Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial

Judith Trotman, Christian Buske, Alessandra Tedeschi, Jeffrey V Matous, David MacDonald, Constantine S Tam, Olivier Tournilhac, Shuo Ma, Steven P Treon, Albert Oriol, Jerry Ping, Eva M Briso, Israel Arango-Hisijara, Meletios A Dimopoulos, Judith Trotman, Christian Buske, Alessandra Tedeschi, Jeffrey V Matous, David MacDonald, Constantine S Tam, Olivier Tournilhac, Shuo Ma, Steven P Treon, Albert Oriol, Jerry Ping, Eva M Briso, Israel Arango-Hisijara, Meletios A Dimopoulos

Abstract

Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported.

Patients and methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed.

Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation.

Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
PFS as assessed by IRC in all patients and by genetic subtype. The single patient with MYD88WT/CXCR4WT genotype is not shown; this patient progressed at 5.6 months.
Figure 2.
Figure 2.
ORR. A, Cumulative best response over time in all patients. ORRs are shown at the top of each bar, and major response rates are shown next to brackets for each bar. B, Best overall response per IRC in all patients and by genetic subtype. The single patient with MYD88WT/CXCR4WT genotype is not shown; this patient had a best response of stable disease. MR, minor response; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
Figure 3.
Figure 3.
Median IgM and Hgb levels over time.
Figure 4.
Figure 4.
OS in all patients and by lines of prior therapy.
Figure 5.
Figure 5.
Prevalence of grade ≥3 AEs of clinical interest by yearly interval. aCombined terms.

References

    1. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M. Waldenström's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000;18:214–26.
    1. Castillo JJ, Advani RH, Branagan AR, Buske C, Dimopoulos MA, D'Sa S, et al. . Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. Lancet Haematol 2020;7:e827–e37.
    1. Gavriatopoulou M, Ntanasis-Stathopoulos I, Kastritis E, Dimopoulos MA. How I treat rituximab refractory patients with WM. Oncotarget 2018;9:36824–5.
    1. Pharmacyclics LLC, an AbbVie Company. IMBRUVICA (ibrutinib) Prescribing Information. Sunnyvale, CA: Pharmacyclics LLC, an AbbVie Company; 2020.
    1. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014;123:2791–6.
    1. Castillo JJ, Xu L, Gustine JN, Keezer A, Meid K, Dubeau TE, et al. . CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib. B J Haematol 2019;187:356–63.
    1. Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, et al. . A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood 2013;122:1222–32.
    1. Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. . Ibrutinib in previously treated Waldenstrom's macroglobulinemia. N Engl J Med 2015;372:1430–40.
    1. Dimopoulos MA, Tedeschi A, Trotman J, Garcia-Sanz R, Macdonald D, Leblond V, et al. . Phase 3 trial of ibrutinib plus rituximab in Waldenstrom's macroglobulinemia. N Engl J Med 2018;378:2399–410.
    1. Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, et al. . Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 2017;18:241–50.
    1. Buske C, Tedeschi A, Trotman J, Garcia-Sanz R, MacDonald D, Leblond V, et al. . Ibrutinib treatment in Waldenström's macroglobulinemia: follow-up efficacy and safety from the iNNOVATE study. In:Proceedings of the 60th American Society of Hematology (ASH) Annual Meeting and Exposition; 2018Dec 1–4; San Diego, CA.
    1. Treon SP, Meid K, Gustine J, Yang G, Xu L, Liu X, et al. . Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol 2020;39:565–75.
    1. Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenström's macroglobulinemia. N Engl J Med 2015;373:584–6.
    1. Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, et al. . A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020;136:2038–50.
    1. Dimopoulos M, Sanz RG, Lee HP, Trneny M, Varettoni M, Opat S, et al. . Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv 2020;4:6009–18.
    1. Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, et al. . Five-year follow-up of ibrutinib plus rituximab vs placebo plus rituximab for Waldenstrom's macroglobulinemia: final analysis from the randomized phase 3 iNNOVATE™ Study. Blood 2020;136(Suppl 1):S24–6.
    1. Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, et al. . Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 2020;34:787–98.
    1. Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, et al. . Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv 2019;3:1799–807.
    1. O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. . Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910–9.
    1. Gustine JN, Meid K, Dubeau T, Severns P, Hunter ZR, Guang Y, et al. . Ibrutinib discontinuation in Waldenstrom macroglobulinemia: etiologies, outcomes, and IgM rebound. Am J Hematol 2018;93:511–7.

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