570 likes | 1.28k Views
Novel treatment options for Waldenstrom Macroglobulinemia. Irene Ghobrial, MD Associate Professor of Medicine Harvard Medical School Dana Farber Cancer Institute Boston, MA. Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009. MYD88 in WM. Treon et al, NEJM 2012.
E N D
Novel treatment options for Waldenstrom Macroglobulinemia Irene Ghobrial, MD Associate Professor of Medicine Harvard Medical School Dana Farber Cancer Institute Boston, MA
MYD88 in WM Treon et al, NEJM 2012
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. • 70-90% of patients have MYD88 mutation. • CXCR4 somatic mutation in 24% of samples Treon et al NEJM 2012
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
Primary Therapy of WM with Rituximab-Based Options Courtesy of Dr. Steven Treon
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
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
PFS: Benda-R vs CHOP-R in Frontline WM 1.0 0.9 Bendamustine-R 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 CHOP-R 0.1 0.0 0 12 24 36 48 60 72 months Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.
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
New developments • PI3K/mTOR inhibitors • Proteasome inhibitors • BTK inhibitors • HDAC inhibitors • IMIDs
A Partial response B Partial response C Stable disease
Phase I/II Study of Everolimus, Bortezomib and/or Rituximab in Relapsed/Refractory WM Study Design • Phase I study • Everolimus/rituximab • Everolimus/bortezomib/rituximab Registration Determine maximum tolerated dose (MTD) Phase II study ongoing with 3 drug combination
MLN128 • TORC1 and 2 inhibitor • Oral agent before after 6 months Maiso, Blood 2010
Targeting PKC in WM Phase II study 38% ORR in 42 patients relapsed/ref Ghobrial, CCR 2012
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
CAL-101 • PI3K delta (p110) • Oral • Well tolerated • 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
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
IMIDs in WM • Thalidomide and rituximab: • Thalidomide 200-400 mg, rituximab weeks 2-5, 13-16 • 25 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, 13-16 • 16 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
Phase II Study of Panobinostat in WM Ghobrial I, et al. Blood. 2010;116:3952.[Oral Presentation].
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
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.
New Proteasome inhibitors Oprozomib in relapsed WM Roccaro et al, Blood 2010 Sacco et al, CCR 2011
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.
Future developments • MYD88 targeting (IRAK4) • CXCR4 targeting • miRNA155 targeting (MiRNA LNA)
miRNA expression in bone marrow CD19+ WM cells vs CD19+ normal counterpart Roccaro et al.Blood 2009
Association between microRNAs and clinical prognostic features P = .009 P = .004 P = .001 Roccaro et al.Blood 2009
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
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.