include a computed
tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a BM
aspirate and biopsy
DIAGNOSTIC WORK-UP
HISTORY B SYMPTOMS
Physical examination Waldeyer’s ring, peripheral lymph nodes, liver, spleen
Blood and differential count
In leukaemic cases: FACS (CD5/CD19/20+)
Laboratory work-up FISH for t(11;14) recommended
LDH, uric acid, liver and renal function
Electrophoresis (optional: Immune fixation)
Serology Hepatitis B, C and HIV serology
Abdominal ultrasound
CT neck, chest, abdomen, pelvis
Imaging
or PET-CT
MRI only in selected locations (CNS)
Histology (cyclin D1 IHC)
Cytology
BM
Recommended: FACS, FISH for t(11;14)
Optional: PCR for IGH gene rearrangement
Electrocardiogram, cardiac ultrasound (prior to anthracyclines, ASCT)
Pulmonary function (prior to ASCT)
Toxicity
Creatinine clearance
Optional: Reproductive counselling in young patients
ASCT, autologous stem cell transplantation; BM, bone marrow; CD, cluster of differentiation; CNS, central nervous system;
CT, computed tomography; FACS, fluorescence-activated cell sorting; FISH, fluorescence in situ hybridisation; HIV, human
immunodeficiency virus; IHC, immunohistochemistry; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging;
PCR, polymerase chain reaction; PET, positron emission tomography
43
• Positron emission tomography (PET)-CT scanning is recommended particularly
for rare limited stages I/II, prior to localised radiotherapy (RT)
• Gastrointestinal endoscopy is also recommended in these rare cases to detect
asymptomatic involvement but otherwise only in symptomatic patients
• Central nervous system (CNS) involvement is rare in asymptomatic patients at
diagnosis, but a lumbar puncture may be considered in high-risk cases, i.e. those
with at least two of the following risk factors: Blastoid variant, elevated lactate
dehydrogenase (LDH), impaired performance status or neurological symptoms
• A full blood count, blood chemistry including LDH and uric acid as well as
screening tests for human immunodeficiency virus (HIV) and hepatitis B and C
are required
• Staging is carried out according to the Lugano classification system, as shown in
the table on page 43, with mention of bulky disease > 5 cm when appropriate
• The Ki-67 proliferative antigen, the most applicable method to evaluate cell
proliferation and the most established biological risk factor in MCL, should be
assessed by a standardised method
• Clinical and biological prognosticators [combined mantle cell lymphoma
International Prognostic Index (MIPI-c)] should be used routinely to estimate
clinical behaviour, as shown in the table on the next page
44
MIPI AND MIPI-C RISK STRATIFICATION
POINTS AGE (YEARS) ECOG LDH (ULN) WBC COUNT (109/L)

0 < 50 0-1 < 0.67 < 6.700
1 50-59 - 0.67-0.99 6.700-9.999
2 60-69 2-4 1.00-1.49 10.000-14.999
3 ≥ 70 - ≥ 1.50 ≥ 15.000
MIPI RISK GROUP KI-67 INDEX MIPI-C RISK GROUP (SUM

(WEIGHT IN MIPI-C) (WEIGHT IN MIPI-C) OF WEIGHTS)
Low (0) < 30% (0) Low (0)
Low (0) ≥ 30% (1) Low-Intermediate (1)
Intermediate (1) < 30% (0) Low-Intermediate (1)
Intermediate (1) ≥ 30% (1) High-Intermediate (2)
High (2) < 30% (0) High-Intermediate (2)
High (2) ≥ 30% (1) High (3)
For each prognostic factor, 0-3 points were given to each patient and points were summed up to a maximum of 11. Patients
with 0-3 points in summary were classified as low-risk, patients with 4-5 points as intermediate-risk, and patients with
6-11 points as high-risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden
(ECOG 2-4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/L, the limits were 180, 240 and
360 U/L for low-, intermediate- and high-risk groups, respectively
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MIPI, mantle cell lymphoma International Prognostic
Index; MIPI-c, combined MIPI; ULN, upper limit of normal range; WBC, white blood cell
Leukaemic non-nodal subtype of MCL

• A subset of patients may exhibit a more indolent evolution of MCL, compared
with the usual aggressive course, and this is commonly characterised by a
leukaemic non-nodal presentation with BM involvement only and splenomegaly
• SOX11 negativity may help to identify these cases
• Conventional MCL (SOX11-positive) with low Ki-67 (≤ 10%) also tends to have
a more indolent course, but additional TP53 mutations may lead to aggressive
clinical evolution, as shown in the figure on the next page
45
MOLECULAR PATHOGENESIS OF MCL Progression
(TP53 and other oncogenic
abnormalities)
Classical MCL Blastoid MCL
Unmutated/minimally
mutated Ig Lymph
SOX11 + B cell node,
extranodal
In situ MC Pleomorphic
CCND1-R neoplasia MCL
Mantle
zone
Germinal centre
Pre-
B cell
Naive
B cell
Hypermutated Ig
Cyclin SOX11 – B cell PB, BM,
D1 neg spleen
BM, bone marrow; Ig, immunoglobulin; MC, mantle cell; MCL, mantle
cell lymphoma; neg, negative; PB, peripheral blood.
Leukaemic
Swerdlow SH et al. Blood 2016;127:2375-90. Republished with
permission. Copyright 2016 American Society of Hematology.
non-nodal MCL
All rights reserved.
• There are no markers that definitely predict indolent behaviour but a short course
of watch-and-wait under close observation is recommended for suspected
indolent cases with low tumour burden
• If treatment is required, recommendations for classical MCL apply
TREATMENT
First line: Stages I-II
• In patients with limited non-bulky disease, RT (involved field, 30-36 Gy) can lead
to long-term remissions, although some studies report relapse within 1 year
A shortened conventional chemotherapy (ChT) induction followed by
consolidation RT (similar to diffuse large cell lymphoma) may be the most
appropriate treatment
• In patients with large tumour burden or adverse prognostic features, systemic
therapy approaches indicated for advanced stages are recommended, with
consideration being given to consolidation RT, depending on tumour location and
46
expected side effects
First line: Stages III-IV
• Induction therapy in all symptomatic patients and in cases with high tumour
burden should be initiated at diagnosis, based on clinical risk factors, symptoms
and patient characteristics, as shown in the figure below
THERAPEUTIC RECOMMENDATIONS
Young patient (≤ 65 years) Elderly patient (> 65 years) Compromised patient
First-line treatment
Dose-intensiﬁed Conventional Best supportive care?

immunochemotherapy immunochemotherapy R-chlorambucil
(e.g. R-CHOP, VR-CAP, BR, R-BAC) BR (dose-reduced)
(e.g. R-CHOP, high dose AraC) R-CVP
ASCT R maintenance
R maintenance
Relapse
Immunochemotherapy Immunochemotherapy Immunochemotherapy

(e.g. R-BAC, BR) (e.g. BR, R-BAC) (e.g. BR dose-reduced)
or targeted approaches or targeted approaches or targeted approaches
Discuss: Discuss:
AlloSCT R
RIT
maintenance
Higher relapse
Targeted approaches: Ibrutinib, lenalidomide

Temsirolimus, bortezomib (preferable in combination with ChT)
Alternatively: Repeat previous therapy (long remissions)
AlloSCT, allogeneic stem cell transplantation; AraC; cytarabine; ASCT, autologous stem cell transplantation; BAC, bendamustine/
cytarabine; BR, bendamustine/rituximab; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ChT, chemotherapy;
CVP, cyclophosphamide/vincristine/prednisolone; R, rituximab; RIT, radioimmunotherapy; VR-CAP, bortezomib/cyclophosphamide/
doxorubicin/prednisolone/rituximab
Elderly patients
• The majority of patients do not qualify for dose-intensified regimens
• Addition of rituximab (R) to ChT improves overall response, progression-free
survival (PFS) and overall survival (OS), as shown in the table on the next page
47
48
CONVENTIONAL FIRST-LINE IMMUNOCHEMOTHERAPY IN MCL (PHASE III STUDIES)
STUDY EVALUABLE THERAPEUTIC ORR % MEDIAN

AUTHOR 2-YEAR OS
FEATURES PATIENTS REGIMEN (CR %) PFS (MONTHS)
CHOP 75 (7) 21 76%
Phase III,
Lenz et al. 112 vs vs vs vs
randomised
R-CHOP 94 (34) 14 (TTF) 76%
MCP 63 (15) 18 52%
Phase III,
Herold et al. 90 vs vs vs vs
randomised 20 55% (4-year OS)
R-MCP 71 (32)
R-CHOP 86 (34) 58% 62%
vs vs vs vs
R-FC 78 (40) 29% (4-year DOR) 47% (4-year OS)
Kluin-Nelemans Phase III,
485
et al. randomised
R 79%
vs - - vs
IFN-α 67% (4-year OS)
R-CHOP 91 (30) 21
Phase III, 514
Rummel et al. vs vs vs No differences
randomised (94 MCL)
BR 93 (40) 35
R-CHOP 89 (42) 16 54%
Robak et al. Phase III, randomised 487 vs vs vs vs
VR-CAP 92 (53) 31 64% (4-year OS)
BR, bendamustine/rituximab; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CR, complete response; DOR, duration of response; FC, fludarabine/cyclophosphamide;
IFN-α, interferon alpha; MCL, mantle cell lymphoma; MCP, mitoxantrone/chlorambucil/prednisolone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab;
TTF, time to treatment failure; VR-CAP, bortezomib/cyclophosphamide/doxorubicin/prednisolone/rituximab
Lenz G et al. J Clin Oncol 2005;23:1984-92; Herold M et al. Ann Oncol 2008;19:abs12; Kluin-Nelemans HC et al. N Engl J Med 2012;367:520-31; Rummel MJ et al. Lancet 2013;381:1203-10;
Robak T et al. N Engl J Med 2015;372:944-53
• R in combination with ChT such as cyclophosphamide/doxorubicin/vincristine/
prednisolone (CHOP) or bendamustine is recommended
• Bortezomib in combination with R doubles median PFS but results in significant
thrombocytopaenia
• R in combination with cyclophosphamide/vincristine/prednisolone (CVP) results
in inferior response rates and PFS
• Purine analogue-based schemes, R with fludarabine/cyclophosphamide (R-FC) or
with fludarabine/mitoxantrone (R-FM), are not recommended due to early failures
and long-lasting myelosuppression
• The addition of high-dose cytarabine (HD-AraC) to CHOP is under investigation
and R/bendamustine/cytarabine (R-BAC) has also been explored
• In frail patients, less intense immunochemotherapy, chlorambucil (Clb)
or vincristine/doxorubicin/oral dexamethasone/chlorambucil (VADC) or
prednisolone/etoposide/procarbazine/cyclophosphamide (PEP-C), or a targeted
therapy with low toxicity may be considered
• Antibody monotherapy [R, radioimmunotherapy (RIT)] achieves only moderate
response rates and is therefore not recommended
• In patients with positive hepatitis B serology, prophylactic antiviral medication
and/or virus load monitoring is strongly recommended
• Maintenance with R significantly improves PFS and OS after R-CHOP
• RIT consolidation also prolongs PFS after ChT, but is inferior to R maintenance
Younger patients
• An intensive approach, e.g. by autologous stem cell transplantation (ASCT),
induces higher response and survival rates in fit patients, independently of the
addition of R, as shown in the table on the next page
49
DOSE-INTENSIFIED FIRST-LINE THERAPY IN MCL (PHASE II, III TRIALS)
STUDY EVALUABLE THERAPEUTIC ORR %

FEATURES PATIENTS REGIMEN (CR %)
ASCT-based regimens
CHOP + TBI + ASCT 98 (81)

Phase III,
Dreyling et al. 122 vs vs
randomised
CHOP + TBI + IFN-α 99 (37)
R-CHOP + TBI + ASCT

98 (63)
Phase III, vs
Hermine et al. 455 vs
randomised R-CHOP/R-DHAP +
99 (61)
HD-AraC + ASCT
R-maxi-CHOP + HD-AraC
Eskelund et al. Phase II 160 96 (54)
+ ASCT
R-CHOP/R-DHAP +
Delarue et al. Phase II 60 100 (96)
HD-AraC + ASCT
R-DHAP + ASCT
Phase III, vs
Le Gouill et al. 299 83 (77)
randomised R-DHAP + ASCT +
R maintenance
non-ASCT-based regimens
Phase II,
Romaguera et al. 97 R-hyper-CVAD n/a
monocentric
Phase II,
Merli et al. 60 R-hyper-CVAD 83 (72)
multicentric
Phase II,
Bernstein et al. 49 R-hyper-CVAD 86 (55)
multicentric
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CR, complete

response; DHAP, dexamethasone/cytarabine/cisplatin; HD-AraC, high-dose cytarabine; hyper-CVAD, hyperfractionated
cyclophosphamide/vincristine/doxorubicin/dexamethasone alternating with methotrexate and cytarabine; IFN-α, interferon
alpha; maxi-CHOP, maximum-strength CHOP; MCL, mantle cell lymphoma; n/a, not applicable; NR, not reached;
ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab; TBI, total body irradiation;
TRM, transplant-related mortality
Dreyling M et al. Blood 2005;105:2677-84; Hermine O et al. Lancet 2016;388:565-75; Eskelund CW et al. Br J Haematol
2016;175:410-8; Delarue R et al. Blood 2013;121:48-53; Le Gouill S et al. Blood 2016;128;abs145; Romaguera JE et al. J
Clin Oncol 2005;23:7013-23; Merli F et al. Br J Haematol 2012;156:346-53; Bernstein SH et al. Ann Oncol 2013;24:1587-93
50
MEDIAN MEDIAN SECONDARY
DROPOUT
PFS OS TRM TUMOUR
RATE
(YEARS) (YEARS) RATE
3.3 NR (83% 3-year OS) 13% 5%

vs vs vs vs 5%
1.4 NR (77% 3-year OS) n/a 0%
3.8 6.8
vs vs n/a 4% n/a
7.3 NR
NR
7.4 9% 5% 4%
(64% 10-year OS)
NR
6.9 18% 1.5% 18%
(75% 5-year OS)
NR (73% 3-year PFS) NR (84% 3-year OS)

vs vs n/a n/a n/a
NR (89% 3-year PFS) NR (93% 3-year OS)
NR
4.6 29% 8% 5%
(64% 10-year OS)
NR
NR (73% 5-year PFS) 63% 6.5% 1.5%
(61% 5-year OS)
4.8 6.8 39% 2% 4%
51
• A cytarabine (AraC)-containing induction regimen improves median time to
treatment failure (P = 0.038) whereas induction with HD-AraC alone leads to poor
response rates
• In a comparison of the Nordic, HOVON and MCL Younger protocols, total body
irradiation (TBI) prior to ASCT is beneficial only in patients with partial response (PR)
There is no benefit of RIT
• An upfront, dose-intensified approach [R/hyperfractionated cyclophosphamide/
vincristine/doxorubicin/dexamethasone alternating with methotrexate and
cytarabine (R-hyper-CVAD)] gives good response and survival rates but is
associated with significant therapy-associated toxicity and a poor stem cell
mobilisation success rate
• R maintenance following induction with R with dexamethasone/high-dose
cytarabine/cisplatin (R-DHAP) and ASCT improves PFS and OS and is the current
standard of care
• The use of allogeneic stem cell transplantation (alloSCT) as part of front-line
treatment cannot be supported
Relapsed disease
• A repeated biopsy is recommended to identify important prognostic features
• Selection of salvage treatment depends on the efficacy of prior regimens
• In early relapses (< 12-24 months), a non-cross-resistant scheme (bendamustine
or HD-AraC-containing regimens, e.g. R-BAC) after CHOP or vice versa, is
recommended, with addition of R if the previous antibody-containing scheme
achieved > 6 months duration of remission
• Newer targeted approaches should be considered for early relapses or refractory
disease, as shown in the table on the next pages and the figure on page 47
52
PUBLISHED CLINICAL STUDIES INVESTIGATING MOLECULAR TARGETED APPROACHES IN RELAPSED MANTLE CELL LYMPHOMA
STUDY EVALUABLE THERAPEUTIC ORR % MEDIAN PFS MEDIAN OS

AUTHOR
FEATURES PATIENTS REGIMEN (CR %) (MONTHS) (MONTHS)
Proteasome inhibitors
Goy et al. Phase II 141 Bortezomib 33 (8) 6.7 (TTP) 23.5
mTOR inhibitors
54 Temsirolimus 175 mg/75 mg 22 (2) 4.8 12.80
Phase III,
Hess et al. 54 Temsirolimus 175 mg/25 mg 6 (0) 3.4 10.00
randomised
53 Investigator's choice 2 (2) 1.9 9.70
Ansell et al. Phase II 69 Temsirolimus, R 59 (19) 9.7 29.50
Hess et al. Phase II 32 Temsirolimus, BR 87 (8) 18 36.00
Immunomodulatory drugs
Zinzani et al. Phase II 57 Lenalidomide 35 (12) 8.8 NR
Goy et al. Phase II 134 Lenalidomide 28 (8) 4 19.00
Lenalidomide 46 (11) 8.7 27.90
Trn ný et al. Phase III 254
Investigator's choice 23 (8) 5.2 21.20
Wang et al. Phase II 44 Lenalidomide, R 57 (36) 11.1 24.3
Antibody-based approaches
90
Wang et al. Phase II 32 Y-ibritumomab tiuxetan 31 (16) 6 (EFS) 21
90
Ferrero et al. Phase II 15*+ Y-ibritumomab tiuxetan 40 (20) 3.7 13.8
53
54
STUDY EVALUABLE THERAPEUTIC ORR % MEDIAN PFS MEDIAN OS
AUTHOR
FEATURES PATIENTS REGIMEN (CR %) (MONTHS) (MONTHS)
BCR signalling inhibitors
NR (58%
Wang et al. Phase II 111 Ibrutinib 68 (21) 13.9
1.5-year OS)
NR (68%
Dreyling et al. Phase III 280 Ibrutinib vs temsirolimus 72 (26) 14.6
1-year OS)
Wang et al. Phase II 50 Ibrutinib, R 88 (44) NR NR
Kahl et al. Phase I 16 Idelalisib 62 (n/a) 3 (DOR) n/a
BCL2 inhibitors
Davids et al. Phase I 32 (8 MCL) Venetoclax† 100 (0) n/a n/a
*15 patients received the antibody as relapse monotherapy, 30 patients as consolidation after salvage treatment
†
Not registered in MCL
BCL2, B-cell lymphoma 2; BCR, B-cell receptor; BR, bendamustine/rituximab; CR, complete response; DOR, duration of response; EFS, event-free survival; MCL, mantle cell lymphoma;
mTOR, mammalian target of rapamycin; n/a, not applicable; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab; TTP, time to
progression
Goy A et al. Ann Oncol 2009;20:520-5; Hess G et al. J Clin Oncol 2009;27:3822-9; Ansell SM et al. Lancet Oncol 2011;12:361-8; Hess G et al. Blood 2016;128(22):abs2977; Zinzani PL et
al. Ann Oncol 2013;24:2892-7; Goy A et al. J Clin Oncol 2013;31:3688-95; Trn ný M et al. Lancet Oncol 2016;17:319-31; Wang M et al. Lancet Oncol 2012;13:716-23; Wang M et al. J Clin
Oncol 2009;27:5213-8; Ferrero S et al. Leukemia 2016;30:984-7; Wang ML et al. N Engl J Med 2013;369:507-16; Dreyling M et al. Lancet 2016;387:770-8; Wang ML et al. Lancet Oncol
2016;17:48-56; Kahl BS et al. Blood 2014;123:3398-405; Davids MS et al. J Clin Oncol 2017;35:826-33
• Ibrutinib achieves the highest response rates and some long-term remissions but
early relapses display very aggressive features
• Lenalidomide (preferably in combination with R) may lead to ongoing remissions
when ibrutinib is contraindicated, particularly when there is a high risk of
bleeding
• Temsirolimus and bortezomib combined with ChT are additional options
• R maintenance has a favourable safety profile and prolongs PFS and OS in
relapsed disease, but second-line maintenance after relapse on front-line
maintenance has not been investigated
• RIT leads to extended remission durations, especially in elderly patients with
comorbidities who are not eligible for dose intensification
• High-dose ChT with ASCT may be considered in patients relapsing after
conventional first-line therapy, although the benefit is marginal
A second autograft at relapse should not be used
• In younger patients, alloSCT with reduced-dose conditioning is potentially
curative and has achieved long-term remissions even in patients following early
relapse and with refractory disease
• Haploidentical BM transplantation achieves high response rates but is still
experimental
• Consideration should be given to enrolment in clinical trials
RESPONSE EVALUATION
• PET-CT according to the Lugano classification for response evaluation is optional
• Radiological tests should be carried out mid- and post-completion of ChT
Patients achieving less than a PR should be considered for early salvage
regimens while those achieving a PR may convert to a complete response after
post-induction treatment
• Minimal residual disease (MRD), applying patient-specific primers, is an
independent prognostic factor but should not be used outside clinical trials,
except in donor lymphocyte infusion post-allograft
• More research is needed to identify molecular markers that could translate into a
more personalised approach
• The selection of the optimal treatment for a patient is based mainly on clinical
and biological risk factors, symptoms and tumour load (see figure on page 47)
55
• PET- and MRD-based tailored treatments are not yet part of routine
clinical practice
• New agents, especially other inhibitors targeting the B-cell receptor (BCR)
pathway, B-cell lymphoma 2 (BCL2) or cyclin-dependent kinases, are under
investigation
• Recommendations, as shown in the table below, are based on consensus rather
than on evidence and include: History and physical examination, blood counts
and routine chemistry every 3 months for 2 years, every 6 months for 3 additional
years, and annually thereafter; annual evaluation of thyroid function in patients after
irradiation of the neck; optional CT scan (or ultrasound examinations) every
3-6 months for 2 years and every 6-12 months up to 5 years
RECOMMENDED FOLLOW-UP
EXAMINATION DETAILS YEAR 1-2 YEAR 3-5 YEAR > 5
History B symptoms Every 3 months Twice annually Annually
Physical Peripheral lymph nodes,
Every 3 months Twice annually Annually
examination liver, spleen
Laboratory Blood and differential count

Every 3 months Twice annually Annually
work-up LDH
Abdominal ultrasound
Optional: Every Optional: Every If progress
Imaging CT neck, chest, 3-6 months 6-12 months suspected
abdomen, pelvis
Toxicity TSH if irradiated Annually
CT, computed tomography; LDH, lactate dehydrogenase; TSH, thyroid-stimulating hormone
• Evidence does not support regular radiological follow-up and PET-CT should not
be used for surveillance
56
Diagnosis of MCL should be based on a surgical specimen, preferably a lymph
node biopsy, with core biopsies reserved for patients without easily accessible
lymph nodes
With leukaemic manifestation only, a BM biopsy with additional diagnostic
measures, such as immunophenotype (CD5+, CD19/20+), detection of t(11;14)
(q13;q32) and overexpression of cyclin D1, is sufficient
Fine-needle aspirations are not recommended for evaluating additional risk factors
(cytology, cell proliferation)
Diagnosis should be made according to the WHO classification and Ki-67, using a
standardised method
Expert haematopathological review is recommended
Immunohistochemistry for detection of cyclin D1 overexpression is mandatory
In cyclin D1-negative cases, detection of SOX11 may help to establish the diagnosis
The initial work-up should include a CT scan of the neck, thorax, abdomen and
pelvis, a BM aspirate and biopsy, a full blood count, blood chemistry, including
LDH and uric acid, and screening tests for HIV and hepatitis B and C
PET-CT scan is recommended for rare limited stage I/II disease, prior to localised
RT, together with gastrointestinal endoscopy in asymptomatic cases, which should
otherwise be reserved for symptomatic patients
Lumbar puncture to assess CNS involvement may be considered in high-risk cases
Staging should be carried out according to the Lugano classification system, with
mention of bulky disease > 5 cm when appropriate
MIPI-c should be used routinely to estimate clinical behaviour
Leukaemic non-nodal subtype of MCL
• SOX11 negativity may help to identify a more indolent evolution of MCL,
characterised by a leukaemic non-nodal presentation with BM involvement only
and splenomegaly
• In conventional MCL (SOX11-positive) with low Ki-67 (≤ 10%) additional TP53
mutations may lead to aggressive clinical evolution
57
• A short course of watch-and-wait under close observation is recommended for
suspected indolent cases with low tumour burden
• If treatment is required, recommendations for classical MCL apply
TREATMENT
First line: Stages I-II
• In patients with limited non-bulky disease, a shortened conventional ChT
induction regimen followed by consolidation RT (involved field, 30-36 Gy) is
recommended
• In patients with large tumour burden or adverse prognostic features, systemic
therapy approaches indicated for advanced stages are recommended, with
consideration being given to consolidation RT
First line: Stages III-IV
• Induction therapy in all symptomatic patients and in cases with high tumour
burden should be initiated at diagnosis, based on clinical risk factors, symptoms
and patient characteristics
Elderly patients
• The majority of patients do not qualify for dose-intensified regimens
• R in combination with ChT such as CHOP or bendamustine is recommended
• Bortezomib in combination with R doubles median PFS but results in significant
thrombocytopaenia and R-CVP results in inferior response rates
and PFS
• R-FC or R-FM and antibody monotherapy (R, RIT) are not recommended
• Less intense immunochemotherapy, e.g. Clb, VADC or PEP-C, or a
low-toxicity targeted therapy may be considered for frail patients
• Prophylactic antiviral medication and/or virus load monitoring is strongly
recommended for patients with positive hepatitis B serology
• Maintenance with R significantly improves PFS and OS after R-CHOP and is
superior to RIT consolidation
58
Younger patients
• An intensive approach, e.g. ASCT, induces higher response and survival rates in
fit patients, independently of R addition
• An AraC-containing induction regimen is more effective than HD-AraC alone
• TBI prior to ASCT is beneficial only in patients with PR and there is no benefit
of RIT
• An upfront, dose-intensified approach, using R-hyper-CVAD with alternating
high-dose methotrexate/cytarabine cycles, gives good response and survival
rates but is associated with significant therapy-associated toxicity and a low stem
cell mobilisation success rate
• R maintenance following induction R-DHAP and ASCT improves PFS and OS and
is the current standard of care
• The front-line use of alloSCT cannot be supported
Relapsed disease
• A repeated biopsy is recommended to identify important prognostic features
• Selection of salvage treatment depends on the efficacy of prior regimens
• In early relapses (< 12-24 months), a non-cross-resistant scheme after CHOP
or vice versa, is recommended, with addition of R if the previous antibody-
containing scheme achieved > 6 months duration of remission
• Newer targeted approaches should be considered for early relapses or
refractory disease
• Ibrutinib achieves the highest response rates, although early relapses display
very aggressive features, and lenalidomide (preferably in combination with R)
may produce ongoing remissions when ibrutinib is contraindicated
• Temsirolimus and bortezomib combined with ChT are additional options
• R maintenance has a favourable safety profile and prolongs PFS and OS in
relapsed disease
• RIT leads to extended remission durations, especially in elderly patients with
comorbidities who are not eligible for dose intensification
• High-dose ChT with ASCT may be considered in patients relapsing after
conventional first-line therapy
• In younger patients, alloSCT with reduced-dose conditioning is potentially
curative and has achieved long-term remissions even following early relapse
and in refractory disease
• Consideration should be given to enrolment in clinical trials
59
RESPONSE EVALUATION
PET-CT according to the Lugano classification for response evaluation is optional
Radiological tests should be carried out mid- and post-completion of ChT; patients
achieving less than a PR should be considered for early salvage regimens while
those achieving a PR may convert to a complete response after post-induction
treatment
MRD should not be used outside clinical trials, except in donor lymphocyte infusion
post allograft
More research is needed to identify molecular markers that could translate into a
more personalised approach
Optimal treatment selection is based mainly on clinical and biological risk factors,
symptoms and tumour load
New agents, especially other inhibitors targeting the BCR pathway, BCL2 or
cyclin-dependent kinases, are under investigation
History and physical examination, blood counts and routine chemistry should be
performed every 3 months for 2 years, every 6 months for 3 additional years, and
once a year thereafter
Annual evaluation of thyroid function is recommended in patients after irradiation
of the neck
A CT scan every 3-6 months for 2 years and every 6-12 months up to 5 years
is optional
60
DIAGNOSIS
• Diagnosis of Waldenström’s macroglobulinaemia (WM) is based on
the histopathological confirmation of bone marrow (BM) infiltration by
lymphoplasmacytic cells/lymphoplasmacytic lymphoma and the detection
of any amount of monoclonal immunoglobulin (Ig) M protein, confirmed by
immunofixation
• The clonal lymphoplasmacytic cell population in the BM should be documented
by a trephine biopsy and/or aspiration and confirmed by immunophenotypic
studies (immunohistochemistry or flow cytometry) showing cluster of
differentiation (CD)19, CD20, CD22 and CD79a expression on the lymphocytic
component as well as CD38 on the plasmacytic component (small variations
can occur)
• Around 90% of WM cases are positive for the MYD88L265P mutation and genetic
testing of lymphoplasmacytic cells can be helpful for the differential diagnosis
from other lymphoma subtypes and IgM multiple myeloma, although detection
of the MYD88L265P mutation alone is not sufficient for the diagnosis of WM
• Activating C–X–C chemokine receptor type 4 (CXCR4) mutations are found in
around 30% of patients with WM. There are no therapeutic implications outside
clinical trials and diagnostic testing for CXCR4 mutations is not routinely
recommended
• In addition to patient history and symptoms documentation, as shown in the
table on the next page, initial evaluation includes a complete blood count (CBC)
and serum chemistry [including lactate dehydrogenase (LDH) and serum
albumin]
61
DIAGNOSTIC WORK-UP
RECOMMENDED
History and physical examination
Include familial history for WM and other B-cell LPDs

Review of systems (B symptoms*, hyperviscosity symptoms, neuropathy, Raynaud's disease,
rash, peripheral oedema, skin abormalities, dyspnoea)
Include fundoscopic examination if IgM is high and hyperviscosity is suspected
Laboratory studies
CBC
Complete metabolic panel
Serum Ig levels (IgA, IgG, IgM)
Serum and urine electrophoresis with immunofixation
Serum B2M level
Viral serology (HBV, HCV and HIV)
BM aspiration and biopsy
IHC (required for diagnostics)
Flow cytometry (optional; consider if IHC not available)
Testing for MYD88L265P gene mutation
CT of the chest, abdomen and pelvis (if clinically indicated and in all patients being considered for therapy)
OPTIONAL (IF CLINICALLY INDICATED)

Cryoglobulins
Cold agglutinin titre
Serum viscosity
Screening for acquired von Willebrand disease
24-h urine protein quantification
Serum FLCs
NTproBNP, cardiac troponins
EMG, anti-MAG, anti-GM1 (consultation with neurologist)
*Fever, night sweats and weight loss

anti-GM1, anti-ganglioside M1; anti-MAG, myelin-associated globulin antibody; B2M, β2 microglobulin; BM, bone marrow;
CBC, complete blood count; CT, computed tomography; EMG, electromyogram; FLC, free light chain; HBV, hepatitis B virus; HCV, hepatitis
C virus; HIV, human immunodeficiency virus; Ig, immunoglobulin; IHC, immunohistochemistry; LPD, lymphoproliferative disorder;
NTproBNP, N-terminal pro B-type natriuretic peptide; WM, Waldenström’s macroglobulinaemia
62
• β2 microglobulin (B2M) should be measured as it is a prognostic marker for survival
• Serum protein electrophoresis and immunofixation and quantification of Ig levels (IgM,
IgG, IgA) are essential at initial assessment
• Serum free light chain measurement is recommended where there is suspicion of light
chain amyloidosis or renal failure
• Urine protein electrophoresis and/or immunofixation to exclude abnormal renal Ig
secretion is required
• Hyperviscosity syndrome related to high IgM is common in WM and fundoscopic
examination is recommended where symptoms are present (headaches, blurry vision
or visual loss, confusion, epistaxis)
• Coombs testing, cold agglutinins, cryoglobulins and iron status should be considered in
patients with anaemia
• Viral serology for hepatitis B virus (HBV), hepatitis C virus (HCV) and human
immunodeficiency virus (HIV) is strongly recommended
• Neuropathy is common in patients with WM and often an indication for treatment of
otherwise asymptomatic patients; in patients with peripheral neuropathy, consultation
of a neurologist is strongly recommended since unrelated causes of neuropathy may
also exist
• Amyloidosis is an uncommon complication in WM and, if suspected, a fat aspirate
stained with Congo red may help the diagnosis and cardiac and renal biomarkers
should be evaluated
• Imaging studies should be included in the initial evaluation to document organomegaly
and/or lymphadenopathy, preferably with computed tomography (CT) or magnetic
resonance imaging (MRI)
• Risk assessment is currently based on the International Prognostic Scoring System for
Waldenström’s macroglobulinaemia (IPSSWM), as shown in the table below, although
this was designed only for symptomatic patients
PROGNOSTICATION OF WM (IPSSWM)
STAGE 2
STAGE 1 STAGE 3
RISK GROUP (INTERMEDIATE
(LOW RISK) (HIGH RISK)
RISK)
Risk factors present* 0 or 1 (except age) Age or 2 ≥3
5-year OS (%) 87 68 36
*Risk factors for IPSSWM include: Age ≥ 65 years, haemoglobin ≥ 11.5 g/dL, platelets ≤ 100 x 109/L, B2M > 3 mg/L and
IgM > 70 g/L. Other risk factors not included in IPSSWM include elevated serum LDH and low serum albumin
B2M, β2 microglobulin; IgM, immunoglobulin M; IPSSWM, International Prognostic Scoring System for Waldenström’s
macroglobulinaemia; LDH, lactate dehydrogenase; OS, overall survival; WM, Waldenström’s macroglobulinaemia
Adapted from: Morel P et al. Blood 2009;113:4163-70.
63
MANAGEMENT
Asymptomatic patients
• Patients with asymptomatic WM should be followed without therapy
• The level of monoclonal IgM alone is not an indication to start treatment. However,
IgM levels > 60 g/L are associated with an imminent risk of symptomatic
hyperviscosity and are therefore considered to be a treatment indication
• Indications for treatment initiation are shown in the table below and most
commonly include anaemia, B symptoms and hyperviscosity; other indications
such as moderate or severe neuropathy, bulky organomegaly and immune-related
cytopaenias are less common
INDICATIONS FOR INITIATION OF THERAPY IN PATIENTS WITH WM
CLINICAL INDICATIONS FOR INITIATION OF THERAPY
Recurrent fever, night sweats, weight loss, fatigue
Hyperviscosity
Lymphadenopathy: Either symptomatic or bulky (≥ 5 cm in maximum diameter)
Symptomatic hepatomegaly and/or splenomegaly
Symptomatic organomegaly and/or organ or tissue infiltration
Peripheral neuropathy due to WM
LABORATORY INDICATIONS FOR INITIATION OF THERAPY
Symptomatic cryoglobulinaemia
Symptomatic cold agglutinin anaemia
Autoimmune haemolytic anaemia and/or thrombocytopaenia
Nephropathy related to WM
Amyloidosis related to WM
Hb ≤ 10 g/dL
Platelets < 100 x 109/L
IgM levels > 60 g/L
Hb, haemoglobin; IgM, immunoglobulin M; WM, Waldenström’s macroglobulinaemia
First-line therapy
• Participation in clinical trials is strongly encouraged for all patients, given the
increasing treatment options and promising new approaches
64
• Treatment choice is guided by the clinical presentation of the disease or
complications requiring immediate treatment response versus immunological
complications without high BM infiltration or presentation with bulky disease
(such as massive organomegaly/lymphadenopathy, hyperviscosity), as shown in
the table and figure below and on the next page
TREATMENT OPTIONS IN FIRST LINE ACCORDING TO DISEASE PRESENTATION
CLINICAL SYNDROME TREATMENT OPTIONS

PI-based therapy (BDR, VR)
Hyperviscosity Ibrutinib
BR
DRC
Cytopaenias
BR
Ibrutinib
BR
Bulky disease PI-based therapy (BDR, VR)
Ibrutinib

Need for immediate tumour reduction
BR
(due to WM-related complications)
Ibrutinib
DRC
Neuropathy BR
R monotherapy

AL amyloidosis
BR
AL, amyloid light chain; BDR, bortezomib/dexamethasone/rituximab; BR, bendamustine/rituximab; DRC, dexamethasone/
rituximab/cyclophosphamide; PI, proteasome inhibitor; R, rituximab; VR, bortezomib/rituximab; WM, Waldenström’s
macroglobulinaemia
65
TREATMENT ALGORITHM FOR PATIENTS WITH NEWLY DIAGNOSED WM
Symptomatic WM*
Fit patient Unfit patient
Low tumour High tumour Low tumour High tumour

burden** burden*** burden** burden***
DRC x 6 cycles BR x 4-6 cycles Oral fludarabine x 6 cycles Ibrutinib 420 mg qd

BR x 4-6 cycles BDR x 5 cycles DRC x 6 cycles BR**** x 4 cycles
BDR x 5 cycles Ibrutinib R x 8 cycles
VR x 6 cycles Ibrutinib 420 mg qd
Ibrutinib 420 mg qd Chlorambucil x 12 cycles
*In case of hyperviscosity, plasmapheresis should be used concomitantly with systemic therapy. In case of high IgM
levels and at risk for IgM-related complications, plasmapheresis may be used pre-emptively
**No major cytopaenias, hyperviscosity or organomegaly
***Presence of any of the following: Severe cytopaenias, hyperviscosity, organomegaly
****BR for unfit patients may require dose reductions for bendamustine and use of G-CSF and/or antibacterial/antiviral
prophylaxis
BDR, bortezomib/dexamethasone/rituximab; BR, bendamustine/rituximab; DRC, dexamethasone/rituximab/
cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; IgM, immunoglobulin M; qd, once a day; R, rituximab;
VR, bortezomib/rituximab; WM, Waldenström’s macroglobulinaemia
• Plasmapheresis should be used for the immediate relief of symptomatic

hyperviscosity along with appropriate systemic therapy
• Combinations of rituximab (R) with alkylating agents [oral or intravenous
cyclophosphamide (plus dexamethasone) or bendamustine] or proteasome
inhibitors (PIs) are the mainstay of first-line treatment
• Dexamethasone/R/cyclophosphamide (DRC) or similar regimens are primary
options for patients with low tumour burden and comorbidities
• Bendamustine/R (BR) is a primary option for patients with high tumour burden
• Combination of bortezomib with R, with or without dexamethasone, should be
individualised to a patient’s characteristics and bortezomib combinations may be
considered as primary choices for patients with very high IgM levels or hyperviscosity
• More intensive chemotherapy combinations are not primary options for
first-line treatment
• The use of single-agent therapy with alkylating agents or nucleoside analogues or
R is considered only for patients with comorbidities that preclude the use of more
effective immunochemotherapy combinations
66
• Single-agent ibrutinib may be considered for patients ineligible for
immunochemotherapy at first line (e.g. elderly patients with comorbidities)
although no full set of data has been published
• Maintenance treatment with R is not recommended for patients with
WM due to the lack of prospective data
Relapsed disease
• Single-agent ibrutinib is the treatment of choice for patients who have relapsed
within 12 months from immunochemotherapy, including R-refractory patients,
as shown in the figure below, and it should be given until disease progression;
relapses are common after discontinuation
TREATMENT ALGORITHM FOR PATIENTS WITH RELAPSED AND REFRACTORY WM
Symptomatic relapse of WM*
Fit patient Unfit patient
< 12 months 1-3 years from > 3 years from < 12 months 1-3 years from > 3 years from
after R-based previous previous after previous previous
therapy R-based therapy R-based therapy R-based therapy R-based therapy R-based therapy
Clinical trial Clinical trial Clinical trial Clinical trial Clinical trial Clinical trial
Ibrutinib Ibrutinib Repeat R-based Ibrutinib Ibrutinib R-based
R-based regimen Alternative regimen
regimen Ibrutinib R-based regimen (repeat or
(repeat or alternate)
alternate) Ibrutinib
*In case of hyperviscosity, plasmapheresis should be used concomitantly with systemic therapy. In case of high IgM levels and
at risk for IgM-related complications, plasmapheresis may be used pre-emptively
IgM, immunoglobulin M; R, rituximab; WM, Waldenström’s macroglobulinaemia
• For patients who relapse between 1 and 2 years after treatment, ibrutinib is an
appropriate treatment choice. An alternative R-based combination might be
considered in patients not eligible for ibrutinib or who relapse later in this time period
• For patients who relapse > 2-3 years after receiving an R-based regimen, an
alternative R-based combination may be considered. If DRC was used, R with
either bendamustine or bortezomib (with or without dexamethasone) may be
used
• R with nucleoside analogues is an active but also toxic combination
and therefore should be used cautiously
67
• For patients who achieve a prolonged remission with their primary therapy
(i.e. > 3-4 years), re-instituting the prior regimen may also be considered
• Ibrutinib may also be a treatment option for patients with late relapses
• High-dose therapy with autologous stem cell transplantation (ASCT) may be
considered in selected young patients with chemosensitive relapse but also early
relapse and a clinically aggressive course
RESPONSE EVALUATION
• Response evaluation in WM is based on serial measurements of monoclonal IgM
in the serum and on the relative reduction or increase of IgM, as shown in the
table below
RESPONSE CATEGORIES AND CRITERIA
RESPONSE CATEGORY DEFINITION

Absence of serum monoclonal IgM protein by
immunofixation
Normal serum IgM level*
CR Complete resolution of lymphadenopathy and
splenomegaly if present at baseline
Morphologically normal BM aspirate
and trephine biopsy
Detectable monoclonal IgM protein
≥ 90% reduction in serum IgM level
from baseline†
VGPR Complete resolution of extramedullary disease,
i.e. lymphadenopathy/splenomegaly if present at
baseline
No new signs or symptoms of active disease
≥ 50% but < 90% reduction in serum IgM level
from baseline†
PR Reduction in extramedullary disease,
i.e. lymphadenopathy/splenomegaly if present
at baseline
≥ 25% but 50% reduction in serum IgM level
MR
from baseline†
68
RESPONSE CATEGORY DEFINITION
< 25% reduction and < 25% increase in serum
IgM level from baseline†
SD
No progression in extramedullary disease,
i.e. lymphadenopathy/splenomegaly
≥ 25% increase in serum IgM level*† from lowest
nadir and/or
PD
Progression in clinical features attributable to
the disease
*IgM responses/progression should be confirmed by a second measurement
†
Sequential changes in IgM levels may be determined either by IgM protein quantification by densitometry or total serum IgM
quantification by nephelometry
BM, bone marrow; CR, complete response; IgM, immunoglobulin M; MR, minor response; PD, progressive disease; PR, partial
response; SD, stable disease; VGPR, very good partial response
• Caution is required not to interpret an IgM flare as disease progression

• BM assessments are not routinely recommended for response evaluation, except
for establishment of complete response
• Response assessment by CT or MRI is only recommended for patients with
baseline lymphadenopathy/organomegaly or extramedullary disease, or if disease
relapse and transformation is suspected
• Treatment decisions in WM should be based on patient characteristics and
disease presentation
• There is ongoing research to identify molecular markers that could lead to
personalised medicine
• Limited data exist on how MYD88 and CXCR4 mutational status may affect
the efficacy of other agents or combinations such as immunochemotherapy
regimens or PIs, thereby impeding the definition of the optimal treatment
approach for different genotypes in WM

• Follow-up should include history, physical examination, blood count, routine
chemistry and serum electrophoresis/quantification of IgM every 3 months for
2 years, every 4-6 months for an additional 3 years, and every 6-12 months
thereafter, with special attention to transformation and secondary malignancies
• Routine imaging is not recommended
• Median survival is > 10 years for younger patients and many elderly patients will
die from causes unrelated to WM
69
DIAGNOSIS
Diagnosis of WM requires histopathological confirmation of lymphoplasmacytic cell
infiltration of trephine biopsy- and/or aspiration-derived BM and the detection of any
amount of IgM protein, confirmed by immunofixation
The BM clonal lymphoplasmacytic cell population should be confirmed by
immunophenotypic studies showing CD19, CD20, CD22 and CD79a expression on
the lymphocytic component as well as CD38 on the plasmacytic component
Genetic testing of lymphoplasmacytic cells for MYD88L265P mutation can aid
differential diagnosis from other lymphoma subtypes and IgM multiple myeloma;
MYD88L265P mutation alone is not sufficient for the diagnosis of WM
Initial evaluation includes a patient history, symptoms, a CBC and serum chemistry
(including LDH and serum albumin)
B2M, serum protein electrophoresis and immunofixation and quantification of IgM,
IgG and IgA are required
Fundoscopic examination is recommended where symptoms of hyperviscosity
syndrome are present
Coombs testing, cold agglutinins, cryoglobulins and iron status should be
considered in patients with anaemia
Viral serology for HBV, HCV and HIV is strongly recommended
CT or MRI should be used to document organomegaly and/or lymphadenopathy
Risk assessment is based on the IPSSWM
MANAGEMENT
Asymptomatic patients
• Patients with asymptomatic WM should be followed without therapy
• Indications for treatment initiation commonly include anaemia, B symptoms,
hyperviscosity and monoclonal IgM levels (> 60 g/L)
First-line therapy
• Participation in clinical trials is strongly encouraged for all patients
• Plasmapheresis should be used for the immediate relief of symptomatic
hyperviscosity along with appropriate systemic therapy
70
• DRC or similar regimens are primary options for patients with low tumour burden
and comorbidities
• BR is a primary option for patients with high tumour burden
• Bortezomib combinations are primary choices for patients with very high IgM
levels or hyperviscosity
• Single-agent alkylating agents, nucleoside analogues or R can be considered
where comorbidities preclude the use of more effective immunochemotherapy
combinations
• Single-agent ibrutinib may be considered for patients ineligible for
immunochemotherapy
Relapsed disease
• Single-agent ibrutinib, administered until progression, is the treatment of choice
for patients who have relapsed within 12 months from immunochemotherapy,
including R-refractory patients
• For patients relapsing 1-2 years after treatment, ibrutinib is appropriate. An
alternative R-based combination might be considered in patients not eligible for
ibrutinib or relapsing later in this time period
• For patients relapsing > 2-3 years after a R-based regimen, an alternative R-based
combination may be considered
• R with nucleoside analogues should be used cautiously
• In cases of a prolonged remission with primary therapy, re-instituting the prior
regimen may be considered
• Ibrutinib may also be a treatment option for patients with late relapses
• High-dose therapy with ASCT may be considered in selected young patients
RESPONSE EVALUATION
Response evaluation is based on serial serum monoclonal IgM measurements and
the relative change in IgM
Assessment by CT or MRI is only recommended for baseline lymphadenopathy/
organomegaly or extramedullary disease, or suspected disease relapse/
transformation
Decisions should be based on patient characteristics and disease presentation
71
Follow-up should include history, physical examination, blood count, routine
chemistry and serum electrophoresis/quantification of IgM every 3 months for
2 years, every 4-6 months for an additional 3 years, and every 6-12 months
thereafter, with special attention to transformation and secondary malignancies
Routine imaging is not recommended
72
• Diagnosis and classification of primary cutaneous lymphomas (PCLs) is based
on a combination of clinical, histological, immunophenotypical and genetic
data. For decisions regarding therapy, clinical and histopathological features are
usually crucial
• Classification of PCLs is made according to revised 2017 World Health
Organization (WHO) criteria, as shown in the table below
WHO-EORTC CLASSIFICATION FOR CUTANEOUS LYMPHOMAS
Cutaneous T-cell lymphoma

MF
Variants of MF
• Folliculotropic MF
• Pagetoid reticulosis
• Granulomatous slack skin
SS

Primary cutaneous CD30+ LPDs
• Primary C-ALCL
• Lymphomatoid papulosis
SPTCL
Extranodal NK/T-cell lymphoma, nasal-type
Primary cutaneous peripheral T-cell lymphoma – not otherwise specified

• Primary cutaneous γ/δ T-cell lymphoma
• Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma*
• Primary cutaneous acral CD8+ T-cell lymphoma†
• Primary cutaneous CD4+ small/medium T-cell LPD*
Cutaneous B-cell lymphoma
PCMZL
PCFCL
PCLBCL-LT
*Provisional entities
†
New provisional entity in the revised 2017 WHO classification
C-ALCL, primary cutaneous anaplastic large-cell lymphoma; CD, cluster of differentiation; EORTC, European Organisation of
Research and Treatment of Cancer; LPD, lymphoproliferative disorder; MF, mycosis fungoides; NK, natural killer; PCFCL, primary
cutaneous follicle centre lymphoma; PCLBCL-LT, primary cutaneous diffuse large B-cell lymphoma, leg type; PCMZL, primary
cutaneous marginal zone lymphoma; SPTCL, Subcutaneous panniculitis-like T-cell lymphoma; SS, Sézary syndrome; WHO, World
Health Organization
Willemze R et al. Blood 2005;105:3768-85. Adapted with permission. 73
• Adequate staging should be performed to exclude the presence of
extracutaneous disease
• Flow cytometry of peripheral blood is usually recommended for all stages of
mycosis fungoides (MF) although it may not be justified in patients without
suspected Sézary syndrome (SS)
• Bone marrow (BM) examination is usually not indicated in patients with MF/SS;
see table below
RECOMMENDATION FOR STAGING EVALUATION IN PATIENTS WITH MF/SS
Complete physical examination including:
Determination of type(s) of skin lesions

Identification of any palpable lymph node, especially those ≥ 1.5 cm in largest diameter or firm, irregular
or fixed
Identification of any organomegaly
Skin biopsy
Most indurated area if only one biopsy

Routine histology and immunophenotyping
Evaluation for clonality of TCR gene rearrangement (optional)
Blood tests
CBC with manual differential, liver function tests, LDH, comprehensive chemistries
TCR gene rearrangement and relatedness to any clone in skin (optional)
Analysis for abnormal lymphocytes by either Sézary cell count with determination of absolute number of
Sézary cells and/or flow cytometry (including CD4+/CD7- or CD4+/CD26-) (optional)
Radiological test
CT scans of chest, abdomen and pelvis alone ± FDG–PET (optional in patients with early-stage MF)
Lymph node biopsy
Excisional biopsy in patients with a node that is either ≥ 1.5 cm in diameter and/or is firm, irregular,
clustered or fixed
Routine histology, IHC and TCR gene rearrangement analysis
CBC, complete blood count; CD, cluster of differentiation; CT, computed tomography; FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose–
positron emission tomography; IHC, immunohistochemistry; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary
syndrome; TCR, T-cell receptor
Olsen E et al. Blood 2007;110:1713-22. Adapted with permission from the American Society of Hematology.
74
• For patients with a PCL other than MF/SS, initial work-up includes complete
physical examination, representative skin biopsy, complete and differential blood
cell count, routine serum biochemistry with lactate dehydrogenase (LDH) and
appropriate imaging studies [computed tomography and/or [18F]2-fluoro-2-
deoxy-D-glucose (FDG)–positron emission tomography (PET) scans]
• In PCLs that are predominantly subcutaneous, FDG–PET is essential to evaluate
the extent of disease
• Patients with cutaneous lymphomas with an intermediate or aggressive clinical
behaviour should undergo BM biopsy and aspirate
Such investigations are required in patients with cutaneous lymphomas with an
indolent clinical behaviour only if indicated by other staging assessments
• Prognosis is extremely variable and depends on the type of PCL and disease
stage. Additionally, older age, large cell transformation and increased LDH values
confer unfavourable prognosis in MF
• For clinical staging of MF and SS, the revised tumour-node-metastasis-blood
(TNMB) staging system should be used, as outlined in the tables below
REVISED TNMB CLASSIFICATION OF MF/SS

T (skin)
T1 Limited patch/plaque (involving < 10% of total skin surface)
T2 Generalised patch/plaque (involving ≥ 10% of total skin surface)
T3 Tumour(s)
T4 Erythroderma
N (lymph node)
N0 No clinically abnormal peripheral lymph nodes
N1 Clinically abnormal peripheral lymph nodes; histologically uninvolved
N2 Clinically abnormal peripheral lymph nodes; histologically involved (nodal architecture uneffaced)
N3 Clinically abnormal peripheral lymph nodes; histologically involved [nodal architecture (partially) effaced]
Nx Clinically abnormal peripheral lymph nodes; no histological confirmation
75
M (viscera)
M0 No visceral involvement
M1 Visceral involvement
B (blood)
B0 No circulating atypical (Sézary) cells (or < 5% of lymphocytes)
B1 Low blood tumour burden (≥ 5% of lymphocytes are Sézary cells, but not B2)
B2 High blood tumour burden (≥ 1000µL Sézary cells and postive clone)
MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour-node-metastasis-blood
Olsen E et al. Blood 2007;110:1713-22. Reprinted with permission from the American Society of Hematology.
REVISED CLINICAL STAGING SYSTEM FOR MF/SS
CLINICAL STAGE
IA T1 N0 M0 B0-1
IB T2 N0 M0 B0-1
IIA T1-2 N1-2 M0 B0-1
IIB T3 N0-2 M0 B0-1
III T4 N0-2 M0 B0-1
IVA1 T1-4 N0-2 M0 B2
IVA2 T1-4 N3 M0 B0-2
IVB T1-4 N0-3 M1 B0-2
MF, mycosis fungoides; SS, Sézary syndrome

Olsen E et al. Blood 2007;110:1713-22. Reprinted with permission from the American Society of Hematology.
TREATMENT
• Treatment recommendations are largely based on (retrospective) cohort studies
and expert opinions during consensus meetings, rather than controlled clinical
trials, owing to the rarity and heterogeneity of PCLs
MF and variants
• A stage-adapted conservative therapeutic approach is recommended for MF and
its variants because early aggressive chemotherapy (ChT) is associated with
considerable toxicity and no survival benefit
76
• Patients with only patches and/or plaques covering < 10% (stage IA) or ≥ 10%
of the skin surface (stage IB) should be treated with skin-directed therapies,
including topical steroids, psoralens plus ultraviolet A (PUVA), narrow-band
ultraviolet B (nb-UVB) and topical cytostatic agents, such as mechlorethamine
(nitrogen mustard), as shown in the figure below
RECOMMENDATIONS FOR THE TREATMENT OF MF
MF
Stage IA-IIA Stage IIB Stage III Stage IV
Expectant policy
Topical steroids SDT * + local RT
(SDT * +) retinoids
nb-UVB (SDT * +) retinoids Gemcitabine
(SDT* +) IFN-α
PUVA (SDT * +) IFN-α Liposomal doxorubicin
ECP ± IFN-α ± retinoids
Topical TSEBT BV
Low-dose MTX
mechlorethamine
Local RT
(SDT* +) retinoids Gemcitabine Combination ChT

(SDT* +) IFN-α Liposomal TSEBT
AlloSCT
Retinoids doxorubicin
IFN-α BV
Retinoids + IFN-α Combination ChT
TSEBT AlloSCT
*Most commonly PUVA

AlloSCT, allogeneic stem cell transplantation; BV, brentuximab vedotin; ChT, chemotherapy; ECP, extracorporeal photopheresis;
IFN-α, interferon alpha; MF, mycosis fungoides; MTX, methotrexate; nb-UVB, narrow-band ultraviolet B; PUVA, psoralens plus
ultraviolet A; RT, radiotherapy; SDT, skin-directed therapy; TSEBT, total skin electron beam therapy
• For patients with patches or very thin plaques, nb-UVB is recommended,

although PUVA is preferred for patients with thicker plaques
• Topical steroids are recommended as monotherapy for disease with patches/flat
plaques (stage IA), and as adjuvant therapy for selected skin lesions in patients
with stage IB disease
• Topical mechlorethamine, available as aqueous solution, ointment or gel, is used
for early-stage MF
77
• For patients with one or few infiltrated plaques or tumours (stage IIB), additional
low-dose local radiotherapy (RT) may suffice
Local RT may be curative in patients with early localised disease, particularly in
the case of unilesional MF and pagetoid reticulosis
• Systemic therapy with interferon alpha (IFN-α) or retinoids commonly combined
with PUVA or other skin-directed therapies, or a combination of IFN-α and
retinoids or total skin electron beam therapy (TSEBT) can be considered in
patients with more extensive infiltrated plaques and tumours, or patients
refractory to skin-directed therapies
• For advanced and refractory disease, gemcitabine or liposomal doxorubicin are
options, although responses are generally short-lived
• Multi-agent ChT is only indicated in patients with effaced lymph nodes or visceral
involvement (stage IV), or in patients with widespread tumour stage MF, which
cannot be controlled with skin-targeted and immunomodulating therapies or who
failed single-agent ChT. However, responses are generally short-lived
• High response rates have been reported in studies of the investigational
anti-CD30 monoclonal antibody brentuximab vedotin (BV) in patients with
advanced MF/SS expressing CD30
• Young patients with refractory, progressive MF or with SS should be considered
for allogeneic stem cell transplantation (alloSCT), as durable responses have
been reported, although the optimal conditioning regimen and timing for alloSCT
are currently unknown
Studies indicate that tumour debulking with TSEBT or BV before transplantation
is beneficial
• In phase I/II and III studies, mogamulizumab has demonstrated promising results
for the treatment of MF and SS
SS
• Systemic therapy is required for SS as it is a systemic disease, as shown in the
figure on the next page
• Skin-directed therapies, such as PUVA or potent topical steroids, may be used as
adjuvant therapy
• Extracorporeal photopheresis (ECP), either alone or in combination with other
treatment modalities such as IFN-α, retinoids, TSEBT and PUVA, has been
suggested as the treatment of choice in SS and erythrodermic MF
Superiority of ECP over the traditional low-dose ChT regimens has not been
demonstrated in controlled randomised trials
78
RECOMMENDATIONS FOR THE TREATMENT OF SS
SS
ECP ± IFN-α ± retinoids

PUVA + IFN-α
Prednisolone (+ Clb)
Low-dose MTX
Low-dose alemtuzumab
Gemcitabine
Liposomal doxorubicin
Combination ChT
AlloSCT
AlloSCT, allogeneic stem cell transplantation; ChT, chemotherapy; Clb, chlorambucil; ECP, extracorporeal photopheresis;
IFN-α, interferon alpha; MTX, methotrexate; PUVA, psoralens plus ultraviolet A; SS, Sézary syndrome
• Effective disease control can be achieved with prolonged treatment with

combination low-dose chlorambucil (Clb)/prednisolone, although a complete
response is unlikely
• Second-line treatment recommendations are: Low-dose alemtuzumab (10 mg
subcutaneous, 3 times weekly for 12 weeks); single-agent ChT (gemcitabine,
PEGylated liposomal doxorubicin); multi-agent ChT; and alloSCT
Primary cutaneous CD30+ lymphoproliferative disorders
• The group of primary cutaneous CD30+ lymphoproliferative disorders (LPDs)
include primary cutaneous anaplastic large-cell lymphoma (C-ALCL) and
lymphomatoid papulosis (LyP), which form a spectrum of disease
Both C-ALCL and LyP have an excellent prognosis, with a 10-year survival of
90% and almost 100%, respectively
• None of the available treatments affects the natural course of LyP and curative
therapy is not available, therefore in patients with relatively few non-scarring
lesions, an expectant treatment policy should be followed, as outlined in the
79
RECOMMENDATIONS FOR THE INITIAL MANAGEMENT OF PRIMARY CUTANEOUS
CD30+ LPDS
LyP C-ALCL
Solitary/localised (90%) Multifocal (10%)
Expectant policy Local RT Low-dose MTX

Excision Low-dose RT
Low-dose MTX
BV
PUVA
BV, brentuximab vedotin; C-ALCL, cutaneous anaplastic large-cell lymphoma; CD, cluster of differentiation; LPD,
lymphoproliferative disorder; LyP, lymphomatoid papulosis; MTX, methotrexate; PUVA, psoralens plus ultraviolet A;
RT, radiotherapy
• Low-dose oral (PO) methotrexate (MTX) (5-20 mg/week) and PUVA are the
most effective therapies for reducing the number of skin lesions for patients with
cosmetically disturbing lesions (e.g. scarring or numerous papulonodules)
Maintenance treatment is often required owing to relapses after withdrawal
of treatment
• Patients with C-ALCL generally present with solitary or localised (ulcerating)
tumours or nodules and should be treated with RT or surgical excision
No further therapy is required in patients with complete spontaneous remission
Patients with multifocal skin lesions should receive treatment with low-dose
MTX, as in LyP, or with RT in the case of only a few lesions
– The International Lymphoma Radiation Oncology Group suggests
radiation with electrons, with bolus, a margin of ≥ 2 cm and a total dose of
24-30 Gy
80
– Study findings in patients with C-ALCL suggest that a total dose of 20 Gy
in 8-10 fractions is effective and well tolerated in patients with solitary or
localised skin lesions
– A radiation dose of 8 Gy (2 x 4 Gy) is suggested for patients with multifocal
or relapsing skin lesions
• BV should be considered in cases with multifocal skin lesions refractory to
conventional therapies and in patients developing extracutaneous disease
• Multi-agent ChT is indicated only in patients presenting with, or developing
extracutaneous disease, and in rare cases of rapidly progressive skin disease
Subcutaneous panniculitis-like T-cell lymphomas
• The term subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is only used
for cases with an α/β T-cell phenotype, which have a favourable prognosis,
particularly if not associated with haemophagocytic syndrome (HPS), which
is frequently an extremely aggressive clinical syndrome requiring immediate
intervention
• In SPTCL without associated HPS, systemic steroids or other
immunosuppressive agents (ciclosporin, MTX) should be considered first; in
cases of solitary skin lesions, RT with electrons is advised
A dose of 40 Gy has been used, although information on radiation doses
is scant
• Bexarotene may also be effective in SPTCL
• Multi-agent ChT is indicated only in cases with progressive disease not
responding to immunosuppressive therapy and in cases with HPS
Primary cutaneous extranodal NK/T-cell lymphoma, nasal type
• Primary cutaneous extranodal natural killer (NK)/T-cell lymphoma, nasal type is
an Epstein–Barr virus-associated type of lymphoma with an aggressive clinical
behaviour, which is very rare in Western countries and more common in Asia and
Central and South America
• Patients presenting with only localised skin lesions (stage IE) have a somewhat
better prognosis than localised lesions in non-cutaneous sites
• In rare cases with small, solitary lesions, RT alone can be considered and
demonstrates long-term disease control in some cases
• RT alone is an option for older or frail patients who cannot tolerate intensive ChT
81
• Generally, combined modality treatment with L-asparaginase-containing ChT,
such as dexamethasone/MTX/ifosfamide/L-asparaginase/etoposide (SMILE) is
the preferred mode of treatment, combined with RT, for localised disease, as it
is for nasal NK/T-cell lymphomas, although there is still a paucity of data on the
outcome of this treatment in primary cutaneous NK/T-cell lymphoma
• Recommended radiation doses are higher than for other lymphomas, with 50 Gy
to the initial lesion and a boost of 5-10 Gy to residual disease
• In patients presenting with generalised skin lesions, the disease shows an
aggressive clinical behaviour and should be treated as other patients with stage
II-IV disease
Primary cutaneous peripheral T-cell lymphoma-not otherwise specified
• Within the group of primary cutaneous peripheral T-cell lymphoma-not otherwise
specified (PTCL-NOS), four somewhat better-defined subgroups have been
included as (provisional) entities, as shown in the WHO-EORTC (European
Organisation for Research and Treatment of Cancer) classification
For cases that do not fit into one of the well-defined types of cutaneous T-cell
lymphoma (CTCL), the term primary cutaneous PTCL-NOS is maintained
• Both primary cutaneous gamma/delta T-cell lymphoma (PCGD-TCL) and primary
cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (CD8+
AECTCL) have a generally aggressive clinical course and poor prognosis, and
should therefore be managed according to the ESMO guidelines for PTCL-NOS
• Patients with primary cutaneous CD4+ small-medium T-cell LPD and patients
with a primary cutaneous acral CD8+ T-cell lymphoma have an indolent clinical
behaviour and excellent prognosis, and solitary skin lesions should be treated
with local RT or surgical excision
Cutaneous B-cell lymphoma
• Three main types of cutaneous B-cell lymphoma (CBCL) are distinguished in the
WHO-EORTC classification
Primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous
follicle centre lymphoma (PCFCL) are indolent types with disease-related
10-year survival > 90%
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT)
has a less favourable prognosis, with disease-related 5-year survival of
approximately 50%
• Treatment options for the three types are outlined in the figures on the next page
82
TREATMENT RECOMMENDATIONS FOR INITIAL MANAGEMENT OF PCMZL AND PCFCL
PCMZL and PCFCL
Solitary/localised Multifocal
Local RT Wait-and-see
Rituximab IL Rituximab IL
Excision IL steroids
IL steroids Topical steroids
(Antibiotics)* Low-dose local RT
Rituximab IV
(Antibiotics)*
Single or combination
ChT **
*In the case of evidence for Borrelia burgdorferi infection
**Single or combination ChT appropriate for low-grade malignant B-cell lymphomas
ChT, chemotherapy; IL, intralesional; IV, intravenous; PCFCL, primary cutaneous follicle centre lymphoma; PCMZL, primary
cutaneous marginal zone lymphoma; RT, radiotherapy
TREATMENT RECOMMENDATIONS FOR INITIAL MANAGEMENT OF PCLBCL-LT
PCLBCL-LT
Solitary/
Multifocal
localised
Local RT
R-CHOP ± IFRT R-CHOP Rituximab IV
Rituximab IV
IFRT, involved-field radiotherapy; IV, intravenous; PCLBCL-LT, primary cutaneous large B-cell lymphoma, leg type; R-CHOP,
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone; RT, radiotherapy
83
• Recommended radiation doses for localised PCMZL and PCFCL are 24-30 Gy, whereas
for palliative treatment of multifocal disease, low-dose RT (4 Gy) is often sufficient
• For PCLBCL-LT, systemic treatment with rituximab/cyclophosphamide/doxorubicin/
vincristine/prednisolone (R-CHOP) is recommended if the patient can tolerate multi-
agent ChT
• For localised disease, systemic treatment is combined with RT, with a recommended
radiation dose of 36-40 Gy or 40 Gy if no systemic treatment is given
• For disseminated or recurrent disease, single-agent rituximab may achieve remissions
• Investigative studies suggest that patients with PCLBCL-LT, which show a high
frequency of MYD88 and CD79B mutations, may benefit from treatment with
Bruton’s tyrosine kinase (Btk) inhibitors, which block the nuclear factor kappa light
chain enhancer of activated B cells (NFkB) pathway
• Personalised approaches in the treatment of PCL remain limited
• BV is used for the treatment of advanced-stage refractory or relapsed CD30 CTCL
(including C-ALCL and MF/SS), partly to enable the provision of alloSCT to these patients
• Mogamulizumab has shown significant clinical efficacy in MF/SS, particularly in
patients with blood involvement
• The efficacy of Btk inhibitors that target this pathway is currently under investigation
but reports on their efficacy in CBCL remain scarce
• Individualised follow-up is recommended depending on the clinical situation
• Follow-up visit frequency depends on the type of PCL and the stage of disease,
varying from every 6 or 12 months in patients with indolent types of PCL and stable
disease or those in complete remission, to every 4-6 weeks in patients with active or
progressive disease
• Follow-up visits should focus on history and physical examination; additional testing
(histology, blood examination, imaging, etc.) should be carried out only if required
• Routine imaging after treatment is not required since tumour responses are visible
to the naked eye and in most cases, recurrences are localised in the skin
• There is an increased long-term risk of developing skin cancers, particularly
squamous cell carcinomas, following long-term treatment with PUVA in patients
with PCL
84
Diagnosis of PCLs is based on clinical, histological, immunophenotypical and
genetic data
Presence of extracutaneous disease should be excluded through adequate staging
Complete physical examination, representative skin biopsy, complete and
differential blood cell count, routine serum biochemistry with LDH and appropriate
imaging studies should be included in the initial work-up
FDG–PET is essential to evaluate the extent of disease in patients presenting with
predominantly subcutaneous PCLs (such as SPTCL and PCGD-TCL)
TREATMENT
Treatment choice depends on PCL type and disease stage
Recommendations are based largely on (retrospective) cohort studies and
expert opinions
MF and variants
• A stage-adapted conservative therapeutic approach is recommended
• Early-stage MF (stage IA-IIA) should be treated with skin-directed therapies
including topical steroids, PUVA, nb-UVB or mechlorethamine
• For patients with patches or very thin plaques, nb-UVB can be used, while in
patients with thicker plaques, PUVA therapy is preferred
• In patients developing one or few infiltrated plaques or tumours (stage IIB),
additional low-dose local RT may suffice
• In patients with unilesional MF and pagetoid reticulosis, local RT (20-24 Gy)
can be curative
• For more extensive infiltrated plaques and tumours, or tumours refractory
to skin-directed therapies, a combination of PUVA and IFN-α or PUVA and
retinoids (including bexarotene), a combination of IFN-α and retinoids or
TSEBT can be considered
• Recently, lower doses of TSEBT (10-12 Gy compared with 30-36 Gy) enable
shorter duration of treatment, fewer side effects and opportunity for re-treatment
• Gemcitabine or liposomal doxorubicin may be considered for advanced and
refractory disease, but responses are generally short-lived
85
• Multi-agent ChT is only indicated in patients with effaced lymph nodes or visceral
involvement (stage IV), or in patients with widespread tumour stage MF, which
cannot be controlled with skin-targeted and immunomodulating therapies or who
failed single-agent ChT
• Local RT (≥ 8 Gy) may achieve local palliation of cutaneous and extracutaneous lesions
• AlloSCT should be considered in relatively young patients with refractory, progressive
MF, although the optimal conditioning regimen and timing are currently unknown
SS
• A combination of systemic treatment and skin-directed therapies with adjuvant
potent topical steroids is required
• ECP, either alone or in combination with other treatment modalities such as IFN-α,
retinoids, TSEBT and PUVA, has been suggested as the treatment of choice in SS
and erythrodermic MF
• Mogamulizumab has shown significant clinical efficacy in MF/SS, particularly in
patients with blood involvement
• AlloSCT should be considered in relatively young patients with refractory, progressive
SS, although the optimal conditioning regimen and timing are currently unknown
• Second-line treatment options for SS are low-dose alemtuzumab (10 mg
subcutaneous, 3 times weekly for 12 weeks), single-agent ChT (gemcitabine,
PEGylated liposomal doxorubicin), multi-agent ChT and alloSCT
• For cosmetically disturbing skin lesions, low-dose PO MTX (5-20 mg/week)
and PUVA are effective for reducing the number of lesions
• Local RT (total dose 20 Gy) is the first choice of treatment in patients with C-ALCL
presenting with solitary or localised skin lesions
• Patients with C-ALCL and LyP presenting with a few lesions can be treated with RT;
those with multifocal skin lesions should receive low-dose MTX
• Multifocal C-ALCL skin lesions refractory to conventional therapies and patients
developing extracutaneous disease should be considered for BV treatment
• Multi-agent ChT is indicated in patients presenting with or developing extracutaneous
disease and in rare patients with rapidly progressive skin disease
86
SPTCLs
• First-choice treatment for SPTCL without associated HPS is systemic steroids or
other immunosuppressive agents (ciclosporin, MTX), while RT with electrons is
advised for solitary lesions
• Multi-agent ChT is indicated for progressive disease not responding to
immunosuppressive therapy or for patients with HPS
Primary cutaneous extranodal NK/T-cell lymphoma, nasal type
• For patients with localised disease, the preference is combined modality treatment
with L-asparaginase-containing ChT, such as SMILE, combined with RT. In rare
cases with small, solitary lesions and in older or frail patients who cannot tolerate
ChT, RT alone may be considered
PTCL-NOS
• Because of their aggressive nature, PCGD-TCL and primary cutaneous CD8+ AECTCL
should be managed as systemic PTCL-NOS
• Local RT or surgical excision is recommended for primary cutaneous CD4+
small-medium T-cell LPD or primary cutaneous acral CD8+ T-cell lymphoma,
as they usually present as a solitary skin lesion
CBCL
• Recommended radiation doses for localised PCMZL and PCFCL are 24-30 Gy, while
for palliative treatment of multifocal disease, low-dose RT (4 Gy) is often sufficient
• For PCLBCL-LT, systemic treatment with R-CHOP plus RT (36-40 Gy) is
recommended for localised disease if the patient can tolerate multi-agent ChT, while
if no systemic treatment is given, a dose of 40 Gy is recommended
BV is used for the treatment of advanced-stage refractory or relapsed CD30+ CTCL
(including patients with C-ALCL or MF/SS) and it also enables patients with MF/SS to
undergo alloSCT
PCLBCL-LT shows a high frequency of MYD88 and CD79B mutations
Btk inhibitors are under investigation for efficacy in this setting
Follow-up should be individualised to the clinical situation and the frequency of visits
tailored to the PCL type and disease stage: From every 6 or 12 months for indolent
PCL types and stable disease, or cases of complete remission, to every 4-6 weeks for
active or progressive disease
Visits should focus on history and physical examination, with additional testing
only if required
Tumour responses are visible to the naked eye and usually, recurrences are
localised in the skin, therefore post-treatment routine imaging is not required 87
DIAGNOSIS
• A peripheral T-cell lymphoma (PTCL) diagnosis should be made by an expert
haematopathologist based on an excisional tumour tissue biopsy
• Clinical features, morphology, immunohistochemistry (IHC), flow cytometry,
cytogenetics and molecular biology are required to distinguish between the
different PTCL entities
• The immunophenotypes, T-cell receptor rearrangement features and putative
cell of origin of the PTCL types covered by these guidelines is shown in the
table below: Angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell
lymphoma (ALCL), anaplastic lymphoma kinase positive/negative (ALK+/-),
enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma
(HSTCL), extranodal natural killer/T-cell lymphoma (ENKTCL), PTCL-not
otherwise specified (PTCL-NOS)
NODAL AND EXTRANODAL PTCL SUBTYPES – CELL OF ORIGIN
AND RELATED PHENOTYPES
PTCL IMMUNOPHENOTYPIC PRESUMED CELL

TCR
ENTITY FEATURES OF ORIGIN
CD4 > CD8, frequent antigen
loss (CD5, CD7), CD30+/-, Variable, mostly
PTCL-NOS αβ, rarely Yδ
CD56+/-, subset FTH features, T helper cell
cytotoxic granules+/-
CD4+, CD10+/-, BCL+/-,

CXCL13+, PD1+, ICOS+/-,
AITL αβ FTH
SAP+/-, CCR5+/-, hyperplasia of
Nodal FDC, EBV+ B blasts
ALK+, CD30+, EMA+, CD25+,

ALCL
cytotoxic granules+, CD4+/-, αβ Cytotoxic T cell
ALK+
CD3+/-
ALK-, CD30+, EMA+, CD25+,

ALCL
cytotoxic granules+, CD4+/-, αβ Cytotoxic T cell
ALK-
CD3+/-
88
Intra-epithelial T cells
EATL, CD8(+)/-, CD56-,
αβ (αβ), pre-existing
type 1 HLA-DQ2/-DQ8
enteropathy
Intra-epithelial T cells
EATL,
CD8+, CD56+, HLA-DQ2/-DQ8 Yδ or αβ or NK, no pre-existing
type 2
enteropathy
Extranodal
CD2+, CD56+, surface CD3-, TCR in germline
NK, rarely cytotoxic
NKTCL cytoplasmic CD3ε+, gr B+, configuration,
T cells
TIA-1+, perforin+, EBV+, LMP1 rarely αβ or Yδ
CD3+, CD56+/-, CD4-, CD8+/-,

Cytotoxic T cell of the
HSTCL CD5, TIA1+, gr M+, gr B-, Yδ, rarely αβ
innate immune system
perforin-
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase;
CD, cluster of differentiation; EATL, enteropathy-associated T-cell lymphoma; EBV, Epstein-Barr virus; EMA, epithelial membrane
antigen; FDC, follicular dendritic cell; FTH, follicular T helper; HLA, human leukocyte antigen; HSTCL, hepatosplenic T-cell lymphoma;
NK, natural killer; NKTCL, natural killer/T-cell lymphoma; PTCL, peripheral T-cell lymphoma; PTCL-NOS, PTCL not otherwise specified;
TCR, T-cell receptor
Adapted from: Gaulard P et al. Semin Hematol 2014;51:5-16.

• A complete blood count, routine blood chemistry, including lactate
dehydrogenase (LDH) and uric acid, as well as screening for human
immunodeficiency virus (HIV), human T-lymphotropic virus-1 (HTLV-1) and
hepatitis B and C are required
• At baseline, computed tomography (CT) scan of the chest and abdomen and
bone marrow (BM) aspirate and biopsy are required
Combined [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission
tomography (PET)-CT is being used increasingly in nodal PTCL at baseline and
re-staging but its role at the subtype-specific level needs further clarification
• PET-CT is recommended for staging and treatment planning for ENKTCL
Prognostic indices
• The International Prognostic Index (IPI) is the recommended prognostic tool for
clinical practice
• Male gender is an adverse prognostic factor
• High Epstein-Barr virus (EBV)-DNA copy number is an adverse outcome predictor
in ENKTCL
TREATMENT
• Treatment algorithms for newly diagnosed and relapsed/refractory PTCLs
are shown on the next page
89
INTEGRATED MANAGEMENT ALGORITHMS IN THE FRONT-LINE AND RELAPSED/
REFRACTORY SETTINGS
PTCL
Clinical trial
Nodal entities (CS II-IV)* Extranodal entities
PTCL-NOS ALCL ALK+** EATL HSTCL ENKTCL

AITL
ALCL ALK-
ALCL ALK+*
CHOEP/ IVE/MTX ICE/IVAC Stage I-II

CHOEP14 x 6
CHOP CHOEP CHOEP RT (> 50 Gy)
+ ChT****
Stage II-IV
ChT****
(+/- RT)
Chemosensitive (PR, CR) and transplant eligible
No further ASCT or
ASCT ASCT ASCT
treatment alloSCT***
90
Relapsed/refractory PTCL*****
Clinical trial
CD30+ ALCL PTCL-NOS ENKTCL

AITL
EATL
HSTCL
Bendamustine SMILE-like
BV
Gemcitabine regimen if not
ICE, DHAP used in ﬁrst line
or
gemcitabine
Chemosensitive (PR, CR) and transplant eligible
AlloSCT (or ASCT)
*Stage I: Shortened ChT schedule (e.g. 3 courses) followed by curatively intended RT

**ALCL ALK+ with high-risk profile (e.g. IPI > 2) should be considered for ASCT consolidation, while ASCT in low-risk profile
patients is not recommended
***If donor available
****SMILE or AspaMetDex
*****Pralatrexate and romidepsin: Food and Drug Administration, but not European Medicines Agency, approved
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase;
alloSCT, allogeneic stem cell transplantation; AspaMetDex, L-asparaginase/methotrexate/dexamethasone; ASCT, autologous
stem cell transplantation; BV, brentuximab vedotin; CD, cluster of differentiation; CHOEP, cyclophosphamide/doxorubicin/
vincristine/etoposide/prednisolone; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ChT, chemotherapy;
CR, complete response; CS, clinical stage; DHAP, dexamethasone/high-dose cytarabine/cisplatin; EATL, enteropathy-associated
T-cell lymphoma; ENKTCL, extranodal natural killer/T-cell lymphoma; HSTCL, hepatosplenic T-cell lymphoma; ICE, ifosfamide/
carboplatin/etoposide; IPI, International Prognostic Index; IVAC, ifosfamide/cytarabine/etoposide; IVE/MTX, ifosfamide/vincristine/
etoposide/methotrexate; PR, partial response; PTCL, peripheral T-cell lymphoma; PTCL-NOS, PTCL-not otherwise specified;
RT, radiotherapy; SMILE, dexamethasone/methotrexate/ifosfamide/L-asparaginase/etoposide
Nodal PTCLs (PTCL-NOS, AITL, ALCL ALK+/-)

• Treatment should be adapted to factors including age, IPI and comorbidities
• Inclusion in a clinical trial is recommended, whenever possible
91
• A dose-dense cyclophosphamide/doxorubicin/vincristine/etoposide/prednisolone
(CHOEP) schedule followed by autologous stem cell transplantation (ASCT) in
chemosensitive and transplant-eligible patients is recommended
• Anthracycline-void regimens are not superior to cyclophosphamide/doxorubicin/
vincristine/prednisolone (CHOP)/CHOEP regimens
• In IPI low-/low-intermediate ALCL ALK+ patients, ASCT consolidation is not
recommended, given the better prognosis of these patients compared with those
with other PTCL subtypes
• A shortened chemotherapy (ChT) schedule (e.g. 3 courses) followed by local
radiotherapy (RT) is recommended for patients with stage I disease
• Less toxic approaches, such as monotherapy with, for example, gemcitabine
or bendamustine, may be considered for patients not eligible for intensive ChT
schedules
Relapse
• With the exception of cluster of differentiation (CD)30+ ALCL, there is no
standard of care for relapsed/refractory nodal PTCLs
Anti-CD30-directed brentuximab vedotin (BV) is recommended for ALCL
and may also be used to bridge eligible patients towards allogeneic stem cell
transplantation (alloSCT)
• Inclusion in clinical trials is recommended for nodal PTCLs other than ALCL
• In fit patients, combination ChT [dexamethasone/high-dose cytarabine/cisplatin
(DHAP) or ifosfamide/carboplatin/etoposide (ICE)] can be used, with the aim of
alloSCT in chemosensitive patients
• In unfit patients, gemcitabine or bendamustine monotherapy are generally well
tolerated, although duration of response is modest
• New compounds, including the anti-folate pralatrexate, the histone
deacetylase inhibitors romidepsin and belinostat and the anti-CCR4 antibody,
mogamulizumab, are approved outside the European Union in this setting
EATL
• In fit patients, improved outcomes compared with standard CHOP may be
achieved with
More aggressive ChT regimens, for example, ifosfamide/vincristine/etoposide/
methotrexate (IVE/MTX), followed by ASCT
CHOEP14 with ASCT consolidation
92
• Patients responding sufficiently to standard-dose therapy may be able to
progress to ASCT
Relapse
• No specific regimen can be recommended and considerations similar to relapsed
nodal PTCLs are applicable (see previous page)
• AlloSCT should be attempted in transplant-eligible patients chemosensitive
at relapse
ENKTCL
• Anthracycline-based regimens are not effective
• Serial monitoring of plasma or whole blood EBV-DNA copy number is
recommended as a response biomarker
Stages I-II
• RT should be administered early
• Stage I disease can be treated with RT alone (≥ 50 Gy)
• Alternatively, and for patients with risk factors or stage II disease,
chemoradiotherapy with a platinum-containing regimen and a RT dose of ≥ 50 Gy
is an option
• With more effective ChT regimens, sequential chemoradiotherapy with RT doses
of 45-50 Gy may be used
• Concurrent and sequential L-asparaginase-containing schedules are equally effective
• The involved-site RT (ISRT) volume should cover the involved organ and adjacent
structures
• Central nervous system (CNS) prophylaxis is not recommended
• RT alone is recommended for elderly and/or frail patients
Stages III-IV
• L-asparaginase-containing regimens are the preferred front-line treatment
High-dose ChT with stem cell transplantation (SCT), preferably ASCT, is
recommended where complete remission is achieved
• Recommendations for elderly and frail patients are L-asparaginase alone or in
combination in the dexamethasone/methotrexate/ifosfamide/L-asparaginase/
etoposide (SMILE) and L-asparaginase/methotrexate/dexamethasone
(AspaMetDex) regimens
93
Relapse
• Repeated pre-therapeutic biopsy is strongly recommended
• In cases of relapse < 12 months following anthracycline-based treatment,
L-asparaginase-containing regimens are recommended
• Gemcitabine-based regimens can be considered for salvage treatment for
patients previously receiving L-asparaginase
• SCT should be considered in transplant-eligible patients
HSTCL
• Treatment with ChT at diagnosis is recommended
• Platinum-cytarabine induction therapy may be effective
• SCT should be offered to patients with chemosensitivity to induction therapy
• Intense regimens such as ICE, ifosfamide/cytarabine/etoposide (IVAC) and dose-
dense CHOEP/EPOCH (etoposide/vincristine/doxorubicin/cyclophosphamide/
prednisolone) are proposed for fit patients
Relapse
• No specific regimen can be recommended
• AlloSCT should be attempted in eligible patients chemosensitive to current
relapse regimens
RT
Front-line treatment
• Localised disease can be treated with local RT (30-40 Gy) after ChT
A dose of 40 Gy is preferred, particularly if there is post-ChT residual
lymphoma
• Pre-ChT imaging is required to allow optimal RT planning
• Modern techniques should be used to minimise long-term toxicity
• For the use of RT in ENKTCLs, see ENKTCL, First-line treatment,
Stages I-II
Relapsed/refractory disease
• Palliative RT (30 Gy in 10 fractions) can be used to treat locally symptomatic
disease
94
SCT
• Phase II data suggest that ASCT in first remission seems feasible and possibly
beneficial in transplant-eligible patients
• Upfront alloSCT should be performed primarily within a clinical trial
• Consolidation with ASCT or alloSCT are options in this setting
• AlloSCT is also a valid treatment option after a failed prior autograft
• The benefit of alloSCT is most evident in chemosensitive patients
• A reduced-intensity conditioning-alloSCT is preferred to a myeloablative approach
to reduce non-relapse mortality
• L-asparaginase in ENKTCL treatment and BV for relapsed/refractory ALCL are
widely accepted, formally approved personalised approaches
• More research is needed to identify molecular markers of use in the management
of PTCL-NOS, AITL, EATL and HSTCL
RESPONSE EVALUATION AND FOLLOW-UP
• In systemic PTCL, a midway interim evaluation should be performed to assess
chemosensitivity
• PTCLs are FDG-avid tumours and PET-CT should be used, particularly in the
context of residual disease
• Diagnostic imaging (CT or PET-CT) should be repeated at the end of treatment,
along with a BM biopsy (if initially involved)
• History and physical examination should be performed every 3 months for 1 year,
every 6 months for a further 2 years and then yearly for detection of secondary
tumours or other long-term side effects
Recommendations are based on consensus rather than evidence
• CT scans at 6, 12 and 24 months after treatment completion are usual practice,
although routine imaging in patients in complete remission may not provide any
outcome advantage
• Routine PET scan surveillance is not recommended
95
DIAGNOSIS
A PTCL diagnosis should be made by an expert haematopathologist based on an
excisional tumour tissue biopsy
Clinical features, morphology, IHC, flow cytometry, cytogenetics and molecular
biology are required to distinguish between the different PTCL entities
complete blood count, routine blood chemistry, including LDH and uric acid, and
A
screening for HIV, HTLV-1 and hepatitis B and C are required
aseline CT or PET-CT scans of the chest and abdomen and BM aspirate and
B
biopsy are required
PET-CT is recommended for staging and treatment planning for ENKTCL
Prognostic indices
• The IPI is the recommended prognostic tool for clinical practice
TREATMENT
Nodal PTCLs (PTCL-NOS, AITL, ALCL ALK+/-)
• Treatment should be adapted to factors including age, IPI and comorbidities
• Inclusion in a clinical trial is recommended, wherever possible
• Dose-dense CHOEP and ASCT in chemosensitive and transplant-eligible patients
is recommended
• Anthracycline-void regimens are not superior to CHOP/CHOEP regimens
• In IPI low-/low-intermediate ALCL ALK+ patients, ASCT consolidation is not
recommended
• A shortened ChT schedule (e.g. 3 courses) followed by local RT is recommended
for patients with stage I disease
• Less toxic approaches, such as monotherapy with gemcitabine or bendamustine,
may be considered for patients not eligible for intensive ChT schedules
Relapse
• BV is recommended for ALCL and for bridging eligible patients towards alloSCT
• Inclusion in clinical trials is recommended for nodal PTCLs other than ALCL
• In fit patients, the aim is to use DHAP or ICE combination ChT, with alloSCT in
chemosensitive patients
96
• In unfit patients, gemcitabine or bendamustine monotherapy are generally
well tolerated
EATL
• In fit patients, aggressive ChT regimens, such as IVE/MTX and CHOEP14 with
ASCT consolidation may improve outcomes compared with CHOP
• Patients responding sufficiently to standard-dose therapy may be able to undergo
ASCT
Relapse
• No specific regimen can be recommended and considerations similar to relapsed
nodal PTCLs are applicable
• AlloSCT should be attempted in transplant-eligible patients chemosensitive
at relapse
ENKTCL
• Anthracycline-based regimens are not effective
• Serial monitoring of plasma or whole blood EBV-DNA copy number is
recommended as a response biomarker
Stages I-II
• Stage I disease can be treated with RT alone (≥ 50 Gy)
• Alternatively, and for patients with risk factors or stage II disease,
chemoradiotherapy with a platinum-containing regimen and a RT dose of ≥ 50 Gy
is an option
• With more effective ChT regimens, sequential chemoradiotherapy with RT doses
of 45-50 Gy may be used
• Concurrent and sequential L-asparaginase-containing schedules are equally
effective
• The ISRT volume should cover the involved organ and adjacent structures
• CNS prophylaxis is not recommended
• RT alone is recommended for elderly and/or frail patients
Stages III-IV
• L-asparaginase-containing regimens are the preferred front-line treatment,
with SCT (preferably ASCT) in cases of complete remission
• Recommendations for elderly and frail patients are L-asparaginase alone
or in combination in the SMILE and AspaMetDex regimens
97
Relapse
• Repeated pre-therapeutic biopsy is strongly recommended
• In cases of relapse < 12 months following anthracycline-based treatment,
L-asparaginase-containing regimens are recommended
• Gemcitabine-based regimens can be considered for salvage treatment for
patients previously receiving L-asparaginase
• SCT should be considered in transplant-eligible patients
HSTCL
• Treatment with ChT at diagnosis is recommended
• Platinum-cytarabine induction therapy may be effective
• SCT should be offered to patients with chemosensitivity to induction therapy
• Intense regimens such as ICE, IVAC and dose-dense CHOEP/EPOCH are
proposed for fit patients
Relapse
• No specific regimen can be recommended
• AlloSCT should be attempted in eligible patients chemosensitive to current
relapse regimens
RT
• Localised disease can be treated with local RT (30-40 Gy) after ChT
• Pre-ChT imaging is required to allow optimal radiation planning
• Modern advanced techniques should be used to minimise long-term toxicity
• Palliative RT (30 Gy in 10 fractions) can be used to treat locally symptomatic
disease
SCT
• ASCT consolidation in first remission seems feasible and possibly beneficial
in transplant-eligible patients
• Upfront alloSCT should be performed primarily within a clinical trial
98
• Consolidation with ASCT or alloSCT (including after a failed autograft)
are options
• A reduced-intensity conditioning-alloSCT is preferred to a myeloablative approach
L-asparaginase in ENKTCL treatment and BV for relapsed/refractory ALCL are
approved personalised approaches
More research is needed to identify molecular markers of use in the management
of PTCL-NOS, AITL, EATL and HSTCL
In systemic PTCL, a midway interim evaluation should be performed to assess
chemosensitivity
PET-CT should be used, particularly in the context of residual disease
Diagnostic imaging (CT or PET-CT) should be repeated at the end of treatment,
along with a BM biopsy (if initially involved)
History and physical examination should be performed every 3 months for 1 year,
every 6 months for a further 2 years and then yearly for detection of secondary
tumours or other long-term side effects
CT scans at 6, 12 and 24 months after treatment completion are usual practice
Routine PET scan surveillance is not recommended
99
EXTRANODAL DIFFUSE LARGE B-CELL LYMPHOMA
AND PRIMARY MEDIASTINAL B-CELL LYMPHOMA
DIAGNOSIS
• The diagnosis of diffuse large B-cell lymphoma (DLBCL) should be carried out
in a reference haematopathology laboratory with expertise in morphological
interpretation and the facilities to carry out the full range of phenotypic and
molecular investigations
• Details on methods for pathological diagnosis, immunohistochemistry (IHC) and
molecular biology have been reported fully in the ESMO guidelines for nodal DLBCLs
Primary mediastinal large B-cell lymphoma
• Primary mediastinal large B-cell lymphoma (PMBCL) is most commonly seen in
women in the third or fourth decade of life
• PMBCL usually presents with a bulky tumour in the anterior mediastinum, with
local compressive symptoms including dyspnoea, cough, dysphagia and a
superior vena cava syndrome in about 50% of cases
• Pleural or pericardial effusions are often present
• Particular extranodal sites such as the kidneys, adrenal glands, liver and ovaries
may be involved, particularly in disease recurrence
• PMBCL represents around 10% of all DLBCLs
• Cells express pan B-cell markers, are negative for surface immunoglobulin (Ig)
and are usually positive for cluster of differentiation (CD)23, weakly positive for
CD30 and negative for CD15
• BCL6, CD10 and IRF4 are expressed in some cases
• Some tumours have morphological, phenotypic and molecular features close
to nodular sclerosing Hodgkin lymphoma (HL)
These tumours are determined by the World Health Organization (WHO) to be
unclassifiable and have features intermediate between DLBCL and classical HL
• The three most common molecular alterations involve: Nuclear factor kappa
light chain enhancer of activated B cells (NFkB) activation (REL amplification,
inactivating mutations of TNFAIP3), JAK-STAT pathway activation (inactivating
mutations of SOCS1, JAK2 amplification and interleukin-13 overexpression) and
modulation of tumour cell interactions with the microenvironment and immune
system [downregulation of human leucocyte antigen (HLA) class II, programmed
death-ligand 1 and 2 (PD-L1 and PD-L2) amplifications or translocations]
100
Primary testicular lymphoma
• Primary testicular lymphoma (PTL) usually presents as a limited-stage disease.
Most patients have a unilateral testicular mass, although 10% show bilateral
testicular involvement
• Clinical behaviour is often aggressive, with dissemination to multiple extranodal
sites, such as lung, pleura, skin (up to 35%), soft tissues and Waldeyer's ring (5%)
• Central nervous system (CNS) relapses are frequent and occur in up to 30%
of PTL patients, usually within 1-2 years of diagnosis
• Most (80-90%) PTLs are DLBCLs
• Some features of DLBCL suggest the possibility of antigen-driven stimulation
• Altered expression of cell surface adhesion molecules may explain the propensity
to disseminate to extranodal sites
• An activated B cell (ABC) pattern is shown by 60-96% of cases
• Mutations of MYD88 are more common in extranodal, compared with nodal,
DLBCLs and 19% of these cases also carry CD79a mutations
• Inactivating mutations of B2M and rearrangements of PDL, CIITA and FOXP1
have been found in 2-10% of cases
Primary central nervous system lymphoma
• Primary central nervous system lymphoma (PCNSL) is a rare disease, defined
by involvement of the cerebral parenchyma, leptomeninges, eyes or spinal cord
without evidence of systemic disease
• Patients usually present with focal neurological deficits and/or neuropsychiatric
symptoms
• Approximately 10-20% of patients have ocular involvement and around one third
have multifocal neurological disease
• Stereotactic biopsy is recommended to obtain histopathological diagnosis.
Resection of PCNSL cannot be recommended because of the associated
morbidity and lack of evidence for benefit
• Glucocorticoid therapy can interfere with an accurate histopathological diagnosis
and so should be avoided before biopsy, without compromising the patient
• At diagnosis, contrast-enhanced brain magnetic resonance imaging (MRI) and
cytological evaluation and flow cytometry of the cerebrospinal fluid (CSF) are required
• Slit lamp examination should be carried out to investigate possible ocular
involvement
• Computed tomography (CT) scans of the chest, abdomen and pelvis or a positron
emission tomography (PET)-CT scan is recommended to exclude systemic disease
101
• Testicular ultrasound (US) examination is recommended for elderly men
• Although the value of a bone marrow (BM) examination is controversial, it is still
part of baseline investigations in current clinical trials
• Most PCNSLs in immunocompetent patients are DLBCLs
• Extraneural dissemination is rare, but clonally related cells have been detected in
the blood of some patients
• Many tumours express both germinal centre (GC) markers and the ABC marker IRF4
• Activation of NFkB and B-cell receptor (BCR)/MYD88 pathways and deletions of
the HLA gene locus at 6p21.32 have been reported
• MYD88 mutations have been detected in 30–75% of cases, and CD79a/b
mutations in up to 45%, with substantial overlap in positive cases
Primary diffuse large B-cell lymphoma of the breast
• Primary diffuse large B-cell lymphoma of the breast (PBL) is uncommon and
almost exclusively affects women, typically those of older age (median
62-64 years)
• The typical presentation is a painless breast mass (median 4 cm diameter),
slightly more frequently on the right side and with systemic symptoms present
in < 5% of patients, almost always those with disseminated disease
• Up to 20% of patients are diagnosed incidentally. There are no definitive
radiological features of PBL and diagnostic biopsy is mandatory
• Histologically, DLBCLs are the most common form
• Molecularly, primary breast DLBCLs are mainly of the ABC subtype
• Trisomy 3 and 18 and chromosome 18 translocations involving IGH/MALT1
as in low-grade mucosa-associated lymphoid tissue (MALT) lymphomas have
been observed
Primary diffuse large B-cell lymphoma of the bone
• Primary diffuse large B-cell lymphoma of the bone (PBoL) is a rare lymphoma,
found most commonly in mid-elderly men
• The median age at diagnosis is 45-60 years
• Patients typically present with bone pain (80-95%), a tumour mass (30-40%)
and pathological fracture (10-15%), most frequently of the humerus
• Approximately 15% of patients show spinal cord compression and 10% have
hypercalcaemia, commonly involving the femur, pelvic bones and spine
• PBoL may present as a single lesion, with or without an associated soft tissue
mass arising from local extension and with or without regional lymphadenopathy,
or as multifocal polyostotic disease, exclusively involving the skeleton
102
• The vast majority of PBoLs are DLBCLs
• Non-GC phenotype is slightly more common than GC
• BCL2, BCL6 and MYC rearrangements may be found in 19%, 14% and 9%
of cases, respectively
• Baseline assessments and procedures do not generally differ from those required
for patients presenting with nodal DLBCLs and include: Physical examination,
determination of performance status (PS), B symptom assessment, complete
blood count, routine blood chemistry with lactate dehydrogenase (LDH) and
screening tests for human immunodeficiency virus (HIV) and hepatitis B and C
Additional and specific staging procedures for different extranodal sites are
summarised in the table below
SUMMARY OF DIAGNOSTIC WORK-UP
DIAGNOSTIC WORK-UP FOR ALL ENTITIES

Physical examination Peripheral lymph nodes, liver, spleen
Laboratory Blood cell and differential count, renal and liver function, LDH, uric acid
Hepatitis B (including HBsAg, anti-HBs and anti-HBc antibodies)
Serology
and C, HIV serology
Imaging CT neck, chest, abdomen and pelvis, PET-CT
BM Histology
ADDITIONAL DIAGNOSTIC WORK-UP FOR A SPECIFIC ENTITY

PTL PCNSL PBL PBoL
Brain MRI Yes Yes Yes No*
Cytology and flow

Yes Yes Yes No*
cytometry of CSF
Testicular ultrasound Yes Elderly males: Yes No No

Ocular slit lamp
No Yes No No
examination
Involved MRI
No No No Yes
of bone lesion
*Only if involvement of skull and/or spine
BM, bone marrow; CSF, cerebrospinal fluid; CT, computed tomography; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen;
HBs, hepatitis B surface; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PBL,
primary breast lymphoma; PBoL, primary bone lymphoma; PCNSL, primary central nervous system lymphoma; PET, positron emission
tomography; PTL, primary testicular lymphoma
103
• Based on consensus recommendations for staging and restaging of
lymphoma, developed at the International Conference on Malignant Lymphomas,
[18F]2-fluoro-2-deoxy-D-glucose (FDG)–PET-CT scanning is the recommended
standard practice both for staging patients with DLBCL and for response
assessment based on the visual Deauville criteria (5-point scale), as shown
in the table below
PET 5-POINT SCALE (DEAUVILLE CRITERIA)
1 No uptake
2 Uptake ≤ mediastinum
3 Uptake > mediastinum but ≤ liver
4 Moderately increased uptake compared with liver
5 Markedly increased uptake compared with liver and/or new lesions

• Disease staging is established as for nodal DLBCL, according to the Ann Arbor
classification system, as shown in the table below
ANN ARBOR STAGING CLASSIFICATION
STAGE
Involvement of a single lymphatic region (I) or localised involvement of single
I
extralymphatic organ or site (IE)
Involvement of two or more lymphatic regions on the same side of the

II diaphragm (II) or localised involvement of a single extralymphatic organ or site
and of one or more lymphatic regions on the same side of the diaphragm (IIE)
III Involvement of lymphatic regions on both sides of the diaphragm
Diffuse or disseminated involvement of one or more extralymphatic organs

IV
with or without lymphatic involvement
• In extranodal DLBCL, while the utility of the International Prognostic Index
(IPI) and age-adjusted IPI (aaIPI) is not fully evaluated, these tools should be
calculated for prognostic purposes, at least to differentiate between localised and
advanced disease stages, as shown in the table on the next page
104
IPI
IPI
Age > 60 years
Serum LDH > Normal
PS 2-4
Extranodal sites > 1
Low 0-1
Low intermediate 2
Risk categories
High intermediate 3
High 4-5
AGE-ADJUSTED IPI IN PATIENTS ≤ 60 YEARS
Serum LDH > Normal
PS 2-4
Low 0
Low intermediate 1
Risk categories
High intermediate 2
High 3
IPI, International Prognostic Index; LDH, lactate dehydrogenase; PS, performance status
PMBCL
• The IPI remains the standard prognostic score, although its discriminatory ability
is limited by the age distribution of the disease and its usual confinement to the
mediastinum
• FDG–PET-CT scan is mandatory to assess disease extent and to obtain better
definition of the residual mediastinal masses at the completion of treatment
PTL
• For staging, in addition to the standard tests, US of the contralateral testis,
brain MRI and diagnostic lumbar puncture with cytological and flow cytometric
analysis of CSF are mandatory
• Orchiectomy is mandatory, both for diagnostic and therapeutic purposes
PCNSL
• The International Extranodal Lymphoma Study Group (IELSG) proposed
a prognostic system for PCNSL based on independent prognostic factors: Age
> 60 years, Eastern Cooperative Oncology Group (ECOG) PS > 1, elevated serum
LDH, elevated CSF protein concentration and tumour localisation within the deep
regions of the brain
105
Three risk classes are defined on the basis of the number of prognostic factors:
0-1 (good-risk), 2-3 (intermediate-risk) or 4-5 (poor-risk), as shown in the
table below
• Another validated score assigns risk on the basis of age and clinical PS: Good-
risk (patients < 50 years), intermediate-risk [patients ≥ 50 years and Karnofsky
performance score (KPS) ≥ 70] and high-risk (patients ≥ 50 years and KPS < 70)
THE INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP PROGNOSTIC

SCORE* FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS
VARIABLE FAVOURABLE FEATURE UNFAVOURABLE

(VALUE “0”) FEATURE (VALUE “1”)
Age (years) ≤ 60 > 60
ECOG PS score 0-1 >1
LDH serum level Normal Elevated
CSF protein level Normal Elevated
Involvement of deep regions of

No Yes
the CNS**
*IELSG score 0-1: Low risk; 2-3: Intermediate risk; 4-5: High risk
**Deep regions include corpus callosum, basal ganglia, brain stem and cerebellum
CNS, central nervous system; CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; IELSG, International
Extranodal Lymphoma Study Group; LDH, lactate dehydrogenase; PS, performance status
Ferreri AJ et al.. J Clin Oncol 2003;21:266-72. Reprinted with permission from American Society of Clinical Oncology. All rights reserved.
PBL
• The specific additional staging procedures recommended include:
Contralateral breast examination for potential bilateral involvement, usually
by whole-body PET-CT
CNS imaging, even in the absence of symptoms, using brain MRI and
cytological and flow cytometric CSF analysis
• Approximately 70% of patients have stage IE disease, 30% have regional nodal
involvement and 4-13% have bilateral breast involvement
• The standard IPI is predictive of outcome, but has low discriminatory ability,
while the stage-modified IPI has a better prognostic discrimination, mainly
through the adverse impact of stage IIE disease
106
• Other reproducible adverse prognostic factors among patients with localised
disease include tumour size > 4-5 cm and bilateral involvement
• Reminiscent of PTL, PBL displays extranodal tropism at relapse
• The ipsilateral and contralateral breasts were involved at relapse in 12-44%
of series with available data
• Other extranodal sites, including the BM, lung or pleura, occur more commonly
in PBL than among nodal DLBCLs
• CNS relapse has been seen in 5-16% of patients, with a weighted average
of approximately 12%. Other than potentially bilateral disease, there are no
reproducible predictors of CNS relapse risk
PBoL
• Most patients have early-stage disease at diagnosis
• PET-CT has increased the detection of asymptomatic bone lesions as part of the
initial presentation of disseminated DLBCL
• Compared with CT scanning, MRI better defines the local extent of the disease
and cortical changes
• An adapted staging system for PBoL, proposed by the IELSG, is shown in the
table below
• The prognosis of primary bone DLBCLs depends mainly on the disease extent:
5-year overall survival (OS) rates vary from ˃ 80% for stage IE to ˂ 40% for
disseminated DLBCL with bone localisation
• The role of the IPI in predicting prognosis of primary DLBCL of the bone appears
to be limited
THE INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP STAGING SYSTEM
FOR DIFFUSE LARGE B-CELL LYMPHOMA OF THE BONE
LYMPHOMA EXTENSION IELSG STAGE

Single bony lesion IE
Single bony lesion with involvement of regional lymph nodes IIE
Multifocal disease in a single bone or lesions in multiple bones in a IVE
disease exclusively limited to the skeleton (without lymph nodal or
visceral disease)*
Disseminated lymphoma with at least one bony lesion IV
*Also called multifocal osteolymphoma or polyostotic lymphoma

IELSG, International Extranodal Lymphoma Study Group
Messina C et al. Cancer Treat Rev 2015;41:235-46. Reprinted with permission from Elsevier.
107
TREATMENT
• Recommended first-line treatment strategies are shown in the table below
• Radiotherapy (RT) should be carried out according to the International
Lymphoma Radiation Oncology Group’s comprehensive guidelines on the use of
RT in extranodal lymphomas
RECOMMENDED FIRST-LINE TREATMENT STRATEGIES IN EXTRANODAL DLBCLS
PRIMARY SITES TREATMENT CONSOLIDATION CNS PROPHYLAXIS

Primary mediastinal R-CHOP or Mediastinal RT (30 Gy) Not recommended
lymphoma R-V/MACOP-B or in responding patients;
R-CHOP14 or RT could be omitted
DA-EPOCH-R in CMR only after
DA-EPOCH-R
HDCT/ASCT is not
recommended in CR1
Primary testicular R-CHOP21 × 6-8 RT to contralateral testis IT MTX or IV systemic
lymphoma (25-30 Gy) MTX
Primary central nervous HD-MTX (MTX ≥ 3g/m2) WBRT is not routinely n/a
system lymphoma plus HD-AraC recommended
HD-MTX-based HDCT/ASCT suggested
(adjusted dose on in young patients
ECOG PS, renal (clinical trial)
function, etc.) in
elderly patients
Primary breast R-CHOP21 × 6 Ipsilateral whole-breast To be considered in
lymphoma RT (30-36 Gy). Partial- all patients
breast RT in selected Mandatory in high risk
cases (see text)
Primary bone R-CHOP21 × 6–8 RT (30-40 Gy) to Only if involvement of
lymphoma RT before ChT is not involved bone skull and/or spine
recommended
ChT, chemotherapy; CMR, complete metabolic response; CNS, central nervous system; CR1, first complete remission; DA-EPOCH-R,
dose-adjusted etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin/rituximab; DLBCL, diffuse large B-cell lymphoma;
ECOG, Eastern Cooperative Oncology Group; HD-AraC, high-dose cytarabine; HDCT/ASCT, high-dose chemotherapy followed by
autologous stem cell transplantation; HD-MTX, high-dose methotrexate; IT, intrathecal; IV, intravenous; MTX, methotrexate; n/a, not
applicable; PS, performance status; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone; R-CHOP14, R-CHOP
treatment combined with rituximab given every 14 days; R-CHOP21, R-CHOP treatment combined with rituximab given every 21 days;
RT, radiotherapy; R-V/MACOP-B, rituximab/etoposide/methotrexate/doxorubicin/cyclophosphamide/vincristine/prednisolone/bleomycin;
WBRT, whole-brain radiotherapy
108
PMBCL
• The current standard treatments shown below can be used according to the
centre’s experience
The combination of rituximab (R) with cyclophosphamide/doxorubicin/
vincristine/prednisolone (CHOP) as R-CHOP or with etoposide/doxorubicin/
cyclophosphamide/vincristine/prednisolone/bleomycin (VACOP-B) or
methotrexate (MTX)/doxorubicin/cyclophosphamide/vincristine/prednisolone/
bleomycin (MACOP-B) as R-V/MACOP-B
Dose-dense CHOP (R-CHOP14)
More intensive ChT regimens, such as dose-adjusted etoposide/prednisolone/
vincristine/cyclophosphamide/doxorubicin/rituximab (DA-EPOCH-R)
• Consolidative mediastinal RT is recommended in responding patients treated with
standard-dose immunochemotherapy (R-CHOP/R-V/MACOP-B)
• A small phase II study showed that consolidative mediastinal RT can be omitted
in patients with a complete metabolic response (CMR) only after DA-EPOCH-R
Validation in a larger, multicentre series is required
• Consolidative mediastinal RT, when required, comprises 30-36 Gy in
1.5-2.0-Gy fractions
• The role of consolidative mediastinal RT in the 50% of patients with CMR
(PET-CT negative) post-immunochemotherapy is being investigated
The ongoing IELSG-37 trial will determine whether it can be omitted following
R-CHOP-like regimens. Outside a clinical trial, there are insufficient data to support
omission, particularly as relapses are difficult to salvage with poor outcomes
• Based on the good results achieved with R ChT combination regimens +/- RT,
high-dose ChT (HDCT) followed by autologous stem cell transplantation (HDCT/
ASCT) is not recommended in patients who achieve complete remission (CR),
even in initially poor-risk patients who attain an adequate response to initial
therapy
• In young patients achieving less than a partial response (PR), with an elevated
FDG uptake at the post-immunochemotherapy PET-CT scan, if residual disease is
confirmed by biopsy when feasible, intensification with HDCT/ASCT is recommended
• A PET-CT scan has an excellent negative predictive value
• However, the high frequency of false positive results necessitates further
investigation of positive scans before planned therapy is modified
Post-treatment PET-CT response evaluation should not be carried out until
at least 5-6 weeks from the last ChT infusion
109
Serial scanning may be required to fully evaluate areas of residual post-treatment
PET tracer uptake, with many patients manifesting gradual resolution
Relapsed/refractory PMBCL
• The probability of recurrence after successful initial therapy for PMBCL appears
to be lower than for other DLBCLs
Patients who achieve a response lasting longer than 18 months are likely
to be cured
• Salvage treatment strategies of relapsed/resistant patients are similar to nodal
DLBCLs, and include attempting reinduction with non-cross-resistant agents
followed by consolidation with HDCT/ASCT in patients with chemosensitive disease
• If not a component of initial therapy, RT should be incorporated into the
treatment programme for relapsed disease, ideally post-transplant, if significant
mediastinal or lung volumes are involved
PTL
• Despite the lack of randomised studies, there is some evidence for the benefit of
R addition to ChT
6-8 cycles of R-CHOP every 21 days (R-CHOP21) is the current standard
• In the absence of orchiectomy, RT (25-30 Gy in 1.5-2.0-Gy fractions) should be
administered to the involved testis
• Prophylactic RT to the contralateral testis and scrotum is strongly recommended
As this is associated with a substantial risk of hypogonadism, sequential
monitoring of testosterone levels and replacement therapy should be included
in the follow-up programme
• Based on indirect data and considerations of increased toxicity, RT to involved
nodes can be safely omitted if PET is negative after R-CHOP
• Prophylactic therapy to reduce the risk of CNS relapse should be used, generally
intrathecal (IT) or intravenous (IV) MTX as part of the overall treatment
• The best strategy to further reduce CNS recurrence is being addressed in an
ongoing phase II study, involving IT liposomal cytarabine (AraC) and systemic
prophylaxis [with a lower dose of MTX (1.5 g/m2) to spare toxicity in elderly
patients]
• In summary, the recommended treatment for stage I-II PTL is 6-8 courses of
R-CHOP21, with the addition of CNS prophylaxis and prophylactic RT to the
contralateral testis
• Therapy of advanced-stage PTLs is not different from the standard treatment
of advanced-stage nodal DLBCLs, but should also incorporate prophylactic
110
testicular RT and CNS prophylaxis
• As in nodal DLBCLs, FDG–PET-CT can be considered the recommended
standard for post-treatment assessment in PTL
Relapsed/refractory PTL
• Standard therapy options have not yet been defined
• HDCT/ASCT, if feasible, should be the preferred treatment strategy in
chemosensitive relapse as in nodal DLBCL
• However, many PTL patients are elderly, with poor PS and multi-organ dysfunction;
the inclusion of these patients in clinical trials testing novel drugs is advisable
PCNSL
• Whole-brain RT (WBRT) is a standard approach. Due to disease relapses in
almost all patients after a few months and a median survival of only 12 months,
the addition of ChT is recommended
• High-dose MTX (HD-MTX; at least 3 g/m² over 2-4-hour rapid infusion time) is
considered the most effective single agent, although CR rates are usually < 30%
A randomised phase II study showed the addition of high-dose AraC
(HD-AraC) to significantly improve response rate (RR) and failure-free
survival but single-arm studies have shown no clear benefit with the addition
of other agents, including ifosfamide, thiotepa, procarbazine, vincristine and
temozolomide
• The role of prophylactic IT ChT is unclear
Some studies have shown no benefit of adding IT ChT to systemic HD-MTX
but others have suggested a reduction in relapse rate with intraventricular
administration combined with MTX-based ChT
• IT ChT cannot be routinely recommended for use with appropriate systemic ChT,
but could be considered for severe meningeal involvement
• RT (40 and 45 Gy in 20-25 fractions) is primarily used as consolidative therapy
following HD-MTX-based ChT
Higher RT doses are associated with an increased risk of neurotoxicity, which
is particularly pronounced in older patients
Lower RT doses (30-36 Gy for WBRT or 23.4 Gy after ChT-induced CR)
appear to be effective and do not exhibit prohibitive RT-related toxicity, even
in elderly patients
111
• An alternative consolidation strategy is HDCT/ASCT, which, mostly using
thiotepa-based conditioning regimens, has shown overall remission rates of up to
91% and a 5-year OS of 87%
• To avoid WBRT, dose-intensive consolidation with conventional ChT, such as
etoposide and AraC, after HD-MTX-based induction, can be used
• Preliminary results of a clinical study suggest the benefit on RR, progression-free
survival (PFS) and OS of adding R and thiotepa in newly-diagnosed disease and
are supported by a retrospective series investigating R combined with HD-MTX
Elderly patients (age > 70 years or patients with comorbidities)
• Selected elderly patients are often able to tolerate HD-MTX-based treatment, with
dosage guided by renal function
• In a systematic review and patient data meta-analysis, HD-MTX-based treatment
was associated with an improved survival outcome
• Further combinations with oral alkylating agents, such as lomustine and
procarbazine +/- vincristine, are feasible and active and comparison with HD-MTX
is warranted
• WBRT should not be routinely used in front-line therapy in elderly patients able
to tolerate other therapies, due to its high rate of neurotoxicity, and should be
reserved for frail patients or those with refractory disease
• In summary, HD-MTX-based regimens, in combination with HD-AraC, are
recommended for induction treatment, based on patient age, PS and organ function
• Consolidation RT should be avoided in elderly patients achieving CR and lower
doses of WBRT (36 Gy or 23.4 Gy), based on response, are preferable for those
not reaching CR
• Whether RT can safely be omitted without compromising long-term outcome in
younger patients in CR remains controversial
HDCT/ASCT as consolidation treatment could be considered as an alternative to
WBRT in eligible patients
• Brain MRI is the standard for response evaluation
• CSF analysis should be added for patients with previous CSF involvement, with
spinal imaging as clinically indicated
• Brain MRI monitoring may help to rule out progression but the clinical utility of
such a surveillance strategy is unproven
• For patients with prior CSF or ocular involvement, specific assessments (i.e. CSF
evaluation or ophthalmologic evaluation) are needed
112
• Based on the rarity of systemic progression, additional systemic evaluation
(i.e. CT or CT-PET scans) is indicated only in case of clinical signs or symptoms
Relapsed/refractory PCNSL
• In patients with disease relapse after HD-MTX, median survival of 58.6 months was
observed for those who received HDCT/ASCT
• Temozolomide (with or without R), topotecan and pemetrexed are the only agents
that have been investigated prospectively in relapsed/refractory disease and none
showed sufficient activity to be established as the standard approach
• Re-exposure to the same HD-MTX-based protocol can be considered
• When RT is used as a single modality therapy, i.e. WBRT as primary treatment for
non-candidates for ChT, higher doses (40-50 Gy, 1.5-1.8 Gy/fraction) are required
Doses of 36 Gy have been shown to be beneficial in a salvage setting, but the
optimal dose and the role of boost doses remains uncertain
• In summary, choice of salvage treatments depends on the clinical status,
toxicities from previous treatments and duration of remission
No standard protocol can currently be recommended
Fit patients should be considered for HDCT/ASCT
WBRT remains an important palliative treatment for patients unable to tolerate
(or those relapsing after) high-dose, CNS-penetrating ChT and who are not fit
for further ChT
PBL
• Surgical resection as a sole modality results in inadequate local control and
mastectomy is associated with inferior outcomes
• Patients who have undergone surgical excision (rare) should be managed in the
same manner as other patients
• The PFS and OS benefits of anthracycline-containing ChT regimens have been
established
• Most recent contemporary series have used CHOP +/- R and RT, with 5-year PFS
and OS of 50-70%
• The use of fewer than 4 ChT cycles is associated with inferior outcomes
• Based on historical comparisons suggesting a favourable impact, and given its
established role in DLBCL treatment, R should be routinely included in front-line
immunochemotherapy as part of R-CHOP21
• There are no data supporting the use of more aggressive or dose-escalated
regimens as part of primary therapy
113
• Whole-breast RT is generally recommended after ChT
• Some experts consider partial-breast RT in cases where the resulting morbidity
reduction is likely to offset the potential increase in marginal relapse rate,
especially where PET scanning has been used in initial staging to allow accurate
delineation of the involved area and nodal status
• Uninvolved lymph nodes do not need to be included in the RT volume, provided
initial staging has used PET
Treatment recommendations
• The recommended treatment for PBL is 6 cycles of R-CHOP, if therapy is
well-tolerated, followed by consolidative, ipsilateral whole-breast RT (30-36 Gy)
• CNS-directed prophylaxis should be considered for individual patients and is
recommended for high-risk patients, i.e. bilateral involvement
• No specific CNS prophylaxis treatment can be recommended due to the lack of
data; in nodal DLBCL, either IT or IV MTX could be appropriate
• Patients with bilateral breast involvement represent a particularly high-risk group
and investigation of more intensive ChT regimens in the context of clinical trials
is justified
• As in nodal DLBCL, FDG–PET-CT can be considered the recommended standard
for post-treatment assessment in PBL
• The Lugano 2014 criteria are also applied to PBL
Relapsed/refractory PBL
• The outcome of patients after relapse is poor; in the IELSG-15 series, the median
survival after relapse was 1.0 year, with a 5-year OS of 20%
• Management is the same as for relapsed DLBCL, with reinduction
immunochemotherapy aiming to proceed to HDCT/ASCT, where feasible, in
patients with responsive disease
PBoL
• Anthracycline-containing ChT regimens, together with R, are recommended,
although the benefit of the addition of R has not been studied in the subset of
patients with PBoL
• The role of consolidation RT is not well-defined and R-CHOP +/- consolidation RT
remains the standard approach for patients with any stage of DLBCL with bone
involvement
• The requirement for RT to sites of bone involvement should be addressed in
appropriately designed prospective randomised trials
114
• Where CR has been achieved with ChT, consolidation RT (30-40 Gy) is
recommended for localised lesions, with limited additional benefit from the use of
extensive radiation volumes
• The risk of CNS recurrence associated with skeletal involvement is a matter of debate
• As CNS involvement is low in patients with localised PBoL, CNS prophylaxis is
not routinely required
• An accurate assessment (CSF flow cytometry and brain MRI) and prophylaxis
can be recommended in patients with involvement of anatomic areas in close
apposition to the CNS (skull and/or spine), on the basis of established risk profiling
• Where pathological fractures are found at presentation, surgical stabilisation
for quality of life improvement should be considered only if ChT delays can be
avoided
Consolidation RT (30-40 Gy) to the fractured bone may be given
Initial RT to a fractured bone before ChT does not improve disease outcome but
may improve pain and potentially hasten healing
Response assessment and post-treatment evaluation
• Post-treatment evaluation is difficult because bone lesions remain detectable
upon CT scan
• PET scan is mandatory in response assessment as in nodal DLBCL, although
persistent PET uptake may represent bone healing rather than active disease
• New treatments such as HDCT/ASCT or alternative immunochemotherapy are
recommended only in the case of biopsy-proven persisting disease or clear
clinical or radiological progression
• Finally, long-term bone health preventive measures should also be taken into
account in patients with PBoL, including evaluation and treatment of any
underlying osteoporosis and/or vitamin D deficiency
• New agents targeting distinct molecular pathways involved in disease
pathogenesis are being tested in ongoing trials but none is yet appropriate for
use in standard clinical practice
• For instance, in PMBCL, the role of biological drugs targeting selective pathways
such as JAK-STAT and PD-L1 and PD-L2 should be evaluated
• PTLs are predominantly of the ABC subtype and lenalidomide and ibrutinib, which
preferentially target this DLBCL subtype and have been proven to be effective in
nodal ABC DLBCL, may be tested in PTL patients
115
• Both PTLs and PCNSLs show a high frequency of MYD88 and CD79a mutations,
indicating sensitivity to ibrutinib
• Ibrutinib has been reported to cross the blood-brain barrier and to have potential
activity in PCNSL
FOLLOW-UP
• Follow-up monitoring is the same as that for nodal DLBCL
116
DIAGNOSIS
The diagnosis of DLBCL should be carried out in a reference haematopathology
laboratory with expertise in morphological interpretation and the facilities to carry
out the full range of phenotypic and molecular investigations
Details on methods for pathological diagnosis, IHC and molecular biology have been
reported fully in the ESMO guidelines for nodal DLBCLs
PMBCL
• PMBCL is most commonly seen in women in the third or fourth decade of life
• PMBCL usually presents with a bulky tumour in the anterior mediastinum, with
local compressive symptoms including dyspnoea, cough, dysphagia and a
superior vena cava syndrome in about 50% of cases
• Pleural or pericardial effusions are often present
• Particular extranodal sites such as the kidneys, adrenal glands, liver and ovaries
may be involved, particularly in disease recurrence
• PMBCL represents around 10% of all DLBCLs
• Cells express pan B-cell markers, are negative for surface Ig and are usually
positive for CD23, weakly positive for CD30 and negative for CD15
• BCL6, CD10 and IRF4 are expressed in some cases
• Some tumours have morphological, phenotypic and molecular features close
to nodular sclerosing HL
These tumours are determined by the WHO to be unclassifiable and have
features intermediate between DLBCL and classical HL
• The three most common molecular alterations involve: NFkB activation
(REL amplification, inactivating mutations of TNFAIP3), JAK-STAT pathway
activation (inactivating mutations of SOCS1, JAK2 amplification and
interleukin-13 overexpression) and modulation of tumour cell interactions
with the microenvironment and immune system (downregulation of HLA class II,
PDL-1 and -2 amplifications or translocations)
PTL
• PTL usually presents as a limited-stage disease. Most patients have a unilateral
testicular mass, although 10% show bilateral testicular involvement
117
• Clinical behaviour is often aggressive, with dissemination to multiple extranodal
sites, such as lung, pleura, skin (up to 35%), soft tissues and Waldeyer's ring (5%)
• CNS relapses are frequent and occur in up to 30% of PTL patients, usually within
1-2 years of diagnosis
• Most (80-90%) PTLs are DLBCLs
• An ABC pattern is shown by 60-96% of cases
• Mutations of MYD88 are more common in extranodal, compared with nodal,
DLBCLs and 19% of these cases also carry CD79a mutations
• Inactivating mutations of B2M and rearrangements of PDL, CIITA and FOXP1
have been found in 2-10% of cases
PCNSL
• PCNSL is a rare disease, defined by involvement of the cerebral parenchyma,
leptomeninges, eyes or spinal cord without evidence of systemic disease
• Patients usually present with focal neurological deficits and/or neuropsychiatric
symptoms
• Approximately 10-20% of patients have ocular involvement and around one third
have multifocal neurological disease
• Stereotactic biopsy is recommended to obtain histopathological diagnosis.
Resection of PCNSL cannot be recommended because of the associated
morbidity and lack of evidence for benefit
• Glucocorticoid therapy can interfere with an accurate histopathological diagnosis
and so should be avoided before biopsy, without compromising the patient
• At diagnosis, contrast-enhanced brain MRI and cytological evaluation and flow
cytometry of the CSF are required
• Slit lamp examination should be carried out to investigate possible ocular
involvement
• CT scans of the chest, abdomen and pelvis or a PET-CT scan is recommended to
exclude systemic disease
• Testicular US examination is recommended for elderly men
• Although the value of a BM examination is controversial, it is still part of baseline
investigations in current clinical trials
• Most PCNSLs in immunocompetent patients are DLBCLs
118
• Extraneural dissemination is rare, but clonally related cells have been detected in
the blood of some patients
• Many tumours express both GC markers and the ABC marker IRF4
• Activation of NFkB and BCR/MYD88 pathways and deletions of the HLA gene
locus at 6p21.32 have been reported
• MYD88 mutations have been detected in 30-75% of cases, and CD79a/b
mutations in up to 45%, with substantial overlap in positive cases
PBL
• PBL is uncommon and almost exclusively affects women, typically those of older
age (median 62-64 years)
• The typical presentation is a painless breast mass (median 4 cm diameter),
slightly more frequently on the right side and with systemic symptoms present
in < 5% of patients, almost always those with disseminated disease
• Up to 20% of patients are diagnosed incidentally. There are no definitive
radiological features of PBL and diagnostic biopsy is mandatory
• Histologically, DLBCLs are the most common form
• Molecularly, primary breast DLBCLs are mainly of the ABC subtype
• Trisomy 3 and 18 and chromosome 18 translocations involving IGH/MALT1
as in low-grade MALT lymphomas have been observed
PBoL
• PBoL is a rare lymphoma, found most commonly in mid-elderly men
• The median age at diagnosis is 45-60 years
• Patients typically present with bone pain (80-95%), a tumour mass (30-40%)
and pathological fracture (10-15%), most frequently of the humerus
• Approximately 15% of patients show spinal cord compression and 10% have
hypercalcaemia, commonly involving the femur, pelvic bones and spine
• PBoL may present as a single lesion, with or without an associated soft tissue
mass arising from local extension and with or without regional lymphadenopathy,
or as multifocal polyostotic disease, exclusively involving the skeleton
• The vast majority of PBoLs are DLBCLs
• Non-GC phenotype is slightly more common than GC
• BCL2, BCL6 and MYC rearrangements may be found in 19%, 14% and 9% of
cases, respectively
119
Baseline assessments and procedures do not generally differ from those required
for patients presenting with nodal DLBCLs and include: Physical examination,
determination of PS, B symptom assessment, complete blood count, routine blood
chemistry with LDH and screening tests for HIV and hepatitis B and C
• There are additional and specific staging procedures for different extranodal sites
Based on consensus recommendations developed at the International Conference
on Malignant Lymphomas, FDG–PET-CT scanning is the standard practice for
staging patients with DLBCL and for response assessment based on the visual
Deauville criteria (5-point scale)
Disease staging is established as for nodal DLBCL, according to the Ann Arbor
classification system
In extranodal DLBCL, while the utility of the IPI and aaIPI is not fully evaluated,
these tools should be calculated for prognostic purposes, at least to differentiate
between localised and advanced disease stages
PMBCL
• The IPI remains the standard prognostic score, although its discriminatory
ability is limited by the age distribution of the disease and its usual confinement
to the mediastinum
• FDG–PET-CT scan is mandatory to assess disease extent and to obtain better
definition of the residual mediastinal masses at the completion of treatment
PTL
• For staging, in addition to the standard tests, US of the contralateral testis,
brain MRI and diagnostic lumbar puncture with cytological and flow cytometric
analysis of CSF are mandatory
• Orchiectomy is mandatory, both for diagnostic and for therapeutic purposes
PCNSL
• The IELSG PCNSL prognostic system bases risk on independent prognostic
factors: Age > 60 years, ECOG PS > 1, elevated serum LDH, elevated CSF protein
concentration and tumour localisation within the deep regions of the brain
Three risk classes are defined on the basis of the number of prognostic factors:
0-1 (good-risk), 2-3 (intermediate-risk) or 4-5 (poor-risk)
120
• Another validated score assigns risk on the basis of age and clinical PS:
Good-risk (patients < 50 years), intermediate-risk (patients ≥ 50 years and KPS ≥
70) and high-risk (patients ≥ 50 years and KPS < 70)
PBL
• The specific additional staging procedures recommended include:
Contralateral breast examination for potential bilateral involvement, usually by
whole-body PET-CT
CNS imaging, even in the absence of symptoms, using brain MRI and
cytological and flow cytometric CSF analysis
• Approximately 70% of patients have stage IE disease, 30% have regional nodal
involvement and 4-13% have bilateral breast involvement
• The standard IPI is predictive of outcome, but has low discriminatory ability,
while the stage-modified IPI has a better prognostic discrimination, mainly
through the adverse impact of stage IIE disease
• Other reproducible adverse prognostic factors among patients with localised
disease include tumour size > 4-5 cm and bilateral involvement
• Reminiscent of PTL, PBL displays extranodal tropism at relapse
• The ipsilateral and contralateral breasts were involved at relapse in 12-44% of
series with available data
• Other extranodal sites, including the BM, lung or pleura, occur more commonly
in PBL than among nodal DLBCLs
• CNS relapse has been seen in 5-16% of patients, with a weighted average
of approximately 12%. Other than potentially bilateral disease, there are no
reproducible predictors of CNS relapse risk
PBoL
• Most patients have early-stage disease at diagnosis
• PET-CT has increased the detection of asymptomatic bone lesions as part of the
initial presentation of disseminated DLBCL
• Compared with CT scanning, MRI better defines the local extent of the disease
and cortical changes
• An adapted staging system for PBoL has been proposed by the IELSG
• The prognosis of primary bone DLBCLs depends mainly on the disease extent:
5-year OS rates vary from ˃ 80% for stage IE to ˂ 40% for disseminated DLBCL
with bone localisation
• The role of the IPI in predicting prognosis of primary DLBCL of the bone appears
to be limited
121
TREATMENT
RT should be carried out according to the International Lymphoma Radiation Oncology
Group’s comprehensive guidelines on the use of RT in extranodal lymphomas
PMBCL
• The current standard treatments shown below can be used according to the
centre’s experience
R-CHOP or R-V/MACOP-B
Dose-dense CHOP (R-CHOP14)
More intensive ChT regimens, such as DA-EPOCH-R
• Consolidative mediastinal RT is recommended in responding patients treated with
standard-dose immunochemotherapy (R-CHOP/R-V/MACOP-B)
• A small phase II study showed that consolidative mediastinal RT can be omitted
in patients with a CMR only after DA-EPOCH-R
• Consolidative mediastinal RT, when required, comprises 30-36 Gy, in
1.5-2.0-Gy fractions
• The role of consolidative mediastinal RT in the 50% of patients with CMR
(PET-CT negative) post immunochemotherapy is being investigated
The ongoing IELSG-37 trial will determine whether it can be omitted following
R-CHOP-like regimens. Outside a clinical trial, there are insufficient data to support
omission, particularly as relapses are difficult to salvage with poor outcomes
• Based on the good results achieved with R ChT combination regimens +/- RT,
HDCT/ASCT is not recommended in patients who achieve CR, even in initially
poor-risk patients who attain an adequate response to initial therapy
• In young patients achieving less than a PR, with an elevated FDG uptake at the
post-immunochemotherapy PET-CT scan, if residual disease is confirmed by biopsy
when feasible, intensification with HDCT/ASCT is recommended
• A PET-CT scan has an excellent negative predictive value
• However, the high frequency of false positive results necessitates further
investigation of positive scans before planned therapy is modified
Post-treatment PET-CT response evaluation should not be carried out until at
least 5-6 weeks from the last ChT infusion
122
Serial scanning may be required to fully evaluate areas of residual post-treatment
PET tracer uptake, with many patients manifesting gradual resolution
Relapsed/refractory PMBCL
• The probability of recurrence after successful initial therapy for PMBCL appears
to be lower than for other DLBCLs
Patients who achieve a response lasting longer than 18 months are likely
to be cured
• Salvage treatment strategies of relapsed/resistant patients are similar to nodal
DLBCLs, and include attempting reinduction with non-cross-resistant agents
followed by consolidation with HDCT/ASCT in patients with chemosensitive disease
• If not a component of initial therapy, RT should be incorporated into the
treatment programme for relapsed disease, ideally post-transplant, if significant
mediastinal or lung volumes are involved
PTL
• Despite the lack of randomised studies, there is some evidence for the benefit of
R addition to ChT
6-8 cycles of R-CHOP21 is the current standard
• In the absence of orchiectomy, RT (25-30 Gy in 1.5-2.0-Gy fractions) should be
administered to the involved testis
• Prophylactic RT to the contralateral testis and scrotum is strongly recommended
As this is associated with a substantial risk of hypogonadism, sequential
monitoring of testosterone levels and replacement therapy should be included
in the follow-up programme
• Based on indirect data and considerations of increased toxicity, RT to involved
nodes can be safely omitted if PET is negative after R-CHOP
• Prophylactic therapy to reduce the risk of CNS relapse should be used, generally
IT or IV MTX as part of the overall treatment
• The best strategy to further reduce CNS recurrence is being addressed in an
ongoing phase II study, involving IT liposomal AraC and systemic prophylaxis
[with a lower dose of MTX (1.5 g/m2) to spare toxicity in elderly patients]
• In summary, the recommended treatment for stage I-II PTL is 6-8 courses of
R-CHOP21, with the addition of CNS prophylaxis and prophylactic RT to the
contralateral testis
• Therapy of advanced-stage PTLs is not different from the standard treatment
of advanced-stage nodal DLBCLs, but should also incorporate prophylactic
testicular RT and CNS prophylaxis
123
• As in nodal DLBCLs, FDG–PET-CT can be considered the recommended standard
for post-treatment assessment in PTL
Relapsed/refractory PTL
• Standard therapy options have not yet been defined
• HDCT/ASCT, if feasible, should be the preferred treatment strategy in
chemosensitive relapse as in nodal DLBCL
• However, many PTL patients are elderly, with poor PS and multi-organ dysfunction;
the inclusion of these patients in clinical trials testing novel drugs is advisable
PCNSL
• WBRT is a standard approach. Due to disease relapses in almost all patients after
a few months and a median survival of only 12 months, the addition
of ChT is recommended
• HD-MTX (at least 3 g/m² over 2-4-hour rapid infusion time) is considered the
most effective single agent, although CR rates are usually < 30%
A randomised phase II study showed the addition of HD-AraC to significantly
improve RR and failure-free survival but single-arm studies have shown no
clear benefit with the addition of other agents, including ifosfamide, thiotepa,
procarbazine, vincristine and temozolomide
• The role of prophylactic IT ChT is unclear
Some studies have shown no benefit of adding IT ChT to systemic HD-MTX
but others have suggested a reduction in relapse rate with intraventricular
administration combined with MTX-based ChT
• IT ChT cannot be routinely recommended for use with appropriate systemic ChT,
but could be considered for severe meningeal involvement
• RT (40 and 45 Gy in 20-25 fractions) is primarily used as consolidative therapy
following HD-MTX-based ChT
Higher RT doses are associated with an increased risk of neurotoxicity, which is
particularly pronounced in older patients
Lower RT doses (30-36 Gy for WBRT or 23.4 Gy after ChT-induced CR) appear
to be effective and do not exhibit prohibitive RT-related toxicity, even in elderly
patients
124
• An alternative consolidation strategy is HDCT/ASCT, which, mostly using
thiotepa-based conditioning regimens, has shown overall remission rates of up
to 91% and a 5-year OS of 87%
• To avoid WBRT, dose-intensive consolidation with conventional ChT, such as
etoposide and AraC, after HD-MTX-based induction can be used
• Preliminary results of a clinical study suggest the benefit on RR, PFS and OS of
adding R and thiotepa in newly-diagnosed disease and are supported by
a retrospective series investigating R combined with HD-MTX
Elderly patients (age > 70 years or patients with comorbidities)
• Selected elderly patients are often able to tolerate HD-MTX-based treatment, with
dosage guided by renal function
• In a systematic review and patient data meta-analysis, HD-MTX-based treatment
was associated with an improved survival outcome
• Further combinations with PO alkylating agents, such as lomustine and
procarbazine +/- vincristine, are feasible and active and comparison with HD-MTX
is warranted
• WBRT should not be routinely used in front-line therapy in elderly patients able
to tolerate other therapies, due to its high rate of neurotoxicity, and should be
reserved for frail patients or those with refractory disease
• In summary, HD-MTX-based regimens, in combination with HD-AraC, are
recommended for induction treatment, based on patient age, PS and organ function
• Consolidation RT should be avoided in elderly patients achieving CR and lower
doses of WBRT (36 Gy or 23.4 Gy), based on response, are preferable for those
not reaching CR
• Whether RT can safely be omitted without compromising long-term outcome in
younger patients in CR remains controversial
HDCT/ASCT as consolidation treatment could be considered as an alternative to
WBRT in eligible patients
• Brain MRI is the standard for response evaluation
• CSF analysis (cytology and flow cytometry) should be added for patients with
previous CSF involvement, with spinal imaging as clinically indicated
• Brain MRI monitoring may help to rule out progression but the clinical utility of
such a surveillance strategy is unproven
• For patients with prior CSF or ocular involvement, specific assessments (i.e. CSF
evaluation or ophthalmologic evaluation) are needed
125
• Based on the rarity of systemic progression, additional systemic evaluation
(i.e. CT or CT-PET scans) is indicated only in case of clinical signs or symptoms
Relapsed/refractory PCNSL
• In patients with disease relapse after HD-MTX, HDCT/ASCT is associated with a
median survival of 18.3 months (58.6 months for those who received HDCT/ASCT)
• Temozolomide (with or without R), topotecan and pemetrexed are the only agents
that have been investigated prospectively in relapsed/refractory disease and none
showed sufficient activity to be established as the standard approach
• Re-exposure to the same HD-MTX-based protocol can be considered
• When RT is used as a single modality therapy, i.e. WBRT as primary treatment
for non-candidates for ChT, higher doses (40-50 Gy, 1.5-1.8 Gy/fraction) are
required
Doses of 36 Gy have been shown to be beneficial in a salvage setting, but the
optimal dose and the role of boost doses remains uncertain
• In summary, choice of salvage treatments depends on the clinical status,
toxicities from previous treatments and duration of remission
No standard protocol can currently be recommended
Fit patients should be considered for HDCT/ASCT
WBRT remains an important palliative treatment for patients unable to tolerate
(or those relapsing after) high-dose, CNS-penetrating ChT and who are not fit
for further ChT
PBL
• Surgical resection as a sole modality results in inadequate local control and
mastectomy is associated with inferior outcomes
• Patients who have, rarely, undergone surgical excision should be managed in the
same manner as other patients
• The PFS and OS benefits of anthracycline-containing ChT regimens have been
established
• Most recent contemporary series have used CHOP +/- R and RT, with 5-year PFS
and OS of 50-70%
• The use of fewer than 4 ChT cycles is associated with inferior outcomes
126
• Based on historical comparisons suggesting a favourable impact, and given its
established role in DLBCL treatment, R should be routinely included in front-line
immunochemotherapy as part of R-CHOP21
• There are no data supporting the use of more aggressive or dose-escalated
regimens as part of primary therapy
• Whole-breast RT is generally recommended after ChT
• Some experts consider partial-breast RT in cases where the resulting morbidity
reduction is likely to offset the potential increase in marginal relapse rate,
especially where PET scanning has been used in initial staging to allow accurate
delineation of the involved area and nodal status
• Uninvolved lymph nodes do not need to be included in the RT volume, provided
initial staging has used PET
Treatment recommendations
• The recommended treatment for PBL is 6 cycles of R-CHOP, if therapy is
well-tolerated, followed by consolidative, ipsilateral whole-breast RT (30-36 Gy)
• CNS-directed prophylaxis should be considered for individual patients and is
recommended for high-risk patients, i.e. bilateral involvement
• No specific CNS prophylaxis treatment can be recommended due to the lack of
data; in nodal DLBCL, either IT or IV MTX could be appropriate
• Patients with bilateral breast involvement represent a particularly high-risk group
and investigation of more intensive ChT regimens in the context of clinical trials
is justified
• As in nodal DLBCL, FDG–PET-CT can be considered the recommended standard
for post-treatment assessment in PBL
• The Lugano 2014 criteria are also applied to PBL
Relapsed/refractory PBL
• The outcome of patients after relapse is poor; in the IELSG-15 series, the median
survival after relapse was 1 year, with a 5-year OS of 20%
• Management is the same as for relapsed DLBCL, with reinduction
immunochemotherapy aiming to proceed to HDCT/ASCT, where feasible, in
patients with responsive disease
PBoL
• Anthracycline-containing ChT regimens, together with R, are recommended,
although the benefit of the addition of R has not been studied in the subset of
patients with PBoL
127
• The role of consolidation RT is not well-defined and R-CHOP +/- consolidation RT
remains the standard approach for patients with any stage of DLBCL with bone
involvement
• The requirement for RT to sites of bone involvement should be addressed in
appropriately designed prospective randomised trials
• Where CR has been achieved with ChT, consolidation RT (30-40 Gy) is
recommended for localised lesions, with limited additional benefit from the
use of extensive radiation volumes
• The risk of CNS recurrence associated with skeletal involvement is a matter
of debate
• As CNS involvement is low in patients with localised PBoL, CNS prophylaxis
is not routinely required
• An accurate assessment (CSF flow cytometry and brain MRI) and prophylaxis
can be recommended in patients with involvement of anatomic areas in close
apposition to the CNS (skull and/or spine), on the basis of established risk profiling
• Where pathological fractures are found at presentation, surgical stabilisation
for quality of life improvement should be considered only if ChT delays can be
avoided
Consolidation RT (30-40 Gy) to the fractured bone may be given
Initial RT to a fractured bone before ChT does not improve disease outcome but
may improve pain and potentially hasten healing
Response assessment and post-treatment evaluation
• Post-treatment evaluation is difficult because bone lesions remain detectable
upon CT scan
• PET scan is mandatory in response assessment as in nodal DLBCL, although
persistent PET uptake may represent bone healing rather than active disease
• New treatments such as HDCT/ASCT or alternative immunochemotherapy are
recommended only in the case of biopsy-proven persisting disease or clear
clinical or radiological progression
• Finally, long-term bone health preventive measures should also be taken into
account in patients with PBoL, including evaluation and treatment of any
underlying osteoporosis and/or vitamin D deficiency
128
New agents targeting distinct molecular pathways involved in disease pathogenesis
are being tested in ongoing trials but none is yet appropriate for use in standard
clinical practice
For instance, in PMBCL, the role of biological drugs targeting selective pathways
such as JAK-STAT and PD-L1 and PD-L2 should be evaluated
PTLs are predominantly of the ABC subtype and lenalidomide and ibrutinib, which
preferentially target this DLBCL subtype and have been proven to be effective in
nodal ABC DLBCL, may be tested in PTL patients
Both PTLs and PCNSL show a high frequency of MYD88 and CD79a mutations,
indicating sensitivity to ibrutinib
Ibrutinib has been reported to cross the blood-brain barrier and to have potential
activity in PCNSL
FOLLOW-UP
Follow-up monitoring is the same as that for nodal DLBCL
129
HAIRY CELL LEUKAEMIA

• A diagnosis of hairy cell leukaemia (HCL) can be established from examination
of peripheral blood (PB) films and immunophenotyping in most cases
• Flow cytometry studies using anti-B-cell monoclonal antibodies can confirm
a diagnosis of HCL based on cytology
• In difficult cases, strong expression of cluster of differentiation (CD)200 may be
useful as it is characteristic of HCL
• Bone marrow (BM) examination is required for diagnosis and to assess response
and is typically performed by a trephine biopsy
Immunohistochemistry will highlight lymphoid infiltrates and support
the diagnosis
• Monoclonal antibodies that detect mutated BRAF protein have also been
effectively used in the diagnosis and detection of minimal residual disease
(MRD), with preliminary data indicating high specificity and sensitivity for HCL
DIAGNOSTIC WORK-UP FOR CLASSICAL HCL
PB film morphology
Flow cytometry in PB and BM aspirate
BM trephine biopsy with IHC
BRAF mutation of exon 15 in difficult cases
BM, bone marrow; HCL, hairy cell leukaemia; IHC, immunohistochemistry; PB, peripheral blood
• There are several features that may be used to distinguish between HCL and
HCL variant (HCL-V), as shown in the table on the next page
• There is no distinct chromosome abnormality in HCL and it is thought that the
disease arises on a memory B cell, as in most cases there are mutations of the
immunoglobulin heavy chain variable (IGHV) region gene
• V600E mutation of the BRAF gene in exon 15 has also been reported in HCL
• Testing for the BRAF mutation may be routinely incorporated into the diagnostic
work-up for HCL given the high frequency of occurrence in this disease
• The BRAF mutation is not present in patients with HCL-V, but TP53 mutations are
present in one third of HCL-V cases
130
DIAGNOSTIC CRITERIA FOR HCL AND HCL-V
CHARACTERISTICS CLASSICAL HCL HCL-V

BM aspiration Difficult (often dry tap) Easy
Lymphocytosis – +
Monocytopaenia + –
Prominent nucleoli – +
Cytoplasmic projections + +
CD25 + –
FMC7, CD20, CD22, CD11c + +
CD103, CD123 + Variable
Annexin + –
BRAF V600E mutation + –
Splenomegaly + +
Response to purine analogues Good Poor
BM, bone marrow; CD, cluster of differentiation; HCL, hairy cell leukaemia; HCL-V, hairy cell leukaemia variant
STAGING AND RISK STRATIFICATION

• There is no globally accepted staging system for HCL
• In addition to the diagnostic tests outlined above, a staging work-up
should include: Full blood cell counts, renal and liver biochemistry, serum
immunoglobulins, β2 microglobulin (B2M), direct antiglobulin test (DAT),
Coombs test and hepatitis B and C virus (HBV and HCV) and human
immunodeficiency virus (HIV) screening
• Computed tomography (CT) imaging is also desirable at the time of diagnosis
and should be performed at relapse
• There is no international prognostic system for risk stratification of HCL
• Several clinical variables are indicative of a poor prognosis: The degree of cytopaenias
[haemoglobin (Hb) < 10 g/dL, platelets < 100 x 109/L] and neutrophils (< 1 x 109/L),
in addition to the presence of lymphadenopathy and a partial response (PR);
131
patients who achieve a complete response (CR) have a significantly longer disease-
free survival than those who achieve a PR
• Biological factors associated with a poor prognosis include the presence of TP53
mutations, a lack of somatic mutations in IGHV genes and VH4-34 family usage
• In HCL-V, the presence of TP53 mutations appears to be an adverse prognostic
factor
TREATMENT
• Treatment is not indicated in asymptomatic patients, but untreated patients
should be closely monitored, with a complete history, physical examination,
complete blood cell count and differential test every 3-6 months
• Treatment should be initiated in patients with symptomatic HCL, characterised by
bulky or progressive and symptomatic splenomegaly, cytopaenias (Hb < 10 g/dL
and/or platelets < 100 x 109/L and/or neutrophils < 1 x 109/L), recurrent or severe
infections and/or systemic symptoms
First line
Purine analogues
• For symptomatic HCL patients who are young and fit, purine analogues
(cladribine or pentostatin) are recommended as initial treatment, as shown
in the treatment algorithm on the next page
• Cladribine and pentostatin appear similar in terms of clinical benefit (high
response rates, duration of response, recurrence rates) and adverse event
profiles, but there has been no randomised direct comparison
• Cladribine is used more frequently than pentostatin as administration
is more convenient
132
TREATMENT ALGORITHM FOR NEWLY DIAGNOSED CLASSICAL HCL
Classical HCL first-line treatment
Symptomatic Asymptomatic
patients patients
Observation only*
Young and fit Pregnancy
patients: or severe
Cladribine neutropaenia
or (neutrophil count
pentostatin < 0.2 x 109/L):
IFN-α
CR PR
Observation Consolidation
with R
*In practice, most patients

* in practice, need treatment
most patients shortly
need treatment afterafter
shortly diagnosis either
diagnosis because
either ofofsymptoms
because symptomsorand
to to
correct
correctcytopaenia
cytopaenia
CR, complete response; HCL,hairy cell leukaemia; IFN-α, interferon alpha; PR, partial response; R, rituximab
133
Cladribine
• Cladribine is administered either as a continuous intravenous (IV) infusion at a
dose of 0.09 mg/kg over a 5-7-day period, or as a 2-hour IV infusion at a dose of
0.12-0.14 mg/kg for 5-7 days
It is also effective at a dose of 0.12-0.15 mg/kg as a 2-hour infusion once per
week over 6 courses
• A CR rate of 85-91% has been reported after a single course of therapy
• Responses (CR and PR) are similar regardless of weekly or daily administration,
and when given as a subcutaneous (SC) injection
• An SC dose of 0.1 mg/kg/day cladribine is given for 5-7 days, or 0.14 mg/kg/day
for 5 days as a single course
• SC seems to be an easier route of administration than IV as it does not require
hospitalisation
• Lower total doses (0.5 mg/kg) are associated with fewer cases of grade 3-4 toxicity
(primarily neutropaenic fevers and infections) than higher total doses (0.7 mg/kg)
• Patients who achieve a PR after the first course of cladribine should receive a
second course [with or without rituximab (R)] at least 6 months after the end of
the first course to achieve a CR
Pentostatin
• In patients with normal creatinine clearance (> 60 mL/minute), pentostatin is
typically administered at a dose of 4 mg/m2 IV every second week until CR, plus
one or two consolidating injections
• Full blood count usually normalises after 8-9 courses and a BM biopsy should be
performed to confirm a CR
Interferon alpha
• The role of interferon alpha (IFN-α) is limited in the treatment of HCL; purine
analogues induce higher and more durable remissions and are more convenient
for patients
• IFN-α may be indicated in pregnant patients or in those with very severe neutropaenia
(neutrophil count < 0.2 x 109/L) prior to therapy with nucleoside analogues
Response evaluation
• In HCL, responses are defined according to ‘Consensus Resolution’ criteria, as
shown in the table on the next page
134
RESPONSE CRITERIA FOR HCL
DEFINITION OF RESPONSE CATEGORIES
No hairy cells on PB and BM aspiration or biopsy specimens, normalisation of

CR
organomegaly and PB counts
Normalisation of PB counts, at least 50% reduction in organomegaly and BM

PR
hairy cells and < 5% circulating hairy cells
Any deterioration in blood counts related to the detection of hairy cells in PB

Relapse
and/or BM and/or increasing splenomegaly
BM, bone marrow; CR, complete response; HCL, hairy cell leukaemia; PB, peripheral blood; PR, partial response
• Evaluation of response requires careful physical examination and a blood cell count
• In addition to a BM biopsy to confirm CR, response evaluation should include a
chest X-ray and abdominal ultrasound (US) or CT
• Absence of hairy cells and a normalisation of any organomegaly or cytopaenia
indicates a CR, while a PR is defined as a normalisation of peripheral counts with
≥ 50% reduction in organomegaly and BM hairy cells and < 5% circulating hairy
cells
• Immunophenotypic analysis of PB or BM is useful to detect MRD but is not
required; eradication of MRD is generally not recommended in routine clinical
practice
• Treatment response should be assessed 4-6 months after cladribine therapy and
after 8-9 courses of pentostatin
Treatment of relapsed patients and patients refractory to purine analogues
• Treatment with cladribine or pentostatin can be successful in patients who
relapse after 12-18 months, as shown in the figure on the next page
135
THERAPEUTIC ALGORITHM FOR RELAPSED AND REFRACTORY CLASSICAL HCL
Classical HCL relapsed and refractory
Relapse Refractory
(after initial patients
treatment with
cladribine or
pentostatin)
Before 12-18 After 12-18

months: months:
R+ Re-treatment
cladribine with cladribine
or or
pentostatin pentostatin
If previously If symptomatic
no treatment splenomegaly
with rituximab: (> 10 cm below
R+ the costal margin)
cladribine with accompanied
or pentostatin low-level bone
marrow infiltration:
Consider
splenectomy
OR consider OR clinical trials OR vemurafenib OR moxetumomab OR R R

alloSCT with new agents if available pasudotox + fludarabine + bendamustine
if available
alloSCT, allogeneic stem cell transplantation; HCL, hairy cell leukaemia; R, rituximab
136
• Second-line treatment with the alternative nucleoside analogue may be given
to those who relapse after 12-18 months
• In early relapse (before 12-18 months), R may be given at a dose of 375 mg/m2 for
4-8 doses as weekly IV infusions, but because it is inferior to purine analogues, it is
not the treatment of choice for relapsed patients as a single agent
• R given concurrently with a purine analogue results in higher response rates, but
also increased toxicity compared with sequential treatment
• For patients who are refractory to purine analogues, clinical trials of new agents
are recommended
Fludarabine + R; bendamustine + R; moxetumomab pasudotox (anti-CD22
recombinant immunotoxin); vemurafenib (BRAF V600E inhibitor); ibrutinib
(Bruton's tyrosine kinase inhibitor)
Splenectomy
• Splenectomy may be indicated in patients who have resistant massive
symptomatic splenomegaly (> 10 cm below the costal margin) and
accompanying low-level BM infiltration
• Splenectomy results in improved and faster responses to subsequent
chemotherapy (ChT), which should not be given until at least 6 months after
splenectomy
• Splenectomy may be considered in pregnant patients with progressive disease,
or in those refractory to nucleoside analogues and IFN-α
• Haemophilus influenzae and pneumococcus vaccination is recommended prior
to splenectomy
Allogeneic stem cell transplantation
• Younger patients who have been heavily pre-treated, have had multiple relapses
and are refractory to purine analogues and R may be candidates for allogeneic
stem cell transplantation (alloSCT)
Treatment during pregnancy
• Treatment during pregnancy should be given only when truly warranted; experience
is limited as only a handful of HCL cases have been reported during pregnancy
• When indicated, the treatment of choice is IFN-α, which is associated with good
tolerability, uncomplicated pregnancy/delivery and normal child development
• Splenectomy is an alternative option early in gestation if IFN-α fails
• Cladribine and R are not indicated during pregnancy
137
Supportive treatment
• Patients with lymphopaenia and treated with nucleoside analogues should
receive prophylactic co-trimoxazole (960 mg three times per week) and aciclovir
(200 mg three times per day) 1 week after purine analogue administration to
prevent pneumocystis infection and herpes reactivation
Treatment should be given until the lymphocyte count increases to > 1 x 109/L
• Granulocyte colony-stimulating factor may be considered for patients with severe
neutropaenia and life-threatening infection
Treatment of HCL-V
• Poor results have been obtained with purine analogues in the treatment
of symptomatic HCL-V
• Cladribine (0.15 mg/kg on days 1-5) immediately followed by R (8 weekly doses
of 375 mg/m2) should be considered as initial treatment for HCL-V as it is more
effective than either agent alone
• Limited data from case reports also suggest benefits with alemtuzumab
(including in patients who have relapsed after R) and moxetumomab pasudotox,
as well as autologous or alloSCT (for refractory patients)
• Splenectomy is recommended in patients with HCL-V as it may induce clinical
responses, correct cytopaenias, remove the bulk of the tumour and improve
responses to purine nucleoside analogues
138
THERAPEUTIC ALGORITHM FOR HCL-V
HCL-V
Symptomatic Asymptomatic
patients patients
Observation only
First-line Refractory
treatment patients
R alone,
R+ or splenectomy
cladribine followed by R
Alemtuzumab OR splenectomy OR moxetumomab OR consider

pasudotox allogeneic or
if available autologous stem
cell transplantation
HCL, hairy cell leukaemia; HCL-V, HCL variant; R, rituximab
139
• The BRAF V600E mutation has been identified as a biomarker for diagnosing HCL
BRAF V600E mutation is present in virtually all cases of HCL and is absent from
the vast majority of diseases that mimic HCL
Immunohistochemical detection of BRAF V600E mutant protein is highly
sensitive and specific for the diagnosis of HCL
FOLLOW-UP AND LONG-TERM IMPLICATIONS
• Asymptomatic patients should be carefully monitored; follow-up should include
a complete history, physical examination, blood cell count and routine chemistry
every 3-6 months
• A small percentage of patients with HCL (approximately 10%) are at risk of
developing a second solid or haematological malignancy, such as chronic
lymphoproliferative disease, melanoma and thyroid cancer
140
A diagnosis of HCL can be established from examination of PB films and
immunophenotyping in most cases
There are several features that may be used to distinguish between HCL and HCL-V
There is no distinct chromosome abnormality in HCL. It is thought that the disease
arises on a memory B cell as in most cases there are mutations of the IGHV gene
V600E mutation of the BRAF gene in exon 15 has also been reported in HCL
Testing for the BRAF mutation may be routinely incorporated into the diagnostic
work-up for HCL given the high frequency of occurrence in this disease
The BRAF mutation is not present in patients with HCL-V, but TP53 mutations are
present in one third of HCL-V cases
STAGING AND RISK STRATIFICATION
There is no globally accepted staging system for HCL
In addition to the diagnostic tests outlined above, a staging work-up
should include: Full blood cell counts, renal and liver biochemistry, serum
immunoglobulins, B2M, DAT, Coombs test and HBV, HCV and HIV screening
There is no international prognostic system for risk stratification of HCL
Several clinical variables are indicative of a poor prognosis: The degree of
cytopaenias, the presence of lymphadenopathy and a PR rather than CR
Biological factors associated with a poor prognosis include the presence of TP53
mutations and a lack of somatic mutations in IGHV genes
TREATMENT
Treatment is not indicated in asymptomatic patients, but untreated patients should
be closely monitored, with a complete history, physical examination, complete
blood cell count and differential test every 3-6 months
Treatment should be initiated in patients with symptomatic HCL, characterised by
bulky or progressive and symptomatic splenomegaly, cytopaenias, recurrent or
severe infections and/or systemic symptoms
First line
Purine analogues
• For symptomatic HCL patients who are young and fit, purine analogues
(cladribine or pentostatin) are recommended as initial treatment
• Cladribine and pentostatin have similar clinical benefit and adverse event profiles,
but there has been no randomised direct comparison
141
• Cladribine is used more frequently than pentostatin due to more convenient
administration
Cladribine
• Cladribine is administered either as a continuous IV infusion over a 5-7-day
period, or as a 2-hour IV infusion for 5-7 days. It is also effective as a 2-hour
infusion once per week over 6 courses
• Responses (CR and PR) are similar regardless of weekly or daily administration,
and when given as a SC injection
• SC administration of cladribine is given for 5-7 days and is considered to be
easier than administration by IV as it does not require hospitalisation
• Lower total doses (0.5 mg/kg) are associated with fewer cases of grade 3-4 toxicity
(primarily neutropaenic fevers and infections) than higher total doses
(0.7 mg/kg)
• Patients who achieve a PR after the first course of cladribine should receive a
second course (with or without R) at least 6 months after the end of the first
course to achieve a CR
Pentostatin
• In patients with normal creatinine clearance (> 60 mL/min), pentostatin is
typically administered at a dose of 4 mg/m2 IV every second week until CR
• Full blood count usually normalises after 8-9 courses and a BM biopsy should be
performed to confirm a CR
IFN- α
• The role of IFN-α is limited in the treatment of HCL; purine analogues induce
higher and more durable remissions and are more convenient for patients
• IFN-α may be indicated in pregnant patients or in those with very severe neutropaenia
(neutrophil count < 0.2 x 109/L) prior to therapy with nucleoside analogues
Response evaluation
• In HCL, responses are defined according to ‘Consensus Resolution’ criteria
• Evaluation of response requires careful physical examination and a blood cell count
• In addition to a BM biopsy to confirm CR, response evaluation should include a
chest X-ray and abdominal US or CT
142
• Treatment response should be assessed 4-6 months after cladribine therapy
and after 8-9 courses of pentostatin
Treatment of relapsed patients and patients refractory to purine analogues
• Treatment with cladribine or pentostatin can be successful in patients who
relapse after 12-18 months
• Second-line treatment with the alternative nucleoside analogue may be given
to those who relapse after 12-18 months
• R may be given in early relapse (before 12-18 months) concurrently with a
purine analogue. This results in higher response rates, but also increased toxicity
compared with sequential treatment
• For patients who are refractory to purine analogues, clinical trials of new agents
are recommended
Fludarabine + R; bendamustine + R; moxetumomab pasudotox (anti-CD22
recombinant immunotoxin); vemurafenib (BRAF V600E inhibitor); ibrutinib
(Bruton's tyrosine kinase inhibitor)
Splenectomy
• Splenectomy may be indicated in patients who have resistant massive
symptomatic splenomegaly (> 10 cm below the costal margin) and
accompanying low-level BM infiltration
• Splenectomy results in improved and faster responses to subsequent ChT
• Splenectomy may be considered in pregnant patients with progressive disease,
or in those refractory to nucleoside analogues and IFN-α
AlloSCT
• Younger patients who have been heavily pre-treated, have had multiple relapses
and are refractory to purine analogues and R may be candidates for alloSCT
Treatment during pregnancy
• Treatment during pregnancy should be given only when truly warranted
• When indicated, the treatment of choice is IFN-α, which is associated with good
tolerability, uncomplicated pregnancy/delivery and normal child development
• Splenectomy is an alternative option early in gestation if IFN-α fails
• Cladribine and R are not indicated during pregnancy
143
Supportive treatment
• Patients with lymphopaenia and treated with nucleoside analogues should
receive prophylactic co-trimoxazole and aciclovir 1 week after purine analogue
administration to prevent pneumocystis infection and herpes reactivation
• Granulocyte colony-stimulating factor may be considered for patients with severe
neutropaenia and life-threatening infection
Treatment of HCL-V
• Poor results have been obtained with purine analogues in the treatment
of symptomatic HCL-V
• Cladribine immediately followed by R should be considered as initial treatment
for HCL-V
• Limited data also suggest benefits with alemtuzumab (including in patients who
have relapsed after R) and moxetumomab pasudotox, as well as autologous or
alloSCT (for refractory patients)
• Splenectomy is also recommended in patients with HCL-V
BRAF V600E mutation is present in virtually all cases of HCL and is absent from the
vast majority of diseases that mimic HCL
Immunohistochemical detection of BRAF V600E mutant protein is highly sensitive
and specific for the diagnosis of HCL
FOLLOW-UP AND LONG-TERM IMPLICATIONS
Asymptomatic patients should be carefully monitored; follow-up should include
a complete history, physical examination, blood cell count and routine chemistry
every 3-6 months
Approximately 10% of HCL patients are at risk of developing a second solid or
haematological malignancy
144
MARGINAL ZONE LYMPHOMAS

• Diagnosis of marginal zone lymphomas (MZLs) should follow the current
2017 World Health Organization (WHO) classification and requires an adequate
tumour biopsy
• Differential diagnosis from MZL mimics depends mainly on
immunohistochemistry (IHC), including at least cluster of differentiation (CD)20,
CD10, CD5, CD23, cyclin D1, SOX11 and immunoglobulin (Ig) D
• Immunohistochemical and molecular markers in MZL are shown in the
table below
• Diagnostic and follow-up biopsies should be reviewed and confirmed by an
expert haematopathologist
• Histopathological diagnoses must be established with the full knowledge of the
clinical and radiological presentation
IMMUNOHISTOCHEMICAL AND MOLECULAR MARKERS IN MZL
MOLECULE TYPE OF TEST EXPECTED RESULT LEVEL OF

RECOMMENDATION
CD20 IHC Positive Mandatory
CD5 IHC Negative* Mandatory
CD23 IHC Negative/positive Suggested†
CD10 IHC Negative Mandatory
IgD IHC Negative‡ Suggested
Cyclin D1 IHC Negative Mandatory§
MYD88 mutation PCR Negative Suggested‖
*
Few exceptions may occur
†
In cases with small cell morphology, irrespective of CD5-concurrent positivity
‡
In cases with splenomegaly, as it is usually positive in SMZL
§
In cases positive for CD5
‖
When present, a differential diagnostic problem with LPL arises (cases of MZL with MYD88 mutation may represent rare exceptions)
CD, cluster of differentiation; IgD, immunoglobulin D; IHC, immunohistochemistry; LPL, lymphoplasmacytic lymphoma;
MZL, marginal zone lymphoma; PCR, polymerase chain reaction; SMZL, splenic marginal zone lymphoma
145
Clonal B-cell lymphocytosis of marginal zone origin
• Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is defined by
the presence of circulating clonal B cells with phenotypic features consistent
with a marginal zone origin in the absence of splenomegaly, hepatomegaly,
lymphadenopathy or other symptoms and signs suggestive of an established
lymphoma
• There is no defined cut-off in the clonal B-cell lymphocyte count for
discriminating CBL-MZ from MZL
Extranodal MZL
• Lymphoepithelial lesions (LELs) are neither essential nor specific for the
diagnosis of extranodal MZL (EMZL)
• In gastric MZL, if the presence of active Helicobacter pylori infection is not
demonstrated by (immuno)histochemistry, it must be ruled out by serology, urea
breath test and/or stool antigen test
• Fluorescence in situ hybridisation (FISH) for t(11;18)(p21;p21), in addition to
routine histology and IHC, may be useful for identifying patients with gastric MZL
who are unlikely to respond to antibiotic therapy
Splenic MZL
• Splenic MZL (SMZL) can usually be established through a combination of
peripheral blood (PB)/bone marrow (BM) aspirate morphology and flow
cytometry, as well as BM biopsy histology and IHC
In a minority of cases, splenectomy may be required for a definitive diagnosis
• Neoplastic lymphocytes often display villi; however, these are not specific
Nodal MZL
• Differential diagnosis of nodal MZL (NMZL) from other indolent lymphomas can
be difficult, unless a so-called ‘monocytoid B-cell morphology’ is prominent
• The presence of an MYD88 mutation, rarely harboured by NMZL, may be used to
distinguish NMZL from lymphoplasmacytic lymphoma (LPL)
Initial work-up
• Mandatory initial staging for all MZL subtypes should include:
History and physical examination, noting lymph node regions, eyes and ears,
nose and throat, liver and spleen
Full blood and differential counts, with flow cytometry of PB being mandatory
for NMZL and SMZL and optional for EMZL
146
Biochemistry, including renal and liver function tests
Protein electrophoresis
Lactate dehydrogenase (LDH) and β2 microglobulin (B2M)
Optional direct antiglobulin (Coombs) test in SMZL
Serum and urine immunofixation
Serology for hepatitis C virus (HCV), with HCV-RNA polymerase chain reaction
(PCR) test and virus genotyping if serology is positive
Cryoglobulins and cryocrit if HCV-positive
Hepatitis B virus (HBV) markers and human immunodeficiency virus (HIV)
serology
• BM aspirate, with morphology and flow cytometry, are mandatory for NMZL and
SMZL and highly recommended for EMZL
• Imaging should include complete chest and abdominal computed tomography
(CT) scan, or magnetic resonance imaging (MRI), and imaging of the orbits and
salivary glands
• Positron emission tomography (PET) scanning may be useful when only localised
treatment is considered, in cases suggestive of transformation to high-grade
histology and to guide decisions on lymph node biopsy targeting
EMZL
• In gastric MZL, the Lugano staging system is being superseded by more modern
systems, such as the Paris staging system, as shown in the table on the next page
147
COMPARISON OF THE LUGANO AND PARIS STAGING SYSTEMS FOR GI TRACT LYMPHOMA
LUGANO PARIS
STAGING SYSTEM STAGING SYSTEM TUMOUR EXTENSION
Stage I Confined to the GI tract T1m N0 M0 Mucosa
(single primary or multiple, T1sm N0 M0 Submucosa
non-contiguous) T2 N0 M0 Muscularis propria
T3 N0 M0 Serosa
Stage II Extending into abdomen

II1 Local nodal involvement T1-3 N1 M0 Perigastric lymph nodes
II2 Distant nodal involvement T1-3 N2 M0 More distant regional nodes

Stage IIE Penetration of serosa to T4 N0-2 M0 Invasion of adjacent structures
involve adjacent organs with or without abdominal
or tissues lymph nodes
Stage IV Disseminated extranodal T1-4 N3 M0 Extra-abdominal lymph nodes
involvement or concomitant T1-4 N0-3 M1 Distant (non-contiguous)
supra-diaphragmatic nodal GI sites involvement
involvement
T1-4 N0-3 M2 Non-GI sites involvement
GI, gastrointestinal
T describes the gastric wall infiltration; N describes the regional lymph node involvement; M describes distant dissemination
Adapted from: Ruskone-Fourmestraux A et al. Gut 2011;60:747-58 and Mazloom A et al. Cancer 2011;117:2461-6.
• For all EMZLs, the initial staging procedures must take into account the specific
site of presentation, as shown in the table on the next page
148
SPECIFIC STAGING AND WORK-UP PROCEDURES FOR EMZL AT DIFFERENT PRIMARY
ANATOMIC SITES
SITE EXAM NOTES

Stomach EGD Mandatory
Endoscopic US Optional, to evaluate the regional lymph nodes and
gastric wall infiltration
IHC Mandatory, to evaluate Helicobacter pylori status.
Faecal antigen or breath test and serology studies
are recommended when the results of histology
are negative
FISH or PCR assay Optional, to detect t(11;18) translocation
Small intestine (IPSID) PCR, IHC or ISH Campylobacter jejuni search in the tumour biopsy
Colon Colonoscopy and EGD
Ocular adnexa Orbital and salivary glands If clinically indicated
imaging (MRI or CT)
Head and neck imaging If clinically indicated
(MRI or CT)
PCR Chlamydophila psittaci search in the tumour biopsy
and PBMCs (optional, according to the geographical
distribution of the infection)
Salivary glands ENT examination and
echography
EGD
Anti-SSA/Ro and To rule out association with Sjögren’s syndrome
anti-SSB/La antibodies
Lung Bronchoscopy and
bronchoalveolar lavage
EGD
Breast Mammography and
breast sonography
MRI (or CT scan)
Thyroid Thyroid echography
CT scan of the neck
Thyroid function tests
Skin PCR Borrelia burgdorferi search in the tumour biopsy
anti-SSA, anti-Sjögren’s-syndrome-related antigen A; anti-SSB, anti-Sjögren’s-syndrome-related antigen B; CT, computed tomography;

EGD, oesophagogastroduodenoscopy; EMZL, extranodal marginal zone lymphoma; ENT, ear, nose and throat; FISH, fluorescence in situ
hybridisation; IHC, immunohistochemistry; IPSID, immunoproliferative small intestinal disease; ISH, in situ hybridisation; MRI, magnetic
resonance imaging; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; US, ultrasound
149
• Routine oesophagogastroduodenoscopy (EGD) is mandatory for gastric MZL
and may also be advisable for some patients with non-gastrointestinal (GI) MZL,
particularly females, patients with primary involvement of the lung, upper airways
and salivary glands and those with high International Prognostic Index (IPI)
score, elevated B2M levels or H. pylori infection
SMZL
• SMZL is usually staged by CT, with the additional use of abdominal sonography
for the detection of splenic focal lesions
• The role of PET is uncertain, but PET–CT should be considered if high-grade
transformation is suspected
NMZL
• Initial staging follows the rules for other nodal lymphomas, the main goal being
to discriminate localised from advanced-stage disease and to have measurable
disease for evaluation of treatment response
• Staging should rule out primary EMZL
Main prognostic factors and prognostic indices
EMZL
• The International Extranodal Lymphoma Study Group developed the EMZL-
specific mucosa-associated lymphoid tissue (MALT)-IPI index based on three
simple clinical risk factors: Age ≥ 70 years, Ann Arbor stage III or IV and elevated
LDH
• The MALT-IPI defines low-risk (0 risk factors), intermediate-risk (one risk factor)
and high-risk (≥ 2 risk factors) disease
• There are no data to recommend that the choice of therapy should be based on
this index
SMZL
• The Intergruppo Italiano Linfomi (IIL)-developed prognostic model is based on
three risk factors: Haemoglobin (Hg) < 12 g/dL, albumin < 35 g/L and elevated
LDH
• The newer HPLL model (named for its determinant factors: Hg concentration,
platelet count, LDH level and extrahilar lymphadenopathy) was developed by the
SMZL Study Group and a simplified form is also available
• There are no data to recommend that the choice of therapy should be based on
these indices
150
NMZL
• There is no specific prognostic score for NMZL, but the Follicular Lymphoma
International Prognostic Index (FLIPI) may help to discriminate between low- and
high-risk patients
TREATMENT
EMZL
Initial therapy with antibiotics in gastric MZL
• H. pylori eradication therapy should be given to all patients with gastric MZL,
irrespective of stage
Triple-therapy regimens, such as a proton pump inhibitor (PPI) for 4 weeks
plus clarithromycin plus either amoxicillin or metronidazole for 10-14 days, are
usually effective
Success should be checked by urea breath test (or monoclonal stool antigen
test) at least 6 weeks after therapy initiation and at least 2 weeks after PPI
withdrawal
• Where H. pylori eradication is unsuccessful, alternative triple- and quadruple-
therapy PPI-containing antibiotic regimens should be attempted
• In patients with localised H. pylori-positive disease, remission following H. pylori
eradication can take between a few months and more than 1 year
• In patients with H. pylori-negative disease, specific anti-lymphoma treatments
may be considered for initiation either immediately or following a trial of H. pylori
eradication therapy that fails to induce lymphoma regression after 3-6 months
• The recommended treatment algorithms for localised gastric MZL and advanced
gastric MZL and non-gastric EMZL are shown in the figures on the next pages
151
TREATMENT ALGORITHM FOR LOCALISED GASTRIC MZL
Gastric MZL, Stage I-IIE *
Helicobacter pylori test
Helicobacter pylori positive Helicobacter pylori negative or

t(11;18) negative or Helicobacter pylori positive
undetermined with t(11;18)
Helicobacter pylori eradication therapy

Standard antibiotics plus PPI
Helicobacter pylori test at least 6 weeks after

starting eradication therapy and at least
2 weeks after PPI withdrawal
Helicobacter pylori Helicobacter pylori Alternative

eradicated detected antibiotics plus
PPI
Helicobacter pylori not

EGD and biopsy at 3-6 months eradicated or no
lymphoma response
Negative Positive for residual Positive for lymphoma,

for lymphoma lymphoma, symptomatic or with other
asymptomatic treatment indications
[overt progression, deep
invasion, nodal involvement,
t(11;18)]
if RT not feasible
or not indicated
EGD and biopsy
every 6 months for EGD and biopsy
2 years, then every every 3-6 months
12-18 months ISRT R-chlorambucil
R-bendamustine
R monotherapy
R-lenalidomide
*Stage is defined according to the Lugano staging system

EGD, oesophagogastroduodenoscopy; ISRT, involved-site radiotherapy; MZL, marginal zone lymphoma; PPI, proton pump
inhibitor; R, rituximab; RT, radiotherapy
152
TREATMENT ALGORITHMS FOR ADVANCED GASTRIC MZL AND NON-GASTRIC EMZL
Gastric MZL, Stage IV* Non-gastric EMZL, Stage IV
Helicobacter pylori test
Helicobacter pylori Helicobacter pylori

positive negative
Helicobacter pylori eradication therapy

Standard antibiotics plus PPI
Asymptomatic lymphoma Symptomatic lymphoma or with other

treatment indications (overt progression,
deep invasion, bulky disease, impending
organ damage, patient preference)
Watch-and-wait R-chlorambucil
EGD and systemic follow-up R-bendamustine
twice per year for 2 years, R monotherapy
then every 12-18 months R-lenalidomide
Consider enrolment in
clinical trials
*Stage is defined according to the Lugano staging system

EGD, oesophagogastroduodenoscopy; EMZL, extranodal marginal zone lymphoma; MZL, marginal zone lymphoma; PPI, proton
pump inhibitor; R, rituximab
153
Anti-infective therapy in non-gastric EMZL
• Eradication therapy with antibiotics in EMZL arising outside the stomach remains
investigational
• Antibiotic therapy may be considered as initial therapy for ocular EMZL, if
treatment is not urgently required to preserve the patient’s sight
• Patients with HCV-associated EMZL may benefit from anti-HCV drugs as initial
therapy
RT in localised EMZL: Recommended doses and schedules at different sites
• Radiotherapy (RT) is the preferred option for localised disease that has not
responded to antibiotic therapy
• Moderate-dose involved-site RT (ISRT) is the preferred approach, according
to volumes described by International Lymphoma Radiation Oncology Group
guidelines
• Low-dose RT (4 Gy in 2 fractions) may be useful for indolent lymphomas to avoid
the risk of side effects, such as cataracts with ocular RT
• Low-dose RT can also be used for the elderly, as palliation for patients with
advanced-stage EMZL unfit for systemic therapy, or where critical sites are
involved
Other treatments for EMZL
• Systemic treatment is preferred for patients with symptomatic systemic disease,
contraindications to RT, failure after antibiotics or local therapy and for those with
histological transformation, as shown in the figure on the previous page
• Patients should be offered enrolment in clinical trials, where available
• Alkylating agents, either cyclophosphamide or chlorambucil, or purine nucleoside
analogues, such as fludarabine and cladribine, have shown activity
• Rituximab (R) plus chlorambucil is an effective option
• R monotherapy may be considered when chemotherapy (ChT) toxicity is an issue
• A short course (4 cycles) of R plus bendamustine may be effective, including in
cases carrying t(11;18)
• There are no data supporting R maintenance
• R plus lenalidomide can be considered
• R plus fludarabine has activity but also carries risks of immunotoxicity and
secondary myelodysplasia
• R/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) should
be reserved for patients with a very aggressive clinical course and clinically
suspected or biopsy-proven histological transformation
154
SMZL
• In asymptomatic patients, a watch-and-wait policy is recommended, with
follow-up every 3-6 months
• The main criteria for initiating treatment are the presence of progressive or
symptomatic splenomegaly and/or progressive cytopaenias
• Any autoimmune disorders should be treated specifically
• The recognised therapeutic options for SMZL are splenectomy, ChT and R alone
or with ChT
• R alone (375 mg/m2, 4-8 weekly doses) is the preferred initial therapy
• R plus ChT may be considered for patients failing to respond to R alone and
is particularly suitable for fit patients with symptomatic disseminated disease,
constitutional symptoms and/or signs of high-grade transformation
• Anti-HCV therapy should be considered for patients with HCV-associated SMZL
• Splenectomy can be considered in selective cases where R is not indicated or is
ineffective
NMZL
• Treatment should follow the principles of therapy for follicular lymphoma
• A watch-and-wait policy may be followed in patients with a low tumour burden
and a lack of clinical symptoms
• R plus ChT [bendamustine, CHOP, cyclophosphamide/vincristine/prednisolone
(CVP), fludarabine] is the backbone of treatment, although R plus fludarabine has
high treatment-related toxicity
• The choice of ChT partner should reflect the fitness of the patient and the risk of
infection
• R maintenance therapy is optional
• Anti-HCV therapy should be considered in patients with HCV-associated NMZL
MZL patients with recurrent disease
• A watch-and-wait policy may be considered for asymptomatic patients and RT
used for MZL patients with localised relapses
• Where systemic treatment is required, options include:
Immunochemotherapy repetition where there has been a long initial remission
(≥ 24 months)
Autologous transplantation in fit patients with clinically aggressive relapse
An alternative immunochemotherapy regimen
A single-agent targeted agent, such as ibrutinib or the phosphoinositide 3-kinase
inhibitor copanlisib
155
General considerations
• Asymptomatic patients with disseminated MZL (SMZL and NMZL) being
managed by a watch-and-wait policy should be monitored by physical
examination, imaging as clinically required, blood counts and biochemistry every
6 months
• [18F]2-fluoro-2-deoxy-D-glucose (FDG)–PET investigation can be considered in
selected cases of suspected histological transformation
• Patients with EMZL at non-gastric sites who have completed treatment can be
re-evaluated with clinical examination, laboratory work-up and imaging/biopsy of
residual lesions if indicated, every 3 months for the first 2 years and every
6 months thereafter
Gastric MZL
• Sequential evaluation of gastric biopsies is essential for gastric MZL
• The Groupe d’Etude des Lymphomes de l’Adulte (GELA) scoring system, as
shown in the table on the next page, is recommended for the comparison of
post-treatment biopsies with previous biopsies to assess response
156
GELA GRADING SYSTEM PROPOSED TO DEFINE THE HISTOLOGICAL RESPONSE OF
GASTRIC MZL AFTER HELICOBACTER PYLORI ERADICATION
RESPONSE (SCORE) DESCRIPTION HISTOLOGICAL

CHARACTERISTICS
CR Complete (histological) remission Normal or empty lamina propria
and/or fibrosis with absent or
scattered plasma cells and small
lymphoid cells in the lamina
propria, no LELs
pMRD Probable minimal residual Empty lamina propria and/or
disease fibrosis with aggregates of
lymphoid cells or lymphoid
nodules in the lamina propria/
muscularis mucosa and/or
submucosa, no LELs
rRD Responding residual disease Focal empty lamina propria
and/or fibrosis with dense,
diffuse or nodular lymphoid
infiltrate, extending around
glands in the lamina propria,
focal LELs or absent
NC No change Dense, diffuse or nodular
lymphoid infiltrate, LEL usually
present
GELA, Groupe d’Etude des Lymphomes de l’Adulte; LEL, lymphoepithelial lesion; MZL, marginal zone lymphoma
Kalpadakis C et al. Best Pract Res Clin Haematol 2018;31:65-72. Reprinted with permission from Elsevier.
• After documented H. pylori eradication, endoscopic follow-up is recommended

2-3 months after treatment to rule out tumour progression and then twice per
year for 2 years to monitor histological lymphoma regression
• For persistent but stable residual disease or histological relapse, a
watch-and-wait policy appears to be safe
• However, long-term endoscopic and systemic follow-up, with a clinical
examination and blood counts every 12-18 months, is recommended
157
SMZL
• Specific criteria for response assessment of SMZL are shown in the table below
• In particular, achievement of a complete response (CR) is defined by normal
spleen size, normal blood counts, negative flow cytometry on blood and negative
IHC on BM biopsy
RESPONSE CRITERIA FOR SMZL
Resolution of organomegaly (spleen longitudinal

diameter < 13 cm)
Hb > 12 g/dL, platelets > 100 × 109/L and
neutrophils > 1.5 × 109/L
Complete response
No evidence of circulating clonal B cells by flow
cytometry (light chain-restricted B cells)
No evidence of BM infiltration detected by IHC
Negative DAT and PET (if positive at diagnosis)
Regression ≥ 50% in all the measurable disease

manifestations
No new sites of disease
Partial response
Improvement of cytopaenias
Decrease of infiltration and improvement of
haematopoietic reserve at BM biopsy
< 10% improvement in disease manifestations

No change
Colonoscopy and EGD
> 50% measurable signs of the disease

Progression
from nadir
Reappearance of any measurable sign

Relapse
of the disease
BM, bone marrow; DAT, direct antiglobulin test; EGD, oesophagogastroduodenoscopy; Hb, haemoglobin;
IHC, immunohistochemistry; PET, positron emission tomography; SMZL, splenic marginal zone lymphoma
158
• Risk stratification using prognostic indices for EMZL and SMZL may help in
discussing treatment options with patients but are not valid tools for deciding
whether and which treatment is indicated
• In gastric MZL:
The absence of H. pylori, the deep invasion of the gastric wall, the involvement
of regional lymph nodes and the presence of certain genetic features may be
associated with a reduced probability of lymphoma regression after antibiotics
t(11;18) may help to identify patients less likely to respond to alkylating agents
• In SMLZ, Ig mutational status, NOTCH2 and KLF2 mutations, TP53 abnormalities
and aberrant promotor methylation are potentially useful biomarkers, which may
be integrated into clinical indices for better risk stratification
159
Diagnosis of MZLs should follow the current 2017 WHO classification and requires
an adequate tumour biopsy
Differential diagnosis from MZL mimics depends mainly on IHC
Diagnostic and follow-up biopsies should be reviewed and confirmed by an expert
haematopathologist
CBL-MZ
• CBL-MZ is defined by the presence of circulating clonal B cells with phenotypic
features consistent with a marginal zone origin in the absence of splenomegaly,
hepatomegaly, lymphadenopathy or other symptoms and signs suggestive of an
established lymphoma
EMZL
• LELs are neither essential nor specific for EMZL diagnosis
• In gastric MZL, if active H. pylori infection is not demonstrated by (immuno)
histochemistry, it must be ruled out by serology, urea breath test and/or stool
antigen test
• FISH for t(11;18)(p21;p21) may be useful for identifying gastric MZL unlikely to
respond to antibiotic therapy
SMZL
• A combination of PB/BM aspirate and flow morphology, BM biopsy histology and
IHC are generally sufficient to establish SMZL
NMZL
• MYD88 mutations are rarely harboured by NMZL and may be used to distinguish
it from LPL
Initial work-up
• Mandatory initial staging for all MZL subtypes should include: History and
physical examination, full blood and differential counts (with PB flow cytometry
being mandatory for NMZL and SMZL and optional for EMZL), biochemistry,
protein electrophoresis, LDH and B2M, serum and urine immunofixation and
serology for HCV, HBV and HIV
160
• BM aspirate, with morphology and flow cytometry, are mandatory for NMZL and
SMZL and highly recommended for EMZL
• Imaging should include chest and abdominal CT scan or MRI and investigation of
the orbits and salivary glands, with PET scans being useful in selected cases
EMZL
• In gastric MZL, the Lugano and Paris staging systems may be used
• EGD is mandatory for gastric MZL and may also be advisable for some patients
with non-GI MZL
SMZL
• SMZL is usually staged by CT, with abdominal sonography for the detection of
splenic focal lesions, and consideration of PET–CT for suspected high-grade
transformation
NMZL
• Staging should rule out primary EMZL
Main prognostic factors and prognostic indices
EMZL
• The MALT-IPI index should be used to estimate clinical behaviour
SMZL
• The IIL and HPLL prognostic models should be used to estimate clinical behaviour
NMZL
• There is no specific prognostic score for NMZL, but the FLIPI may help to
discriminate between low- and high-risk patients
TREATMENT
EMZL
Initial therapy with antibiotics in gastric MZL
• H. pylori eradication therapy should be given to all patients with gastric MZL
• PPI for 4 weeks plus clarithromycin plus either amoxicillin or metronidazole for
10-14 days, are usually effective, with success being checked by urea breath test
at least 6 weeks after therapy initiation and at least 2 weeks after PPI withdrawal
• Where H. pylori eradication is unsuccessful, alternative triple- and quadruple-
therapy PPI-containing antibiotic regimens should be attempted
• In H. pylori-negative disease, specific anti-lymphoma treatments may be
considered for initiation either immediately or following failure of H. pylori
eradication therapy
161
Anti-infective therapy in non-gastric EMZL
• Antibiotic therapy may be considered as initial therapy for ocular EMZL, where
sight preservation is not urgently required
• Anti-HCV drugs may be considered for HCV-associated EMZL
RT in localised EMZL: Recommended doses and schedules at different sites
• Moderate-dose ISRT is the preferred approach for localised disease not
responding to antibiotics
• Low-dose RT may avoid the risk of side effects in indolent lymphomas and may
also be useful for the elderly and as palliation for patients with advanced-stage
EMZL unfit for systemic therapy
Other treatments for EMZL
• Other treatments including ChT, immunotherapy or combination
immunochemotherapy are indicated in patients with symptomatic disseminated
disease, contraindications to RT, failure after antibiotics or after local therapy or
clinical suspicion of histological transformation, including R monotherapy,
R/chlorambucil, R/bendamustine and R/lenalidomide
• Patients should be offered enrolment in clinical trials, where available
• R-CHOP should be reserved for patients with a very aggressive clinical course
and clinically suspected or biopsy-proven histological transformation
SMZL
• In asymptomatic patients, a watch-and-wait policy is recommended, with
follow-up every 3-6 months
• R alone (375 mg/m2, 4-8 weekly doses) is the preferred initial therapy
• R plus ChT may be considered for patients failing to respond to R alone
• Anti-HCV therapy should be considered for patients with HCV-associated SMZL
• Splenectomy can be considered in selective cases where R is not indicated or is
ineffective
162
NMZL
• Treatment should follow the principles of therapy for follicular lymphoma
• A watch-and-wait policy may be followed in patients with a low tumour burden
and a lack of clinical symptoms
• R combined with ChT (bendamustine, CHOP or CVP) is recommended
• Anti-HCV therapy should be considered in patients with HCV-associated NMZL
MZL patients with recurrent disease
• A watch-and-wait policy may be considered for asymptomatic patients and RT
used for MZL patients with localised relapses
• Where systemic treatment is required, options include: Immunochemotherapy
(repetition or an alternative regimen), autologous transplantation or a targeted
agent, such as ibrutinib or copanlisib
General considerations
• Asymptomatic patients with SMZL and NMZL being managed by a
watch-and-wait policy should be monitored by physical examination, imaging
as clinically required, blood counts and biochemistry every 6 months
• FDG–PET investigation can be considered for suspected histological
transformation
• Patients completing treatment for EMZL at non-gastric sites can be re-evaluated
with clinical examination, laboratory work-up and imaging/biopsy of residual
lesions if indicated, every 3 months for the first 2 years and every 6 months
thereafter
Gastric MZL
• Sequential evaluation of gastric biopsies is essential for gastric MZL
• After documented H. pylori eradication, endoscopic follow-up is recommended
2-3 months after treatment and then twice per year for 2 years
• Long-term endoscopic and systemic follow-up, with a clinical examination and
blood counts every 12-18 months, is recommended
SMZL
• Specific criteria for response assessment of SMZL should be observed
• Achievement of CR is defined by normal spleen size, normal blood counts,
negative flow cytometry on blood and negative IHC on BM biopsy
163
In gastric MZL, the absence of H. pylori, the deep invasion of the gastric wall, the
involvement of regional lymph nodes and the presence of certain genetic features
may be associated with a reduced probability of lymphoma regression after
antibiotics; t(11;18) may help to identify patients less likely to respond to alkylating
agents
In SMLZ, Ig mutational status, NOTCH2 and KLF2 mutations, TP53 abnormalities
and aberrant promotor methylation are potentially useful as biomarkers to improve
risk stratification
164
NEWLY DIAGNOSED AND RELAPSED
FOLLICULAR LYMPHOMA
• Diagnosis of follicular lymphoma (FL) should be based on a surgical specimen/
excisional lymph node (LN) biopsy
• Core biopsies should only be carried out in patients without easily accessible LNs
to evaluate possible transformation at such sites
Rebiopsy may be required if the material is not adequate
• Fine-needle aspirations are insufficient for a reliable diagnosis
• Diagnosis should be made according to the World Health Organization (WHO)
classification
• Histological grading is carried out according to the average number of
centroblasts/high-power field, as shown in the table below
GRADING OF FL
GRADE DESCRIPTION
1 ≤ 5 blasts/HPF
2 6-15 blasts/HPF
3A > 15 blasts/HPF, centroblasts with intermingled centrocytes
3B > 15 blasts/HPF, pure sheets of blasts
FL, follicular lymphoma; HPF, high-power field

Swerdlow SH et al (eds). WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. (revised). Lyon, France:
IARC; 2017. Reprinted with permission.
• Pathological review by an expert haematopathologist, especially for grade 3A or

3B, is advised
• FL grade 3B should be treated as an aggressive lymphoma, whereas grades
1, 2 and 3A should be treated as indolent disease
• Treatment depends largely on staging, which should be carried out according to
the Ann Arbor classification system, as shown in the table on the next page
Bulky disease (> 6 cm) should be mentioned when applicable
165
ANN ARBOR CLASSIFICATION
STAGE AREA OF INVOLVEMENT
I (IE) One LN region or extralymphatic site (IE)
Two or more LN regions or at least one LN region plus a localised extralymphatic site
II (IE)
(IIE) on the same side of the diaphragm
LN regions or lymphoid structures (e.g. thymus, Waldeyer’s ring) on both sides of the
III (IIIE, IIIS)
diaphragm with optional localised extranodal site (IIIE) or spleen (IIIS)
IV Diffuse or disseminated extralymphatic organ involvement

Ann Arbor staging further classifies patients with lymphoma into A or B categories:
A: Without symptoms
B: With symptoms including unexplained fever of > 38°C, drenching night sweats or loss of > 10% body weight within 6 months
E, extranodal; LN, lymph node; S, spleen
Swerdlow SH et al (eds). WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. (revised). Lyon, France:
IARC; 2017. Reprinted with permission.
• Initial work-up should include a bone marrow (BM) aspirate and biopsy of
sufficient size (≥ 20 mm) and a computed tomography (CT) scan of the neck,
thorax and abdomen, as shown in the table below
DIAGNOSTIC WORK-UP
History B symptoms (see ANN ARBOR CLASSIFICATION table)
Physical
Peripheral LNs, liver, spleen
examination
Blood and differential count
Optional: Immunophenotyping of peripheral blood
Laboratory Coombs test (DAT)
work-up LDH, uric acid
Electrophoresis (optional: Immune fixation)
B2M (FLIPI 2 and PRIMA PI)
Serology HBV, HCV and HIV
CT neck, chest, abdomen
Optional: PET-CT*
Imaging
Optional: Abdominal US
Histology
Bone marrow† Cytology
Optional: Immunophenotyping
Creatinine clearance
Toxicity Electrocardiogram, cardiac US (before anthracyclines), pulmonary function (ASCT)
Reproductive counselling in young patients
166
*To confirm localised disease or in case of suspected transformation
†
In advanced stages: If clinically indicated (necessary for prognostic index classification)
ASCT, autologous stem cell transplantation; B2M, β2-microglobulin; CT, computed tomography; DAT, direct antiglobulin test or
direct Coombs test; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HBV, hepatitis B virus; HCV, hepatitis C virus;
HIV, human immunodeficiency virus; LDH, lactate dehydrogenase; LN, lymph node; PET, positron emission tomography; PRIMA PI,
PRIMA prognostic index; US, ultrasound
• A positron emission tomography (PET)-CT scan is recommended for routine

staging and is mandatory to confirm localised stage I/II disease before involved-
site radiotherapy (ISRT)
• A complete blood count (CBC), routine blood chemistry, including
immunoglobulin (Ig) levels, lactate dehydrogenase (LDH), β2-microglobulin (B2M)
and uric acid as well as screening tests for human immunodeficiency virus (HIV),
hepatitis B virus (HBV) and hepatitis C virus (HCV) are required
• The Follicular Lymphoma International Prognostic Index (FLIPI) 2, which is a
revision of the FLIPI 1 incorporating B2M, diameter of largest LN, BM involvement
and haemoglobin level, along with a simplified PRIMA prognostic index (PRIMA-
PI), can be used for prognostic purposes, as shown in the table below
FLIPI AND PRIMA-PI RISK FACTORS
DEFINITION OF RISK FACTORS

PARAMETER
FLIPI 1 FLIPI 2 PRIMA-PI
Long diameter or largest
Nodal sites > 4 LN regions –
LN > 6 cm
Age > 60 years > 60 years –
Serum marker Elevated LDH Elevated B2M Elevated B2M
Advanced stage III-IV

Stage BM involvement BM involvement
(Ann Arbor classification)
Haemoglobin < 12 g/dL < 12 g/dL –
FLIPI:
• Low risk: 0-1 risk factor
• Intermediate risk: 2 risk factors
• High risk: 3-5 risk factors
PRIMA-PI:
• Low risk: B2M normal and BM not involved
• Intermediate risk: B2M normal and BM involved
• High risk: B2M elevated
B2M, β2-microglobulin; BM, bone marrow; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase;
LN, lymph node; PRIMA-PI, PRIMA prognostic index
167
• Biology-based prognostic indicators, including gene mutation status and
gene expression panels, have been devised but are not yet suitable for clinical
decision-making
If possible, additional biopsy material should be stored to enable future
molecular analyses
TREATMENT OF LOCALISED FL (STAGES I-II)
• In localised stages, 24-30-Gy ISRT is the preferred approach with curative intent
The 2 × 2 Gy schedule is less durably effective but might be used in special
situations to minimise side effects (e.g. lacrimal gland, parotid glands)
• A combination of localised irradiation with single-agent rituximab may potentially
provide the best balance between efficacy and side effects
• In selected cases (e.g. limited life expectancy, large abdominal fields),
watch-and-wait or rituximab monotherapy may be considered
• In patients with stage I-II disease and a high tumour burden or adverse clinical
prognostic features, or in cases where ISRT is not feasible, systemic therapy, as
indicated for advanced disease stages, should be applied
TREATMENT OF ADVANCED FL (STAGES III-IV)
Induction
• In the majority of patients with advanced stage III and IV disease, no curative
therapy is yet established
• Early initiation of rituximab in asymptomatic patients did not prolong survival and
the benefit of rituximab maintenance in this setting appears doubtful
• Therapy should be initiated only upon the development of symptoms, including
B symptoms (unexplained fever > 38°C, drenching night sweats or loss of > 10%
body weight within 6 months), haematopoietic impairment, bulky disease, vital
organ compression, ascites, pleural effusion or rapid lymphoma progression, as
shown in the table on the next page
• The currently recommended therapeutic approach is based on clinical risk factors,
symptoms and patient perspective, as shown in the figure on the next page
• The addition of rituximab to chemotherapy (ChT) improves response rate,
progression-free survival (PFS) and overall survival (OS), as shown in the table
on pages 170-171
168
HIGH TUMOUR BURDEN CRITERIA IN FL (MODIFIED FROM GROUPE D’ETUDE DES
LYPHOMES FOLLICULAIRES AND BRITISH NATIONAL LYMPHOMA INVESTIGATION)
PARAMETER HIGH TUMOUR BURDEN CRITERIA

LNs Bulk (> 7 cm) or 3 LNs in distinct areas > 3 cm
Spleen Symptomatic splenic enlargement
(Potential) complication Organ compression by tumour, pleural or peritoneal effusion
Serum markers Elevated LDH or elevated B2M
Leukaemic phase (> 5 × 109/L)

Blood count
Cytopaenia (neutrophils < 1 × 109/L, platelets < 100 × 109/L)
Clinical presentation B symptoms (see ANN ARBOR CLASSIFICATION table)
B2M, β2-microglobulin; FL, follicular lymphoma; LDH, lactate dehydrogenase; LN, lymph node
THERAPEUTIC TREATMENT ALGORITHM FOR FL
Evaluate
Prognosis Symptoms Patient priority

Stage* No symptoms Long remission
FLIPI 1-2 Mild symptoms Better quality of life
Grade Life-/organ-threatening
Choose among
Mild symptoms: High tumour burden:

Asymptomatic cases:
Non-ChT treatment ImmunoChT
Watch-and-wait
Rituximab (G/R-B,G/R-CHOP, G/R-CVP)
Consider:
Antibody maintenance (or radioimmunotherapy)
In selected cases:
*According to the Ann Arbor classification system Rituximab-lenalidomide**
**Off-label
B, bendamustine; CHOP, cyclophosphamide/doxorubicin/vincristine/
prednisolone; ChT, chemotherapy; CVP, cyclophosphamide/vincristine/
prednisolone; FL, follicular lymphoma; FLIPI 1-2, Follicular Lymphoma
International Prognostic Index 1-2; G, obinutuzumab; R, rituximab
169
170
COMBINED IMMUNOCHEMOTHERAPY IN FL (FIRST-LINE)
TOTAL MEDIAN OVERALL

TIME TO TREATMENT OVERALL
STUDY NUMBER OF FOLLOW-UP RESPONSE
FAILURE (MONTHS) SURVIVAL (%)
PATIENTS (MONTHS) (%)
Marcus et al. J Clin Oncol 2008

R-CVP 159 53 81 (P < 0.0001) 27 (P < 0.0001) 83 (4 years)
(P = 0.029)
Hiddemann et al. Blood 2005

R-CHOP 223 58 96 NR (P < 0.001) 90 (2 years)
(P = 0.0493)
Herold et al. J Clin Oncol 2007

R-MCP 105 48 92 (P = 0.0009) NR (P < 0.0001) 87 (4 years)
(P = 0.0096)
Bachy et al. Haematologica 2013

R-CHVP-IFN 175 99 81 (P = 0.035) 66 (P < 0.0004) 79 (8 years)
(P = 0.076)
Rummel et al. Blood 2017, Lancet 2013
BR 139 34 93 78 (median) NR (median)
BR + R maintenance 595 34 90 NR (median) NR (median)
Luminari et al. J Clin Oncol 2018

R-CVP 178 84 88 38% 85%
R-CHOP 178 84 93 45% (P = 0.033) 83% (NS)
R-FM + R maintenance 178 84 91 49% (P = 0.016) (8 years) 79% (NS) (8 years)
Bachy et al. J Clin Oncol 2019

R-CHOP/CVP/FM 1018 118 NA 35% (10 years) 80 (10 years)
R-CHOP/CVP/FM + R maintenance 51% (10 years) 80 (10 years)
(P < 0.001) (NS)
Marcus et al. N Engl J Med 2017

R-CHOP/CVP/B + R maintenance 601 34 86.9 73.3% (3 years) 92.1 (3 years)
G-CHOP/CVP/B + G maintenance 601 34 88.5 80.0% (3 years) 94.0 (3 years)
(P = 0.001) (NS)
Morschhauser et al. N Engl J Med 2018

R-CHOP/BR + R maintenance 517 38 84 78% (3 years) 94 (3 years)
R-lenalidomide + R maintenance 513 38 89 77% (3 years) 94 (3 years)
(NS) (NS)
P values correspond to significance levels compared with ChT only
B, bendamustine; BR, bendamustine/rituximab; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ChT, chemotherapy; CHVP, cyclophosphamide/doxorubicin/etoposide/prednisone;

CVP, cyclophosphamide/vincristine/prednisolone; FL, follicular lymphoma; FM, fludarabine/mitoxantrone; G, obinutuzumab; IFN, interferon; MCP, mitoxantrone/chlorambucil/prednisone;
NA, not applicable; NR, not reached; NS, not significant; R, rituximab; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone
171
• If complete remission and long PFS are the therapeutic goals, rituximab in
combination with ChT such as cyclophosphamide/doxorubicin/vincristine/
prednisolone (CHOP) or bendamustine should be used
• Cyclophosphamide/vincristine/prednisolone (CVP) is inferior to these two
regimens in terms of PFS but similar in OS
• If there is evidence of more aggressive lymphoma (histological grade 3B
or clinical signs of transformation), an anthracycline-based regimen
[rituximab/CHOP (R-CHOP)] should be applied
• Extended anti-infectious prophylaxis should be considered, especially after
bendamustine-containing induction therapy
• Awareness of a potential adverse impact on future cellular immunotherapeutic
options, such as chimeric antigen receptor T (CAR-T)-cell treatment, is important
• The anti-cluster of differentiation (CD)20 antibody obinutuzumab (in combination
with ChT, and maintenance for 2 years) is an additional option that is potentially
more efficacious than rituximab
• Lenalidomide/rituximab appears to have similar efficacy to immunochemotherapy
and a longer PFS than rituximab monotherapy
• Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil
plus rituximab remain alternatives for patients with a low-risk profile or when
conventional ChT is contraindicated
• In patients with positive HBV serology, prophylactic antiviral medication up to 2
years beyond the last rituximab exposure is strongly recommended
• Strict monitoring of HBV, DNA and liver enzymes represents another option in
regions where HBV infection is endemic
Consolidation/maintenance
• Rituximab maintenance every 2 months for 2 years is recommended after
immunochemotherapy
• Radioimmunotherapy consolidation is inferior to rituximab maintenance and may
increase the cumulative risk of myeloid malignancies
• Myeloablative consolidation followed by autologous stem cell transplantation
(ASCT) has no OS advantage over rituximab-containing induction therapy and is
not recommended as first-line therapy in responding patients
Relapsed disease
• At suspected disease relapse or progression, a new confirmatory biopsy to
exclude transformation to an aggressive lymphoma is strongly recommended
PET-guided biopsy of the site with highest tracer intensity uptake (maximum
standardised uptake value) may be useful
172
• Observation is an accepted approach in asymptomatic patients with low tumour
burden and confirmed follicular histology at relapse or progression
Induction
• Salvage treatment regimen depends on efficacy and duration of response of prior
regimens and stage at relapse
• Localised symptomatic disease may be managed with low-dose ISRT (2 × 2 Gy)
• In early systemic relapses (< 12-24 months), a non-cross-resistant regimen is
preferred (e.g. bendamustine after CHOP or vice versa)
Other options, including fludarabine-based, platinum-based or alkylating
agent-based regimens, could also be useful
• Rituximab should be added if the previous antibody-containing scheme achieved
a > 6-12-month duration of remission
• In rituximab-refractory cases or remissions lasting < 6 months,
obinutuzumab/bendamustine (plus obinutuzumab maintenance) improves
PFS and OS compared with bendamustine alone
• In symptomatic cases with low tumour burden, rituximab monotherapy may be
used
• In relapsed FL, lenalidomide/rituximab may be considered, especially for patients
with a short remission after ChT
• Radioimmunotherapy (yttrium-90 ibritumomabtiuxetan) may be an effective
approach in elderly patients with comorbidities not appropriate for ChT
• In later relapses, monotherapy is an established option with palliative intent
• The phosphoinositide 3-kinase (PI3K) inhibitor idelalisib has been registered
in double-refractory FL, but is associated with infections, late-onset colitis and
pulmonary toxicity, so anti-infectious prophylaxis (cotrimoxazole/acyclovir) and
cytomegalovirus (CMV) monitoring are strongly recommended
Other PI3K inhibitors display a more favourable toxicity profile
• Rituximab maintenance every 3 months for up to 2 years has a favourable
side-effect profile and substantially prolongs PFS and OS in relapsed disease
• Second-line maintenance treatment should not be routinely used for patients who
have relapsed during their first maintenance period, but is reasonable for other
patient subsets
• High-dose ChT with ASCT should be considered, especially in patients who
experience brief first remissions (< 2-3 years) after rituximab-containing
regimens
173
Subsequent rituximab maintenance achieves some improvement in PFS
• In selected younger patients with later relapses and a high-risk profile or relapse
after ASCT, a potentially curative allogeneic stem cell transplantation (alloSCT)
(preferably with dose-reduced conditioning) may be considered, especially in
patients with early relapse and refractory disease
AlloSCT in first relapse may worsen OS
Innovative approaches
• The benefit of new approaches, including inhibitors of the B-cell signalling
pathway and other targeted agents, has yet to be confirmed in randomised
phase III studies
• Bortezomib/rituximab has shown only a minor benefit compared with antibody
monotherapy and is not recommended
• Treatment with CD19-specific CAR-T is reserved for transformed FL due to
toxicities (registered indication); its use in indolent lymphoma is limited to clinical
trials for refractory disease or relapsing patients with poor prognostic features
• Consensus-driven recommended treatment strategies outside of clinical studies
for low tumour burden and high tumour burden FL are shown in the figures on
the following pages
174
CONSENSUS-DRIVEN RECOMMENDATIONS – LOW TUMOUR BURDEN FL
Low tumour burden
Stage I/II Stage III/IV
ISRT 24-30 Gy
Watch-and-wait
+/- rituximab
In selected cases: In selected cases:
Rituximab monotherapy
Watch-and-wait
Rituximab monotherapy
INRT 2 x 2 Gy
Relapse/progression
Watch-and-wait Watch-and-wait
Rituximab monotherapy Rituximab monotherapy
INRT 2 x 2 Gy ImmunoChT
Radioimmunotherapy
ChT, chemotherapy; FL, follicular lymphoma; INRT, involved-node radiotherapy; ISRT, involved-site radiotherapy
175
CONSENSUS-DRIVEN RECOMMENDATIONS – HIGH TUMOUR BURDEN FL
High tumour burden – Stage III/IV
< 65 years* > 65 years*
ImmunoChT (G/R-B, G/R-CHOP, G/R-CVP) ImmunoChT (G/R-B,G/R-CHOP, G/R-CVP

CR/PR: Discuss antibody maintenance CR/PR: Discuss antibody maintenance
Rituximab-lenalidomide** Rituximab-lenalidomide**
First relapse/progression
ImmunoChT*** ImmunoChT***
CR/PR: Discuss antibody maintenance CR/PR: Discuss antibody maintenance
ASCT (early relapses, transformation) Radioimmunotherapy
Rituximab-lenalidomide** (early relapses) Rituximab-lenalidomide** (early relapses)
Later relapse/progression
ImmunoChT*** (long prior remissions)

Rituximab monotherapy ImmunoChT*** (long prior remissions)
Rituximab-lenalidomide** Rituximab monotherapy
Rituximab-lenalidomide**
In selected cases:
ASCT (early relapses, transformation) In selected cases:
Radioimmunotherapy Radioimmunotherapy
Idelalisib (double refractory) Idelalisib (double refractory)
alloSCT
*Biological age (years)

**Off-label
***Preferred in rituximab-refractory cases
alloSCT, allogeneic stem cell transplantation; ASCT, autologous stem cell transplantation; B, bendamustine;
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ChT, chemotherapy; CR, complete response;
CVP, cyclophosphamide/vincristine/prednisolone; FL, follicular lymphoma; G, obinutuzumab; PR, partial response;
R, rituximab
176
Response evaluation
• Appropriate structural imaging evaluation should be carried out mid-treatment
and after completion of ChT
• Patients with an inadequate response [less than partial response (PR)] should be
evaluated for early salvage regimens
• Patients with a PR may convert to complete response under rituximab
maintenance
• PET-CT after completion of induction ChT has been recommended for prognostic
reasons, but therapeutic consequences remain undefined
• There is no established role for interim PET-CT scan
• Minimal residual disease (MRD) analysis by PCR at the end of treatment and
during follow-up is an independent predictor of long-term outcome but should
not guide therapeutic strategies outside of clinical studies
• Data are limited regarding the use of circulating tumour DNA in FL
• The selection of optimal treatment is based mainly on clinical risk factors,
symptoms and individual patient priorities
• PET- and MRD-based tailored treatments are currently being evaluated in ongoing
studies but are not yet routine clinical practice
• Paediatric FL also occurs rarely in adults
Characterised by typically localised disease, the absence of B-cell lymphoma 2
aberrations, lack of t(14;18), grade III histology and a high proliferation, it
shows a much more indolent disease course and can be managed with local
therapy only
• Duodenal-type FL should also be followed with observation only as long as it is
asymptomatic
• The recommended follow-up after completion of therapy are shown in the table
on the following page
177
RECOMMENDED FOLLOW-UP AFTER END OF THERAPY
EXAMINATION DETAILS YEAR 1-2 YEAR 3-5 YEAR > 5
B symptoms (see ANN

Every 3-6 Every 6-12
History ARBOR CLASSIFICATION Annually
months months
table)
Particular:
Physical Every 3-6 Every 6-12
Peripheral LNs, liver, Annually
examination months months
spleen
Blood and differential Every 3-6 Every 6-12

Annually
Laboratory count months months
work-up Every 3-6 Every 6-12 If progression
LDH, IgG levels
months months suspected
Every 12 If progression
Abdominal US Every 6 months
months suspected
Imaging (optional)
Every 6-12 Every 12-24 If progression
CT neck, chest, abdomen
months months suspected
CT, computed tomography; Ig, immunoglobulin; LDH, lactate dehydrogenase; LN, lymph node; US, ultrasound
• The following minimal recommendations are based on consensus rather than

evidence:
After local radiotherapy: History and physical examination every 6 months for
2 years, subsequently once a year if clinically indicated
Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and
5 years
After (during continuous) systemic treatment: History and physical examination
every 3-6 months for 2 years and every 6-12 months subsequently
Blood count and routine chemistry including IgG levels every 6 months for
2 years, then only as needed for evaluation of suspicious symptoms
Minimal adequate radiological or other examinations every 6 months for
2 years and annually (optional) up to 5 years
– CT scans are not mandatory outside of clinical trials, and PET-CT should not
be used for surveillance
178
Adequate prophylaxis (antibiotics and/or IgG supplementation) in patients
with symptomatic recurrent infections and based on prior treatment (e.g. with
fludarabine or bendamustine)
• MRD screening may be carried out in clinical studies but should not guide
therapeutic strategies in clinical practice
• Yearly seasonal flu vaccination may be considered
179
Diagnosis should be based on a surgical specimen/excisional LN biopsy
Core biopsies should only be carried out in patients without easily accessible LNs
Diagnosis should be made according to the WHO classification
Pathological review by an expert haematopathologist, especially for grade 3A or 3B,
is advised
FL grade 3B should be treated as an aggressive lymphoma, whereas grades
1, 2 and 3A should be treated as indolent disease
Staging should be carried out according to the Ann Arbor classification
Initial work-up should include a BM aspirate and biopsy of sufficient size (≥ 20
mm) and a CT scan of the neck, thorax and abdomen
A PET-CT scan is recommended for routine staging and is mandatory to confirm
localised stage I/II disease before ISRT
A CBC, routine blood chemistry, including Ig levels, LDH, B2M and uric acid, plus
screening for HIV, HBV and HCV are required
The FLIPI 1/2 and simplified PRIMA-PI can be used for prognostic purposes
TREATMENT OF LOCALISED FL (STAGES I-II)
In localised stages, 24-30-Gy ISRT is the preferred approach, although the 2 × 2 Gy
schedule might be used in special situations to minimise side effects
A combination of localised irradiation with single-agent rituximab may potentially
provide the best balance between efficacy and side effects
In selected cases, watch-and-wait or rituximab monotherapy may be considered
In patients with stage I-II disease and a high tumour burden or adverse clinical
prognostic features, or in cases where ISRT is not feasible, systemic therapy, as
indicated for advanced disease stages, should be applied
TREATMENT OF ADVANCED FL (STAGES III-IV)
Induction
• In asymptomatic patients, watch-and-wait is the standard approach
180
• Therapy should be initiated only upon the development of symptoms, including
B symptoms, haematopoietic impairment, bulky disease, vital organ
compression, ascites, pleural effusion or rapid lymphoma progression
• If complete remission and long PFS are the therapeutic goals, rituximab in
combination with ChT such as CHOP or bendamustine should be used
• If there is evidence of more aggressive lymphoma (histological grade 3B or
clinical signs of transformation), an anthracycline-based regimen (R-CHOP)
should be applied
• Extended anti-infectious prophylaxis should be considered, especially after
bendamustine-containing induction therapy
• Obinutuzumab (immunochemotherapy and maintenance for 2 years) is an
additional option
• Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil
plus rituximab remain alternatives for patients with a low-risk profile or when
conventional ChT is contraindicated
• In patients with positive HBV serology, prophylactic antiviral medication up to
2 years beyond the last rituximab exposure is strongly recommended
• Rituximab maintenance every 2 months for 2 years is recommended after
immunochemotherapy
Relapsed disease
• At suspected disease relapse or progression, a new confirmatory biopsy is
strongly recommended
• Observation is an accepted approach in asymptomatic patients with low tumour
burden and confirmed follicular histology at relapse or progression
Induction
• Localised symptomatic disease may be managed with low-dose ISRT (2 × 2 Gy)
• In early systemic relapses (< 12-24 months), a non-cross-resistant regimen is
preferred, with other options including fludarabine-based, platinum-based or
alkylating agent-based regimens
• Rituximab should be added if the previous antibody-containing scheme achieved
a > 6-12-month duration of remission
• In rituximab-refractory cases or remissions lasting < 6 months,
obinutuzumab/bendamustine (plus obinutuzumab maintenance) is recommended
• In symptomatic cases with low tumour burden, rituximab monotherapy may be
used
181
• In relapsed FL, lenalidomide/rituximab may be considered
• Radioimmunotherapy may be an effective approach in elderly patients with
comorbidities not appropriate for ChT
• In later relapses, monotherapy is an established option with palliative intent
• Idelalisib can be used in double-refractory cases only with anti-infectious
prophylaxis (cotrimoxazole/acyclovir) and CMV monitoring
• Rituximab maintenance every 3 months for up to 2 years has a favourable
side-effect profile and substantially prolongs PFS and OS in relapsed disease
• Second-line maintenance treatment is reasonable except in patients who have
relapsed during their first maintenance period
• High-dose ChT with ASCT should be considered, especially in patients who
experience brief first remissions (< 2-3 years) after rituximab-containing
regimens
• Subsequent rituximab maintenance achieves some improvement in PFS
• In selected younger patients with later relapses and a high-risk profile or relapse
after ASCT, alloSCT may be considered
Innovative approaches
• The benefit of new approaches, including inhibitors of the B-cell signalling
pathway and other targeted agents, has yet to be confirmed in randomised
phase III studies
Response evaluation
• Appropriate structural imaging evaluation should be carried out mid-treatment
and after completion of ChT
• Patients with less than PR should be evaluated for early salvage regimens
• Patients with a PR may convert to CR under rituximab maintenance
• PET-CT after completion of induction ChT has been recommended for prognostic
reasons
• MRD analysis at the end of treatment and during follow-up is an independent
predictor of long-term outcome
182
The selection of optimal treatment is based mainly on clinical risk factors,
symptoms and individual patient priorities
Paediatric FL, which also occurs rarely in adults, can be managed with local therapy
only
Duodenal-type FL should be followed with observation only as long as it is
asymptomatic
The following minimum recommendations are based on consensus rather than
evidence:
• After local RT: History and physical examination every 6 months for 2 years,
subsequently once a year if clinically indicated
• Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and
5 years
• After (during continuous) systemic treatment: History and physical examination
every 3-6 months for 2 years and every 6-12 months subsequently
• Blood count and routine chemistry including IgG levels every 6 months for
2 years, then only as needed for evaluation of suspicious symptoms
• Minimal adequate radiological or other examinations every 6 months for 2 years
and annually (optional) up to 5 years
• Adequate prophylaxis (antibiotics and/or IgG supplementation) in patients with
symptomatic recurrent infections and based on prior treatment
Yearly seasonal flu vaccination may be considered
183
• Diagnosis of chronic lymphocytic leukaemia (CLL) is by immunophenotyping of
peripheral blood and is established by:
≥ 5 × 109/L monoclonal B lymphocytes in the peripheral blood, the clonality
of which need to be confirmed by flow cytometry-demonstrated light chain
restriction
Characteristically small, mature-appearing lymphocytes in the blood smear,
which have a narrow border of cytoplasm and a dense nucleus lacking
discernible nucleoli and partially aggregated chromatin. Larger, atypical
lymphocytes or prolymphocytes must not exceed 55%
• CLL B cells co-express the surface antigens, cluster of differentiation (CD)19 and
CD20, together with CD5, CD23, CD43 and CD200
• CLL B-cell expression of surface CD20, surface immunoglobulin (Ig) and CD79b
is low compared with that found on normal B cells
• Each clone is restricted to expression of kappa or lambda Ig light chains or has
no apparent expression of either
• CLL should be differentiated from mantle cell lymphoma (MCL), leukaemic
marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma, which, in
most cases, do not express CD23
• In cases expressing CD23, RT-PCR for cyclin D1 overexpression, fluorescence
in situ hybridisation (FISH) for t(11;14) and CD200 expression are useful for
establishing a diagnosis of MCL
• An MZL diagnosis is supported by negative or low CD43 expression and high
expression of CD180
• If there are < 5 × 109/L peripheral blood B lymphocytes and lymphadenopathy
and/or splenomegaly, the diagnosis is small lymphocytic lymphoma (SLL)
• Lymph node (LN) and/or bone marrow (BM) biopsy may be helpful if
immunophenotyping is not conclusive for the diagnosis of CLL
• If there are < 5 × 109/L peripheral blood B lymphocytes in the absence of
lymphadenopathy, organomegaly, cytopaenia and clinical symptoms, the
diagnosis is monoclonal B lymphocytosis (MBL)
184
Early, asymptomatic stage
• Early, asymptomatic stage disease (according to the Rai or Binet staging
systems, as shown in the table below) requires no further risk assessment
STAGING SYSTEMS FOR CLL
STAGE DEFINITION
Binet system
Hb ≥ 100 g/L (6.21 mmol/L), platelets ≥ 100 × 109/L
Binet A
< 3 involved lymphoid sites*
Hb ≥ 100 g/L (6.21 mmol/L), platelets ≥ 100 × 109/L
Binet B
≥ 3 involved lymphoid sites*
Binet C Hb < 100 g/L (6.21 mmol/L), platelets < 100 × 109/L
Rai system
Low risk Rai 0 Lymphocytosis > 5 × 109/L
Rai I Lymphocytosis and lymphadenopathy

Intermediate risk Rai II Lymphocytosis and hepatomegaly and/or splenomegaly
with/without lymphadenopathy
Lymphocytosis and Hb < 110 g/L (6.83 mmol/L)

High risk Rai III
with/without lymphadenopathy/organomegaly
Lymphocytosis and platelets < 100 × 109/L with/without

Rai IV
lymphadenopathy/organomegaly
Originally described overall survival times were deleted, because they have changed during the past 30 years and do not reflect
the survival impact of novel treatments
*Binet’s system takes into account five potential sites of involvement: Cervical, axillary, inguinal lymphadenopathy (either uni- or
bilateral), spleen and liver. Involvement is judged only by physical exam and does not take into consideration the results of
imaging studies for staging purposes
CLL, chronic lymphocytic leukaemia; Hb, haemoglobin
Binet JL et al. Cancer 1981;48:198-206 and Rai KR et al. Blood 1975;46:219-34. Adapted with permission.
185
• Patients should be seen at 3-monthly intervals for the first year then every
3-12 months, depending on disease burden and dynamics
• Assessments should include a history and physical examination, including
palpation of LN areas, spleen and liver and complete blood count (CBC) and
differential count, as shown in the table below
DIAGNOSTIC AND STAGING WORK-UP
INITIAL PRE- STAGING AT

STAGING AT TREATMENT THE END OF FOLLOW-UP
DIAGNOSIS EVALUATION THERAPY
History, physical
examination and + + + +
performance status
CBC and differential + + + +
Serum chemistry
including serum
– + + +
immunoglobulin and
direct antiglobulin test
Cytogenetics (FISH)
and molecular
(+)* + – –
genetics for TP53
mutation or del(17p)
IGHV mutational status (+)* + – –
Marrow aspirate and

– +† +‡ –
biopsy
HBV, HCV, CMV and
– + –
HIV serology
Radiological imaging
– +§ +§
(CT scan)
*Only if patient requests the evaluation of his prognostic score
†
Only if clinically indicated
‡
Only for confirmation of CR within clinical studies
Only within clinical studies in patients with clinical symptoms and before any venetoclax treatment
§
CBC, complete blood count; CMV, cytomegalovirus; CR, complete remission; CT, computed tomography; FISH, fluorescence
in situ hybridisation; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IGHV, immunoglobulin
heavy chain variable; TP53, tumour protein P53
186
Advanced or symptomatic stage
• A number of examinations are recommended before treatment
History and physical examination, including palpation of LN areas, spleen and
liver
CBC and differential count
Serum chemistry, including lactate dehydrogenase (LDH), bilirubin, serum Igs,
direct antiglobulin test or direct Coombs test (DAT), haptoglobin and kidney
and liver function
The history and status of relevant infections [i.e. hepatitis B virus (HBV),
hepatitis C virus, cytomegalovirus, human immunodeficiency virus] should be
evaluated to prevent virus reactivation
FISH for chromosome 17 deletion [del(17p)] and, in the absence of del(17p),
tumour protein P53 (TP53) sequencing (at least exons 4-10 and exons 2-11
recommended), as shown in the table below. As genetic lesions may evolve
throughout the disease, the analysis should be carried out as close as possible
(e.g. < 6 months) to initiation of therapy
Molecular analysis for detecting immunoglobulin heavy chain variable (IGHV)
gene mutation status
Chest imaging: See section on imaging on the next page
PERSONALISED MEDICINE SYNOPSIS
BIOMARKER METHOD USE

Strongest prognostic and
TP53 mutation or del(17p) FISH and Sanger or NGS predictive relevance together
with del(17p)
Strong prognostic evidence;
IGHV Sanger or NGS predictive evidence for
immunochemotherapy
Possible prognostic and
CKT Chromosome handling predictive relevance but not yet
established prospectively
CKT, complex karyotype; FISH, fluorescence in situ hybridisation; IGHV, immunoglobulin heavy chain variable;
NGS, next-generation sequencing
• Additional examinations before treatment are desirable

BM examination for the diagnostic evaluation of unclear cytopaenia or in the
presence of a non-conclusive phenotype; BM biopsy can also be used as a
baseline parameter to assess treatment response
An extended FISH analysis (or array-based analysis) may allow the detection of
additional cytogenetic abnormalities [e.g. del(11q) or trisomy 12]
187
Hepatitis E virus testing should particularly be considered if the patient is
positive for HBV
Serum β2-microglobulin (B2M) is an important prognostic marker and a part
of the CLL International Prognostic Index (IPI)
Imaging
• Routine radiographic imaging is not generally recommended in asymptomatic
patients
• Computed tomography (CT) scan is recommended in symptomatic patients
Magnetic resonance imaging (MRI), chest radiography or abdominal ultrasound
(US) are alternatives where CT cannot be carried out
• CT scans of the neck, chest, abdomen and pelvis, or MRI, may be helpful to
assess tumour load and risk of tumour lysis syndrome (TLS)
CT scans may be useful for response assessment
• In elderly patients, US and radiographic chest imaging are alternatives to CT
Prognostication
• In addition to the Binet and Rai staging systems, additional markers are available
to predict prognosis
• Patients with a detectable del(17p) or a TP53 mutation have the poorest
prognosis, at least in the era of immunochemotherapy
Prognosis has improved with the introduction of B-cell receptor inhibitors
(BCRis) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax
• The formerly poor prognosis of patients with del(11q) has been strongly
improved by immunochemotherapy with fludarabine/cyclophosphamide/
rituximab (FCR) and by novel targeted agents such as BCRis and venetoclax
• Other gene mutations, such as those in NOTCH1, splicing factor 3b subunit 1
(SF3B1), baculoviral IAP repeat-containing 3 (BIRC3) or ribosomal protein
S15 (RPS15), as well as complex karyotype (CKT) (≥ 3 or ≥ 5 abnormalities
in chromosomal banding analysis) predict an unfavourable prognosis in the
absence of TP53 deletion/mutation and should be studied in clinical trials
• FISH for del(17p) and TP53 mutation analyses should be repeated before any line
of therapy
• Patients with CLL cells with an unmutated IGHV status have a shorter overall
survival (OS) and time to treatment intervention
• Different prognostic scores have been proposed to predict the outcome of
patients, including the CLL-IPI, which uses stage, age, TP53 status, IGHV status
and serum B2M to describe four different prognostic subgroups and which has
been validated extensively
188
Goals of therapy
• CLL remains mainly an incurable disease and the goals of therapy are to improve
quality of life (QoL) and prolong survival
• Clinical trial endpoints, such as response rate, minimal residual disease (MRD)
status or progression-free-survival (PFS), may be more relevant in daily life
for young and/or fit patients than older patients and/or patients with relevant
comorbidity
• In most patients, survival depends on the effect and choice of treatment
sequences given during the disease course
MANAGEMENT OF EARLY DISEASE
Binet stage A and B without active disease; Rai 0, I and II without active disease
• The standard treatment of patients with early disease is a watch-and-wait strategy
• Blood cell counts and clinical examinations should be carried out every 3 months
during the first year and every 3-12 months thereafter
• No evidence-based treatment can be given for localised, early-stage SLL, but the
consensus is that management is similar to CLL
• Locoregional radiotherapy (RT) may only be considered for symptomatic
lymphadenopathy in selected patients with localised SLL
MANAGEMENT OF ADVANCED DISEASE
Binet stage A and B with active disease or Binet stage C; Rai 0-II with active disease
or Rai III-IV
• Whenever possible, patients should be treated within a clinical trial for all lines of
therapy
Treatment indication
• Patients with intermediate- (stage I and II) and high-risk (stage III and IV) disease
(according to the modified Rai classification or at Binet stage B or C) usually
benefit from the initiation of treatment, although some (in particular those with
Rai intermediate-risk or Binet stage B) can be monitored without therapy until
they have evidence of progressive or symptomatic disease (summarised as
‘active disease’), meeting at least one of the following criteria:
Progressive marrow failure, as manifested by the development or worsening of
anaemia and/or thrombocytopaenia. Cut-off levels of haemoglobin < 100 g/L
(< 6.21 mmol/L) or platelet counts < 100 × 109/L are indications for treatment,
although in some patients, platelet counts at this level may remain stable over a
long period of time and may not require therapeutic intervention
Massive (i.e. ≥ 6 cm below the left costal margin) or progressive or
symptomatic splenomegaly
189
Massive (i.e. ≥ 10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy
Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period,
or lymphocyte doubling time (LDT) < 6 months, although patients with initial
blood lymphocyte counts of < 30 × 109/L may require a longer observation
period to determine the LDT
– Factors contributing to lymphocytosis other than CLL (e.g. infections, steroid
administration) should be excluded
Autoimmune complications including anaemia or thrombocytopaenia poorly
responsive to corticosteroids
Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung,
spine)
Disease-related symptoms as defined by any of the following: Unintentional
weight loss ≥ 10% within the previous 6 months, significant fatigue (i.e.
Eastern Cooperative Oncology Group performance status 2 or worse; cannot
work or unable to perform usual activities), fevers ≥ 38.0°C for ≥ 2 weeks
without evidence of infection, night sweats for ≥ 1 month without evidence of
infection
• Factors other than CLL contributing to these symptoms should be excluded
• Front-line treatment comprises continuous treatment with Bruton tyrosine
kinase inhibitors (BTKis) such as ibrutinib until progression, time-limited therapy
with a chemotherapy (ChT) backbone plus a CD20 antibody or venetoclax/
obinutuzumab, as shown in the figure on the next page
190
FRONT-LINE THERAPY
Symptomatic early-stage CLL or advanced-stage CLL
IGHV-unmutated IGHV-mutated
TP53 mutation or del(17p)
No TP53 mutation or del(17p) No TP53 mutation or del(17p)
Fit patients Unfit patients Fit patients Unfit patients All patients
Venetoclax/obinutuzumab*** Venetoclax/obinutuzumab*** Ibrutinib or acalabrutinib****

Ibrutinib ImmunoChT: FCR** Venetoclax/obinutuzumab***
Ibrutinib or acalabrutinib**** ImmunoChT: CLBO
ImmunoChT*: FCR** Ibrutinib Venetoclax
ImmunoChT*: CLBO Ibrutinib or acalabrutinib****
Idelalisib/rituximab
The order of the recommended treatments for each subgroup is based on expert opinion. If there is equal evidence for two different treatment options, time-limited is considered as the more
valuable therapy
*Immunochemotherapy as an alternative treatment only if there are reasons against treatment with targeted therapies or non-availability
**BR might be considered as an alternative in patients > 65 years of age
***If available
****If approved and available
BR, bendamustine/rituximab; ChT, chemotherapy; CLBO, chlorambucil/obinutuzumab; CLL, chronic lymphocytic leukaemia; FCR, fludarabine/cyclophosphamide/rituximab; IGHV, immunoglobulin
heavy chain variable; immunoChT, immunochemotherapy; TP53, tumour protein P53
191
• Treatment decisions should include an assessment of IGHV and TP53 status
along with patient-related factors, such as comedication, comorbidities,
preferences, drug availability and potential for treatment adherence
• Regarding the choice between venetoclax/obinutuzumab compared with ibrutinib
or other BTKis, time-limited therapy is preferred, but the side-effect profile (renal
impairment and TLS risk versus atrial fibrillation and bleeding risk), application
mode (intravenous with the combination versus oral medication), intensity of
controls (5-week ramp-up period with the combination) and shorter follow-up
should be taken into consideration
• In fit patients with CLL, unmutated IGHV status and without TP53 mutation or
del(17p) (if there was similar efficacy, the panel gives preference to time-limited
therapies)
Ibrutinib is recommended (data for other BTKis for fit patients are still pending)
Immunochemotherapy may still be considered an appropriate first-line therapy
for fit patients with CLL and mutated IGHV status but the long-term risk of
secondary neoplasia, leukaemias/myelodysplastic syndromes and infections
should be considered, along with a history of cardiovascular disorders,
comedication and any compliance problems
Venetoclax/obinutuzumab might be an alternative to BTKis, but data for fit
patients are still pending
• In unfit patients with CLL, unmutated IGHV status and without TP53 mutation or
therapies), recommended treatment options are venetoclax/obinutuzumab,
ibrutinib, acalabrutinib or chlorambucil/obinutuzumab (CLBO)
• In fit patients with CLL, mutated IGHV status and without TP53 mutation or
therapies)
Young fit patients receiving immunochemotherapy should be treated with FCR,
although bendamustine/rituximab (BR) should be considered for fit patients
> 65 years
Ibrutinib is also recommended
Venetoclax/obinutuzumab is an alternative, although data for fit patients are still
pending
• In unfit patients with CLL, mutated IGHV status and without TP53 mutation or
therapies), recommended treatment options are venetoclax/obinutuzumab, CLBO,
ibrutinib or acalabrutinib
192
• Patients with TP53 mutation or del(17p) should receive front-line therapy with
BTKis
Immunochemotherapy is not an option due to poor prognosis independent of
IGHV status
Cardiovascular and haematological side effects and drug–drug interactions
with ibrutinib may be a concern in patients with arrhythmias or significant
cardiovascular comorbidity or those on concomitant antiplatelet, anticoagulant
or CYP34A inhibitors
Other BTKis may have a different side effect profile, at least with respect to
arrhythmias
Alternatively, venetoclax, either as continuous monotherapy or as time-limited
combination therapy with obinutuzumab (if approved and available), would be
the preferred option
The phosphoinositide 3 kinase inhibitor idelalisib plus rituximab may be used in
patients not eligible for any other therapies
• Therapy until progression with ibrutinib alone or in combination with CD20
antibodies provides longer PFS than fixed-duration immunochemotherapy
(FCR, BR, CLBO)
• The optimum duration of ibrutinib treatment has not been defined
• In elderly patients
Acalabrutinib may have a PFS benefit compared with immunochemotherapy
The potential benefit of adding obinutuzumab to BTKi therapy remains unclear
• There is no disease control benefit of adding rituximab to ibrutinib in elderly
patients or younger patients with unfavourable genetic profiles
Treatment of relapsed and refractory disease
• Many patients with relapsed but asymptomatic CLL can be followed without
medication for a long time and treatment should be started only in symptomatic
patients and not simply at the time of disease reappearance, as shown in the
193
194
RELAPSE THERAPY
Symptomatic relapsed CLL
Short remission duration Long remission duration

TP53 mutation or del(17p)
(< 36 months) (> 36 months)
Ibrutinib or acalabrutinib Repeat front-line or

Venetoclax/rituximab* Ibrutinib or acalabrutinib Change to: Ibrutinib or acalabrutinib
Venetoclax alone** Venetoclax/rituximab*
Venetoclax alone** Venetoclax/rituximab*
Idelalisib/rituximab Idelalisib/rituximab
Idelalisib/rituximab
Consider alloSCT in fit patients ImmunoChT***
*After prior ibrutinib, preferred therapy

**After prior immunochemotherapy and BCRi
***Repetition of FCR not recommended
alloSCT, allogeneic stem cell transplantation; BCRi, B-cell receptor inhibitor; CLL, chronic lymphocytic leukaemia; FCR, fludarabine/cyclophosphamide/rituximab; ImmunoChT,
immunochemotherapy; R, rituximab
• In the case of rapid progression on targeted agents, an immediate change of
therapy is recommended
• For symptomatic relapse within 3 years of fixed-duration therapy or
non-response to therapy, the therapeutic regimen should be changed to either
venetoclax/rituximab for 24 months or ibrutinib, acalabrutinib or other BTKis
as continuous therapy
Alternative options are
– Idelalisib/rituximab
– Immunochemotherapy, unless TP53 mutation or del(17p) is found and no
other treatment options with inhibitors or cellular therapy are available; a
response to prior BR should have lasted ≥ 3 years to justify re-administration
Repeated administration of FCR is not recommended due to toxicity and the
risk of secondary myeloid neoplasm
• Treatment choice should consider treatment duration, administration,
compliance, evidence, risk of complications, response to and side effects of
prior therapies, number and complexity of clinical controls
• After progression on BCRi therapy after prior immunochemotherapy,
venetoclax-based therapy is the preferred treatment
• In case of long-lasting remissions (> 3 years) to prior time-limited therapy,
patients may be re-exposed to the same treatment regimen, although data are
limited
Role of haematopoietic stem cell transplantation and cellular therapies
• Autologous stem cell transplantation (ASCT) is not useful in CLL
• Allogeneic stem cell transplantation (alloSCT) should be considered in the
following cases:
Patients refractory to immunochemotherapy with TP53 mutation or del(17p),
but fully responsive to novel inhibitor therapy, with a low risk of transplantation
Patients refractory to immunochemotherapy and novel inhibitor therapy, even
if there is a higher risk of non-relapse mortality (haematopoietic cell transplant
comorbidity index score ≥ 3)
Patients with Richter’s transformation in remission after therapy and clonally
related to CLL
• Treatment with chimeric antigen receptor T (CAR-T) cells or bi-specific T-cell
engager (BiTE) antibodies within clinical trials could be an alternative to alloSCT
for all three groups
195
Treatment of CLL complications
• Patients with autoimmune cytopaenia should be treated according to the
statement from the ‘ESMO guidelines consensus conference on malignant
lymphoma’ (Ghielmini M et al. Ann Oncol 2013) and from the ‘International
Workshop on CLL guidelines’ (Hallek M et al. Blood 2008)
• Most patients with autoimmune cytopaenia, specifically those with warm
auto-antibodies, respond to high-dose corticosteroids
In those not responding to corticosteroids, rituximab alone or combined
with cyclophosphamide and dexamethasone, or BR are reasonable treatment
options
BCRis have also shown promising efficacy
• In patients with resistant autoimmune cytopaenia, treatment of the underlying
CLL is recommended before considering splenectomy
• Infectious complications are common in patients with CLL and so the use of
immunosuppressive agents, such as corticosteroids, should be restricted
• Prophylactic systemic Ig replacement therapy is only recommended in patients
with severe hypogammaglobulinaemia and repeated or severe infections
• Antibiotic and antiviral prophylaxis should mostly be used in patients with
recurrent infections and/or very high risk of developing infections (for
example, pneumocystis prophylaxis with co-trimoxazole during treatment with
immunochemotherapy based on purine analogues or idelalisib)
• Routine antifungal prophylaxis is not recommended
• There are no data available supporting the prophylactic use of any antibiotics
in early-stage CLL, but pneumococcal and seasonal flu vaccinations are
recommended in early-stage CLL
Response evaluation
• Response evaluation includes a careful physical examination and a blood cell
count
• BM biopsy and MRD assessment should be carried out to define complete
remission and MRD status within clinical trials as well as CT scans
• Outside clinical trials, BM biopsy and CT scan may be helpful but are not
mandatory
• MRD assessment is not generally recommended for monitoring after therapy
outside clinical trials
• For novel treatments with continuous administration within clinical trials, more
than one CT scan might be necessary
196
• RT-PCR has a strong prognostic value following immunochemotherapy as well as
venetoclax/CD20-antibody combinations
• Life-long observation and follow-up is recommended for all patients
• In asymptomatic patients, the follow-up should include a blood cell count and
palpation of the LNs, liver and spleen every 3-12 months, depending on the
disease dynamics
• Special attention should be paid to the appearance of autoimmune cytopaenia
Richter’s transformation
• Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in 2-15%
of CLL patients, in particular after several lines of immunochemotherapy, and
usually has a poor prognosis
• Diagnosis must be confirmed by LN histopathological examination
• A positron emission tomography (PET)-CT scan can be useful to guide the biopsy
• Defining the clonal relationship between DLBCL and CLL by comparison of IGHV
sequences is strongly advised
• Treatment regimens include rituximab/cyclophosphamide/doxorubicin/vincristine/
prednisolone (R-CHOP)
More intense regimens have not improved outcome and may cause
considerable toxicity
• Response duration is typically short
• For clonally related Richter’s transformation, alloSCT should be recommended to
all sufficiently fit patients
ASCT can be considered for those unsuitable for alloSCT
• For clonally unrelated disease, treatment is as for de novo DLBCL, comprising
first-line R-CHOP, with stem cell transplantation being reserved for cases not
responding or relapsing
• For CLL transforming into Hodgkin lymphoma (HL), conventional ChT against HL
often achieves long-lasting remission
197
Diagnosis of CLL is established by ≥ 5 × 109/L monoclonal B lymphocytes in the
peripheral blood, the clonality of which need to be confirmed by flow
cytometry-demonstrated light chain restriction, and characteristically small,
mature-appearing lymphocytes in the blood smear, which have a narrow border
of cytoplasm and a dense nucleus lacking discernible nucleoli and partially
aggregated chromatin
CLL should be differentiated from MCL, leukaemic MZL and lymphoplasmacytic
lymphoma, which, in most cases, do not express CD23
Where peripheral blood B lymphocytes are < 5 × 109/L, the presence of
lymphadenopathy and/or splenomegaly suggest SLL; otherwise MBL is the likely
diagnosis
Early, asymptomatic stage
• Early, asymptomatic stage disease requires no further risk assessment
• Patients should be seen at 3-monthly intervals for the first year then every
3-12 months, depending on disease burden and dynamics, and assessments
should include a history and physical examination, including palpation of LN
areas, spleen and liver and CBC and differential count
Advanced or symptomatic stage
• Patients should have a pre-treatment history and physical examination, including
palpation of LN areas, spleen and liver; CBC and differential count; serum
chemistry, including LDH, bilirubin, serum Igs, DAT and haptoglobin; history and
status of relevant infections; FISH for del(17p) and, in the absence of del(17p),
TP53 sequencing
• Additional desirable pre-treatment examinations before treatment include BM
examination for the diagnostic evaluation of unclear cytopaenia, extended
FISH analysis for additional cytogenetic abnormalities, hepatitis E testing and
assessment of B2M
Imaging
• Routine radiographic imaging is not generally recommended in asymptomatic
patients
198
• CT scan is recommended in symptomatic patients, with MRI, chest radiography
or abdominal US as alternatives
• CT scans of the neck, chest, abdomen and pelvis, or MRI, may be helpful to
assess tumour load and risk of TLS
Prognostication
• Patients with a detectable del(17p) or a TP53 mutation have the poorest
prognosis, at least in the era of immunochemotherapy
• The formerly poor prognosis of patients with a del(11q) has been strongly
improved by immunochemotherapy with FCR and by novel targeted agents such
as BCRis and venetoclax
• Other gene mutations, such as NOTCH1, SF3B1, BIRC3 or RPS15, as well as CKT,
predict an unfavourable prognosis in the absence of TP53 deletion/mutation
• FISH for del(17p) and TP53 mutation analyses should be repeated before any line
of therapy
• Patients with CLL cells with an unmutated IGHV status have a shorter OS and
time to treatment intervention
Goals of therapy
• The goals of therapy are to improve QoL and prolong survival
• Survival depends mainly on the effect and choice of treatment sequences given
during the disease course
MANAGEMENT OF EARLY DISEASE
Binet stage A and B without active disease; Rai 0, I and II without active disease
• The standard treatment of patients with early disease is a watch-and-wait strategy
• Blood cell counts and clinical examinations should be carried out every 3 months
during the first year and every 3-12 months thereafter
• Management of early-stage SLL is similar to that of CLL
MANAGEMENT OF ADVANCED DISEASE
Binet stage A and B with active disease or Binet stage C; Rai 0-II with active
disease or Rai III-IV
• Whenever possible, patients should be treated within a clinical trial for all lines of
therapy
199
Treatment indication
• Patients with intermediate- (stage I and II) and high-risk (stage III and IV) disease
usually benefit from the initiation of treatment, although some can be monitored
without therapy until they have evidence of active disease that is not excluded
by other factors, namely: Progressive marrow failure; massive or progressive
or symptomatic splenomegaly; massive or progressive or symptomatic
lymphadenopathy; progressive lymphocytosis; autoimmune complications;
symptomatic or functional extranodal involvement; disease-related symptoms,
including significant fatigue, fevers ≥ 38.0°C for ≥ 2 weeks without evidence of
infection or night sweats for ≥ 1 month without evidence of infection
• Front-line treatment comprises continuous treatment with BTKis, such as
ibrutinib, until progression, or time-limited therapy with a ChT backbone plus a
CD20 antibody or venetoclax/obinutuzumab
• Decision for the type of front-line treatment is based on TP53 mutation or
del(17p), IGHV mutation status, age, comorbidities and comedication
• In fit patients with CLL, unmutated IGHV status and without TP53 mutation or
therapies), ibrutinib is recommended (data for other BTKis for fit patients are
still pending); immunochemotherapy should be avoided, if possible, but can be
considered if other options are not available; venetoclax/obinutuzumab might be
an alternative to BTKis, but data for fit patients are still pending
• In unfit patients with CLL, unmutated IGHV status and without TP53 mutation or
therapies), recommended treatment options are venetoclax/obinutuzumab,
ibrutinib, acalabrutinib or CLBO
• In fit patients with CLL, mutated IGHV status and without TP53 mutation or
therapies), immunochemotherapy according to age (FCR or BR) or ibrutinib are
recommended, with venetoclax/obinutuzumab as an alternative, although data for
fit patients are still pending
• In unfit patients with CLL, mutated IGHV status and without TP53 mutation or
therapies), recommended treatment options are venetoclax/obinutuzumab, CLBO,
ibrutinib or acalabrutinib
200
• In the case of TP53 mutation or del(17p), ibrutinib, acalabrutinib,
venetoclax/obinutuzumab, venetoclax alone or idelalisib/rituximab are
recommended
• In elderly patients, acalabrutinib may have a PFS benefit compared with
immunochemotherapy
Treatment of relapsed and refractory disease
• Treatment should be started only in symptomatic patients and not simply at the
time of disease reappearance
• In the case of rapid progression on targeted agents, an immediate change of
therapy is recommended
• For symptomatic relapse within 3 years of fixed-duration therapy or
non-response to therapy, the therapeutic regimen should be changed to either
venetoclax/rituximab for 24 months or ibrutinib, acalabrutinib or other BTKis as
continuous therapy
• Alternative options are idelalisib/rituximab or immunochemotherapy, unless TP53
mutation or del(17p) is found and no other treatment options with inhibitors or
cellular therapy are available
• Treatment choice should consider treatment duration, administration,
compliance, evidence, risk of complications, response to and side effects of prior
therapies, number and complexity of clinical controls
• In late relapse and no del(17p) or TP53 mutation, ibrutinib or
venetoclax/rituximab or repeat front-line therapy are recommended
• After progression on BCRi therapy after prior immunochemotherapy,
venetoclax-based therapy is the preferred treatment
• In case of long-lasting remissions (> 3 years) to prior time-limited therapy,
patients may be re-exposed to the same treatment regimen
Role of haematopoietic stem cell transplantation and cellular therapies
• AlloSCT should be considered for patients refractory to immunochemotherapy
with TP53 mutation or del(17p) and a low risk of transplantation, patients
refractory to immunochemotherapy and novel inhibitor therapy, even if
there is a higher risk of non-relapse mortality, and for patients with Richter’s
transformation in remission after therapy and clonally related to CLL
201
Treatment of CLL complications
• Patients with autoimmune cytopaenia should be treated according to the ESMO
guidelines consensus conference on malignant lymphoma and the International
Workshop on CLL guidelines
• Most patients with autoimmune cytopaenia, specifically those with warm
auto-antibodies, respond to high-dose corticosteroids; otherwise, rituximab
alone or combined with cyclophosphamide and dexamethasone, BR or BCRis are
reasonable treatment options
• In patients with resistant autoimmune cytopaenia, treatment of the underlying
CLL is recommended before considering splenectomy
• Infectious complications are common in patients with CLL and so the use of
immunosuppressive agents, such as corticosteroids, should be restricted
• Antibiotic and antiviral prophylaxis should mostly be used in patients with
recurrent infections and/or very high risk of developing infections
• There are no data available supporting the prophylactic use of antibiotics in
early-stage CLL, but pneumococcal and seasonal flu vaccinations are
recommended in early-stage CLL
Response evaluation
• Response evaluation includes a careful physical examination and a blood cell
count
• Outside clinical trials, BM biopsy and CT scan may be helpful but are not
mandatory
• RT-PCR has a strong prognostic value following immunochemotherapy as well as
venetoclax plus CD20-antibody combinations
• MRD assessment is not generally recommended for monitoring after therapy
outside clinical trials
Life-long observation and follow-up is recommended for all patients
In asymptomatic patients, follow-up should include a blood cell count and
palpation of the LNs, liver and spleen every 3-12 months, depending on the disease
dynamics
Special attention should be paid to the appearance of autoimmune cytopaenia
202202
Richter’s transformation
• Diagnosis must be confirmed by LN histopathological examination
• A PET-CT scan can be useful to guide the biopsy
• Defining the clonal relationship between DLBCL and CLL is strongly advised
• For clonally related Richter’s transformation, alloSCT should be recommended to
all sufficiently fit patients
• For clonally unrelated disease, treatment is as de novo DLBCL, comprising
first-line R-CHOP, with stem cell transplantation being reserved for cases not
responding or relapsing
• CLL transforming into HL should be treated with conventional ChT against HL
203
aaIPI, age-adjusted International Prognostic Index
ABC, activated B-cell
ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine
AITL, angioimmunoblastic T-cell lymphoma
ALCL, anaplastic large cell lymphoma
ALK, anaplastic lymphoma kinase
alloSCT, allogeneic stem cell transplantation
AraC, cytarabine
ASCT, autologous stem cell transplantation
AspaMetDex, L-asparaginase/methotrexate/dexamethasone
autoHSCT, autologous haematopoietic stem cell transplantation
AVD, doxorubicin/vinblastine/dacarbazine
B2M, β2 microglobulin
BCL2, B-cell lymphoma 2
BCR, B-cell receptor
BCRi, B-cell receptor inhibitor
BEACOPPesc, escalated dose of bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/
procarbazine/prednisolone
BEAM, carmustine/etoposide/cytarabine/melphalan
BIRC3, baculoviral IAP repeat containing 3
BiTE, bi-specific T-cell engager
BM, bone marrow
BR, bendamustine/rituximab
Btk, Bryton's tyrosine kinase
BTKi, Bruton tyrosine kinase inhibitor
BV, brentuximab vedotin
C-ALCL, cutaneous anaplastic large cell lymphoma
CAR-T cell, chimeric antigen receptor T
CBC, complete blood count
CBCL, cutaneous B-cell lymphoma
CBL-MZ, clonal B-cell lymphocytosis of marginal zone origin
CD, cluster of differentiation
CD8+ AECTCL, aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma
cHL, classical Hodgkin lymphoma
CHOEP, cyclophosphamide/doxorubicin/vincristine/etoposide/prednisolone
CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone
ChT, chemotherapy
CKT, complex karyotype
Clb, chlorambucil
CLBO, chlorambucil/obinutuzumab
CLL, chronic lymphocytic leukaemia
CMR, complete metabolic response
204
CMV, cytomegalovirus
CNS, central nervous system
CPG, Clinical Practice Guideline
CR, complete response/remission
CSF, cerebrospinal fluid
CT, computed tomography
CTCL, cutaneous T-cell lymphoma
CVP, cyclophosphamide/vincristine/prednisolone
CXCR4, C–X–C chemokine receptor type 4
DA-EPOCH-R, dose-adjusted etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin/rituximab
DAT, direct antiglobulin test or direct Coombs test
del(17)p, chromosome 17 deletion
DHAP, dexamethasone/high-dose cytarabine/cisplatin
DLBCL, diffuse large B-cell lymphoma
DRC, dexamethasone/rituximab/cyclophosphamide
EATL, enteropathy-associated T-cell lymphoma
EBV, Epstein-Barr virus
ECOG, Eastern Cooperative Oncology Group
ECP, extracorporeal photopheresis
EGD, oesophagogastroduodenoscopy
EMZL, extranodal marginal zone lymphoma
ENKTCL, extranodal natural killer/T-cell lymphoma
EORTC, European Organisation for Research and Treatment of Cancer
EPOCH, etoposide/vincristine/doxorubicin/cyclophosphamide/prednisolone
ESMO, European Society for Medical Oncology
ESR, erythrocyte sedimentation rate
FCR, fludarabine/cyclophosphamide/rituximab
FDG, [18F]2-fluoro-2-deoxy-D-glucose
FISH, fluorescence in situ hybridisation
FL, follicular lymphoma
FLIPI, Follicular Lymphoma-specific International Prognostic Index
GC, germinal centre
GELA, Groupe d’Etude des Lymphomes de l’Adulte
GI, gastrointestinal
Hb, haemoglobin
HBc, hepatitis B core
HBs, hepatitis B surface
HBsAg, hepatitis B surface antigen
HBV, hepatitis B virus
HCL, hairy cell leukaemia
HCL-V, hairy cell leukaemia variant
HCV, hepatitis C virus
HD-AraC, high-dose cytarabine
HDCT, high-dose chemotherapy
HDCT/ASCT, high-dose chemotherapy followed by autologous stem cell transplantation
HD-MTX, high-dose methotrexate
205
HIV, human immunodeficiency virus
HL, Hodgkin lymphoma
HLA, human leucocyte antigen
HPS, haemophagocytic syndrome
HSTCL, hepatosplenic T-cell lymphoma
HTLV-1, human T lymphotropic virus-1
ICE, ifosfamide/carboplatin/etoposide
IELSG, International Extranodal Lymphoma Study Group
IFN-α, interferon alpha
IFRT, involved-field radiotherapy
Ig, immunoglobulin
IGEV, ifosfamide/gemcitabine/vinorelbine
IGHV, immunoglobulin heavy chain variable
IHC, immunohistochemistry
IIL, Intergruppo Italiano Linfomi
ILROG, International Lymphoma Radiation Oncology Group
IPI, International Prognostic Index
IPSSWM, International Prognostic Scoring System for Waldenström’s macroglobulinaemia
ISRT, involved-site radiotherapy
IT, intrathecal
IV, intravenous
IVAC, ifosfamide/cytarabine/etoposide
IVE, ifosfamide/vincristine/etoposide
KPS, Karnofsky performance score
LDH, lactate dehydrogenase
LDT, lymphocyte doubling time
LEL, lymphoepithelial lesion
LN, lymph node
LP, lymphocyte predominant
LPD, lymphoproliferative disorder
LPL, lymphoplasmacytic lymphoma
LVEF, left ventricular ejection fraction
LyP, lymphomatoid papulosis
MACOP-B, methotrexate/doxorubicin/cyclophosphamide/vincristine/prednisolone-bleomycin
MALT, mucosa-associated lymphoid tissue
MBL, monoclonal B lymphocytosis
MCL, mantle cell lymphoma
MF, mycosis fungoides
MIPI-c, combined mantle cell lymphoma International Prognostic Index
MRD, minimal residual disease
MRI, magnetic resonance imaging
MTX, methotrexate
MZL, marginal zone lymphoma
nb-UVB, narrow-band ultraviolet B
NF-κB, nuclear factor kappa light chain enhancer of activated B cells
NK, natural killer
206
NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma
NMZL, nodal marginal zone lymphoma
OS, overall survival
PB, peripheral blood
PBL, primary diffuse large B-cell lymphoma of the breast
PBoL, primary diffuse large B-cell lymphoma of the bone
PCFCL, primary cutaneous follicle centre lymphoma
PCGD-TCL, primary cutaneous gamma/delta T-cell lymphoma
PCL, primary cutaneous lymphoma
PCLBCL-LT, primary cutaneous diffuse large B-cell lymphoma, leg type
PCMZL, primary cutaneous marginal zone lymphoma
PCNSL, primary central nervous system lymphoma
PCR, polymerase chain reaction
PD-1, programmed cell death protein 1
PD-L1/2, programmed death-ligand 1/2
PEP-C, prednisolone/etoposide/procarbazine/cyclophosphamide
PFS, progression-free survival
PI, proteasome inhibitor
PI3K, phosphoinositide 3-kinase
PMBCL, primary mediastinal large B-cell lymphoma
PO, oral
PPI, proton pump inhibitor
PR, partial response
PRIMA-PI, PRIMA prognostic index
PS, performance status
PTCL, peripheral T-cell lymphoma
PTCL-NOS, primary cutaneous peripheral T-cell lymphoma-not otherwise specified
PTL, primary testicular lymphoma
PUVA, psoralens plus ultraviolet A
QoL, quality of life
R, rituximab
R-ACVBP, rituximab/doxorubicin/vindesine/cyclophosphamide/bleomycin/prednisolone
R-BAC, rituximab/bendamustine/cytarabine
R-CHOEP, rituximab/cyclophosphamide/doxorubicin/vincristine/etoposide/prednisolone
R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone
R-CHOP14, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone, every 14 days
R-CHOP21, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone, every 21 days
R-DHAP, rituximab/dexamethasone/high-dose cytarabine/cisplatin
R-FC, rituximab/fludarabine/cyclophosphamide
R-FM, rituximab/fludarabine/mitoxantrone
R-GDP, rituximab/cisplatin/gemcitabine/dexamethasone
R-GEMOX, rituximab/gemcitabine/oxaliplatin
R-hyper-CVAD, rituximab/hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone
alternating with methotrexate and cytarabine
R-ICE, rituximab/ifosfamide/carboplatin/etoposide
207
RIT, radioimmunotherapy
R-miniCHOP, rituximab with attenuated chemotherapy
RPS15, ribosomal protein S15
RR, response rate
RT, radiotherapy
SC, subcutaneous
SCT, stem cell transplantation
SF3B1, splicing factor 3b subunit 1
SLL, small lymphocytic leukaemia
SMILE, dexamethasone/methotrexate/ifosfamide/L-asparaginase/etoposide
SMZL, splenic marginal zone lymphoma
SPTCL, subcutaneous panniculitis-like T-cell lymphoma
SS, Sézary syndrome
TBI, total body irradiation
TLS, tumour lysis syndrome
TNMB, tumour-node-metastasis-blood
TP53, tumour protein 53
TSEBT, total skin electron beam therapy
US, ultrasound
VACOP-B, etoposide/doxorubicin/cyclophosphamide/vincristine/prednisolone-bleomycin
VADC, vincristine/doxorubicin/oral dexamethasone/chlorambucil
WBRT, whole-brain radiotherapy
WHO, World Health Organization
WM, Waldenström’s macroglobulinaemia
208
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ESMO POCKET GUIDELINES
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European Society for Medical Oncology (ESMO) tmc strategic communications

via Ginevra 4, 6900 Lugano, Switzerland www.wearetmc.co.uk

ESMO CLINICAL PRACTICE GUIDELINES

Distributed with support from F. Hoffmann-La Roche Ltd.

Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the

NEWLY DIAGNOSED AND RELAPSED MANTLE CELL LYMPHOMA (MCL)

WALDENSTRÖM'S MACROGLOBULINAEMIA (WM)

PRIMARY CUTANEOUS LYMPHOMAS (PCLs)

MARGINAL ZONE LYMPHOMAS

CHRONIC LYMPHOCYTIC LEUKAEMIA

• A medical history, including presence of B symptoms (fever, drenching night

Diagnosis of limited-stage HL*

2 cycles of ABVD 2 cycles of ABVD

20-Gy ISRT PET-CT scan

2 cycles of BEACOPPesc 1 cycle of ABVD

30-Gy ISRT 20-Gy ISRT

*The maximum absolute dose of vincristine is 2 mg

2 cycles of BEACOPPesc + 2 cycles of ABVD

2 cycles of BEACOPPesc 2 cycles of ABVD

30-Gy ISRT 30-Gy ISRT

• Four cycles of ABVD followed by conventionally fractionated RT at 30 Gy is

6 cycles of 2 cycles of BEACOPPesc 2 cycles of ABVD

PET-CT scan PET-CT scan

4 cycles of 2 cycles of 4 cycles of 4 cycles of

PET-CT scan PET-CT scan

PET-positive PET-negative PET-positive PET-negative

Localised RT Observation Localised RT Observation

Diffuse or disseminated involvement of one or more extralymphatic organs with

Serum LDH > normal

Low 0-1 91 (89-94)

High 4-5 59 (49-69)

Risk factors Serum LDH > normal

ELDERLY (> 60 YEARS)

Consider alloSCT in patients relapsed after

aaIPI, age-adjusted IPI; ACVBP, doxorubicin/vindesine/cyclophosphamide/bleomycin/prednisolone; alloSCT, allogeneic stem

• Inclusion in a clinical trial is recommended whenever possible

3 Uptake > mediastinum but ≤ liver

4 Moderately increased uptake compared to liver

5 Markedly increased uptake to liver and/or new lesions

POINTS AGE (YEARS) ECOG LDH (ULN) WBC COUNT (109/L)

MIPI RISK GROUP KI-67 INDEX MIPI-C RISK GROUP (SUM

Leukaemic non-nodal subtype of MCL

Dose-intensiﬁed Conventional Best supportive care?

Immunochemotherapy Immunochemotherapy Immunochemotherapy

Targeted approaches: Ibrutinib, lenalidomide

STUDY EVALUABLE THERAPEUTIC ORR % MEDIAN

STUDY EVALUABLE THERAPEUTIC ORR %

CHOP + TBI + ASCT 98 (81)

R-CHOP + TBI + ASCT

ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CR, complete

3.3 NR (83% 3-year OS) 13% 5%

NR (73% 3-year PFS) NR (84% 3-year OS)

4.8 6.8 39% 2% 4%

STUDY EVALUABLE THERAPEUTIC ORR % MEDIAN PFS MEDIAN OS

Laboratory Blood and differential count

CT, computed tomography; LDH, lactate dehydrogenase; TSH, thyroid-stimulating hormone

Include familial history for WM and other B-cell LPDs

OPTIONAL (IF CLINICALLY INDICATED)

*Fever, night sweats and weight loss

Hb, haemoglobin; IgM, immunoglobulin M; WM, Waldenström’s macroglobulinaemia

CLINICAL SYNDROME TREATMENT OPTIONS

PI-based therapy (BDR, VR)

PI-based therapy (BDR, VR)

Fit patient Unfit patient

• A medical history, including presence of B symptoms (fever, drenching night

• Four cycles of ABVD followed by conventionally fractionated RT at 30 Gy is