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«Megan O’Meara, M.D. Heme Fellows Conference January 28, 2011 Faculty Advisor: Paul Hendrie, MD, PhD First, a Clinical Vignette. ...»

Hairy Cell Leukemia: 

A Review of Underlying 

yg

Biology and Treatment

Megan O’Meara, M.D.

Heme Fellows Conference

January 28, 2011

Faculty Advisor: Paul Hendrie, MD, PhD

First, a Clinical Vignette…

First, a Clinical Vignette…

TE is a 60M from Kodiak, Alaska.

HPI: Presented to PMD with night sweats, early satiety, LUQ pain.  No fevers, 

infections, or bleeding/bruising.  PMH otherwise unremarkable

PE: VS normal. Well‐appearing. Palpable splenomegaly 25 cm below L costal  margin.  No LAD, hepatomegaly, skin changes.

LABS: WBC 3.3, ANC 2, Hct 41%, plts LABS: WBC 3 3 ANC 2 Hct 41% plts 69K CT Abdomen: 36cm spleen. No lymphadenopathy.

Peripheral Blood Flow Cytometry:  42% population of cells with abnormal expression of CD11c, CD25 (low),  CD20(bright), CD19 (bright), CD103, CD5 (low to absent), and normal expression of  CD45 and CD38 without CD10 CD45 and CD38 without CD10.

HAIRY CELL LEUKEMIA OUTLINE 

– Basics and Epidemiology – History – Morphology and Pathogenesis – Clinical characteristics Clinical characteristics – Diagnostic workup – Th Therapeutic options ti ti Hairy Cell Leukemia Hairy Cell Leukemia

• Rare Indolent B cell neoplasm Rare Indolent B cell neoplasm – 2% of all leukemias – 600 new cases in US/yr 600 new cases in US/yr – Splenomegaly, cytopenias, marrow fibrosis – “H i “Hairy cells” found in blood and marrow ll ” f d i bl d d Positive for CD19, CD20, CD22  Neg for CD5 CD10 CD23 for CD5, CD10,  CD23 Strong CD11c, FMC7, CD25, CD103 History of Hairy Cell Leukemia History of Hairy Cell Leukemia

• First reported by Ewald 1923 First reported by Ewald, 1923 RE cells in blood “Leukemic Reticuloendotheliosis” Was actually describing an AML case

• Bouroncle et al, 1958 26 case series 26 case series  Distinct clinical and pathologic features

• Schrek & Donelly, 1966 Hairy cells in blood Flagellated cells in LN and spleen  “Hairy Cell Leukemia” Hairy Cell Morphology Hairy Cell Morphology

• Microvilli • “Fluffy”

• Light basophilic  cytoplasm

• Spongy chromatin

• Folded or oval Folded or oval  nucleus

• Inconspicuous  p nucleoli ASH Image Bank Hairy Cells: Diagnostic Assays

• TRAP stain

• Flow Cytometry Positive for CD19, CD20, CD22  Neg for CD5, CD10,  CD23 Strong CD11c FMC7 CD25 CD103 Strong CD11c, FMC7, CD25, CD103

• IHC Annexin A1 + High cyclin D1

• Clonal Cytogenetic Abnormalities  40% chr 5.  Also Chr 7 or 14.

Translocations uncommon

• Molecular Studies Molecular Studies Ig heavy chain rearrangement ASH Image Bank What is the Cell Origin of HCL?

What is the Cell Origin of HCL?

• HCL: Late clonal B cells HCL: Late clonal B cells – No discrete B cell  development stage  – Mutated VH genes  – Post‐germinal center B cell – Related most to memory cells  ld ll on gene expression array

• Etiology unclear Etiology unclear – Environmental exposures:

Pesticides/Fuel/Agent orange?

/ /g g Basso et al J Exp Med, 2004 Wh A H i C ll H i ?

Why Are Hairy Cells Hairy?

• Microfilamentous cell  surface projections

•UUpregulation of actin li fi and pp52 (Miyoshi et al,  Leuk Res 2001) Res 2001)

• Reversible with IFNα

• Growth pathways Growth pathways  linked with morphology

–  –  –

ASH Image Bank

HCL Pathophysiology:

HCL Pathophysiology:

Bone Marrow Fibrosis – Autocrine/paracrine – FGF2 – IL‐3R and FLT3  overexpression – Fibronectin synthesis by HCL – Interaction with stromal hyaluronan – Fine reticulin fibers – “Dry tap” ry tap ASH Image Bank

HCL Pathophysiology:

Splenomegaly l l SPLEEN

• White pulp obliterated

• Red pulp replaced with HCs Red pulp replaced with HCs

• Vascular channels and anemia “pseudosinuses” and “red cell pooling”  (aka “blood lakes”) via adhesion molecules ( k “bl d l k ”) i dh i ll

• Invasion and homing defects splenic vitronectin and other  p chemoattractants

• Lack of fibrosis no hyaluronan in spleen no hyaluronan in spleen

–  –  –

ASH Image Bank HCL Pathophysiology

LYMPH NODES

• Not typically involved

• LNs lack L‐selectin

• HCs lack CCR7

• Abdominal LNs can be  involved in late disease

–  –  –

TNFα, GM‐CSF: cell survival • M‐CSF: chemotaxis • FGF: fibronectin production FGF: fibronectin • TGFβ: bone marrow suppression and fibrosis • Other HCL Cytokine Effects on Blood Cells

• Pancytopenia

• Monocytopenia

• T Cell Abnormalities Reversed CD4:CD8 ratio Reversed CD4:CD8 ratio • Skewed T cell repertoire • Clonally expanded T cells not HC‐specific yp p • Increased incidence LGL leukemia • HCL and Autoimmunity HCL and Autoimmunity Seen in many NHLs Seen in many NHLs • Often improves/resolves with HCL treatment • Vasculitis most common most common • Others • – Hemolytic anemias (WAIHA CAIHA) Hemolytic anemias (WAIHA, CAIHA) – ITP – Evan’s Syndrome Evan s Syndrome – IgA nephropathy – Demyelinating neuropathy Demyelinating neuropathy Epidemiology and Etiology • 2% of all leukemias – 400 to 600 new cases in US/yr HCL Clinical Presentation HCL Clinical Presentation





• Presentation – Male:Female 4:1 – White:Non‐White 3:1 – Median age 52

• Symptoms:

Abdominal fullness: 25% – Systemic complaints: 25% – Bruising/bleeding or recurrent infection: 25% Br ising/bleeding or rec rrent infection 25% – Asymptomatic: 25% –

• Exam:

– Splenomegaly: 90% – Hepatomegaly and LAD uncommon – Other:  soft tissue infiltration, vasculitic rash, ascites, effusion HCL Laboratory Findings HCL Laboratory Findings • 60‐80% present with pancytopenia 60 80% present with pancytopenia – Anemia: 85% – Thrombocytopenia: 80% yp – Neutropenia: 80% – Monocytopenia: 80% yp – Azotemia: 30% – Hypergammaglobulinemia: 20% – Abn LFTs: 20% – Leukocytosis: 10‐20%

–  –  –

• Mid 1980s:  Purine analogs become standard Pentostatin shown to improve CRs (Spiers et al, Kraut et al) Cladribine high CR rate with a single 7d course (Piro et al)  PURINE ANALOGS: Cladribine

• CdA phosphylated to CdATP  DNA t d b k i hibiti DNA strand breaks, inhibition of DNA synthesis,  f DNA th i and cell death  • 7‐day continuous infusion or 5‐day bolus equivalent 7 day continuous infusion or 5 day bolus equivalent

• The evidence:

Piro et al, 1990: 11/12 pts CR p – Estey et al, 1992: 36/46 pts CR – Others: 76‐91% CR rate – L Largest series: Cheson et al, JCO 1998 t i Ch t l JCO 1998 – 50% CR, 37% PR, 4yr OS 86% PURINE ANALOGS: Pentostatin PURINE ANALOGS: Pentostatin

• Irreversible ADA inhibitor Irreversible ADA inhibitor

• Variable dose regimens, longer duration

• ECOG study 1992:

COG d 992 – 50 pts (5mg/m2/d IV x 2d q2wks until max response)  – ORR 84%, CRR 64% – Max response within 6 mo

• Similar results with lower dosing regimens

• Typically effective in IFNα‐refractory disease Typically effective in IFNα refractory disease

Choice of Purine Analog:

Cladribine vs Pentostatin

• Controversial, institutional decision

• RR, CR rate, 10 yr OS very similar and excellent

• Both prolonged immunosuppression Both prolonged immunosuppression – PCP proph, HZV risk

• 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) i) Is There Still a Role for Splenectomy or IFNα?

p y

• Splenectomy p y – Improves cytopenias; No path. remissions – Median response 20 months Median response 20 months – Role in splenic rupture/infarct or pregnancy

• IFNα – Improves cytopenias; true CRs uncommon – After p rine analogs as maintenance After purine analogs as maintenance – To improve counts before purine analog (not  routinely used) routinely used) H i C ll L k i D fi iti Hairy Cell Leukemia: Definition of CR f CR Recovery of cytopenias for 1 month • No evidence of HCL in blood by morphology y p gy • Resolution of organomegaly • Asymptomatic from their disease Asymptomatic from their disease • MRD may still persist… • – Presence of HCL by flow, IHC, or PCR despite above  criteria What To Do With MRD?

What To Do With MRD?

Dx via immunophenotyping blood or BM p yp g • Molecular studies: clone specific PCR • May or may not predict future relapse •

MRD eradication:

• – Chemoimmunotherapy 92% success, change in OS  unclear (Ravandi et al Blood 2006) unclear (Ravandi et al Blood 2006) – More clinical trials needed  Unclear what disease characteristics should  determine who should be retreated at time of  MRD… H i C ll L k i R l Hairy Cell Leukemia Relapse

• Disease control but not cure is common – PFS curve for HCL does not plateau • 30‐40% of patients who achieve CR will  relapse within 10 years of initial treatment p y

• Predictors of relapse – MRD?

– Soluble IL‐2R What to do for HCL Disease Relapse?

What to do for HCL Disease Relapse?

• Retreat with purine analog Retreat with purine – Time to CR may dictate whether to switch drugs

• Chemoimmunotherapy: purine analog + Chemoimmunotherapy: purine analog +  rituximab  – ORR 64‐100%, CRR 53‐92%, Molecular RR 70%,, – Regimen unclear: concurrent or sequential – Trial ongoing: Cladribine plus simultaneous vs gg p delayed rituximab – Risks of rituximab: cytokine storm What to Do for Resistant Disease?

What to Do for Resistant Disease?

• Rituximab alone – If contraindication to standard tx – 13‐55% CR

• Al t Alemtuzumab b – HCs CD52+ – Concern re: prolonged immunosuppression o ce e p o o ged u osupp ess o

• HSCT in severe cases

• Other investigational therapies – Rituximab plus pentostatin or bendamustine – Immunotoxin conjugates….

BL22 Immunotoxin Kreitman et al NEJM 2001 Immunotoxin Conjugates

• LMB‐2 – Immunotoxin against CD25  – Some PRs in Phase I trial – 20% HCL CD25‐neg 20% HCL CD25 neg

• BL22 Recombinant immunotoxin against CD22 – Durable remissions in heavily treated pts – 41% CR at 50 months – Later phase testing underway p g y –

• CAT‐8015 – 2nd gen CD22 immunotoxin – Phase I trial dose escalation Phase I trial dose escalation Figure 1 Recommended treatment schema for HCL

Grever, M. R. Blood 2010;115:21-28

Copyright ©2010 American Society of Hematology. Copyright restrictions may apply.

Now, Back to the Case… 60M from Alaska with LUQ pain, splenomegaly, thrombocytopenia, PB flow with 42% hairy cells ‐2005: INITIAL TREATMENT:  5‐day bolus dose cladribine 0.15 mg/kg/d; also bactrim, levofloxacin proph.

‐2006: CBC and spleen size normalized after therapy ‐2007: spleen and CBC still normal. PB flow 5% residual HCs (MRD) ‐2008: Found to have pancytopenia, sent to SCCA Heme Clinic for further care.

‐Seen at SCCA, presenting with fatigue, early satiety, increasing abd girth, night sweats.  Spleen 20cm below L costal margin. BM Bx “dry tap.”  BM Aspirate: 10% HCs (above phenotype).

 RETREATMENT with chemoimmunotherapy, 7 day CI cladribine 0.1 mg/kg/day CI x 7d plus rituximab,  then rituximab maintenance q6mo x 2 years.  *First dose rituximab given over 10 hrs in diluted fashion q y g ‐2009: Achieved CR. Also repeat bone marrow with no MRD.  

–  –  –

‐Jan 2011: Feels great. Still in CR.



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