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 and Medicinal Chemistry Co-Director, Division of Hematology-Oncology Associate Director for Translational Research The Ohio State University Comprehensive Cancer Center Presenter Disclosure Information Chronic Lymphocytic Leukemia The following relationships exist related to this presentation: Dr Byrd serves as a consultant for Calistoga Pharmaceuticals and has stock options in this company. Dr Byrd has a use patent on the application of flavopiridol in CLL. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. The most prevalent type of adult leukemia Defined by CD5, CD19, CD20, CD23, sig (dim)+ cells in blood; < 5 x 10 9 /L cells is monoclonal B-cell lymphocytosis (MBL) 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 service- connected status Genetic predisposition present, with approximately 10% of patients having a first-generation relative with CLL 3 Audience Response Question? A 54-yo malpractice attorney with kidney stone is found to have WBC 15.9 x 10 9 /L with 78% lymphs with smudge cells. Normal physical exam, hemoglobin, and platelet count. Of these tests, which is least useful in determining diagnosis or predicting outcome? 1. Flow cytometry 2. Interphase cytogenetics (FISH) 3. IgV H mutational analysis 4. Lymphocyte doubling time 5. Bone marrow biopsy and aspirate The Big Question at Diagnosis in Asymptomatic Patient How will this bad leukemia influence my quality of life and life expectancy? Stage not helpful to the individual with CLL; many retrospective biomarkers predicting time to first treatment 1
CLL Outcome From Diagnosis by Interphase Chromosomal (FISH) Abnormalities Survival: IgV H Gene Mutation Status and CD38 Expression as a Surrogate for This Abnormality % Pts Median Time to Treatment (mo) Median Overall Survival (mo) del(17)(p13.1) 7 9 32 del (11)(q22.3) 18 13 79 24.5 yrs Trisomy 12 16 33 114 del(13)(q14) 55 49 133 None Detected 18 92 111 9.75 yrs Döhner H, et al. N Engl J Med. 2000;343(26):1910-1916. Hamblin TJ, et al. Blood. 1999;94(6):1848-1854. ZAP-70 as a Surrogate Marker of V H Mutational Status Ig-mutated CLL Relative expression Ig-unmutated CLL ZAP-70 Probability of Progression (%) ZAP-70 Expression Predicts Early Progression and Short Survival in CLL Risk of Disease Progression Years After Diagnosis Likelihood of Survival 100 100 < 20% ZAP-70 positive cells 90 90 20% ZAP-70 positive cells 80 80 70 70 60 60 50 50 < 20% ZAP-70 positive cells 20% ZAP-70 positive cells 40 40 30 20 30 P =.009 20 P =.01 10 10 0 0 14 16 32 36 0 2 4 6 8 10 12 0 4 8 12 16 20 24 28 Probability of Survival (%) Years After Diagnosis Rosenwald A, et al. J Exp Med. 2001;194(11):1639-1647. Wiestner A, et al. Blood. 2003;101(12):4944-4951. Crespo M, et al. N Engl J Med. 2003;348(18):1764-1775 Problem: ZAP70 not measurable in real practice German CLL Study Group Prospective Validation of New Genetic Markers Randomized phase III study of early versus late Rx with fludarabine for patients with high-risk (LDT, TK, β 2 M level, and diffuse marrow involvement) Evaluation of untreated group in both high-risk and low-risk patients allows prospective assessment of new and old prognostic factors. «Short PFS in del(11q22.3), del(17p13.1) and +12 pts «Shorter PFS in patients with IgV H un-mutated disease «del(11q22.3) with IgV H un-mutated disease (20% versus 2%) 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 My Initial Work-up of CLL Patients All patients at diagnosis: «Flow cytometry to confirm CLL diagnosis «Interphase cytogenetics looking for del(17)(p13.1) and del(11)(q22.3) which portend for more aggressive disease «Unmutated V H gene status assessment (good lab) «B 2 M «Many other markers worthwhile but require further validation ZAP-70 expression by flow cytometry not reliable Bone marrow biopsy and aspirate not necessary in absence of cytopenias 2
Audience Question 1 (Post)? A 54-yo malpractice attorney with kidney stone is found to have WBC 15.9 10 9 /L with 78% lymphs with smudge cells. Normal physical exam, hemoglobin, and platelet count. Of these tests, which is least useful in determining diagnosis or predicting outcome? 1. Flow cytometry 2. Interphase cytogenetics 3. IgV H mutational analysis 4. Lymphocyte doubling time 5. Bone marrow biopsy and aspirate Audience Question 2? A 59-yo malpractice attorney with stage 0 CLL diagnosed 2 years ago with IgV H unmutated, del(11q) disease. Over the past year, WBC has risen from 25 to 190 x 10 9 /L with onset of anemia (10.5 g/dl), low platelet count (80 x 10 12 /L), and 10-cm spleen tip. What is the best management strategy for this patient? 1. Fludarabine, cyclophosphamide, and rituximab 2. Fludarabine, rituximab 3. Pentostatin, cyclophosphamide, and rituximab 4. Chlorambucil 5. CHOP-R chemotherapy History of CLL Therapy: 1970-2010 Treat only when patients meet IWCLL 2008 criteria with symptoms Chlorambucil ± prednisone-historical therapy with response (30%-89%) varying upon dose Fludarabine: Higher CR, ORR, and PFS compared with alkylator therapy; outcome not improved in patients > 65 years Fludarabine/cyclophosphamide combinations: Improved CR, ORR and PFS as compared to fludarabine in three studies Chemoimmunotherapy with addition of rituximab: Improved CR, ORR, and PFS compared with FC Alemtuzumab and bendamustine: New therapies with improved CR and PFS compared with chlorambucil CALGB 9712: A Randomized Phase II Study of Rituximab + Fludarabine 104 symptomatic untreated CLL patients randomized Fludarabine 25 mg/m 2 days 1-5 6 28-day cycles 4 weekly doses rituximab 375 mg/m 2 Sequential Arm ORR 77%, CR 28% Byrd JC, et al. Blood. 2003;101(1):6-14. Fludarabine + rituximab 375 mg/m 2 two days during cycle 1, day 1 of cycle 2-6 6 28-day cycles 4 weekly doses rituximab 375 mg/m 2 Concurrent Arm ORR 90%, CR 47% Long-term Outcome of CALGB 9712 Long-term Outcome CALGB 9712 Extended remission duration and overall survival as compared to historic results with fludarabine monotherapy Less optimal results in high-risk genomic patients «IgV H un-mutated patients «del(11q22.3) and del(17p13.1) patients Complications with this regimen minimal «No unusual infections «No secondary MDS or AML during follow up «No increased risk of Richter s transformation Very reasonable therapy for low risk CLL patients Woyach JA, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 539. Probability of Survival 0.0 0.2 0.4 0.6 0.8 1.0 Median F/U for PFS: 90.4 months (n = 42) Median F/U for OS: 92.2 months (n = 17) OS Median OS 85 months PFS Median PFS 42 months n = 104 0 12 24 36 48 60 72 84 96 108 120 Woyach JA, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 539. Months 3
Fludarabine, Cyclophosphamide, and Rituximab in Previously Untreated CLL Three-day MDA FC regimen with addition of rituximab repeated q 28 days for 6 cycles of therapy 300 patients enrolled with 36% being Rai stage III/IV Well-tolerated with 75% of patients finishing therapy and low frequency of infectious morbidity (2.6% of courses) Responses noted in 95% of patients, including 70% CR rate and extended PFS as compared to historical FC controls 69% of CR patients attained CD19/CD5- flow cytometry status which is predictive of extended PFS Keating MJ, et al. J Clin Oncol. 2005;23(18):4079-4088. Long-term Follow-up FCR At a median f/u of 72 months, actuarial 6- year OS is 77%, whereas PFS is 51% Recurrent late cytopenias occurred in 69 (28%) pts usually in first year remission Opportunistic infections 10% year 1; 4% year 2; infection risk < 1.5%/yr beginning 3 rd year Richter s syndrome in 6 patients (2%) Secondary MDS and AML in 8 patients (3%) Tam CS, et al. Blood. 2008;112(4):975-980. Long-term Follow-up of FCR Versus Other Regimens at MDA CLL8 Study Design 6-year survival 54 % 59 % 77 % 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 Updated results of the 2nd analysis Median observation time 37.7 months Followup Tam CS, et al. Blood. 2008;112(4):975-980. Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. CLL8: Adverse Events CTC Grade 3 & 4 CLL8: Response to Treatment FC FCR P Total number of patients 248 (62.9%) 309 (76.5%) <.0001 with 1 grade 3/4 event Hematological toxicity 39.6% 55.7 % <.0001 Neutropenia 21.0% 33.7% <.0001 Leukocytopenia 12.1% 24.0% <.0001 Thrombocytopenia 11.1% 7.4%.07 Anemia 6.8% 5.4%.42 Infection 21.5% 25.5%.18 Tumor lysis syndrome 0.5% 0.2%.55 Cytokine release syndrome 0.0% 0.2%.32 FC FCR CR* 21.8% 44.1% PR 66.6% 51.0% Overall response rate 88.4% 95.1% *According NCI WG Criteria, confirmatory BM assessment performed up to 6 months after final restaging P < 0.01 Treatment-related mortality 2% for both arms. Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. 4
CLL8: Progression-free Survival CLL8: Overall Survival Median observation time 25.5 months Median PFS: FCR: 51.8 months FC: 32.8 months (N = 790, Hazard ratio 0.563, ranges 0.460-0.689, P <.001) PFS rate 3 yrs postrandomization: FCR: 64.9% FC: 44.7% P<0.001 Overall survival 3 years postrandomization: FCR: 87.2% FC: 82.5% N = 817, HR 0.664, P =.012 Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Abstract 535. Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Abstract 535. CLL8: Conclusions New Chemoimmunotherapy Regimens Addition of rituximab to FC first-line therapy improves the outcome of patients with CLL with regard to: «Response rates (CR, ORR, MRD) «Progression-free survival «Overall survival Majority of cytogenetic groups benefit from FCR except del(17p13.1) and normal karyotype First trial to definitively show a survival advantage with addition of immune therapy in CLL Bendamustine/rituximab (Fischer et al, ASH 2009) 1 «90% ORR, 33% CR Fludarabine, cyclophosphamide, ofatumumab (Wierda et al, ASH 2009) 2 «73% ORR, 50% CR FCR + alemtuzumab or FR followed by alemtuzumab tested with no benefit over historical controls and significant infectious morbidity PCR: No clear advantage over FR or FCR in young patients Hallek M, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Abstract 535. 1. Fischer K, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Abstract 205. 2. Wierda WG, et al. Presented at: 51st American Society of Hematology Annual Meeting and Exposition. December 5-8, 2009; New Orleans, LA. Abstract 535. Abstract 207. How Do Genetics Interact With Treatment? Is the Winner FCR or FR? Patients with del(17p13.1) respond but not as well to FR, FCR, or PCR therapy. Patients with del(11q22.3) have similar response and PFS to FCR and PCR but shorter PFS with FR. Patients with IgV H un-mutated disease have shorter remission with FR, FCR, and PCR. No randomized comparative trial available ORR and CR rate similar to slightly higher with FCR compared with FR PFS with much shorter follow-up similar to slightly higher with FCR vs FR Patients with del(11q22.3) appear to do well with FCR whereas outcomes with FR not as good Less secondary MDS/AML with FR Patients with IgV H un-mutated and del(17p13.1) disease do poorly with FCR or FR 5
My Approach for Patients < 70 Repeat interphase cytogenetics, bone marrow Clinical trial offered to all patients (CALGB 10404) which assigns therapy based on genetics Off trial «Del(17p13.1): FCR or trial followed by nonmyeloablative allogeneic stem cell transplant «Del(11q22.3): FCR «Other genetic features: FR Do not use PCR, BR, alemtuzumab, CLB, or rituximab Audience Question 2 (Post)? A 59-yo malpractice attorney with stage 0 CLL diagnosed 2 years ago with IgV H un-mutated, del(11q) disease. Over past year, WBC has risen from 25 to 190 x 10 9 /L with onset of anemia (10.5 g/dl), low platelet count (80 x 10 12 /L), and 10-cm spleen tip. What is the best management strategy for this patient? 1. Fludarabine, cyclophosphamide, and rituximab 2. Fludarabine, Rituximab 3. PCR 4. Chlorambucil 5. CHOP-R CLL5: Let s Start Over Again in the Elderly Randomized study targeting previously untreated, 65- to 80-yr-old CLL patients; 206 patients enrolled Treatment includes fludarabine 25 mg/m 2 days 1-5 6 months vs CLB 0.4-0.8 mg/kg Q15 days 12 months Outcome: 72% ORR (8% CR) with Flu vs 51% (0% CR) with CLB PFS: 19 months with Flu vs 18 months with CLL OS: 46 months with Flu vs 64 months with Flu Less Flu patients re-treated; borderline increase AIHA (8% vs 2%) and 2 nd malignancies (12% vs 7%) Elderly CLL Therapy No standard therapy agreed upon for this patient population Little clinical trial data available that is relevant to this patient population Fit 70- to 80-year-old can be treated similar to younger patient with careful attention to toxicity Infirmed 70- to 80-year-old and those > 80 years old can be treated with chlorambucil or rituximab Eichhorst BF, et al. Blood. 2009;114(16):3382-3391. Other Important Considerations For Initial CLL Treatment Audience Question 3? Check for prior history of hepatitis B exposure; consider prophylaxis for patients who have positive exposure Adjust fludarabine dose for renal insufficiency; avoid in the setting of renal failure Uncontrolled or prior history of AIHA is not a contraindication to using FCR or FR but ideal to have this under control before treatment Avoid continued treatment if ANC and platelets stop recovering to baseline after each cycle; cumulative myelosuppression with these regimens can be severe 61-yo patient diagnosed 8 years ago with IgV H mutated, del(13q14) disease treated with fludarabine 4 yrs ago with CR, now with slowly progressive LN (> 5 cm), anemia, and fatigue. What is appropriate therapy for this patient? 1.Fludarabine, cyclophosphamide, rituximab 2.Alemtuzumab 3.CHOP-R 4.Lenalidomide 5.Erythropoietin 6
Relapsed CLL REACH Study: R-FC versus FC Favorable Relapsed CLL (our patient) «Minimal therapy with fludarabine, alkylator, or rituximab «Long remission with last therapy «Slow progression of disease when present «Relatively maintained hematopoiesis «Low risk genomic features Unfavorable Referral Center Relapsed CLL «Prior treatment with FCR with short remission (< 2 years) «Rapid progression of disease when present «Genomic instability and high risk karyotype «Richter s syndrome without proof «Poor hematopoietic reserve 552 patients enrolled Relapsed / refractory CLL One previous therapy Binet A, B, C ECOG PS 0 1 FC or prior antibody therapy not allowed R A N D O M I Z E MDA R-FC q4wk 3 MDA FC q4wk 3 R E S T A G E MDA R-FC q4wk 3 CR, PR, (SD) MDA FC q4wk 3 PD off study Outcomes: ORR and CR significantly greater with FCR (70%/24%) than with FC (58%/13%) Median remission time of FCR 30.6 months vs 20.6 months with FC (P = 0.002) Toxicity similar between 2 arms Robak T, et al. J Clin Oncol. 2010;28(10):1756-1765 Bendamustine + Rituximab in CLL How About the Unfavorable Referral Center Relapsed CLL (not our patient) Old Eastern German drug with uncertain mechanism of action Phase II study of B (70 mg/m 2 ) day 1, 2 and R (375 mg/m 2, c1 and 500 mg/m 2, c2) Q28 days 6 cycles in pts with 1-3 prior Rx Mean 4.5 courses administered with grade 3/4 anemia (6%) neutropenia (12%), thrombocytopenia (9%), and infections (4.9%) most common; Rx mortality in 4% of pts ORR 77%; with CR in 14% and PR in 63% of pts; no CR/lower ORR (44%) in del(17p13.1) pts Bendamustine + rituximab an active therapy in early-relapsed CLL, must monitor counts closely «Strategies include: «Alemtuzumab if predominately marrow/spleen/blood disease (no one uses) «Ofatumumab (new CD20 antibody) «Consideration of clinical trial with new agent (What are these?) «Refer for transplant immediately Fischer K, et al. Blood. 2008;112:330 (abstr). Ofatumumab Lenalidomide CD20 antibody with different binding site and improved biologic properties against CLL cells compared with rituximab Administered as 8 weekly infusions of ofatumumab followed by 4 monthly infusions (dose 1, 300 mg; doses 2 12, 2000 mg); 6 months of therapy Overall response rate of 58% for the fludarabine & alemtuzumab refractory and 47% for the bulky LN, fludarabine-refractory group PFS approximately 6 months; OS 14-15 months Cytopenias and infections common; 13 (10%) pts had fatal infections within 30 days of Rx Impact of this over dose-intensive rituximab uncertain Thalidomide derivative with novel properties including innate and d cellular immune activation, stromal cell interaction, apoptosis in subset of cell types; clinical trials in CLL promising Chanan-Khan et al 1 «45 pt relapsed phase II study of lenalidomide 25 mg/day 21 days with 7 days off «47% response including 9% CR «Cytopenias, fatigue, and tumor flare observed; Tumor flare treated with ibuprofen Ferrajoli et al 2 «42 pt relapsed phase II study of lenalidomide 10 mg day with dose escalation to 25 mg as tolerated (median dose 10 mg) «32% response (7% CR) «Cytopenias and tumor flare observed. Tumor flare treated with corticosteroids Tricky to administer due to tumor flare and other toxicities; response takes considerable time ( 6 months) making use in highly refractory patient of little value Coiffier B, et al. Blood. 2008;111(3):1094-1100. Wierda WG, et al. J Clin Oncol. 2010;28(10):1749-1755. 1. Chanan-Khan A, et al. J Clin Oncol. 2006;24(34):5343-5349. 2. Ferrajoli A, et al. Blood. 2008;111(11):5291-5297. 7
Other Active Novel Agents in CLL Audience Question 3 (Post)? Flavopiridol (Alvocidib) CDK inhibitor ABT 263 Bcl-2 antagonist SCH727965 CDK inhibitor GA101 CD20 antibody TRU-016 CD37 SMIP PCI-32765 BTK Inhibitor CAL-101 PI3K-delta inhibitor 61-yo patient diagnosed 8 years ago with IgV H mutated, del(13q14) disease treated with fludarabine 4 yrs ago with CR, now with slowly progressive LN (> 5 cm), anemia, and fatigue. What is appropriate therapy for this patient? 1.Fludarabine, cyclophosphamide, rituximab 2.Alemtuzumab 3.CHOP-R 4.Lenalidomide 5.Erythropoietin Important Conclusions Select genomic studies can assist in risk stratification of newly diagnosed patients. Rituximab chemoimmunotherapy offers a survival advantage for symptomatic CLL. Patients with del(17p13.1) who require therapy have very poor outcomes and should be considered for early aggressive intervention. In the setting of relapsed CLL it is important to consider transplant early. Several promising therapies offer opportunities for improving outcome for pts with CLL. 46 Questions & Answers? 8