RECENT ADVANCES IN

MANAGEMENT OF
HODGKIN’S LYMPHOMA

MODERATOR: PRESENTER:
DR. RAKESH DR. ANIL
DHANKHAR KHURANA
Lymphoid cell neoplasms

LYMPHOMA LEUKEMIA MYELOMA

Cancer: Principles and Practice of Oncology 8 ed, Devita

 LYMPHOMA

HODGKIN’S NON HODGKIN’S

Lymphatic System
 Hodgkin’s Lymphoma
 Almost always begins in lymph nodes.

 Follows theory of contiguity.

 > 80% - present with cervical L.N involvement.

 > 50% - mediastinal disease.

 Isolated extra lymphatic involvement - rare.

Epidemiology and Risk Factors

 0.58% of all cancers diagnosed

 0.23% of all cancer deaths in the United States
each year.
 Incidence - < 3 per 100,000.
 M : F - 1.1 : 1
 Rare in children < 10 years of age
 Median age at the time of diagnosis - 26 years.
 2-3% of all cases in India
 Epidemiology – Hodgkin’s
 Bimodal
 Postulated to
have infectious
association eg.
With Epstein-
Barr virus (EBV)
infection- 2.55
times higher
incidence
Multiple
cervical
lymph
nodes
Recommended Staging Procedures of Patients with
Hodgkin Disease

 History and physical examination

– Special attention of history of B symptoms (i.e. fever, night sweats,
weight loss of >10% in past 6 months)
– Examination of all peripheral lymph node regions, liver and spleen
 Radiologic studies
– Chest X-ray
– CT scan of thorax
– CT scan of abdomen and pelvis
 Laboratory studies
– Hb, Hematocrit, TLC, DLC, Platelet Count
– ESR
– BUN, Creatinine
– Bilirubin, SAP, LDH, Liver enzymes
 Investigations
 Excisional biopsy (Recommended)
 FNAC alone is inadequate
 Immunohistochemistry (Recommended)
 Serum LDH
 Bone Marrow Biopsy/Aspiration
 PET scan
 Bone Scan (if indicated)
 Pathology
 Diagnosed on M/E - Reed-Sternberg cells
are found.
 R.S cell
– lymphoid cell, usually it is a monoclonal B cell
– comprise <10% of diseased tissue
– classic RS. Cell has 2 mirror-image nuclei,
which are often described as “ owl’s eyes ”.
Lymphoma - Gross
 Reed-Sternberg Cell

Popcorn cell variant

 Described 1898 Sternberg, 1902

Reed
 Nodular Sclerosis - Hodgkins

Classic Reed
Sternberg
cells

Atypical
multinucleated
RS cells
(Popcorn cells)
 PET-CT
 Now a days PET-CT has become the
integral part in management of Lymphomas
for
– Staging
– Restaging
– Assessment of treatment response
PET-CT
EVOLUTION OF STAGING FOR HODGKIN’S
LYMPHOMA
1965, RYE, NEWYORK

1970, ANN ARBOR, MICHIGAN

1988, COTSWOLD, ENGLAND

1989, REAL CLASSIFICATION Jaffe ES, Harris NL, Stein H,

Vardiman JW, eds.
World Health Organization
Classification of Tumours.
Pathology and Genetics of
Tumours of Haematopoietic
2001, WHO MODIFICATION and Lymphoid Tissues. Lyon:
IARC, 2001.
 Ann Arbor Staging Classification
 Stage I
– Involvement of a single lymph node region or
– Localized involvement of a single extralymphatic organ or
site ( IE)

 Stage II
– Involvement of two or more lymph node regions on the
same side of the diaphragm (II) or
– localized involvement of an extralymphatic organ or site
and one or more lymph node regions on the same side of
the diaphragm (IIE).
– No. of L.N regions involved may be indicated by subscript
e.g II3
Ann Arbor Staging Classification

 Stage III
– Involvement of lymph node regions on both sides of the
diaphragm (III) which may also be accompanied by
 by localized involvement of an extralymphatic organ or site (IIIE)
 involvement of the spleen (IIIS)
 by both (IIIS+E).
 Stage IV
– Diffuse or disseminated involvement of one or more
extralymphatic organs or tissues with or without
associated lymph node involvement or
– Isolated extralymphatic organ involvement with distant
(non-regional ) nodal involvement.
The lymph node regions
as defined in the Ann
Arbor staging system.

Note that the ipsilateral

supraclavicular, cervical,
preauricular, and
occipital nodes are
defined as a single
region.

The mediastinum and

pulmonary hilar are
defined as separate
regions.
 Staging Contd.

COTSWOLD’S modification-1989
1. III
III1 - above renal hila (splenic hilar,coeliac,portal nodes)
III2 - below renal hila (paraaortic,iliac mesenteric)
2. CECT for detection of intra abdominal & chest disease
3. Bulky disease- X
4. CR(u)-CR with radiological evidence of disease but cannot be
pathologically proven
5. Mediastinal region - hilar, internal mammary & paravertebral nodes not
included
World Health Organization (WHO) Classification
2001

 Nodular lymphocyte predominance Hodgkin

lymphoma.

 Classical Hodgkin lymphoma

– Nodular sclerosis Hodgkin lymphoma.
– Lymphocyte-rich classical Hodgkin lymphoma.
– Mixed-cellularity Hodgkin lymphoma.
– Lymphocyte depletion Hodgkin lymphoma.
 World Health Organization (WHO)
classification (IHC wise)
 Classical Hodgkin lymphoma
 CD15+
 CD20-
 CD30+
 CD45-
 Nodular lymphocyte predominant
 CD15-
 CD20+
 CD30-
 CD45+
Lymphocyte-Predominant Mixed Cellularity

Lymphocyte-Depleted Nodular Sclerosis Lacunar

cell
Hasenclever’s prognostic score
•Stage – Major prognostic factor in HL and major basis on which
treatment is based
Prognostic score for Advanced HD Prognostic score for Localized HD
Factor Unfavorable Factor Unfavorable
S.albumin < 4 g/dl Bulky >1/3
mediastinum
Hb <10.5 g/dl
Any nodal mass >10 cm
Sex Male
Age >/= 45 y
ESR >50
Stage IV( Ann Arbor) No of involved >3
sites
TLC >/=15,000
Lymphocyte <600(<8% of TLC)

FFP 84% with no risk factors,

77% with 1 risk factors,
67% with 2 risk factors,
60% with 3 risk factors.
 Treatment modalities
 Chemotherapy
 Radiation therapy
 Bone Marrow Transplantation
 Targeted therapy
 Treatment Strategies - HL
Stage Bulk Treatment

IA Low ABVD x 2- 4 cycles

IIA + IFRT
Any stage + B Low ABVD till 2 cycles post CR,
symptom, Minimum -6
III Maximum -8
IV
Any stage Bulk ABVD x 6
+ IFRT
DRUG COMBINATION REGIME DOSE (mg/m2) DAYS
Dexamethasone 40 1-4
DHAP( 28 days ) Cisplatin 100 1( continuous infusion)
Ara-C 2000q 12hr X 2
Bleomycin 10 8
Etoposide 200 1-3
Doxorubicin 35 1
BEACOPP ( escalated)
Cyclophosphamide 1250 1
Vincristine 1.4 8
Procarbazine (PO) 100 1-7
Prednisolone (PO) 40 1-14
Vincristine 1.4 8, 22
Doxorubicin 35 1, 15
Prednisolone (PO) 50 (total) Daily for first 6 weeks
VAPEC-B ( 28days )
25 (total) Daily for latter 6 weeks
Etoposide 100 15, 16, 17, 18, 19
Cyclophosphamide 350 1
Blemycin 10 8
 Complications of chemotherapy
 The acute toxicities are
– nausea
– vomiting
– peripheral neuropathy
– constipation
– leukopenia
– thrombocytopenia.
 Late effects of concern included
– sterility (especially in men)
– secondary myelodysplastic syndrome
– leukemia.
Chemotherapy Complete Disease free
Regimes Response progression
ABVD 80% 61%

MOPP 67% 50%

BEACOP 88%

Escalated 95%
BEACOP
 ROLE OF RADIOTHERAPY

 AS COMBINED MODALITY
– Stage IA, IIA- 2-4 ABVD + IFRT to involved sites
– Any Stage in Bulky Disease- IFRT after 6-ABVD
– Myeloablation prior to ABMT

 PRESENT DAY INDICATION FOR RT ALONE IN HL

– IA, low bulk, mediastinal NSHL : Mantle field irradiation
– IA, high neck (suprahyoid) epitrochlear or inguinal NLPHL : IFRT
only
 Principles of Radiotherapy
 Combined Modality RT Doses
– Bulky Disease State ( all Stages )
 30-36 Gy - if treated with ABVD
 36 Gy - if treated with Stanford V
– Non-Bulky Disease State I – II
 30 Gy - if treated with ABVD
 30 Gy - if treated with Stanford V
– Non-Bulky Disease State IB – IIB and bulky & nonbulky
disease Stage III-IV
 30-40 Gy - if treated with BEACOPP
 RT Alone Doses
– 30-36 Gy - for involved regions
– 25-36 Gy - for uninvolved regions
 Radiation Therapy

 Optimal irradiation technique

– pretreatment simulation
– use of megavoltage photon beams
– fields individually contoured to the patient's anatomy
and tumor configuration
– adequate dose
– Treatment at an extended source–skin distance of
110 to 140 cm may be necessary to achieve the large
field sizes required
– multifield fractionated treatment
– portal film verification during therapy
 TARGET VOLUME
EXTENDED FIELD
Involved areas + areas suspected to have subclinical extension
(usually includes two echelon lymphatic regions)
Mantle - base of skull to D10
Inverted Y - paraaortic + inguinofemoral
STLI - mantle+ splenic pedicle+ upper paraaortic till
L1-2
TLI - STLI+ pelvic+ inguinofemoral
INVOLVED FIELD
Primary area +/- first echelon lymphatic region above and below
 MANTLE FIELD

Field marks simulation port film

Extended Field

INVERTED Y FIELD
 Extended Field

TLI STLI
 Involved Field RT
 Treatment to the entirety of an involved lymphoid
region when any portion of that region was
involved
 For e.g,
– if only the supraclavicular nodes are involved it is not
necessary to treat the entire neck.
– On the other hand, the supraclavicular region is often
included when the superior mediastinum is involved
and portions of the iliac nodes may be irradiated
when the inguinal-femoral nodes are involved
 INVOLVED FIELD

Cervical Cervical

Mediastinal Axillary
 INVOLVED FIELD

Waldayer Paraaortic

Pelvic Inguinal
 Paediatric Patients
 Higher doses - associated with unacceptable
risks for growth impairment and late effects .
 Doses should not exceed -15 to 25 Gy.
 5-year survival rates - 90%
 Relapse-free rates - 80%.
 Geriatric Patients
 The treatment in older patients (>60 years) -poses a
challenge .
– Patients more likely have intercurrent disease - compromises the
aggressive management programs.
 Chemotherapy programs may often be modified to
– minimize cardiac or pulmonary toxicity and
– the hematologic reserve in elderly patients more often results in dose
reductions or premature discontinuation.
 Drug combinations that seem to be more tolerable include
– ChlVPP (Chorambucil PO, Vinblastine, Procarbazine PO,
Prednisolone PO)
– PAVe (procarbazine, Alkeran, and vinblastine)
– VBM (vinblastine, bleomycin, and methotrexate; used primarily for
stage I to II)
 Management Of
Relapse/Progressive Disease
 Most relapses occur with in first 3 years
 Salvage Therapy more successful in pts.
– With initial remission >12 months
– Relapse confined to limited sites
– No bone marrow or pulmonary involvement at relapse

 Standard Second line chemotherapy regimens

(MOPP, DHAP, EVA, VAPEC-B, CEP)

– Prolonged Remission in 10 to 30 % cases

 All patients younger than 70 yrs who relapse after CT or
CMT should be considered for Hematopoietic Autologous
stem cell transplant

 High Dose Chemotherapy with Autologous stem cell

transplant
– 40-50 % - Achive PFS
– 20-30 % - Achieve long term remission
 Patients with frank progression on
salvage therapy should be considered
for investigational agents
– Monoclonal Antibodies
– Radioimmunotherapy
 Monoclonal Antibodies (MAbs)
 MAbs
– antibodies that are identical – produced by
one type of immune cells & are all clones of
parent cells
– Can specifically bind to the substance against
which antibodies are produced  can serve to
detect or purify the substance
 Radioimunmunotherapy (RIT)
 RIT involves the use of radioactivity conjugated
murine antibodies against cellular antigens
 Most research currently involved their
application to Lymphomas as these are highly
radio-sensitive malignancies
Targets for therapy in Relapsed HL
 Ferritin

 CD20

 CD25

 CD30

 CD40
 Radioimmunotherapy:
Antiferritin
 131I-labelled antiferritin antibody
– Phase II trial N=37 patient with relapsed HL
– Dosing
 Day 0: patients received 30 mCi 131I-antiferritin
 Day 5: 20mCi 131I-antiferritin
– Responses
 Overall response rate was 40%, with 1 CR and 14 PR.
– Toxicities
 Predominantly hematologic: leukopenia and thrombocytopenia

J Clin Oncol 1985;3:1296-1300

 Radioimmunotherapy:
Antiferritin
 Yttrium-90 antiferritin
– Protocol:
 20-50mCi 90Y -labelled polyclonal antiferritin
– Toxicities:
 All patients experienced hematologic toxicity
– Response:
 ORR was 51% with 10 CR and 10 PR

J Clin Oncol 1991;9:918-928

 Radioimmunotherapy:
Anti-CD30
 –Ki-4: murine anti-CD30 monoclonal antibody
131I

(MAb) Ki-4 labeled with iodine-131

 Patients
– 22 patients with relapsed, refractory, documented
CD30+ HL
 Toxicity:
– Hematologic toxicity was significant and prolonged,
 Response:
– The overall response rate was 27%, with 1 CR lasting 5
months and 5 PR (median duration of response 4 months)

J Clin Oncol 2005;23:4669-4678

 Rituximab in LPHL:
German Hodgkin Lymphoma Study Group
 14 patients, including 10 with LPHL, 2 with
transformed HL and 1 with CD20+ classical HL
enrolled
– Rituximab 375 mg/m2 weekly for 4 weeks
– Response
 ORR 86%, with 8 CR and 4PR
 Median duration of response had not yet been
reached at >20months of follow-up

Blood 2003;101:420-424
 Rituximab in LPHL:
Another Phase II Trial
 22 patients with LPHL
– 10 had recurrent disease
– 12 were previously untreated
 Response
– ORR was 100%
– 9 patients (41%) with CR
– 1 patient (5%) with CRu
– 12 patients (54%) with PR
– 9 patients who relapsed did so a median of 9 months from initiation
of therapy
 Repeat treatment with rituximab in 3 of the relapsed
patients resulted in one CR and two with stable disease

Blood 2003;101:485-489
 SGN-30
 Anti CD-30 chimeric monoclonal antibody
 Phase II study
– 15 patients with relapsed HL enrolled
– Subjects received SGN-30 6mg/kg IV weekly
for 6 weeks.
– Of the initial 12 patients evaluable for
response, 6 had stabilization of disease for a
mean duration of 4.8 months

ASH Annual Meeting Abstracts 2004;104:2635

ASCO Annual Meeting Proceedings 2005;23:2553[Abstract]
 MDX-060

 Anti-CD30 antibody
– binds to a different epitope than does SGN-30
 Phase II
– 27 patients were treated with MDX-060 10mg/kg or 15
mg/kg IV weekly for 4 weeks
– One patient in the phase II cohort developed grade 3/4
pulmonary toxicity (pneumonia/ARDS); otherwise the
drug was extremely well tolerated
 Responses
– Among the 40 HL patients, 1 CR and 2 PR
ASH Annual Meeting Abstracts 2003;102:Abstract 632
ASH Annual Meeting Abstracts 2004;104:Abstract 2636
 Bortezomib
 CD30+ HL cell lines
– bortezomib exhibited antiproliferative effects, induced
cell cycle arrest and caused apoptosis
 Clinical trial: pilot study
– single-agent bortezomib in 14 heavily pretreated
patients with relapsed HD
– Dosing: 1.3 mg/m2 IV on days 1, 4, 8, 11 every 21 days
– Toxicities
 one event of neutropenic fever and one of dyspnea
 Thrombocytopenia was the major hematologic toxicity
– Responses
 1 PR and 2 minor responses

Clin Cancer Res 2004;10:3207-15

ASH Annual Meeting Abstracts 2004;104:2638
Blood 2006;107:1731a-1732
 Follow-Up
 Typical follow-up intervals include
– every 2 to 4 months during the first 2 years
– every 3 to 6 months during the 3-5 years
– annually thereafter.

 The most important component of subsequent

follow-up is
– an interim history and physical examination –identify 2/3rd
of relapses.
 Second most productive examination - chest
radiograph - detecting 1/4th of relapses.
 Follow-Up
 Laboratory Studies
– CBC, Platelets & ESR(if elevated during initial diagnosis)
 Every 2-4 months for 1-2 yrs.
 Every 3-6 months for 3-5 yrs.
– TSH annually – if RT to neck
 IMAGING
– Chest X-Ray
 every 6-12 months during first 3-5 yrs
– Abdominal / Pelvic CT
 every 6-12 months during first 3-5 yrs
 Overall Survival

 Stage I - up to 90%
 Stage II - 78 - 90%
 Stage III - 50 - 78%
 Stage IV - 40 - 50%

Advanced / Bulky - cure rate 60-80% with

combination chemotherapy
 Conclusions
• 75-80% of cases are curable in both localized and
advanced stages
 Relapsed HL has a poor prognosis with limited
therapeutic options.
 New targeted therapies hold promise for relapsed
disease
 Development of better prognostics models that
incorporate potential biological markers of HL such
CD30 levels, soluble IL2 receptors, adhesion molecules
CD44 & EBV.
 PET-CT emerging as latest diagnostic modality in
staging, restaging & assessment of treatment response.