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Chronic MyelogenousLeukemiaSteven Devine, MD

Associate Professor of MedicineDivision of Hematology/Oncology

The Ohio State University Comprehensive Cancer Center

Epidemiology of CML• In 2008, there will be about 4,800 new cases

of CML and 450 people will die of CML• Median age at diagnosis is 66 years• Age adjusted incidence rate is 1.5/100,000• Incidence is higher in men than women• No difference in incidence based on

race/ethnicity

SEER database 2008

Molecular Etiology of Ph+ CML:Bcr-Abl Structure and Function

Clinical Presentation of Ph+ CML

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Therapeutic options in CML• Historical

Chemotherapy with busulfan or hydroxyureaInterferon alpha +/- Ara-CAllogeneic bone marrow transplantation

• CurrentTyrosine kinase inhibitors (TKI)• First generation

– Imatinib (Gleevec): introduced in 1998

• Second generation– Dasatinib (Sprycel); nilotinib (Tasigna): FDA

approved in last 2 years

Mechanism of Action of Imatinib:Inhibition of Bcr-Abl

Goals of Therapy

Summary of Gleevec Efficacy in Phase II Trials

31 [25, 37]71 [65, 77]95 [92, 96]Hematologic response (%) [95% CI]

21639Complete cytogenetic response (CCR) (%)

7 [5, 11]21 [16, 27]60 [55, 64]Major cytogenetic response (MCR) (%) (95% CI)

75

18

381320

95NANA

Complete hematologic response (CHR)No evidence of leukemia (NEL)Return to chronic phase (RTC)

Study 102: Myeloid

Blast Crisis (n = 260)600 mg n = 223

400 mg n = 37

Study 109: Accelerated

Phase (n = 235)600 mg n = 158

400 mg n = 77

Study 110: Chronic

Phase IFN Failure

(n = 532)400 mg

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Summary of Phase II Trial Results

• Gleevec produced high response rates inPatients with chronic phase disease after failure of IFN therapyPatients with accelerated phase diseasePatients with myeloid blast crisis

• In late chronic and accelerated phase Ph+ CML, 87.8% and 63.8% of patients, respectively, maintained their major cytogenetic response over 2 years

• An estimated 18.3% of all patients with blast crisis were alive 2 years after start of study, with a median survival of 6.9 months

Long-Term Benefit of imatinib for Patients Newly Diagnosed with Chronic

Myeloid Leukemia in Chronic Phase:The 5-Year Update from IRIS Study

Presented by Brian J. Druker, MDOregon Health & Science University, Portland, OR

On Behalf of the IRIS Study Group

Study Design and Current Patient Status

Cumulative Best Response at 12 and 60 Months on First-Line Imatinib

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Event-Free Survival and Survival Without AP/BC on First-Line Imatinib

Annual Event Rates on First-Line Imatinib

Survival Without AP/BC by Level of CyRat 12 Months of First-Line Imatinib

Annual Event Rates in Patients After Achievement of CCyR on

First-Line Imatinib

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Survival Without AP/BC by Molecular Response at 12 Months on First-Line Imatinib

Overall Survival on First-Line Imatinib(ITT Principle)

Grade 3-4 Toxicity to First-Line Imatinib

Discontinuations

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Conclusions• Imatinib is confirmed as the standard first

line therapy for all CML patients.

• Late responses to Imatinib occur andresponses are durable.

• Annual risk of progression is decreasingwith time.

• 89% overall survival at 5 years with Imatinibexceeds that of all other CML therapies with< 5% of deaths related to CML.

Conclusions• Overall risk of progression to advanced phase islow and is associated with the degree of response,regardless of when achieved

How should we monitor patients on Imatinib?

• Perform bone marrow biopsy with cytogenetics and quantitative PCR for bcr/abl at diagnosis

• At onset of treatment, monitor CBC every 2 weeks until counts normalize, then at least every 3 months

• FISH study or cytogenetics of marrow every 3-6 months until complete remission obtained or treament milestone not reached

• If cytogenetic CR obtained, move to quantitative PCR for bcr/abl every 3 months

• Consider repeat marrow biopsy every 1-2 years while in CR

Baccarini et al, Blood 2006NCCN Guidelines V2 2009

Definitions of Failure and Suboptimal Response to Imatinib

Less than complete cytogenetic response

Less than partial cytogenetic response (>35% Ph+)

12 months from diagnosis

Less than partial cytogenetic response (>35% Ph+)

No CHR or cytogeneticresponse

6 months from diagnosis

No complete hematologicresponse (CHR)

No hematologic response3 months from diagnosis

Suboptimal response

FailureTime

Baccarini et al, Blood 2006NCCN Guidelines V2 2009

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Validation of Response Criteria

• Patients failing to meet Leukemia Net/NCCN response criteria associated with worse outcomes

Marin et al, Blood 2008• Based on these criteria as well as drug

tolerability, about one third of patients will be off imatinib within 5 years due to failure or intolerance

De Lavallade et al, J Clin Oncol 2008

Discontinuation of Imatinib in patients achieving a major

molecular response• Three patients described who lost

response within a few months of discontinuation

Cortes et al, Blood, 2004• Recent data relapse may not be the rule in

all patientsRousselot, Blood 2007

von Bubnoff et al. Leukemia. 2003;17:829.

Gleevec Bcr-Abl Clonal evolution

bcr-abl gene amplification/

overexpressionMutations in thekinase domain

Secondary geneticalterations

Cell growth independentof Bcr-Abl activity

Cell growth dependent onreactivation of Bcr-Abl

Mutated Bcr-Abl

Potential Mechanisms of Resistance to Gleevec

Options in Overcoming Gleevec Resistance

• Primary approachesDose escalation/optimizationManagement of adverse eventsNovel agentsCombination therapy

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Targeting Bcr-Abl in Gleevec-Resistant CML:

Rationale• Mutations in bcr-abl may cause varying degrees

of clonal resistance to GleevecBcr-Abl mutants have decreased sensitivityto GleevecThe disease remains Bcr-Abl–driven in patients with Bcr-Abl mutations

• Mutated Bcr-Abl is likely a valid therapeutic targetin Gleevec-resistant CML

Branford et al. Blood. 2004;104:2926.Corbin et al. Blood. 2003;101:4611.von Bubnoff et al. Leukemia. 2003;17:829.

C

Novel ABL inhibitors in clinical trials

N

N

NH

N

CH3

NH

O

F

F

F

N

NH3

N

N

NH

N

CH3

NH N

O

NCH3

Imatinib (STI571) Nilotinib (AMN 107)

Dasatinib (BMS-354825)

30x1x

300x

Binds inactive and active conformations, multitargeted (SRC)

Binds inactive conformation Binds inactive conformation

Dasatinib (BMS-354825)• A novel, orally available tyrosine kinase

inhibitor of BCR-ABL, SRC family kinases, PDGFRa and b, and c-KIT

• ~300 times more potent than imatinib in BCR-ABL inhibition assays

• Active against 19/20 imatinib-resistant BCR-ABL mutants tested in vitro with the exception of T315I [Shah et al, O'Hare et al, Burgess et al]

Nilotinib versus Imatinib:Nilotinib Has Increased Potency and

Selectivity for Abl

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Role of Second Generation TKI in CML

• Dasatinib (Sprycel)For imatinib failure or intolerance• High dose imatinib vs dasatinib

–Kantarjian et al, Blood 2007• As single agent

–Hochhaus et al, Blood, 2007In accelerated or blast phase CML after imatinib• Cortes et al, Blood 2007• Guilhot et al, Blood 2007

Role of Second Generation TKI in CML

• Nilotinib (Tasigna)For imatinib failure or intolerance

• Chronic Phase: Kantarjian et al, Blood, 2007

• Accelerated phase: le Coutre et al, Blood 2008

Dasatinib or Nilotinib for Imatinibresistant/intolerant CML in CP

• Hematologic responses in > 90%• Major cytogenetic responses in 50-60% of

patients• Complete cytogenetic responses in 30-40%

of patients• Failure to attain a major cytogenetic

response within 12 months or any cytogenetic response within 3-6 months may predict overall prognosis

What about using higher doses of Imatinib at diagnosis?

• MD Anderson and Australian Group suggest 600-800mg dose at onset may diminish risk of failure (but how well tolerated?)

Hughes et al, Blood 2008

Kantarjian et al, Blood 2004

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What about using higher doses of Imatinib at diagnosis?

• SWOG A Phase IIb Study of Molecular Responses to Imatinib, at Standard or Increased Doses, or Dasatinib for Previously Untreated Patients With Chronic Myelogenous leukemia in chronic phase

Randomization to Imatinib at 400mg or 800mg or to dasatinib at 100mg dailyPrimary objective–Assess for differences in rate of major

molecular response at 12 months • Roughly 300 patients to be accrued

Key questions in CML patients receiving imatinib

• What do you do with patient in cytogenetic CR who now has a rising bcr/abl transcript level?

Declare them an imatinib failure?Refer for BMT?Increase dose of imatinib?Switch to nilotinib or dasatinib?Send off a mutational analysis?Panic?

• If you switch to a second generation TKI, which one should you choose?

• When is transplantation the right option for the patient?

Does prior Imatinib have any effects on outcomes of

transplantation?• No clear evidence that prior imatinib leads to

higher risk of toxicityJabbour, Blood 2005Oehler, Blood 2007Lee, Blood 2008

• Patients with suboptimal response or loss of response prior to transplant have higher risk of mortality, primarily related to disease relapse

Oehler, Blood 2007

When should an allograft be performed in chronic phase CML?• Should every patient, regardless of age, be first

given a trial of imatinib?• Should patients developing evidence of

resistance to imatinib be taken immediately to transplant or be given a trial of second generation TKI?

• Should patients responding to second generation TKI be followed or taken then to transplant?

• How should young patients (<40 years) responding to Imatinib but requesting transplant be counseled?

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Targeted Therapy of Newly Diagnosed

CML: Future Directions• What is the optimal first-line kinase inhibitor for CML?

imatinib, nilotinib, dasatinib

• Is combination molecular therapy (e.g. imatinib + dasatinib, imatinib + nilotinib) safe and more efficacious than sequential targeted therapy?

• Can strategies be developed to eradicate minimal residual disease (e.g. vaccines, other immunological therapies)?

• What about combinations with other agents (HDAC inhibitors, Aurora kinase inhibitors, hypomethylatingagents, etc)

Conclusions• Imatinib initiated at 400 mg daily remains

the standard of care outside a clinical trial• Patients should be monitored according to

NCCN guidelines • Very reasonable to refer patients upfront to

BMT programs for typing and formulation of overall treatment plan

• Second generation TKI may play significant role as upfront therapies in near future

Chronic Lymphocytic Leukemia

(CLL)

Thomas S. Lin, M.D., Ph.D.Associate Professor of Medicine Division of

Hematology & OncologyThe Ohio State University

Outline• Diagnosis of CLL

Clinical presentationImmunophenotyping (flow cytometry)

• Clinical staging systemMolecular prognostic factors in CLL

• Treatment of CLLClinical criteria for initiating chemotherapy for CLLChemotherapy options for CLLGoals (and limitations) of chemotherapy for CLL

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CLL: Epidemiology• Most common adult leukemia in USA• Median age at diagnosis: 72 years• 12,000-16,000 new cases per year• Patients surviving 5 years: 73% (1998)• Variable clinical course• Responds to therapy but invariably

relapses• Therapy is not curative

CLL: Clinical Presentation• Peripheral blood lymphocytosis

Mature appearing lymphocytesSmudge cellsNo risk of vascular thrombosis (small cells)

• Focus exam on lymph nodes and spleenAdenopathy +/- splenomegaly may be presentHard, rubbery, painless lymph nodes

CLL Cells(Peripheral Blood)

CLL Cells(Bone Marrow)

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CLL cell (L) and Smudge Cell (R)

Smudge Cell

CLL: Clinical Presentation• Anemia or thrombocytopenia may be

presentBone marrow replacement by CLLSplenic sequestrationAutoimmune hemolytic anemia or ITP

• Patients may be asymptomatic or have fatigue and/or weight loss

Many patients are diagnosed incidentallyFever or night sweats suggest aggressive lymphoma

CLL: Potential Complications• Hypogammaglobulinemia

Frequent infections (URI, sinusitis, pneumonia)Replacement IVIGConsider starting chemotherapy

• Evans syndromeAutoimmune thrombocytopeniaAutoimmune hemolytic anemiaTreat with IVIG or steroids, then start therapy for underlying CLL

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Autoimmune Hemolytic Anemia

Diagnosis of CLL• 5000 CLL cells / microliter

• Immunophenotyping of peripheral bloodCD5 (aberrant T cell marker) positive

Negative for other T cell markers (CD2, CD3, CD4, CD8)

CD19, CD20 (dim), CD22 (dim) positive

CD23 positive

Surface Ig (SIg) weakly positive

Rai staging system (USA)• Stage 0: lymphocytosis

• Stage I: lymphadenopathy

• Stage II: splenomegaly

• Stage III: hemoglobin < 11.0 g/dL

• Stage IV: platelet count < 100,000/ml

• Median survival dependent on stageStage 0 Low risk > 10 years

Stage I/II Intermediate 7 years

Stage III/IV High risk 2 - 4 years

Prognostic factors in CLL:Risk stratification

• Clinical staging does not predict time to progression or response to therapy

• Genetic / molecular risk stratificationβ-2-microglobulinInterphase (FISH) cytogenetic analysisIgVH mutational statusCD38 expressionZAP-70 expression

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CLL: β2-microglobulin predicts survival

Pro

porti

on s

urvi

ving

1.0

0

0.8

0.6

0.4

0.2

0.02

Years4 6 8 10 12 14 16 18

Pts Died β2M (μg/ml)445 53 <2.1429 95 2.1-3.0183 53 3.1-4.0175 67 >4.0

Keating, M. Unpublished dataHallek M, et al. Leukaemia Lymphoma. 1996;22:439-447.Sarfati M, et al. Blood. 1996;88:4259-4264.Fayad L, et al. Blood. 2001; 97: 256-263

Cytogenetic Analysis• Traditional metaphase cytogenetic analysis

Requires dividing cells in metaphase (condensed chromatin)Often limited # of metaphases in CLLHowever, do not need specific probes

• Interphase cytogenetic analysisFISH using specific probes to examine 200+ cells in interphase (non-dividing; dispersed chromatin)Greater sensitivity in CLL (low # dividing cells)Only detects abnormalities specifically probed

Metaphase Cytogenetic(karyotype) Analysis

Metaphase FISH cytogenetic analysis

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Interphase FISH CytogeneticAnalysis

Dohner, H. et al. N Engl J Med 2000; 343:1910-1916

Chromosomal Abnormalitiesin 325 CLL Patients

CLL: Cytogenetic Abnormalities

• Del 17p13Loss of p53 tumor suppressor genep53 can be mutated (loss of function) without loss of geneWorst genetic prognosis group in CLL

• Del 11q22-23Loss of ATM (Ataxia Telangiectasia Mutated) tumor suppressor geneLoss of ATM leads to inactivation of p53Poor prognosis

Median Treatment Free Interval and Survival

by Cytogenetics

< 0.00192

493313

9

Median treatment free interval

(mo.)

133Del 13q

111Normal

79Del 11q114Trisomy 12

P value

32Del 17p

Median survival (months)

Cytogenetic abnormality

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IgVH Mutational Status in CLL

• Immunoglobulin heavy chain variable region (IgVH) undergoes hyper-mutation during B cell development

• Mutational status of IgVH predicts clinical outcome in CLL

• Mutated IgVH usually defined as < 97 or 98% sequence homology

• Unmutated IgVH: earlier therapy, poorer response, inferior survival

DNA expression profile by IgVH status:Two different populations of CLL cellsWiestner et al, Blood 101: 4944, 2003

Survival by IgVH mutational statusHamblin et al, Blood 94: 1848, 1999

293 (mutated) vs. 117 months (unmutated)

ZAP-70 predicts outcome in CLL

• Zeta-associated protein (ZAP)-70• 70-kDa T-cell receptor associated tyrosine

kinase• Aberrantly expressed in CLL cells• Surrogate marker of IgVH status• ZAP-70 is generally expressed if IgVH is

unmutated (i.e. ZAP-70 is bad)

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Crespo, M. et al. N Engl J Med 2003; 348:1764-1775

ZAP-70 Expression Correlates with IgVHMutational Status (Panel A) and IgVH

Sequence Homology (Panel B)

Crespo, M. et al. N Engl J Med 2003; 348:1764-1775

ZAP-70 Expression Correlates with Disease Progression (A) and Survival (B) in Patients with

Binet Stage A CLL

Prognostic Factors in CLL: Summary

• Interphase (FISH) cytogenetic analysis is standard of care

Chromosomal abnormalities may change with time

• IgVH status – does not change with timeUseful for risk stratification in clinical trials

• ZAP-70 remains investigationalResults are hard to reproduce

• Tests should be left to oncologist to order

CLL: When to start therapy?• CLL responds to treatment but invariably

relapses. Chemotherapy is NOT curative.

• Early therapy of asymptomatic patients does NOT result in survival benefit.

• More aggressive therapies achieve better response (esp. complete response) rates and progression-free survival, but overall survival benefit is rarely seen.

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Definitions• Complete response (CR): All cancer

(including in the bone marrow) goes away• Overall response (OR): CR + PR (partial

response; >50% reduction in cancer) • Progression free (or disease free) survival

(PFS, DFS): Cancer has not grown (i.e. in remission)

• Overall survival (OS): Patient is aliveCancer can grow back, but patient can receive the same or another therapy and still be alive

Criteria for initiating therapy

• Constitutional symptoms (fatigue, weight loss, fever, sweats, etc.) due to CLL

• Progressive marrow failure (cytopenias)• Autoimmune anemia or thrombocytopenia• Massive or progressive splenomegaly• Massive or progressive lymphadenopathy• Lymphocyte doubling time < 6-12 months

• No data that early therapy of asymptomatic patients achieves survival benefit

Chemotherapy Options in CLL• Alkylators (chlorambucil, bendamustine)

• Purine analogs (fludarabine, pentostatin)

• Monoclonal antibodies (Rituximab, Campath)

• Combination therapy (FR, FCR, PCR)

• Stem cell transplantation (only curative therapy)

Fludarabine 25 mg/m2 d1-5Repeat Q28d x 6-12 m

Chlorambucil 40 mg/m2 d1Repeat Q28d x 6-12 m

Fludarabine 20 mg/m2 d1-5Chlorambucil 20 mg/m2 d1

Repeat Q28m x 6-12 m

Randomize

Symptomatic Un-Treated CL

CALGB 9011Fludarabine vs. chlorambucil

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CALGB 9011Fludarabine: CR 20%,

ORR 63%Response Duration Overall Survival

Rai et al: NEJM 343:1750, 2000

Overall response

Flu vs. Chl in untreated CLL (age > 65)206 pts (193 evaluable); median F/U 41.5 months

Flu Chl86 % 59 %

Complete response 8 % 0 %Prog-free survival 19 mo 18 moOverall survival 46 mo 64 moAlive 54 % 66 %Received salvage Rx 39 % 62 %

What about patients older than age 65?

Eichhorst et al, 2007 ASH (abstract # 629)

Chemotherapy Optionsin CLL

• Alkylators (chlorambucil, bendamustine)• Purine analogs (fludarabine, pentostatin)• Monoclonal antibodies (Rituximab,

Campath)• Combination therapy (FR, FCR, PCR)• Stem cell transplantation (only curative

therapy)

Overall response

Flu vs. Flu/Cy in untreated CLL (age < 65)N = 375 pts (328 evaluable)

Flu Flu/Cy83 % 95 %

Complete response 7 % 24 %Prog-free survival 20 mo 48 mo3-year survival 81 % 80 %All grade 3-4 toxicities 54 % 73 %Treat. related deaths 3 2

Combining Fludarabine and Alkylating Agent

Eichhorst et al, Blood 107: 885 (2006)

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Adding cyclophosphamide improves PFSEichhorst et al, Blood 107: 885 (2006)

Rituximab: An Anti-CD20Monoclonal Antibody

•Genetically engineered chimeric (humanized) murine antibody

•First FDA-approved monoclonal antibody therapy for treatment of cancer

0.0023820% CR

0.00038463% Overall Response

<0.00016745% 2-year PFS

0.00099381% 2-year OS

104179Patients, #

P valueFludara + rituximab

FludaraTrial

CALGB 9011 vs. CALGB 9712:Improved 2-year PFS and OS with FR

Byrd et al, Blood 105: 49 (2005): Retrospective analysis

First-line therapy of CLL• Adding cyclophosphamide or rituximab to

fludarabine improves the response rate, CR rate and PFS

• Unclear if overall survival is impacted• No data that any other therapy is better

than chlorambucil in patients > 65 (majority of CLL patients in community)

• Most studies enroll younger patients –significant selection bias

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Who should be treated?

• Asymptomatic patients with good risk CLL should NOT be treated

• Asymptomatic patients with poor risk CLL (unmutated IgVH, del 11q, del 17p) should NOT be treated except on a clinical trial

• Symptomatic patients should be treatedHigh risk patients should be considered for clinical trials

Relapse: When CLL Returns• Chemotherapy is NOT curative

Patients will eventually relapse

• Cytogenetics should be repeatedPatients will acquire more abnormalities

• Treatment will depend upon:Age and health of the patientDuration of response to prior therapyCytogenetic risk factors

Long Term Considerations• Increased risk of infections

HypogammaglobulinemiaImmunosuppression from treatmentsViral reactivation (HSV, VZV, CMV)Opportunistic infections (PCP, fungus)

• Reduced intensity allogeneic stem cell transplants are potentially curative

Younger or healthier patientsPatients with high-risk CLL

Treatment of CLL:Important points to remember

• Chemotherapy is NOT curativeNo matter how good the CR rate, patients will relapse

• The ultimate goal is improvement in overall survival, not response rate or PFS

• Demographics (age, health) and cytogenetic factors must be considered when interpreting results of clinical studies or picking a therapy

• #1 cause of death is infectionMost treatments are immunosuppressive

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OSU CLL Program• OSU Hematology

Leslie Andritsos MDKristie Blum MDJohn Byrd MDBeth Fischer RNJoseph Flynn MDMichael Grever MDAmy Johnson PhDJeffrey Jones MDThomas Lin MDPhDDavid Lucas PhDMollie Moran RN CNPLarry Schaaf PhD

• OSU College PharmacyMitch Phelps PhD

• OSU PathologyNyla Heerema PhDGerard Lozanski MD

Financial support:National Cancer InstituteLeukemia and Lymphoma Society D. Warren Brown FoundationCLL Research Consortium