Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy?
Abstract
:1. Introduction
2. First Line Therapies
2.1. Cytotoxic Agents and AntiCD20 Monoclonal Antibodies
2.2. Proteasome Inhibitor-Based Therapy
2.3. Rituximab Maintenance
2.4. BTK Inhibitors
3. Making a Choice in First Line
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author | Regimen | N. pts | Responses (%) | Survival Rates | Genotype Impact | F/U (m) |
---|---|---|---|---|---|---|
Leblond 2013 [7] | Chlorambucil 8 mg/m2 daily for 10 d every 28 d vs. Fludarabine 40 mg/m2 daily for 5 d every 28 d | 170 169 | ORR 36% ORR 46% | mPFS 27 m mPFS 38 m | NA | 36 m |
Treon 2009 [19] | R + Fludarabine: R 375 mg/m2/w at w 1 to 4, 17, 18, 30, 31 + 6 cycles of F 25 mg/m2 daily for 5 d at w 5, 9, 13, 19, 23, and 27 | 43 (27 TN) | ORR 95% MRR 86% CR + VGPR% 37% | mPFS 77.6 m | NA | 40.3 m |
Tedeschi 2012 [20] | FCR: R 375 mg/m2 on d 1 + F 25 mg/m2 and C 250 mg/m2 on d 2–4, every 28 d for 6 cycles | 43 (28 TN) | ORR 79% MRR 74% CR + VGPR% 32% | mPFS NR 2 y OS 88.4% 4 y OS 69.1% | NA | 37.2 m |
Kastritis 2015 [23] | DRC: D 20 mg + R 375 mg/m2 on d 1 + C 100 mg/m2 bid on d 1–5, every 21 d for 6 cycles | 72 | ORR 83% MRR 74% CR 7% | mPFS 35 m mOS 95 m | NA | 7 y |
Rummel 2013 [8] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles | 22 | ORR 93% CR 40% | mPFS 69.5 m | NA | 45 m |
Laribi 2018 [24] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles | 69 | ORR 97% MRR 96% CR + VGPR 56% | 2 y PFS 87% 2 y OS 97.1% | MYD88L265P vs. MYD88WT: ORR, PFS: NS CXCR4MUT vs. CXCR4WT: ORR; PFS: NS | 23 m |
Zanwar 2022 [25] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles | 208 | ORR 95% MRR 93% VGPR 31% | Est mPFS 5.9 y Est 5 y OS 90% | MYD88L265P vs. MYD88WT: ORR, PFS: NS CXCR4MUT vs. CXCR4WT: ORR; PFS: NS | 4 y |
Paludo 2018 [26] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles vs. DRC: D 20 mg + R 375 mg/m2 on d 1 + C 100 mg/m2 bid on d 1–5, every 21 d for 6 cycles | 60 (17 TN) 100 (50 TN) | ORR 93% MRR 86% VGPR 29% ORR 96% MRR 87% VGPR 17% | 2 y PFS 88% 2 y PFS 61% | MYD88L265P vs. MYD88WT: ORR, PFS: NS | 30 m |
Treon 2015 [34] | BDR: Bortezomib 1.3 mg/m2 IV + D 40 mg on d 1, 4, 8, 11 + R 375 mg/m2 on d 11. A total of 4 cycles of induction + 4 cycles, each 3 months apart, for maintenance | 23 | ORR 96% MRR 91% CR + VGPR 52% | 5 y PFS 57% 5 y OS 95% | NA | 8.5 y |
Ghobrial 2010 [35] | Bortezomib + R: Bortezomib 1.6 mg/m2 IV on d 1, 8, 15, every 28 d for 6 cycles + R 375 mg/m2/w on cycles 1 and 4 | 26 | ORR 89% MRR 66% CR + VGPR 8% | 1 y EFS 79% | NA | 14 m |
Gavriatopoulou 2017 [37] | BDR: Bortezomib 1.3 mg/m2 IV on d 1, 4, 8, 11 (cycle 1), B 1.6 mg/m2 IV on d 1, 8, 15, 22 (cycles 2–5) + D 40 mg and R 375 mg/m2/w in cycle 2 and 5. Every 35 d for 5 cycles | 59 | ORR 85% MRR 68% CR + VGPR 10% | mPFS 43 m 7 y OS 66% | NA | 86 m |
Abeykoon 2021 [38] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles vs. BDR: Bortezomib 1.3 mg/m2 IV on d 1, 4, 8, 11 (cycle 1), B 1.6 mg/m2 IV on d 1, 8, 15, 22 (cycles 2–5) + D 40 mg and R 375 mg/m2/w in cycle 2 vs. DRC: D 20 mg + R 375 mg/m2 on d 1 + C 100 mg/m2 bid on d 1–5, every 21 d for 6 cycles | 83 45 92 | ORR 98% MRR 96% ORR 84% MRR 68% ORR 78% MRR 53% | mPFS 5.2 y 4 y OS 90% mPFS 1.8 y 4 y OS 87% mPFS 4.3 y 4 y OS 87% | MYD88L265P vs. MYD88WT: ORR, PFS: NS | 2.3 y 5.2 y 6.3 y |
Castillo 2018 [39] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles vs. BDR: bortezomib 1.6 mg/m2 + D 20 mg on d 1, 4, 8 and 11 or 1, 8, 15 and 22, every 3 and 4 w, respectively, + rituximab 375 mg/m2 on d 11 or 22, respectively, for 4 cycles vs. DRC: C 1000 mg/m2 + plus D 20 mg + R 375 mg/m2 on d 1, for 6 cycles | 57 87 38 | ORR 98% MRR 94% CR + VGPR 45% ORR 90% MRR 83% CR + VGPR 35% ORR 89% MRR 84% CR + VGPR 42% | mPFS 5.5 m 10 y OS 95% mPFS 5.8 m 10 y OS 96% mPFS 4.8 m 10 y OS 81% | NA | 3 y 4 y 5 y |
Buske 2020 [9] | B-DRC: DRC + Bortezomib sc 1,6 mg/m2 on d 1, 8, 15, every 28 d for 6 cycles vs. DRC: D 20 mg + R 375 mg/m2 on d 1 + C 100 mg/m2 bid on d 1–5, every 21 d for 6 cycles | 100 100 | ORR 91% MRR 79% CR + VGPR 19% ORR 87% MRR 69% CR + VGPR 11% | mPFS NR mPFS 50.1 m | MYD88L265P vs. MYD88WT: ORR, PFS: NS CXCR4MUT vs. CXCR4WT: ORR; PFS: NS | 27.5 m |
Meid 2017 [40] | CaRD: carfilzomib 20 mg/m2 (cycle 1) and 36 mg/m2 (cycles 2 and beyond), D 20 mg on d 1, 2, 8, 9; Rituximab 375 mg/m2 on d 2, 9 of each 21-d cycle. Six induction cycles +8 cycles, each 8 w apart for maintenance | 31 | ORR 81% MRR 71% CR + VGPR 39% | mPFS 46 m | MYD88L265P vs. MYD88WT: ORR: NS CXCR4MUT vs. CXCR4WT: ORR: NS | NA |
Castillo 2018 [41] | IDR: ixazomib 4 mg and D 20 mg on d 1, 8, and 15 every 4 w for cycles 1 and 2, + R 375 mg/m2 on d 1, e 4 weeks for cycles 3 to 6. Then 6 cycles, each 8 w apart, for maintenance | 26 | ORR 96% MRR 77% | mPFS NR | CXCR4MUT vs. CXCR4WT: ORR: NS | 22 m |
Author | BTKi | N. pts | Responses | Survival Rates | Genotype Impact | F/U |
---|---|---|---|---|---|---|
Castillo 2022 [47] | Ibrutinib 420 mg daily | 30 | ORR 100% MRR 87% VGPR 30% | 4 y PFS 76% | longer TTMR in CXCR4MUT vs. CXCR4WT | 50.1 m |
Buske 2022 [48] | ibrutinib 420 mg daily + R 375 mg/m2 on d1 of w 1–4, 17–20 vs. placebo + R 375 mg/m2 on d1 of w 1–4, 17–20 | 75 (45 TN) 75 (45 TN) | ORR 91% MRR 76% CR + VGPR: 27% ORR 53% MRR 41% CR + VGPR 9% | 48 m PFS 70% 48 m PFS 32% | MYD88L265P vs. MYD88WT: ORR, PFS: NS CXCR4MUT vs. CXCR4WT: ORR; PFS: NS | 50 m |
Owen 2022 [49] | Acalabrutinib 100 mg bid | 106 (14 TN) | ORR 93% MRR 79% | 66 m PFS 84% 66 m OS 91% | NA | 63.7 m |
Trotman 2020 [50] | zanubrutinib 160 mg bid | 77 (24 TN) | ORR 100% MRR 87.5% CR + VGPR 33% | Est 2 y EFS 92% | MYD88L265P vs. MYD88WT: ORR, PFS: NS CXCR4MUT vs. CXCR4WT: ORR; PFS: NS | 23.5 m |
Tam 2020 [10] | ibrutinib 420 mg daily vs. zanubrutinib 160 mg bid | 99 (18 TN) 102 (19 TN) | ORR 89% MRR 67% CR + VGPR 14% ORR 95% MRR 74% CR + VGPR 26% | mPFS NR Est 18 m OS 97% mPFS NR Est 18 m OS 93% | CXCR4MUT vs. CXCR4WT: ORR: NS | 18.5 m |
Dimopoulos 2022 [51] | ibrutinib 420 mg daily vs. zanubrutinib 160 mg bid | 99 (18 TN) 102 (19 TN) | All pts CR + VGPR 22% All pts CR + VGPR 36% | All pts mPFS NR mOS NR All pts mPFS NR mOS NR | CXCR4WT Ibr CR + VGPR 28% Zanu CR + VGPR 45% (p = 0.04) CXCR4MUT ibr CR + VGPR 5% Zanu CR + VGPR 21% (p = 0.15) * | 43 m |
Dimopoulos 2020, 2022 [51,52] | zanubrutinib 160 mg bid | 28 (5 TN) | ORR 80% MRR 40% VGPR 20% | All pts 43 m PFS 53.8% 43 m OS 83.9% | only MYD88WT pts | 43 m |
Abeykoon 2022 [53] | BR: Bendamustine 90 mg/m2 on d 1, 2 + R 375 mg/m2 on d 1, every 4 w for 6 cycles Vs. ibrutinib 420 mg daily | 208 139 | ORR 94% MRR 92% CR + VGPR 50% ORR 94% MRR 83% CR + VGPR 33% | 4 y PFS 73% 4 y OS 94% 4 y PFS 73% 4 y OS 82% | NA | 4.2 y |
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Deodato, M.; Frustaci, A.M.; Zamprogna, G.; Cotilli, G.; Cairoli, R.; Tedeschi, A. Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy? Hemato 2022, 3, 689-703. https://doi.org/10.3390/hemato3040046
Deodato M, Frustaci AM, Zamprogna G, Cotilli G, Cairoli R, Tedeschi A. Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy? Hemato. 2022; 3(4):689-703. https://doi.org/10.3390/hemato3040046
Chicago/Turabian StyleDeodato, Marina, Anna Maria Frustaci, Giulia Zamprogna, Giulia Cotilli, Roberto Cairoli, and Alessandra Tedeschi. 2022. "Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy?" Hemato 3, no. 4: 689-703. https://doi.org/10.3390/hemato3040046