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Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma

Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma. ASH Review 2012 Stephen Spurgeon (spurgeos@ohsu.edu). Disclosures. Speakers Bureau: GSK, Millenium , Cephalon. CLL: Pertinent Topics. ASH treatment updates James DF, et al. ASH 2011. Abstract 291.

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Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma

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  1. Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma ASH Review 2012 Stephen Spurgeon (spurgeos@ohsu.edu)

  2. Disclosures Speakers Bureau: GSK, Millenium, Cephalon

  3. CLL: Pertinent Topics • ASH treatment updates • James DF, et al. ASH 2011. Abstract 291. • Foa R, et al. ASH 2011. Abstract 294. • Badoux XC, et al. ASH 2011. Abstract 980. • FCR treatment expectations • Fink A, et al. ASH 2011. Abstract 977. • Rational therapeutic targets and novel agents

  4. Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Phase II • Patients with previously untreated CLL (n = 69) • Patients younger than 65 yrs of age: n = 40 • Patients 65 yrs of age or older: n = 29 • Primary endpoint: CR in patients <65 yrs vs. > 65 yrs • Secondary endpoints • Safety, ORR, PFS James DF, et al. ASH 2011. Abstract 291.

  5. Rituximab + Lenalidomide in Previously Untreated CLL: Study Design • Treatment protocol: 7 cycles • Cycle 1: lenalidomide on 21 of 35 days • Cycles 2-7: lenalidomide on 21 of 28 days • Rituximab • 50 mg/m2 on Day 29 of C 1 • 325 mg/m2 on Day 31 of C 1 • 375 mg/m2 on Day 33 of C 1 • 375 mg/m2/wk x 4 for cycle 2 • 375 mg/m2 on Day 1 of C 3-7 • Lenalidomide • Day 1: Starting dose: 2.5 mg/day • Day 8: Escalated to 5 mg/day • Day 1 cycle 3: increase to 10 mg/day • Tumor lysis syndrome prophylaxis with allopurinol 300 mg/day and oral hydration • Thromboprophylaxis (aspirin 81 mg/day) added after 2 cases of pulmonary embolism • Methylprednisolone for tumor flare reaction and growth factor support as needed James DF, et al. ASH 2011. Abstract 291.

  6. Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Efficacy • ORR associated with higher median lenalidomide dose in younger patients (P = .05) • Greater exposure to lenalidomide in younger patients vs older patients James DF, et al. ASH 2011. Abstract 291.

  7. Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Toxicity *P = .05 vs older patients. James DF, et al. ASH 2011. Abstract 291.

  8. Patients with previously untreated CLL (N = 97) Ineligible for first-line R-FC 8 cycles (q 28 days) Primary endpoint: ORR at end of induction ML21445: Rituximab + Chlorambucil Induction Therapy in Elderly Patients observation • Chlorambucil 8 mg/m2/day • Days 1-7 PR, CR • Rituximab • 375 mg/m2 Day 1 of cycle 3 • 500 mg/m2 on Day 1 > C4 R 375 mg/m2 8 wks for 12 doses Foa R, et al. ASH 2011. Abstract 294.

  9. ML21445: Responses *By flow cytometry. Foa R, et al. ASH 2011. Abstract 294.

  10. ML21445: Efficacy • No correlation between treatment response and standard prognostic factors • Pretreatment gene expression differed between responders and nonresponders • Up-regulation of transcripts relevant to pro-proliferative and antiapoptotic pathways, including Ras (K-Ras, N-Ras) and Rho • Up-regulation of genes related to protein metabolism • CD20 down-regulation detected by gene profiling (P = .018 vs responders) but not by flow cytometry (P = .19 vs responders) Foa R, et al. ASH 2011. Abstract 294.

  11. ML21445: Toxicity • Chlorambucil dose reduction required in 7.8 % of cycles • Grade 3/4 Hematologic AEs during induction: • Neutropenia: 19.6% • Thrombocytopenia: (1.0%) • Infections: (1.0%) • Grade 3/4 neutropenia during maintenance: • 11.8% with rituximabvs 3.1% on observation Foa R, et al. ASH 2011. Abstract 294.

  12. Identifying High Risk for Progression in CLL Patients Receiving FCR • CLL8 study: FC vs FCR as primary CLL therapy[1] • Median PFS: 57.9 mos FCR vs 32.9 mos FC (P < .0001) • OS dependent on length (< vs ≥ 2 yrs) of PFS (P < .001) • shortened PFS: • del(17p) + TP53 mutations • MRD,[2]IgVHunmutatedstatus,[3] shorter PFS • Elevated β2-microglobulin or high WBC count not predictive of short PFS 1.. Hallek M, et al. Lancet. 2010;376:1164-1174. 2. Boettcher S, et al. ASH 2008. Abstract 326. 3. Stilgenbauer S, et al. ASH 2008. Abstract 781.

  13. Identifying High Risk for Progression in CLL Patients on FCR: Study Design • Subset analysis of GCLL CLL8[1] randomized phase III trial (FC vs. FCR) • FCR-treated patients from CLL8 with short PFS and MRD at final restaging(N = 143) • Definition of high risk for early progression • MRD levels > 10-2or • MRD levels > 10-4 to < 10-2 plus either • del(17p), TP53 mutation, or IgVHunmutated status Fink A, et al. ASH 2011. Abstract 977. 1.. Hallek M, et al. Lancet. 2010;376:1164-1174

  14. Identifying High Risk for Progression in CLL Patients Receiving FCR: PFS and OS • Survival outcomes significantly better in patients with CLL and low risk • Median PFS in low-risk vs high-risk patients • 69 vs 22 months • HR: 6.4 (95% CI: 3.97-10.347; P < .0001) • Median OS in low-risk vs high-risk patients • Not reached vs 57 mos • HR: 5.758 (95% CI: 2.799-11.844; P < .0001) Fink A, et al. ASH 2011. Abstract 977.

  15. Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy *Minimal residual disease-negative CR. Badoux XC, et al. ASH 2011. Abstract 980.

  16. Lenalidomide + Rituximab Combination Therapy in Relapsed/Refractory CLL • Patients with relapsed/refractory CLL (N = 59) • Treatment protocol: 28-day cycles • Rituximab 375 mg/m2 • Cycle 1: Days 1, 8, 15, 22 • Cycle 2: no administration • Cycles 3-12: Day 1 • Lenalidomide 10 mg/day starting Day 9 • Allopurinol 300 mg orally Days 1-14 for tumor lysisprophylaxis • Primary endpoint: ORR • ITT analysis • Assessed at end of cycles 3, 6, then Q 6 months Badoux XC, et al. ASH 2011. Abstract 980.

  17. Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy • Lenalidomide/rituximab responses not correlated with disease biology • Rai stage, bulky disease, cytogenetics by FISH: correlation insignificant • Fludarabine refractory patients do worse • Lower ORR(P < .05) • Shorter PFS (P = .019) Badoux XC, et al. ASH 2011. Abstract 980.

  18. Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Toxicity • Frequent grade 1/2 AEs • Fatigue (37%) • Diarrhea (36%) • Tumor flare (27%) • Sensory neuropathy (24%) • Rash (22%) • 4 patients experienced secondary malignancies on treatment • Myelodysplastic syndrome: n = 1 • Squamous cell carcinoma: n = 1 • Melanoma in situ: n = 1 • Head/neck cancer recurrence: n = 1 Badoux XC, et al. ASH 2011. Abstract 980.

  19. Summary • Rituximab + lenalidomide active, well tolerated in both younger and older patients (younger than 65 or 65 yrs or older) with previously untreated CLL but produced higher ORR and CR in the younger cohort • Rituximab + chlorambucil induction therapy active, well tolerated in elderly patients with previously untreated CLL • In patients with CLL receiving FCR, cytogenetic analysis plus MRD detection identifies patients at high risk of disease progression • Lenalidomide + rituximab combination is active as salvage therapy for patients with relapsed/refractory CLL and has a manageable AE profile; response rates were lower among patients with fludarabine-refractory disease

  20. CLL is a Complex Disease Diagram courtesy of Jan Burger

  21. Therapeutic targeting of the BCR Signaling Pathway Stevenson et al. Blood. 2011.

  22. Rationale for Targeting PI3K-δ in CLL • PI3-kinase active in CLL vs normal B-cells • PI3K-δ inhibition in CLL cells promotes • ↑ Apoptosis • ↓ Proliferation • ↓ Chemokines • ↓ Microenvironment • response Herman S et al: Blood 2010 Lanutti B, et al: Blood 2011

  23. Phase I Cal-101 (GS-1101)Patient Demographics

  24. CAL-101 (GS-1101) Response in CLL Coutre S, et al: ASCO 2011

  25. Patient B.C.Diagnosed with CLL in 2002 70 year old man with relapsed bulky CLL Since 2005: 8 treatment regimens 2010 progressive disease

  26. Refractory CLL-after 1 cycle of CAL-101 Refractory CLL-pre treatment

  27. GS-1101 Progression Free Survival Coutre S, et al: ASCO 2011

  28. GS-1101 Grade 3-4 Toxicity Coutre S, et al: ASCO 2011

  29. Where is GS-1101 Going in CLL? • Completion of phase I or II studies in untreated and relapsed CLL • GS-1101 +combinations (Sharman et al. Abstract # 1787) • Registration studies in CLL • OHSU expects to have: • GS1101 (CAL-101) registration trial for relapsed CLL • Novel combinations with other kinase inhibitors

  30. The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study (abstract # 983) Susan O'Brien, MD1, Jan A. Burger, MD, PhD1, Kristie A. Blum, MD2, Richard R. Furman, MD3, Steven E. Coutre, MD4, Jeff Sharman, MD5, Ian W. Flinn, MD, PhD6, Barbara Grant, MD7, Nyla A. Heerema, PhD2, Amy J. Johnson, PhD2, Tasheda Navarro8, Eric Holmgren, PhD8, Eric Hedrick, MD8 and John C. Byrd, MD2 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH
3Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
4Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
5US Oncology, Springfield, OR
6Sarah Cannon Research Institute, Nashville, TN
7Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT
8Pharmacyclics, Inc, Sunnyvale, CA

  31. PCYC-1102-CA

  32. Patient Characteristics (cont.)

  33. Best Response *Per IWCLL 2008 criteria

  34. Splenomegaly before and after 2 months of PCI-32765 2 months of PCI-32765 Before PCI-32765

  35. Pattern of Response: Blood Lymphocytes vs Lymph Nodes

  36. Best Response by Risk Features

  37. Progression-free Survivalby 17p Del Status

  38. Common AEs (All Grades)Events occurring in > 15% of Patients (n=61) Grade 1 Grade 2 Grade 3 Grade 4

  39. Grade 3/4 Infectious and Hematologic Toxicity 1 Reported as AEs

  40. Dasatinib in CLL • Inhibits SRC, LYN, BTK • Results published on 15 relpased/refractory patients • ORR 20% • Nodal response 66% • Can we do better? Amrein et al. Clinical Cancer Research 2011

  41. Dasatinib in CLL at OHSUCan we predict who will respond to treatment? • Dasatinib Clinical Trial (NCT01441882) • Relapsed/refractory of if age > 70, Tx naive • Test patient CLL samples in the lab • Only enroll patients on trial if the drug first demonstrates in vitro killing activity • Measure cell death signaling pathways • Examine signaling and gene expression in vivo while receiving treatment

  42. C-F: Response to treatment C-F pretreatment scan C-F after 6 months of dasatinib

  43. CF Response to treatment Lymphocyte Count 93 % change from baseline

  44. Summary: Targeting BCR signaling in CLL • Promising activity including in poor risk patients • Most effective for nodal disease • Often results in lymphocytosis as CLL cells are mobilized from the micro-environement • Well tolerated, oral agents • Studies to predict response and with novel combinations are ongoing

  45. Mantle Cell Lymphoma • Role of Rituximab • Kluin-Nelemans, et al. ASH 2011. Abstract 439 • R-Cladribine Based Treatment • Spurgeon, et al. ASH 2011. Abstract 441 • PCI 32765 in Mantle Cell Lymphoma • Wang, et al. ASH 2011. Abstract 442

  46. Progression-free survival after CHOP and R-CHOP There were no significant differences between the two treatment arms (P=0.31) MCL: Poor Prognosis and Long–Term Outcome 18 months Patients at risk R-CHOP 58 45 28 15 5 1 CHOP 44 35 17 10 3 Lenz G. et al. J Clin Oncol. 2005;23:1984-1992.

  47. Possible Improved Survival in Elderly Patients Receiving Rituximab Percentage Surviving Griffiths, R, et. al. Blood 2011 Nov 3;118(18):4808-16

  48. R-Maintenance • SAKK[1] •  NO BENEFIT after R induction • GLSG[2] • PFS BENEFIT after R-FCM induction • Modified R-HyperCVAD[3] • 2 years of R-Maintenance • PFS = 37 months • Median OS = 70 months 1. Ghielmini M, et al. J ClinOncol. 2005, 2. Forstpointner, R, et al. Blood 2006) , 3. (Kenkre, V, et al. Leuk Lymphoma 2011)

  49. R-CHOP vs R-FC followed by maintenance with Rituximabvs. Interferon-alfa in elderly patients with Mantle cell lymphoma Hanneke C. Kluin-Nelemans for the European MCL Network University Medical Center Groningen The Netherlands

  50. European MCL Network First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review 8 x R-CHOP 6 x R-FC PR, CR IFN-a maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) Rituximab maintenance (all 2 months)

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