FREE ELECTRONIC LIBRARY - Dissertations, online materials

«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 


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.


– 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


• 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.

Similar works:

«The Status of Wild Atlantic Salmon: A River by River Assessment The Status of Wild Atlantic Salmon: A River by River Assessment Table of contents Foreword 1. Introduction 2. Summary of findings 3. Scenarios for the future 4. The biology of Atlantic salmon 5. Threats to salmon populations 5.1 Pollution 5.2 River infrastructure and engineering 5.3 The effect of fisheries on wild Atlantic salmon stocks. 42 5.4 Salmon aquaculture industry 5.5 Stocking and sea-ranching 5.6 Climate change 6. The...»

«Genome instability induced by triplex forming mirror repeats in S.cerevisiae A Dissertation Presented to The Academic Faculty By Hyun-Min Kim In partial fulfillment of the requirements for the degree Doctor of Philosophy in the School of Biology Georgia Institute of Technology May 2009 Copyright 2009 by Hyun-Min Kim Genome instability induced by triplex forming mirror repeats in S.cerevisiae Approved by: Dr. Kirill Lobachev Dr. Nicholas Hud Academic advisor School of Chemistry and Biochemistry...»

«Radiative transfer modelling for sun glint correction in marine satellite imagery Submitted by Susan Barbara Kay to the University of Exeter as a thesis for the degree of Doctor of Philosophy in Biological Sciences In December 2011. This thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been...»

«Biosensors: Introduction Overview A biosensor is a device that in some way makes use of a biological detection system. Biosensing is the process of using biosensors to gather information about living systems. The precise interpretation of the term „biosensing‟ depends on the research domain. In embodied robotics, for example, biosensing is interpreted as the various ways in which natural systems „sense‟ their environments. Understanding these processes is important to this domain as...»

«THEA M. EDWARDS, Ph.D. Sewanee: The University of the South Office: Spencer Hall 176A Department of Biology Office Phone: (931) 598-3167 735 University Avenue Email: tmedward@sewanee.edu Sewanee, TN 37383-1000 EDUCATION B.S. 1991 Virginia Tech, Department of Horticulture, Blacksburg, VA Masters 1994 University of Florida, Department of Environmental Horticulture, Gainesville, FL. Thesis directed by Profs. Terril Nell and Jim Barrett, entitled “Effects of Ethylene on Postharvest Physiology of...»

«International Journal of Comparative Psychology, 2003, 16, 65-84. Copyright 2003 by the International Society for Comparative Psychology Application of Behavioral Knowledge to Conservation in the Giant Panda Ronald R. Swaisgood Zoological Society of San Diego, U.S.A. Xiaoping Zhou, Gwiquan Zhang, Wolong Nature Reserve, China Donald G. Lindburg, Zoological Society of San Diego, U.S.A. and Hemin Zhang Wolong Nature Reserve, China Over the past several years we have developed a research program to...»

«TOHOKU LABORATORY OF SUSTAINABLE UNIVERSITY ENVIRONMENTAL BIOLOGY Molecular identification and epidemiological characterization of cryptosporidiosis and fasciolosis in central Vietnam (ベトナム中部におけるクリプトスポリジウム症および肝蛭症の分子疫学的研究) Nguyen Thi Sam Dissertation submitted in fulfillment of the requirements for the degree of Doctor (PhD) in Agricultural Sciences, 2013 Advisors: Prof. Dr. Yutaka Nakai Dr. Nguyen Duc Tan Laboratory of...»

«Reaction Integration Using Electrochemically Generated Cationic Species Yosuke Ashikari 2013 ii Preface The studies presented in this thesis have been carried out under the direction of Professor Jun-ichi Yoshida at the Department of Synthetic Chemistry and Biological Chemistry of Kyoto University during 2007−2013. The studies are concerned with reaction integration using electrochemically generated cationic species. The author would particularly like to express his sincerest gratitude to...»

«‫ة‬ – ‫ا‬ ‫ا‬ The Islamic University – Gaza ‫دة ا را ت ا‬ Deanery of Higher Education ‫م‬ ‫ا‬ ‫آ‬ Faculty of Science ‫ما‬ ‫ا‬ Master of Biological Sciences Medical Technology Calpain 10 Gene Polymorphism in Type 2 Diabetes Mellitus Patients in Gaza Strip Prepared by Mazen M. El Zaharna Supervisors: Prof. Fadel A. Sharif Dr. Abdalla Abed Submitted in Partial Fulfillment of Requirements for the Degree of Master of Biological Sciences/Medical...»

«Protocols for Surveying and Evaluating Impacts to Special Status Native Plant Populations and Natural Communities State of California CALIFORNIA NATURAL RESOURCES AGENCY Department of Fish and Game November 24, 20091 INTRODUCTION AND PURPOSE The conservation of special status native plants and their habitats, as well as natural communities, is integral to maintaining biological diversity. The purpose of these protocols is to facilitate a consistent and systematic approach to the survey and...»

«The invasive guttural toad, Amietophrynus gutturalis   Nicolas S. Telford       A thesis submitted in partial fulfilment of the requirements for the degree of Magister Scientiae in the Department of Biodiversity and Conservation Biology, University of the Western Cape. Funding provided by the National Research Foundation (NRF) Ethics clearance Ethics clearance for this project was granted by the UWC Ethics Committee 11 September 2013, ref 04/4/10         ‘They have a predilection for...»

«1 Human Papillomavirus: Biology and Pathogenesis José Veríssimo Fernandes1 and Thales Allyrio Araújo de Medeiros Fernandes2 1Federal University of Rio Grande do Norte 2University of Rio Grande do Norte State Brazil 1. Introduction The human papillomavirus (HPV) is one of the most common causes of sexually transmitted disease in both men and women around the world, especially in developing countries, where the prevalence of asymptomatic infection varies from 2 to 44%, depending on the...»

<<  HOME   |    CONTACTS
2016 www.dissertation.xlibx.info - Dissertations, online materials

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.