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’dCladribine 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/refractoryhairy 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.” VoltairePaint: hygeia( ancient greek Goddess of good health, cleanliness, and sanitation) for Gustave Klimt