Hairy Cell Leukemia

in nutshell
Ahmed Allam A.H. Mohamed.
Assiatant Lecturer, Clinical Oncology
and Nuclear med. Depart.
Assiut University Hospitals
• Hairy cell leukemia is a chronic Lymphoprolifrative
disorder.
• In 1958, Bouroncle et al. used “leukemic
reticuloendotheliosis” to describe the clinical entity now
recognizable as HCL.*
• Eight years later (1966), Schrek and Donnelly also reported
on the same disease and commented on “peculiar cells” that
had numerous short villi and were arbitrarily called “hairy
cells” on phase contrast microscopy. “Hairy cell leukemia”
gained popular and official recognition.**

Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood 1958.
Schrek R, Donnelly WJ. “Hairy” cells in blood in lymphoreticular neoplastic disease and “ flagellated” cells of normal lymph nodes. Blood 1966.
WHO 2008: mature B-cell neoplasms.
• Chronic lymphocytic leukemia/small lymphocytic
lymphoma
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• Splenic lymphoma/leukemia, unclassifiable
• Splenic diffuse red pulp small B-cell lymphoma*
• Hairy cell leukemia-variant*
• Lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia
• Heavy chain diseases
• Alpha heavy chain disease
• Gamma heavy chain disease
• Mu heavy chain disease
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Extranodal marginal zone B-cell lymphoma of mucosa-
associated
• lymphoid tissue (MALT lymphoma)
• Nodal marginal zone B-cell lymphoma (MZL)
• Pediatric type nodal MZL
• Follicular lymphoma
• Pediatric type follicular lymphoma
• Primary cutaneous follicle center lymphoma
• Mantle cell lymphoma
• Diffuse large B-cell lymphoma (DLBCL), not otherwise
specified
• T cell/histiocyte rich large B-cell lymphoma
• DLBCL associated with chronic inflammation
• Epstein-Barr virus (EBV)+ DLBCL of the elderly
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Primary cutaneous DLBCL, leg type
• ALK+ large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Large B-cell lymphoma arising in HHV8-associated
multicentric
• Castleman disease
• Burkitt lymphoma
• B-cell lymphoma, unclassifiable, with features intermediate
• between diffuse large B-cell lymphoma and Burkitt
lymphoma
• B-cell lymphoma, unclassifiable, with features intermediate
between
• diffuse large B-cell lymphoma and classical Hodgkin
lymphoma
• Hodgkin Lymphoma
• Nodular lymphocyte-predominant Hodgkin lymphoma
• Classical Hodgkin lymphoma
• Nodular sclerosis classical Hodgkin lymphoma
• Lymphocyte-rich classical Hodgkin lymphoma
• Mixed cellularity classical Hodgkin lymphoma
• Lymphocyte-depleted classical Hodgkin lymphoma
Epidemiology
• HCL constitutes approximately 2% of all lymphoid
leukemias.
• It is predominantly a male disease, with the male:female
ratio ranging from 4:1 to 7:1.
• The vast majority of affected people are white, with
Ashkenazi Jews being an overrepresented group.
• The median age of onset is in the early fifth decade
Biology:
• In the schema of B-cell ontogeny, the hairy cell
can be considered an activated, late-stage, pre-
plasma cell B lymphocyte.
• Hairy cells display immunoglobulins that are
light-chain restricted, but have multiple heavy-
chain isotypes (IgM, IgD, IgA, and IgG)
• Hairy cells also displayed the pan-B-cell
markers CD19, CD20, and CD22.
Diagnostic tests
Morphology in peripheral blood films:
• approximately twice as large as normal lymphocytes
• Microvilli
• “Fluffy”
• Light basophilic
cytoplasm
• Spongy chromatin
• Folded or oval nucleus
• Inconspicuous nucleoli
 Bone marrow examination:
• B.M aspiration is not a valid method as it is successful in
only approximately 10% of patients.
• definitive diagnosis usually requires a bone marrow
trephine biopsy due to the high frequency of a dry tap on
aspiration
• IHC on paraffin section: TRAP stain, CD20, CD72,
Annexin A1 +, High cyclin D1

Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant,BJH, 2011
 Flow Cytometry:
• either peripheral blood or aspirated bone marrow, flow
cytometric studies can be very helpful.
• Markers of B cells, such as CD19, CD20 and CD22, are
always positive
• Negative for CD5, CD10, CD23
• Strong postive CD11c, FMC7, CD25, CD103

Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant,BJH, 2011
Clinical features
• Patients may be asymptomatic and the disease is
identified because a full blood count is taken for
an unrelated reason.
• Symptoms related to Cytopenias:

• Spleen, liver, and lymph nodes

Treatment
• If the patient is asymptomatic and cytopenias
are minimal, however, it is reasonable to adopt a
watch-and-wait policy.
• Indications of treatment:
- cytopenias associated problems (anaemia,
infections and bleeding.)
- Symptomatic splenomegaly, Hepatomegaly ,
Lymphadenopathy.
History of Treatment Options

Up until mid‐1980s
• Splenectomy: overall survival 4‐6 yrs
• IFNα: 80% response, rare CRs

Mid 1980s: Purine analogs become standard

• Pentostatin.
• Cladribine.

21 century: Anti-CD20 mAb (rituximab)

PURINE ANALOGS: Cladribine
• CdA phosphylated to CdATP DNA strand
breaks, inhibition of DNA synthesis, and cell
death
• The largest series of cladribine in HCL, reported
by Saven et al., included 358 patients,, and
reported 91% CRs and 7% PRs for an OR rate of
98%.*

Saven A, Burian C, Koziol JA, et al. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment.
Blood1998
PURINE ANALOGS: Cladribine cont’d
Cladribine has been delivered in a variety of ways

• Cladribine (2-chlorodeoxyadenosine; 2-CDA)

• 0.14 mg/kg/d as a continuous i.v. infusion for 7 d and
repeat at 6 months if no CR achieved
• 0,14 mg/kg/d as an i.v. infusion over 2 hours for five
consecutive days and repeat at 6 months if no CR achieved
• 0.14 mg/kg/d as an i.v. infusion once weekly for six
consecutive weeks and repeat at 6 months if no CR achieved
• 0.14 mg/kg/d as a sc bolus injection for five consecutive
days and repeat at 6 months if no CR achieved
• 0.14 mg/kg/d as a sc bolus injection once weekly for five
consecutive weeks and repeat at 6 months if no CR achieved
PURINE ANALOGS: Cladribine cont’d
• Cladribine causes suppression of CD4+
lymphocytes for extended periods of time
• Myelosuppression and culture-negative fevers
were the most common acute toxicities
• Co-trimoxazole and aciclovir should be started,
once treatment is completed, to prevent
pneumocystis infections and herpes reactivation
respectively
 PURINE ANALOGS: Pentostatin
• Irreversible ADA inhibitor
• A large cohort of previously untreated patients
had 76% CRs, 3% PRs, and 79% OR*
• Pentostatin :4 mg/m2 every 2 weeks until
maximum response plus one or two extra
injections.
• Measure creatinine clearance before treatment –
avoid if clearance <60 ml/min; halve dose if 40–
60 ml/min.
Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy
cell leukemia: an intergroup study. J Clin Oncol 1995
PURINE ANALOGS: Pentostatin
• Anti-emetics should be given with each injection
prophylaxis
• Cotrimoxazole commenced when the patient
becomes lymphopenic, continued for at least 6
months.
• give a 1.5 litre intravenous fluid infusion with the
drug to reduce renal toxicity
Choice of Purine Analog:
Cladribine vs Pentostatin

• Controversial, institutional decision

• RR, CR rate, 10 yr OS very similar and excellent
• Both prolonged immunosuppression
• Second malignancy risk controversial
• Pentostatin
– Less myelosuppressive if use prolongated dosing
• Cladribine
– Ease of administration
– CD4 recovery time: 40 months (2‐CdA) vs 54
months (pentostatin)
Hairy Cell Leukemia: Definition of CR

• Recovery of cytopenias for >1 month

• No evidence of HCL in blood by morphology
• Resolution of organomegaly
• Asymptomatic from their disease
• In CR, immunohistochemistry reveals no clustering
(>3 cells) of CD20-positive or DBA.44- positive cells
*** MRD may still persist…
– Presence of HCL by flow, IHC, or PCR despite
above criteria
PR is defined as:

• a normalization of cytopenias
• a minimum 50% improvement in both
organomegaly and bone marrow infiltration
• No circulating hairy cells.
Treatment at relapse
• The majority of relapsed patients achieve second
remission when re-treated with either
pentostatin or cladribine.
• Choice of agent at relapse may depend on the
duration of first remission: if short, i.e. <1 year,
use the alternative agent; if longer (>1 years)
retreat using the same agent
Rituximab
• Rituximab has been an effective salvage therapy for
relapsed and/or refractory HCL
• Study treated 15 relapsed and/or refractory patients
with rituximab 350mg/m2 for eight consecutive
weeks. OR rate was 80%, including eight CRs, two
CRs with minimal residual disease, and two PRs.*
• A retrospective study evaluated eight patients who
had relapsed HCL to prior purine analog therapy. All
eight patients received salvage therapy with
rituximab in combination (either sequential or
concomitant) with a purine analog. The OR rate was
100%, including 87.5% CRs**
Thomas DA, O’Brien S, Bueso-Ramo C, et al. Rituximab in relapsed or refractory hairy cell leukemia. Blood2003
ElseM, OsujiN, Forconi F, et al. The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory
hairy cell leukemia. Cancer 2007
interferon alpha
• The role of interferon alpha is nowadays limited
to patients who present with severe
pancytopenia and for whom there is a pressing
need for cell count recovery as quickly as
possible.
• A regimen of 3 mega-units three times a week
will gradually improve blood counts and
facilitate the subsequent use of either nucleoside
analogue.
BL-22 recombinant immunotoxin
• BL-22 is a recombinant immunotoxin composed of an
anti- CD22 variable domain fused to a fragment of
pseudomonas exotoxin.
“The art of medicine consists of amusing the patient while nature cures the disease.”
Voltaire
Paint: hygeia( ancient greek Goddess of good health, cleanliness, and sanitation) for
Gustave Klimt