CLL: What s New from ASH
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2 CLL: What s New from ASH John C. Byrd, MD D. Warren Brown Chair in Leukemia Research Professor of Medicine and Medicinal Chemistry Director, Division of Hematology The Ohio State University 2
3 Chronic Lymphocytic Leukemia The most prevalent type of adult leukemia Median age of diagnosis of CLL is approximately 72, with only 10% of patients under age 50 More common in men than women (2:1 ratio) Environmental predisposition uncertain, although Vietnam Veterans with Agent Orange exposure warrant serviceconnected status Genetic predisposition present, with approximately 10% of patients having a first-generation relative with CLL No clear gene predisposing to CLL outside of DAPK1
4 Making the Diagnosis of CLL Immunophenotype (flow cytometry) that measures surface markers on CLL cells necessary CD5+,CD19+, CD20+ (dim), CD23+, sig dim+ is typically observed Diagnoses that can appear as CLL without flow cytometry Mantle cell lymphoma Follicular lymphoma Monocytoid lymphoma Hairy cell leukemia LGL leukemia
5 Other Diagnosis with CLL Immunophenotype Small lymphocytic lymphoma Immunophenotype of CLL with presence of enlarged lymph nodes but < 5 x 10 9 /L blood lymphocytes Same biology and natural history as CLL Treatment similar to CLL Monoclonal B-cell Lymphocytosis Immunophenotype of CLL with < 5 x 10 9 /L blood lymphocytes, no lymph node/spleen enlargement Precursor of CLL with 1-2% chance per year of progressing to actual disease of CLL
6 Symptoms of CLL at Diagnosis Majority (80%) of CLL patients will not have symptoms at diagnosis Symptoms can include Fatigue Early satiety (get full after eating quickly) Painful lymph nodes Shortness of breath Petechiae and bleeding Abdominal pain/distension Night sweats (not common) Weight loss (not common)
7 The Big Question at Diagnosis in Asymptomatic Patient How will this bad leukemia influence my quality of life and life expectancy? NCCN Provides Recommendations to Help with This
8 Staging: Predicting Outcome at Diagnosis Clinical Staging (Rai or Binet Staging) Interphase cytogenetics IgV H mutational status Surrogates of IgV H mutational status that translate to biology more exactly Bone marrow not helpful relative to pattern with new prognostic factors
9 Stage at Presentation and Outcome of CLL Rai Stage Clinical Features Percent of Cases Survival Low Risk Lymphocyte Count > 5 x 10 9 /L 30 >10 years Intermediate Risk High Risk Enlarged LN or Organomegaly Hbg < 11 g/dl Plts < 100 x 10 9 /L 60 6 years 10 2 years Rai KR et al: Blood 46: 219, 1975
10 CLL Outcome From Diagnosis by Interphase Chromosomal (FISH) Abnormalities Abnormality % Pts Median Time to Treatment (mo) Median Overall Survival (mo) del(17)(p13.1) del (11)(q22.3) Trisomy del(13)(q14) None Detected Döhner H, et al. N Engl J Med. 2000;343(26):
11 Survival: IgV H Gene Mutation Status and CD38 Expression as a Surrogate for This Surviving (%) IgV H Mutated Unmutated (P=0.0001) Surviving (%) CD38 8 CD38 <30% CD38 30% (P=0.0001) Damle et al. Blood. 1999;94:1840.
12 ZAP-70 Expression Predicts Early Progression and Short Survival in CLL Risk of Disease Progression Likelihood of Survival Probability of Prog gression (%) % ZAP-70 positive cells Years After Diagnosis Probability of Su urvival (%) < 20% ZAP-70 positive cells 50 < 20% ZAP-70 positive cells 40 20% ZAP-70 positive cells Crespo M, et al. N Engl J Med. 2003;348(18): P =.009 P = Years After Diagnosis
13 German CLL Study Group Prospective Validation of New Genetic Markers Prospective study examining each of the new biomarkers in patients at time of diagnosis Prospective study avoids bias of examining samples through out natural history of CLL; this limits reliability of most biomarker studies Multivariate analysis shows IgV H un-mutated, del(11q22.3), del(17p13.1), LDT, B 2 M, and thymidine kinase activity are independent predictors of early progression. Stilgenbauer S et al: German CLL Group 2008
14 Validated Tests That I do in Newly Diagnosed CLL Patients Immunophenotype to confirm diagnosis Interphase cytogenetics for del(13q14), +12, del(11q22.3) and del(17p13.1) IgV H mutational status CD38 expression on CLL cells by flow cytometry ZAP-70 expression by flow cytometry is not reliable nor recommended outside of clinical trials
15 Other Information for Newly Diagnosed Patients Immune deficiency, vaccines, and risk of infections Autoimmune complications Secondary malignancies Richter s Transformation
16 CLL Immune Dysfunction Immune defect in CLL represents major threat to patients B-cells defective with reduced production of IgG, IgA, and IgM resulting in increase frequency of bacterial infections (sinus, lung, urinary tract) T-cells defective that is worsened with disease progression and treatment resulting in increased viral infections (Herpes zoster, Varicella zoster (shingles)) Interventions that can help «Replacement of IgG (immunoglobulin) in subset of pts «Vaccinate to influenza and pneumovax although response poor; prevnar response better «Avoid live vaccines (i.e. Varicella zoster) due to risk of dissemination
17 Autoimmunity and CLL Autoimmune hemolytic anemia (AIHA) «20% of CLL pts; often occurs when disease active «Treated independent of CLL (prednisone, rituximab, cyclosporin, splenectomy) «AIHA developing on fludarabine should not be rechallenged with this Less frequent complications described «Idiopathic thrombocytopenic purpura (ITP)-treated same as AIHA; «Pure red blood cell aplasia (cyclosporin) «Transfusion associated GVHD-irradiate blood products
18 CLL and Secondary Malignancy 10-20% of CLL pts develop secondary malignancy (skin most common) Etiology of 2 o Malignancies Uncertain? Decreased immune surveillance Routine follow-up should include age appropriate screening tests
19 Richter s Transformation 5-10% of patients will develop Richter s Transformation (usually IgV H un-mutated)» Usually large cell lymphoma but rarely can be Hodgkin s disease» Frequent clinical findings include fevers, sweats, elevated LDH and a new focal mass» PET scan is helpful to identify lesion to biopsy» Outcome of Richter s is poor; my approach includes infusion therapy (R-EPOCH) followed by non-ablative stem cell transplant
20 When To Treat CLL? For CLL related anemia (hemoglobin < 11 g/dl) or thrombocytopenia (< 100 x 109/L) At time of developing symptoms definitely referable to CLL (and not another cause) «Night sweats, weight loss, or fevers «Fatigue that limits daily activities «Painful or truly symptomatic lymph nodes or spleen «Poorly responsive autoimmune hemolytic anemia or thrombocytopenia «Rapid lymphocyte doubling time (< 6 months)? High lymphocyte count and frequent infections are not good indications to initiate treatment
21 What to Do Prior to Treatment Detailed exam and routine labs to follow organ and hematopoeitic function Repeat FISH to be sure del(11q22.3) and del(17p13.1) are not present Bone marrow biopsy and aspirate Hepatitis B testing if rituximab therapy planned Individual demarcation also important Fertility in younger patients (male and female) PET scan if Richter s suspected DAT, haptoglobin, LDH, reticulocyte count for anemia CT scan to evaluate abdominal adenopathy if symptoms Quantitative immunoglobulins if frequent infections
22 How Do We Delegate Initial Therapy in the NCCN Guidelines New guideline recognizes importance of rituximab from German CLL8 and REACH trials that are highlighted due to importance to field New guidelines focus on genetic subtypes del(17p13.1) del(11q22.3) Other groups Age and performance status of patient Young versus frail
23 CLL8 Study Design 817 Patients with untreated, active CLL and good physical fitness (CIRS 6, creatinine clearance 70 ml/min) R FCR FC 6 courses C1 C2 C3 C4 C5 C6 Demographics similar between 2 treatment arms Followup Updated results of the 2nd analysis Median observation time 37.7 months Hallek M, et al: Lancet. 376:1164, 2010
24 Summary of this and other FCR pilots Improved response, progression free and overall survival with addition of rituximab demonstrating importance of anti-cd20 antibody Toxicity of this regimen relates to cytopenias, infection, and late myelodysplasia/aml Abrogates poor outcome associated with del(11q23) but not del(17p13.1) Generally applied to younger pts (<70) without significant co-morbidities
25 Initial Treatment of Patients without del(17p) or del(11q): NCCN Guidelines First line therapy for young pt Fludarabine + Rituximab (FR) Fludarabine + Cyclophosphamide + Rituximab (FCR) Pentostatin + Cyclophosphamide + Rituximab (PCR) BR Age > 70 or younger pt with morbidities Chlorambucil ± prednisone Chlorambucil ± ± rituximab BR (bendamustine, rituximab) Rituximab Alemtuzumab Fludarabine ± rituximab Cladribine
26 Initial Treatment of Del(11q22.3) Patients: NCCN Guidelines First line therapy for young pt (alkylator therapy important) FCR PCR BR First line therapy for the frail patient Chlorambucil ± prednisone Chlorambucil ± rituximab BR (bendamustine, rituximab) Reduced-dose FCR Alemtuzumab Rituximab
27 Data for Chlorambucil + Rituximab Phase II study of chlorambucil + rituximab in previously untreated CLL patients CLB 10 mg/m2 days 1-7 every month x 6 Rituximab 375 mg/m 2 month 1 and 500 mg/m 2 months 2-6 Pts with good response could receive 6 additional cycles of chlorambucil Overall response rate of 82% with 9% CR rate and 15% npr Median PFS 23.5 months with short follow up Toxicity mainly due to cytopenias and infection Hillmen P, et al: ASH 2010 (abstr 697)
28 Initial Treatment of Del(17p13.1) Patients: NCCN Guidelines First line therapy (None are good!-consider trial) FCR (fludarabine, cyclophosphamide, rituximab) FR (fludarabine, rituximab) HDMP (high-dose methylprednisolone) + rituximab Alemtuzumab rituximab Bendamustine rituximab Non-ablative stem cell transplant should be considered for this patient group in first remission if this is a feasible therapy
29 Treatment of Relapsed CLL Same IWCLL criteria used to initiate therapy in relapsed CLL patients Similar prognostic factors are predictive of response in relapsed disease Survival following relapse after receiving chemoimmunotherapy is short «Following FCR 30 months «Following FR 45 months Non-ablative stem cell transplant should be considered in most of these patients after 2 nd or 3 rd treatment
30 Non-Ablative Allogeneic Transplant in CLL Transplant with traditional ablative regimens carry a 40-50% 100 day mortality in CLL patients age making application minimal in past Non-ablative transplant with immunosuppressive therapy followed by administration of donor cells significantly lowers 1-year mortality (10-20% at year 1) Non-ablative transplant approach to regular transplant (despite curative potential) «Patients with significant adenopathy (> 5 cm) have high incidence of relapse «Chronic graft versus host disease represents big problem in many patients (40-50%)
31 Chemoimmunotherapy Strategies in Relapsed CLL FCR treatment 70% response with 24% complete remission and 31 month average response duration (works less versus del(17p)) Bendamustine/rituximab (BR) 77% response with 14% complete remission; cytopenias most problematic (efficacy in del(17p) pts less) Lymphoma regimens generally not effective for CLL unless Richter s transformation present R-EPOCH R-ICE R-CHOP R-CVP
32 Ofatumumab CD20 antibody with improved biologic properties against CLL cells versus rituximab 206 pt study with fludarabine/alemtuzumab refractory or fludarabine/bulky refractory CLL Response rate of 51% for the fludarabine & alemtuzumab refractory and 44% for the bulky LN, fludarabine-refractory group PFS approximately 5.5 months; OS months Does not work (14% response) in del(17p13.1) pts with bulky LN Wierda WG, et al: J Clin Oncol. 2010;28(10): Wierda WG et al: ASH abstr 921, 2010
33 Alemtuzumab Humanized antibody that targets CD52 that is on most normal immune cells Effective in fludarabine-refractory CLL with 33% response rate; favorable features of response include «Absence of lymph nodes > 5 cm «Performance status 0-1 Toxicities of alemtuzumab have limited use «Infusion toxicities (particularly with IV formulation) «Opportunistic infections due to depletion of T-cells Supportive care includes prophylaxis for PCP and VZV infections and CMV monitoring (or prophylaxis)
34 Other Active Agents in Clinical Trials Lenalidomide-immune modulating agent TRU-016 CD37 SMIP PCI BTK Inhibitor CAL-101 PI3K-delta inhibitor Flavopiridol (Alvocidib) CDK inhibitor SCH CDK inhibitor ABT 263 Bcl-2 antagonist GA101 CD20 antibody
35 Lenalidomide Immune modulating agent FDA approved for the treatment of MDS and multiple myeloma Early studies reported 31-47% response rate including CRs in small proportion of pts Tumor flare/tls identified to be DLT making widespread use in CLL problematic Company sponsored phase 1 study beginning at low dose (2.5 mg) with escalation to 20 mg over several months shown to be feasible 12% response rate with PFS 5.5 months suggesting only modest activity at low doses Wendtner C, et al: ASH abstr 1376, 2010
36 Other Applications of Lenalidomide in CLL Therapy Consolidation after PCR chemoimmunotherapy where 4 of 34 pts improved response and PFS over historical controls (Shanafelt et al; ASH abstr 1379, 2010) Combination with chemotherapy (difficult) Combination with antibody therapy (rituximab)- CRC study Early intervention treatment in high risk patients to boost vaccine response
37 TRU-016 in CLL TRU-016 is an peptide therapy (small modular immune pharmaceutical-smip) with properties similar to a monoclonal antibody Targets CD37 which is expressed relatively selectively on mature B-cells Phase I dose escalation study that included 56 pts demonstrates favorable tolerability at all dose levels tested Best responses in less treated pts (2 or <) 44% PR including del(17p) Combination based therapies being pursued with this Furman R, et al: ASH 2010 (abstr 56)
38 PCI32765 in CLL PCI32765 is an oral agent that targets Bruton s Tyrosine Kinase (BTK) Bruton s tyrosine kinase is essential for B-cell activation, and proliferation, and microenvironment signals Phase IA and IB study in CLL presented including 54 pts Response to therapy remarkable 34 of 39 (88%) with node/spleen response 38% response overall due to transient lymphocytosis produced by this class of drugs Only 4 pts off therapy due to PD! Toxicity profile modest (diarrhea, N/V, fatigue) with minimal myelosuppression Burger J, et al: ASH 2010 (Abstr 57)
39 CAL-101 in CLL CAL-101 is an oral agent that targets PI3K-delta PI3K-delta is essential for B-cell activation, and proliferation, and microenvironment signals Phase I study of CAL-101 in CLL/NHL presented with focus on CLL pts (n=31) Response to therapy remarkable 91% with node/spleen response 33% response overall due to transient lymphocytosis produced by this class of drugs Toxicity modest (LFT abnormalities, pneumonia) Furman R, et al: ASH 2010 (abstr 55)
40 Significance of PCI32765 and CAL-101 Similar to imatinib in chronic myeloid leukemia, these agents target an enzyme that is necessary for B-cell development and growth Therapy with CAL-101 and PCI32765 will be both cytoreductive and suppressive with patients being on continuous therapy Dramatic, durable responses in many patients point to significant promise of these agents Clinical trials with these agents will ultimately define their importance to changing natural history of CLL
41 Flavopiridol in CLL Cyclin dependent kinase inhibitor reported to have activity in refractory and high risk CLL Pivotal study reporting efficacy in multi-center trial 108 pts treated with 30% response rate in those evaluable for response Response noted in del(17p), del(11q) and bulky LN pts Major toxicity of this treatment tumor lysis syndrome, neutropenia, infection, and diarrhea First demonstration that this treatment can be given in multi-center trial Lanasa M, et al: ASH Abstr 58, 2010
42 Other Abstracts on Flavopiridol Flavopiridol effective in high risk genomic CLL Flavopiridol can be safely administered in elderly CLL pts (age 70 or >) Flavopiridol is effective at bridging patients to allogeneic stem cell transplant Flavopiridol + Lenalidomide combination in CLL Factors predicting development of tumor lysis syndrome in CLL pts receiving flavopiridol
43 Dinaciclib (SCH727965) in CLL Cyclin dependent kinase inhibitor with preclinical data supporting favorable therapeutic agent Phase I dose escalation study in relapsed and refractory CLL Activity seen at all dose levels tested Dose limiting toxicity pneumonia and tumor lysis syndrome 15 of 33 (45%) pts with response to therapy Toxicity tolerable with many pts on therapy for a prolonged time as predicted by pre-clinical work Flynn J et al: ASH Abstr 1396, 2010
44 Other Active Agents in CLL ABT263 Bcl-2 antagonist with single agent activity in CLL Promotes thrombocytopenia/t-cell lymphocytopenia In combination studies with FCR, BR, and rituximab GA-101 Type 2 anti-cd20 antibody that is engineered to recruit immune system to tumor cells better Single agent study in relapse CLL shows activity Ongoing studies as monotherapy in previously untreated CLL and in combination with FCR and CLB
45 Question-and-Answer Session
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Update on Management of CLL. Presenter Disclosure Information. Chronic Lymphocytic Leukemia. Audience Response Question?
Welcome to Master Class for Oncologists New York, NY May 14, 2010 Session 5: 4:20 PM - 5:00 PM Update on Management of CLL John C. Byrd, MD D Warren Brown Professor of Leukemia Research Professor of Medicine
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