Novel treatment options for Waldenstrom Macroglobulinemia

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1 Novel treatment options for Waldenstrom Macroglobulinemia Irene Ghobrial, MD Associate Professor of Medicine Harvard Medical School Dana Farber Cancer Institute Boston, MA

2 Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009

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4 MYD88 in WM Treon et al, NEJM 2012

5 Molecular characteristics 30-50% of patients: deletion 6q by FISH BLIMP (on 6q21): a tumor-suppressor gene, is the master gene regulator for B-lymphocytic cell proliferation % of patients have MYD88 mutation. CXCR4 somatic mutation in 24% of samples Treon et al NEJM 2012

6 Consensus recommendations of the 4th International WM meeting First Line therapy: Combination therapy (RCD or CPR; Cytoxan+nucleoside analogues+r; R-CHOP, R-CVP) Rituximab single agent Nucleoside analogues Alkylators Salvage therapy: Re-use therapies Bortezomib Thalidomide+steroids Alemtuzumab AHSCT Dimopoulos, JCO 2009, Treon et al Clin Lymph and Myeloma 2009

7 Primary Therapy of WM with Rituximab- Based Options Regimen ORR CR Rituximab x % 0% Rituximab x % 0% Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, RCD Rituximab/nucleoside analogues i.e. FR, FCR, CDA-R 70-80% 8-10% 70-90% 5-10% Rituximab/thalidomide 70% 5% Rituximab/bortezomib i.e. BDR, VR 70-90% 10-25% Rituximab/bendamustine 90% NA Courtesy of Dr. Steven Treon

8 Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. 72 patients cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). 83% of patients achieved a response Including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67% Dimopoulos, JCO 2007

9 Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-Line- Treatment of Patients with Waldenstrom disease: Randomized Phase III Study of the Studygroup Indolent Lymphomas (StiL) 42 pts with WM, report on 40 evaluable in interim analysis, BR=23 and CHOP-R=17. The ORR for pts treated with B-R was similar to that associated with CHOP-R (96% vs 94%, respectively). The median follow-up time for both groups is 26 months. Progressive or relapsed disease: 2 in pts treated with B-R and 7 in the CHOP-R group. Less toxicity and non-inferior response. Rummel, WM-Workshop2012

10 PFS: Benda-R vs CHOP-R in Frontline WM 1.0 Probability Bendamustine-R CHOP-R months Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

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12 Phase II trial of bortezomib+ rituximab in upfront or R/R WM ORR 80-90%. CR 10-15% Minimal peripheral neuropathy A total of 6 cycles, a cycle= 28 days No rituximab maintenance No dexamethasone Ghobrial et al, JCO 2010 Ghobrial et al, AJH 2011

13 New developments PI3K/mTOR inhibitors Proteasome inhibitors BTK inhibitors HDAC inhibitors IMIDs

14 The PI3K/mTOR pathway

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16 Phase II trial of RAD001 in WM

17 A Partial response Stable disease Partial response B C

18 Phase I/II Study of Everolimus, Bortezomib and/or Rituximab in Relapsed/Refractory WM Study Design Registration Phase I study Everolimus/rituximab Everolimus/bortezomib/rituximab Determine maximum tolerated dose (MTD) Phase II study ongoing with 3 drug combination

19 The RVR phase I study Response N= 23 evaluable CR 1 (5%) PR 7 (30%) MR 9 (39%) ORR (CR+PR+MR) 17 (74%) Stable Disease 6 (26%)

20 MLN128 TORC1 and 2 inhibitor Oral agent before after 6 months Maiso, Blood 2010

21 Targeting PKC in WM Phase II study 38% ORR in 42 patients relapsed/ref Ghobrial, CCR 2012

22 Phase II trial of perifosine in patients with relapsed/refractory WM ORR 35%, with another 54% showing stabilization of their disease Only 11% of patients demonstrated progression. Ghobrial et al, CCR 2010

23 PI3K delta (p110) Oral Well tolerated CAL-101 Significant Lymph node response but increase in peripheral blood lymphocytes in CLL 60% ORR in indolent lymphomas, 86% in MCL, 95% ORR in CLL in lymph nodes

24 Roccaro et al, Blood 2011

25 New Proteasome inhibitors Upfront therapy with Carfilzomib/dex/rituxan (CARD study) Onyx 0912 in relapsed WM Roccaro et al, Blood 2010 Sacco et al, CCR 2011

26 IMIDs in WM Thalidomide and rituximab: Thalidomide mg, rituximab weeks 2-5, pts (20 untreated) 70% ORR TTP 38 months observed among responders. 44% >G2 PN Lenalidomide and rituximab: 25 mg lenalidomide 21 days, and rituximab weeks 2-5, pts (12 untreated) 50% response rate, TTP of 18.9 months 88% discontinuation of therapy Most due to anemia that occurred early with therapy Median decrease in Hct from 32 to 27%, 4 pts required hospitalization Phase I trials of lenalidomide ongoing, phase I pomalidomide/rituximab ongoing. Treon et al, Blood 2008, CCR 2008

27 Phase II Study of Panobinostat in WM Best overall response CR VGPR PR MR SD PD Unevaluable Total PR or better MR or better N % (90%CI:18, 46) 55 (90%CI:41,70) Ghobrial I, et al. Blood. 2010;116:3952.[Oral Presentation].

28 IgM response to Panobinostat

29 Bruton s Tyrosine Kinase (BTK) IgM B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation Bruton s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway Inhibitors of Btk block BCR signaling and induces apoptosis Nat Rev Imm 2:945

30 Ibrutinib Breakthrough designation by the FDA for WM. Over 80% response rate. Very well tolerated. Currently, no trials available. Awaiting approval and more trials or expanded access in the next few months.

31 New Proteasome inhibitors Oprozomib in relapsed WM Roccaro et al, Blood 2010 Sacco et al, CCR 2011

32 Oprozomib Oral agent. Proteasome inhibitor without neuropathy. Over 80% response rate so far in WM Considering breakthrough designation in WM. Study open in multiple sites and accruing now.

33 Future developments MYD88 targeting (IRAK4) CXCR4 targeting mirna155 targeting (MiRNA LNA)

34 mirna expression in bone marrow CD19+ WM cells vs CD19+ normal counterpart Roccaro et al. Blood 2009

35 Association between micrornas and clinical prognostic features P =.009 P =.004 P =.001 Roccaro et al. Blood 2009

36 Summary Significant advances in WM specifically MYD88 mirna155 as a prognostic maker and therapeutic target New agents including mtor inhibitors, BTK inhibitors, PI3K inhibitors, HDAC inhibitors, new proteasome inhibitors Can we personalize therapy in WM? Should we treat earlier to prevent complications/clonal heterogeneity and resistance FDA approval for agents in WM

37 Acknowledgement Ken Anderson, MD, Steven Treon, MD, Paul Richardson, MD, Nikhil Munshi, MD, Jacob Laubach, MD, Claudia Paba-Prada, MD Supported by the NIH, FDA, IWMF, LLS, Kirsch Lab for WM, Heje Fellowship, All our patients.