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Drugs
Published in: Drugs 1/2024

06-12-2023 | Ibrutinib | Review Article

Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage

Authors: Shayna Sarosiek, Jorge J. Castillo

Published in: Drugs | Issue 1/2024

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Abstract

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.
Literature
1.
Hunter ZR, Xu L, Yang G, 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(11):1637–46.PubMedCrossRef
2.
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367(9):826–33.PubMedCrossRef
3.
Gustine JN, Tsakmaklis N, Demos MG, et al. TP53 mutations are associated with mutated MYD88 and CXCR4, and confer an adverse outcome in Waldenstrom macroglobulinaemia. Br J Haematol. 2019;184(2):242–5.PubMedCrossRef
4.
Krzisch D, Guedes N, Boccon-Gibod C, et al. Cytogenetic and molecular abnormalities in Waldenstrom’s macroglobulinemia patients: correlations and prognostic impact. Am J Hematol. 2021;96(12):1569–79.PubMedCrossRef
5.
Poulain S, Roumier C, Bertrand E, et al. TP53 mutation and its prognostic significance in Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2017;23(20):6325–35.PubMedCrossRef
6.
Varettoni M, Zibellini S, Defrancesco I, et al. Pattern of somatic mutations in patients with Waldenstrom macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica. 2017;102(12):2077–85.PubMedPubMedCentralCrossRef
7.
Munshi M, Liu X, Kofides A, et al. A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas. Blood Adv. 2022;6(11):3332–8.PubMedPubMedCentralCrossRef
8.
Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia. Leukemia. 2015;29(1):169–76.PubMedCrossRef
9.
Castillo JJ, Xu L, Gustine JN, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenstrom macroglobulinaemia treated with ibrutinib. Br J Haematol. 2019;187(3):356–63.PubMedCrossRef
10.
Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenstrom macroglobulinemia. J Clin Oncol. 2019;37(16):1403–11.PubMedPubMedCentralCrossRef
11.
Kyle RA, Treon SP, Alexanian R, 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(2):116–20.PubMedCrossRef
12.
Zanwar S, Abeykoon JP, Ansell SM, et al. Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia. Br J Haematol. 2021;195(2):210–6.PubMedCrossRef
13.
Rummel MJ, Niederle N, Maschmeyer G, 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(9873):1203–10.PubMedCrossRef
14.
Paludo J, Abeykoon JP, Shreders A, et al. Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenstrom macroglobulinemia. Ann Hematol. 2018;97(8):1417–25.PubMedCrossRef
15.
Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenstrom macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25(22):3344–9.PubMedCrossRef
16.
Kastritis E, Gavriatopoulou M, Kyrtsonis MC, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study. Blood. 2015;126(11):1392–4.PubMedCrossRef
17.
Auer RL, Owen RG, D’Sa S, et al. Subcutaneous bortezomib, cyclophosphamide and rituximab (BCR) versus fludarabine, cyclophosphamide and rituximab (FCR) for Initial Therapy of Waldenstrőm’s macroglobulinemia: a randomised phase II study. Blood. 2016;128(22):618.CrossRef
18.
Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, 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(19):3276–82.PubMedCrossRef
19.
Ghobrial IM, Hong F, Padmanabhan S, 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.PubMedPubMedCentralCrossRef
20.
Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05–180. J Clin Oncol. 2009;27(23):3830–5.PubMedPubMedCentralCrossRef
21.
Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of Waldenstrom’s macroglobulinemia with rituximab. J Clin Oncol. 2002;20(9):2327–33.PubMedCrossRef
22.
Treon SP, Emmanouilides C, Kimby E, et al. Extended rituximab therapy in Waldenstrom’s macroglobulinemia. Ann Oncol. 2005;16(1):132–8.PubMedCrossRef
23.
Treon SP, Gustine J, Meid K, et al. Ibrutinib monotherapy in symptomatic, treatment-naive patients with Waldenstrom macroglobulinemia. J Clin Oncol. 2018;36(27):2755–61.PubMedCrossRef
24.
Owen RG, McCarthy H, Rule S, et al. Acalabrutinib monotherapy in patients with Waldenstrom macroglobulinemia: a single-arm, multicentre, phase 2 study. Lancet Haematol. 2020;7(2):e112–21.PubMedCrossRef
25.
Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib versus ibrutinib in symptomatic waldenstrom macroglobulinemia: the aspen study. Blood. 2020;136(18):2038–50.PubMedPubMedCentralCrossRef
26.
Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372(15):1430–40.PubMedCrossRef
27.
Buske C, Tedeschi A, Trotman J, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenstrom’s macroglobulinemia: final analysis from the randomized phase III innovate study. J Clin Oncol. 2022;40(1):52–62.PubMedCrossRef
28.
Owen R, McCarthy H, Rule S, et al. P1130: acalabrutinib in treatment-naive or relapsed/refractory Waldenström macroglobulinemia: 5-year follow-up of a phase 2. Single-arm study. HemaSphere. 2022;6:1020–1.PubMedCentralCrossRef
29.
Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441–52.PubMedPubMedCentralCrossRef
30.
Dimopoulos MA, Opat S, D'Sa S, et al. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenstrom Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023:JCO2202830.
31.
Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv. 2020;4(23):6009–18.PubMedPubMedCentralCrossRef
32.
Cao XX, Jin J, Fu CC, et al. Evaluation of orelabrutinib monotherapy in patients with relapsed or refractory Waldenstrom’s macroglobulinemia in a single-arm, multicenter, open-label, phase 2 study. EClinicalMedicine. 2022;52: 101682.PubMedPubMedCentralCrossRef
33.
Sekiguchi N, Rai S, Munakata W, et al. A multicenter, open-label, phase II study of tirabrutinib (ONO/GS-4059) in patients with Waldenstrom’s macroglobulinemia. Cancer Sci. 2020;111(9):3327–37.PubMedPubMedCentralCrossRef
34.
Castillo JJ, Gustine JN, Meid K, Dubeau T, Severns P, Treon SP. Ibrutinib withdrawal symptoms in patients with Waldenstrom macroglobulinemia. Haematologica. 2018;103(7):e307–10.PubMedPubMedCentralCrossRef
35.
Sarosiek S, Gustine JN, Flynn CA, et al. Dose reductions in patients with Waldenstrom macroglobulinaemia treated with ibrutinib. Br J Haematol. 2023;201(5):897–904.PubMedCrossRef
36.
Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553–62.PubMedPubMedCentralCrossRef
37.
Rogers KA, Thompson PA, Allan JN, et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021;106(9):2364–73.PubMedPubMedCentralCrossRef
38.
Shadman M, Flinn IW, Levy MY, et al. Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study. Lancet Haematol. 2023;10(1):e35–45.PubMedCrossRef
39.
Gustine JN, Meid K, Dubeau T, et al. Ibrutinib discontinuation in Waldenstrom macroglobulinemia: etiologies, outcomes, and IgM rebound. Am J Hematol. 2018;93(4):511–7.PubMedCrossRef
40.
Xu L, Tsakmaklis N, Yang G, et al. Acquired mutations associated with ibrutinib resistance in Waldenstrom macroglobulinemia. Blood. 2017;129(18):2519–25.PubMedPubMedCentralCrossRef
41.
Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286–94.PubMedPubMedCentralCrossRef
42.
Palomba ML, Patel MR, Eyre TA, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in relapsed/refractory Waldenström macroglobulinemia: results from the phase 1/2 bruin study. Blood. 2022;140(Supplement 1):557–60.CrossRef
43.
Woyach JA, Flinn IW, Awan FT, et al. Efficacy and safety of nemtabrutinib, a wild-type and C481S-mutated bruton tyrosine kinase inhibitor for B-cell malignancies: updated analysis of the open-label phase 1/2 dose-expansion bellwave-001 study. Blood. 2022;140.
44.
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29.PubMedCrossRef
45.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.PubMedCrossRef
46.
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.PubMedCrossRef
47.
Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenstrom macroglobulinemia. J Clin Oncol. 2022;40(1):63–71.PubMedCrossRef
48.
Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095–103.PubMedCrossRef
49.
Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–23.PubMedCrossRef
50.
Castillo JJ, Sarosiek S, Branagan AR, et al. Ibrutinib and venetoclax in previously untreated Waldenström macroglobulinemia. Blood. 2022;140:564–5.CrossRef
51.
Buhimschi AD, Armstrong HA, Toure M, et al. Targeting the C481S ibrutinib-resistance mutation in bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57(26):3564–75.PubMedCrossRef
52.
53.
Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood. 2022;140(2329-2332).
54.
Castillo JJ, Moreno DF, Arbelaez MI, Hunter ZR, Treon SP. CXCR4 mutations affect presentation and outcomes in patients with Waldenstrom macroglobulinemia: a systematic review. Expert Rev Hematol. 2019;12(10):873–81.PubMedCrossRef
55.
Roccaro AM, Sacco A, Jimenez C, 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.PubMedCrossRef
56.
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(18):2791–6.PubMedCrossRef
57.
Castillo JJ, Meid K, Gustine JN, et al. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Leukemia. 2022;36(2):532–9.PubMedCrossRef
58.
Treon SP, Meid K, Hunter ZR, et al. Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenstrom macroglobulinemia. Blood. 2021;138(17):1535–9.PubMedPubMedCentralCrossRef
59.
Hailfinger S, Lenz G, Ngo V, et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2009;106(47):19946–51.PubMedPubMedCentralCrossRef
60.
Hunter ZR, Xu L, Tsakmaklis N, et al. Insights into the genomic landscape of MYD88 wild-type Waldenstrom macroglobulinemia. Blood Adv. 2018;2(21):2937–46.PubMedPubMedCentralCrossRef
61.
Fontan L, Yang C, Kabaleeswaran V, et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell. 2012;22(6):812–24.PubMedPubMedCentralCrossRef
62.
Yang G, Liu X, Chen J, et al. Targeting IRAK1/IRAK4 Signaling in Waldenstrom’s Macroglobulinemia. Blood. 2015;126(23):4004.CrossRef
63.
Ni H, Shirazi F, Baladandayuthapani V, et al. Targeting myddosome signaling in Waldenstrom’s macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191. Clin Cancer Res. 2018;24(24):6408–20.PubMedCrossRef
64.
Hatcher JM, Yang G, Wang L, et al. Discovery of a selective, covalent IRAK1 inhibitor with antiproliferative activity in MYD88 mutated B-cell lymphoma. ACS Med Chem Lett. 2020;11(11):2238–43.PubMedPubMedCentralCrossRef
65.
Nowakowski GS, Leslie LA, Younes A, et al. Safety, pharmacokinetics and activity of CA-4948, an irak4 inhibitor, for treatment of patients with relapsed or refractory hematologic malignancies: results from the phase 1 study. Blood. 2020;136:44–5.CrossRef
66.
Kuiatse I, Baladandayuthapani V, Lin HY, et al. Targeting the spleen tyrosine kinase with fostamatinib as a strategy against Waldenstrom macroglobulinemia. Clin Cancer Res. 2015;21(11):2538–45.PubMedPubMedCentralCrossRef
Metadata
Title
Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage
Authors
Shayna Sarosiek
Jorge J. Castillo
Publication date
06-12-2023
Publisher
Springer International Publishing
Published in
Drugs / Issue 1/2024
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-023-01974-6

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