Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia

Jorge J Castillo, Kirsten Meid, Joshua N Gustine, Carly Leventoff, Timothy White, Catherine A Flynn, Shayna Sarosiek, Maria G Demos, Maria L Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Lian Xu, Guang Yang, Andrew R Branagan, Elizabeth O'Donnell, Noopur Raje, Andrew J Yee, Christopher J Patterson, Zachary R Hunter, Steven P Treon, Jorge J Castillo, Kirsten Meid, Joshua N Gustine, Carly Leventoff, Timothy White, Catherine A Flynn, Shayna Sarosiek, Maria G Demos, Maria L Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Lian Xu, Guang Yang, Andrew R Branagan, Elizabeth O'Donnell, Noopur Raje, Andrew J Yee, Christopher J Patterson, Zachary R Hunter, Steven P Treon

Abstract

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Conflict of interest statement

JJC received research funds and/or honoraria from Abbvie, Beigene, Janssen, Pharmacyclics, Roche, and TG Therapeutics. ARB received research funds and/or honoraria from Adaptive, Beigene, CSL Behring, Genzyme, Karyopharm, Pharmacyclics, and Sanofi. AJY received research funds and/or honoraria from Adaptive, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, Takeda. SPT received research funds and/or honoraria from Abbvie, Beigene, BMS, Pharmacyclics, and X4. All other authors have no conflicts of interest to disclose.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
CONSORT diagram.
Fig. 2. Response to therapy.
Fig. 2. Response to therapy.
Categorical responses at the best response in 30 treatment-naive patients with WM treated with ibrutinib for the entire cohort (A), and according to CXCR4 mutational status (B); and serial serum IgM levels (C) and hemoglobin levels (D) throughout ibrutinib therapy according to CXCR4 mutational status. MR minor response, PR partial response; VGPR very good partial response; WT wildtype; MUT mutated; C cycle.
Fig. 3. Time to response analyses.
Fig. 3. Time to response analyses.
Time to response estimates in 30 treatment-naive WM patients treated with ibrutinib monotherapy for the entire cohort (A), and according to hemoglobin level (B) and CXCR4 mutational status (C), and time to major response estimates for the entire cohort (D), and according to hemoglobin level (E) and CXCR4 mutational status (F). WT wildtype, MUT mutated.
Fig. 4. Survival analyses.
Fig. 4. Survival analyses.
Progression-free survival (PFS) estimates for the entire cohort (A), according to International Prognostic Scoring System for WM (B), and according to CXCR4 mutational status (C), and overall survival (OS) estimates in 30 treatment-naive patients with WM treated with ibrutinib monotherapy. VGPR very good partial response, PR partial response, WT wildtype, MUT mutated.

References

    1. Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637–46. doi: 10.1182/blood-2013-09-525808.
    1. Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826–33. doi: 10.1056/NEJMoa1200710.
    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 Waldenstrom macroglobulinemia. Blood. 2013;122:1222–32. doi: 10.1182/blood-2012-12-475111.
    1. Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;168:701–7. doi: 10.1111/bjh.13200.
    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. doi: 10.1056/NEJMoa1501548.
    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 Waldenstrom macroglobulinemia. J Clin Oncol. 2021;39:565–75. doi: 10.1200/JCO.20.00555.
    1. Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, et al. Ibrutinib monotherapy in symptomatic, treatment-naive patients with Waldenstrom macroglobulinemia. J Clin Oncol. 2018;36:2755–61. doi: 10.1200/JCO.2018.78.6426.
    1. Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol. 2003;30:116–20. doi: 10.1053/sonc.2003.50038.
    1. Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol. 2003;30:110–5. doi: 10.1053/sonc.2003.50082.
    1. Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013;160:171–6. doi: 10.1111/bjh.12102.
    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. doi: 10.1016/S1470-2045(16)30632-5.
    1. Trotman J, Buske C, Tedeschi A, Matous JV, MacDonald D, Tam C, et al. Long-term follow-up of ibrutinib treatment for rituximab-refractory Waldenström’s macroglobulinemia: final analysis of the open-label substudy of the Phase 3 iNNOVATETM Trial. Blood. 2020;136:38–9. doi: 10.1182/blood-2020-133916.
    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 iNNOVATETM Study. Blood. 2020;136:24–6. doi: 10.1182/blood-2020-134460.
    1. Vos JM, Tsakmaklis N, Patterson CJ, Meid K, Castillo JJ, Brodsky P, et al. CXCL13 levels are elevated in patients with Waldenstrom macroglobulinemia, and are predictive of major response to ibrutinib. Haematologica. 2017;102:e452–e455. doi: 10.3324/haematol.2017.172627.
    1. Castillo JJ, Gustine JN, Meid K, Dubeau T, Severns P, Xu L, et al. Low levels of von Willebrand markers associate with high serum IgM levels and improve with response to therapy, in patients with Waldenstrom macroglobulinaemia. Br J Haematol. 2018;184:1011–4. doi: 10.1111/bjh.15200.
    1. Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN) Blood. 2013;122:3276–82. doi: 10.1182/blood-2013-05-503862.
    1. Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, et al. Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009;27:3830–5. doi: 10.1200/JCO.2008.20.4677.
    1. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203–10. doi: 10.1016/S0140-6736(12)61763-2.
    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. doi: 10.1056/NEJMoa1802917.
    1. Xu L, Hunter ZR, Tsakmaklis N, Cao Y, Yang G, Chen J, et al. Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia. Br J Haematol. 2016;172:735–44. doi: 10.1111/bjh.13897.
    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 Waldenstrom macroglobulinaemia treated with ibrutinib. Br J Haematol. 2019;187:356–63. doi: 10.1111/bjh.16088.
    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. doi: 10.1182/blood.2020006844.
    1. Guha A, Derbala MH, Zhao Q, Wiczer TE, Woyach JA, Byrd JC, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72:697–8. doi: 10.1016/j.jacc.2018.06.002.
    1. Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017;129:2581–4. doi: 10.1182/blood-2016-10-742437.

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