Contemporary regimens used for the therapy of WM
| Regimen . | Phase/disease setting/number of patients . | Regimen details and duration of therapy . | ORR . | Major RR (at least PR) . | IgM flare . | Time to response . | PFS . | OS . | Comments . |
|---|---|---|---|---|---|---|---|---|---|
| Rituximab64 | Phase 3, untreated and pretreated (all rituximab sensitive; N = 75) | Rituximab intravenously 375 mg/m2 on day 1 of weeks 1-4 and 17-20; 8 infusion total | 48% | 33% | 47% | NR | 20.3 months | 3-year OS: 90% | IgM flare common |
| DRC43,99 | Phase 2, untreated (N = 72) | 6 cycles | 83% | 74% | 32% | 4.1 months | 35 months | 95 months | MDS ∼1% DLBCL ∼3% |
| BR44 | Phase 3 (subanalysis), untreated (N = 22) | Bendamustine intravenously 90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles | 95% | 95% | NR | NR | 69 months | 90.4% at 5 years | Subgroup analysis of a larger study comparing BR with R-CHOP |
| BR45 | Retrospective, untreated (N = 69) | Bendamustine intravenously 90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles; 56% completed 6 cycles | 97% | 96% | NR | <3 months | 2-year PFS: 87% | 2-year PFS: 97% | In 30% bendamustine, reduction to ≤70 mg/m2 |
| BR46 | Retrospective, pretreated (N = 71) | Bendamustine intravenously 50-90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles; 66% completed 6 cycles | 80.2% | 74.6% | NR | 3 months | NR | NR | 37% received bendamustine ≤70 mg/m2 |
| BDR48,53 | Phase 2, untreated (N = 59) | Cycle 1: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11 (21-day cycle); cycles 2-5: bortezomib 1.6 mg/m2 intravenously days 1, 8, 15, and 22 every 35 days; cycles 2 and 5: dexamethasone 40 mg; rituximab intravenously 375 mg/m2 (total 8 infusions of rituximab); 5 cycles | 85% | 68% | 11% | 3 months | 43 months | 66% at 8 years | No MDS DLBCL in 5% |
| BDR51,54 | Phase 2, untreated (N = 23) | Cycles 1-4: bortezomib intravenously 1.3 mg/m2; dexamethasone 40 mg on days 1, 4, 8, and 11; rituximab 375 mg/m2 day 11; cycles 5-8: as above, given 3 months apart; 4 + 4 cycles | 96% | 91% | 9% | 1.4 months | 57% at 5 years | 95% at 5 years | Neuropathy leading to discontinuation of bortezomib 60% |
| VR49 | Phase 2, untreated (N = 26) | Cycles 1-6: bortezomib intravenously 1.6 mg/m2 weekly days 1, 8, and 15, every 28 days; cycles 1 and 4: rituximab intravenously 375 mg/m2 weekly, 6 cycles | 88% | 66% | 31% | 3.7 months | 37 months | 94% at 5 years | Weekly bortezomib |
| VR50 | Phase 2, pretreated (N = 37) | Cycles 1-6: bortezomib intravenously 1.6 mg/m2 weekly, days 1, 8, and 15, every 28 days; cycles 1 and 4: rituximab intravenously 375 mg/m2 weekly, 6 cycles | 81% | 51% | 22% | 2 months | 19 months | 65% at 5 years | Weekly bortezomib |
| IRD56 | Phase 2, untreated (N = 26) | Cycles 1-2: ixazomib, by mouth 4 mg, days 1, 8, and 15; dexamethasone, by mouth or intravenously 20 mg, days 1, 8, and 15 every 4 weeks; cycles 3-6: ixazomib, by mouth 4 mg, days 1, 8, and 15; dexamethasone, by mouth or intravenously 20 mg, days 1, 8, and 15; rituximab intravenously 375 mg/m2, on day 1, every-4-week maintenance therapy: as above every 8 weeks for 6 cycles; 6 + 6 cycles | 96% | 77% | 8% | 2 months (8 wk) | 73% at 22 months | 100% at 22 months | Response was slower among those with CXCR4WHIM |
| FCR58 | Phase 2, pretreated (N = 40) | Rituximab intravenously 375 mg/m2 day 1; fludarabine intravenously 25 mg/m2 days 2-4; cyclophosphamide intravenously 250 mg/m2 days 2-4; 6 cycles | 80% | 80% | 0% | 3 months | Not reached at 55 months | NR | MDS/AML, 5%; transformation, 2.5%; infectious deaths 5% |
| FCR59 | Retrospective untreated (N = 25); pretreated (N = 57) | Rituximab intravenously 375 mg/m2 day 1; fludarabine by mouth 40 mg/m2 days 1-3; cyclophosphamide by mouth 250 mg/m2 days 1-3 in 28-day cycles; 6 cycles | 85.4% | 64.6% | 0 | NR (time to best response 10.8 months) | 67% at 48 months | 90% at 3 years | MDS/AML (N = 2); transformation (N = 3); long-lasting cytopenias (N = 19) late improved responses in 25 patients |
| Ibrutinib62 | Phase 2 pretreated (N= 63) | Ibrutinib by mouth 420 mg/ continuous | 90.5% | 73% | 0% | 1 months | 60% at 5 years | 87% at 5 years | Response and PFS lower in CXCR4WHIM and MYD88WT |
| Ibrutinib63 | Phase 3 (companion study), pretreated (N = 31; all rituximab refractory) | Ibrutinib by mouth 420 mg/day continuous | 90% | 71% | 0% | 1 months | 86% at 18 months | 97% at 18 months | Response and PFS similar in CXCR4WHIM, but slower |
| Ibrutinib65 | Phase 2, untreated (N = 30) | Ibrutinib by mouth 420 mg/day continuous | 100% | 83% | 0% | 1 months | 92% at 18 months | 100% at 18 months | Major responses (94% vs 71%) and VGPRs (31% vs 7%) higher and time to major response shorter (1.8 vs 7.3 months) in patients with CXCR4WT vs CXCR4WHIM |
| Ibrutinib-Rituximab64 | Phase 3, untreated and pretreated (all rituximab sensitive; N = 75) | Ibrutinib by mouth 420 mg/day, continuous (given before rituximab infusion), rituximab intravenously 375 mg/m2 on day 1 of weeks 1-4 and 17-20; 8 infusion total | 92% | 72% | 8% | 1 months | 82% at 30 months | 94% at 30 months | Randomized study, PFS and response not affected by MY88 and CXCR4 mutation status |
| Venetoclax93 | Phase 2, pretreated (N=30); ibrutinib exposed (N=15) | Venetoclax by mouth 200 mg/day, increased to 800 mg for 2 years | 87% | 74%* | NR | NR | NR | NR | Effective in ibrutinib-exposed patients |
| Regimen . | Phase/disease setting/number of patients . | Regimen details and duration of therapy . | ORR . | Major RR (at least PR) . | IgM flare . | Time to response . | PFS . | OS . | Comments . |
|---|---|---|---|---|---|---|---|---|---|
| Rituximab64 | Phase 3, untreated and pretreated (all rituximab sensitive; N = 75) | Rituximab intravenously 375 mg/m2 on day 1 of weeks 1-4 and 17-20; 8 infusion total | 48% | 33% | 47% | NR | 20.3 months | 3-year OS: 90% | IgM flare common |
| DRC43,99 | Phase 2, untreated (N = 72) | 6 cycles | 83% | 74% | 32% | 4.1 months | 35 months | 95 months | MDS ∼1% DLBCL ∼3% |
| BR44 | Phase 3 (subanalysis), untreated (N = 22) | Bendamustine intravenously 90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles | 95% | 95% | NR | NR | 69 months | 90.4% at 5 years | Subgroup analysis of a larger study comparing BR with R-CHOP |
| BR45 | Retrospective, untreated (N = 69) | Bendamustine intravenously 90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles; 56% completed 6 cycles | 97% | 96% | NR | <3 months | 2-year PFS: 87% | 2-year PFS: 97% | In 30% bendamustine, reduction to ≤70 mg/m2 |
| BR46 | Retrospective, pretreated (N = 71) | Bendamustine intravenously 50-90 mg/m2 days 1 and 2; rituximab intravenously 375 mg/m2 on day 1; up to six 28-day cycles; 66% completed 6 cycles | 80.2% | 74.6% | NR | 3 months | NR | NR | 37% received bendamustine ≤70 mg/m2 |
| BDR48,53 | Phase 2, untreated (N = 59) | Cycle 1: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11 (21-day cycle); cycles 2-5: bortezomib 1.6 mg/m2 intravenously days 1, 8, 15, and 22 every 35 days; cycles 2 and 5: dexamethasone 40 mg; rituximab intravenously 375 mg/m2 (total 8 infusions of rituximab); 5 cycles | 85% | 68% | 11% | 3 months | 43 months | 66% at 8 years | No MDS DLBCL in 5% |
| BDR51,54 | Phase 2, untreated (N = 23) | Cycles 1-4: bortezomib intravenously 1.3 mg/m2; dexamethasone 40 mg on days 1, 4, 8, and 11; rituximab 375 mg/m2 day 11; cycles 5-8: as above, given 3 months apart; 4 + 4 cycles | 96% | 91% | 9% | 1.4 months | 57% at 5 years | 95% at 5 years | Neuropathy leading to discontinuation of bortezomib 60% |
| VR49 | Phase 2, untreated (N = 26) | Cycles 1-6: bortezomib intravenously 1.6 mg/m2 weekly days 1, 8, and 15, every 28 days; cycles 1 and 4: rituximab intravenously 375 mg/m2 weekly, 6 cycles | 88% | 66% | 31% | 3.7 months | 37 months | 94% at 5 years | Weekly bortezomib |
| VR50 | Phase 2, pretreated (N = 37) | Cycles 1-6: bortezomib intravenously 1.6 mg/m2 weekly, days 1, 8, and 15, every 28 days; cycles 1 and 4: rituximab intravenously 375 mg/m2 weekly, 6 cycles | 81% | 51% | 22% | 2 months | 19 months | 65% at 5 years | Weekly bortezomib |
| IRD56 | Phase 2, untreated (N = 26) | Cycles 1-2: ixazomib, by mouth 4 mg, days 1, 8, and 15; dexamethasone, by mouth or intravenously 20 mg, days 1, 8, and 15 every 4 weeks; cycles 3-6: ixazomib, by mouth 4 mg, days 1, 8, and 15; dexamethasone, by mouth or intravenously 20 mg, days 1, 8, and 15; rituximab intravenously 375 mg/m2, on day 1, every-4-week maintenance therapy: as above every 8 weeks for 6 cycles; 6 + 6 cycles | 96% | 77% | 8% | 2 months (8 wk) | 73% at 22 months | 100% at 22 months | Response was slower among those with CXCR4WHIM |
| FCR58 | Phase 2, pretreated (N = 40) | Rituximab intravenously 375 mg/m2 day 1; fludarabine intravenously 25 mg/m2 days 2-4; cyclophosphamide intravenously 250 mg/m2 days 2-4; 6 cycles | 80% | 80% | 0% | 3 months | Not reached at 55 months | NR | MDS/AML, 5%; transformation, 2.5%; infectious deaths 5% |
| FCR59 | Retrospective untreated (N = 25); pretreated (N = 57) | Rituximab intravenously 375 mg/m2 day 1; fludarabine by mouth 40 mg/m2 days 1-3; cyclophosphamide by mouth 250 mg/m2 days 1-3 in 28-day cycles; 6 cycles | 85.4% | 64.6% | 0 | NR (time to best response 10.8 months) | 67% at 48 months | 90% at 3 years | MDS/AML (N = 2); transformation (N = 3); long-lasting cytopenias (N = 19) late improved responses in 25 patients |
| Ibrutinib62 | Phase 2 pretreated (N= 63) | Ibrutinib by mouth 420 mg/ continuous | 90.5% | 73% | 0% | 1 months | 60% at 5 years | 87% at 5 years | Response and PFS lower in CXCR4WHIM and MYD88WT |
| Ibrutinib63 | Phase 3 (companion study), pretreated (N = 31; all rituximab refractory) | Ibrutinib by mouth 420 mg/day continuous | 90% | 71% | 0% | 1 months | 86% at 18 months | 97% at 18 months | Response and PFS similar in CXCR4WHIM, but slower |
| Ibrutinib65 | Phase 2, untreated (N = 30) | Ibrutinib by mouth 420 mg/day continuous | 100% | 83% | 0% | 1 months | 92% at 18 months | 100% at 18 months | Major responses (94% vs 71%) and VGPRs (31% vs 7%) higher and time to major response shorter (1.8 vs 7.3 months) in patients with CXCR4WT vs CXCR4WHIM |
| Ibrutinib-Rituximab64 | Phase 3, untreated and pretreated (all rituximab sensitive; N = 75) | Ibrutinib by mouth 420 mg/day, continuous (given before rituximab infusion), rituximab intravenously 375 mg/m2 on day 1 of weeks 1-4 and 17-20; 8 infusion total | 92% | 72% | 8% | 1 months | 82% at 30 months | 94% at 30 months | Randomized study, PFS and response not affected by MY88 and CXCR4 mutation status |
| Venetoclax93 | Phase 2, pretreated (N=30); ibrutinib exposed (N=15) | Venetoclax by mouth 200 mg/day, increased to 800 mg for 2 years | 87% | 74%* | NR | NR | NR | NR | Effective in ibrutinib-exposed patients |
MDS, myelodysplastic syndrome; PR, partial response; R-CHOP, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone; VGPR, very good partial response.
87% in ibrutinib naive and 60% in ibrutinib exposed.