Advances in Treatment of Waldenström Macroglobulinemia

Treon SP, Xu L, Guerrera ML, Jimenez C, Hunter ZR, Liu X, et al. Genomic landscape of Waldenström macroglobulinemia and its impact on treatment strategies. J Clin Oncol. 2020;38(11):1198–208. https://doi.org/10.1200/JCO.19.02314. This article is a comprehensive review on how recent genomic discoveries have influenced treatment progress in WM.

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Yang G, Buhrlage SJ, Tan L, Liu X, Chen J, Xu L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood. 2016;127(25):3237–52. https://doi.org/10.1182/blood-2016-01-695098.

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Roccaro AM, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, et al. C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood. 2014;123(26):4120–31. https://doi.org/10.1182/blood-2014-03-564583.

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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(11):e827–37. https://doi.org/10.1016/S2352-3026(20)30224-6. This is the latest recommendations on treatment in WM.

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Kastritis E, Leblond V, Dimopoulos MA, Kimby E, Staber P, Kersten MJ, ESMO Guidelines Committee, et al. Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv41–50. https://doi.org/10.1093/annonc/mdy146. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv270. Erratum in: Ann Oncol. 2019 May 1;30(5):860-862.

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NCCN Guidelines Version 2.2019 WM/LPL; National Comprehensive Cancer Network (NCCN): Plymouth Meeting, PA, USA, 2019.

Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström’s macroglobulinemia: final analysis from the randomized phase III iNNOVATE study. J Clin Oncol. 2022;40(1):52–62. https://doi.org/10.1200/JCO.21.00838.

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Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. Blood. 2015;126(11):1392–4. https://doi.org/10.1182/blood-2015-05-647420.

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Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25(22):3344–9. https://doi.org/10.1200/JCO.2007.10.9926.

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Paludo J, Abeykoon JP, Kumar S, Shreders A, Ailawadhi S, Gertz MA, et al. Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenstrom macroglobulinemia. Br J Haematol. 2017;179(1):98–105. https://doi.org/10.1111/bjh.14826.

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Castillo JJ, Gustine JN, Meid K, Dubeau TE, Severns P, Xu L, et al. Response and survival for primary therapy combination regimens and maintenance rituximab in Waldenström macroglobulinaemia. Br J Haematol. 2018;181(1):77–85. https://doi.org/10.1111/bjh.15148.

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Abeykoon JP, Zanwar S, Ansell SM, Muchtar E, He R, Greipp PT, et al. Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia. Am J Hematol. 2021;96(8):945–53. https://doi.org/10.1002/ajh.26210.

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Buske C, Dimopoulos MA, Grunenberg A, Kastritis E, Tomowiak C, Mahé B, et al. Bortezomib-dexamethasone, rituximab, and cyclophosphamide as first-line treatment for waldenström's macroglobulinemia: A prospectively randomized trial of the European Consortium for Waldenström's Macroglobulinemia. J Clin Oncol. 2023;41(14):2607–2616. https://doi.org/10.1200/JCO.22.01805This recent randomized study demonstrates the efficacy and safety of fixed-duration immunochemotherapy and highlights the role of PI to induce faster response and improve overall response rate.

Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al. Study group indolent Lymphomas (StiL). 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(9873):1203–10. https://doi.org/10.1016/S0140-6736(12)61763-2. Erratum in: Lancet. 2013 Apr 6;381(9873):1184

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Uppal E, Khwaja J, Bomsztyk J, McCarthy H, Kothari J, Walton P, et al. Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder. Br J Haematol. 2023. https://doi.org/10.1111/bjh.18680.

Tohidi-Esfahani I, Warden A, Malunis E, DeNardis PL, Haurat J, Black M, et al. WhiMSICAL: A global Waldenström's Macroglobulinemia patient-derived data registry capturing treatment and quality of life outcomes. Am J Hematol. 2021;96(6):E218–22. https://doi.org/10.1002/ajh.26173.

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Laribi K, Poulain S, Willems L, Merabet F, Le Calloch R, Eveillard JR, et al. Bendamustine plus rituximab in newly-diagnosed Waldenström macroglobulinaemia patients. A study on behalf of the French Innovative Leukaemia Organization (FILO). Br J Haematol. 2019;186(1):146–9. https://doi.org/10.1111/bjh.15718.

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Paludo J, Abeykoon JP, Shreders A, Ansell SM, Kumar S, Ailawadhi S, et al. Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Ann Hematol. 2018;97(8):1417–25. https://doi.org/10.1007/s00277-018-3311-z.

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Arulogun SO, Brian D, Goradia H, Cooney A, Menne T, Koo R, et al. Bendamustine plus rituximab for the treatment of Waldenström macroglobulinemia: Patient outcomes and impact of bendamustine dosing. Am J Hematol. 2023. https://doi.org/10.1002/ajh.26895. This recently published study reports a large cohort of patients treated with BR and confirmed the efficacy of this treatment.

Rummel MJ, Lerchenmüller C, Hensel M, Goerner M, Buske C, Schulz H, et al. two years rituximab maintenance vs. observation after first line treatment with Bendamustine plus Rituximab (B-R) in patients with Waldenström's Macroglobulinemia (MW): Results of a prospective, randomized, multicenter phase 3 study (the StiL NHL7-2008 MAINTAIN trial). Blood. 2019;134(Supplement_1):343. First randomized study showing no PFS and OS benefit of rituximab maintenance after BR.

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Zanwar S, Abeykoon J, Castillo J, Durot E, Kastritis E, Uppal E, et al. A multicenter, international collaborative study evaluating frontline therapy with bendamustine rituximab for Waldenström macroglobulinemia. HemaSphere. 2022;6:1046–7. https://doi.org/10.1097/01.HS9.0000847504.29146.b9.

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Gavriatopoulou M, García-Sanz R, Kastritis E, Morel P, Kyrtsonis MC, Michalis E, et al. BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood. 2017;129(4):456–9. https://doi.org/10.1182/blood-2016-09-742411. Erratum in: Blood. 2022 Mar 17;139(11):1772

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Treon S, Meid K, Gustine J, Patterson CJ, Matous JV, Ghobrial I, Castillo JJ. Long-term outcome of a prospective study of bortezomib, dexamethasone and rituximab (BDR) in previously untreated, symptomatic patients with Waldenstrom's macroglobulinemia. Blood. 2015;126(23):1833.

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Ghobrial IM, Hong F, Padmanabhan S, Badros A, Rourke M, Leduc R, et al. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010;28(8):1422–8. https://doi.org/10.1200/JCO.2009.25.3237.

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Meid K, Dubeau T, Severns P, Gustine J, Ghobrial IM, Castillo JJ, Treon SP. Long-term follow-up of a prospective clinical trial of carfilzomib, rituximab and dexamethasone (CaRD) in Waldenstrom's macroglobulinemia. Blood. 2017;130(Supplement 1):2772.

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Castillo JJ, Meid K, Flynn CA, Chen J, Demos MG, Guerrera ML, et al. Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up. Blood Adv. 2020;4(16):3952–9. https://doi.org/10.1182/bloodadvances.2020001963.

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Kersten MJ, Amaador K, Minnema MC, Vos JMI, Nasserinejad K, Kap M, et al. Combining ixazomib with subcutaneous rituximab and dexamethasone in relapsed or refractory Waldenström's macroglobulinemia: final analysis of the phase I/II HOVON124/ECWM-R2 study. J Clin Oncol. 2022;40(1):40–51. https://doi.org/10.1200/JCO.21.00105.

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Castillo JJ, Gustine JN, Meid K, Flynn CA, Demos MG, Guerrera ML, et al. CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors. Am J Hematol. 2020;95(4):E95–8. https://doi.org/10.1002/ajh.25730.

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Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, et al. Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol. 2018;36(27):2755–61. https://doi.org/10.1200/JCO.2018.78.6426.

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Castillo JJ, Meid K, Gustine JN, Leventoff C, White T, Flynn CA, et al. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Leukemia. 2022;36(2):532–9. https://doi.org/10.1038/s41375-021-01417-9.

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Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):1430–40. https://doi.org/10.1056/NEJMoa1501548.

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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. 2021;39(6):565–75. https://doi.org/10.1200/JCO.20.00555. This study is the actualization of the pivotal phase 2 study leading to the approval of ibrutinib in WM.

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Trotman J, Opat S, Gottlieb D, Simpson D, Marlton P, Cull G, et al. Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up. Blood. 2020;136(18):2027–37. https://doi.org/10.1182/blood.2020006449. Erratum in: Blood. 2021 Feb 25;137(8):1131

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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(18):2038–50. https://doi.org/10.1182/blood.2020006844. First randomized study between 2 BTKi reporting comparable efficacy but a better toxicity profile for zanubrutinib.

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