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Muñoz, J.;  Paludo, J.;  Sarosiek, S.;  Castillo, J.J. Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia. Encyclopedia. Available online: https://encyclopedia.pub/entry/33371 (accessed on 30 April 2025).
Muñoz J,  Paludo J,  Sarosiek S,  Castillo JJ. Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia. Encyclopedia. Available at: https://encyclopedia.pub/entry/33371. Accessed April 30, 2025.
Muñoz, Javier, Jonas Paludo, Shayna Sarosiek, Jorge J. Castillo. "Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia" Encyclopedia, https://encyclopedia.pub/entry/33371 (accessed April 30, 2025).
Muñoz, J.,  Paludo, J.,  Sarosiek, S., & Castillo, J.J. (2022, November 07). Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia. In Encyclopedia. https://encyclopedia.pub/entry/33371
Muñoz, Javier, et al. "Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia." Encyclopedia. Web. 07 November, 2022.
Safety and Efficacy of Zanubrutinib in Waldenström Macroglobulinemia
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This entry is adapted from the peer-reviewed paper 10.3390/cells11203287

Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient’s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment regimens for patients with WM, and the choice of therapy should be made in a personalized fashion considering the patient’s symptoms, comorbidities, and genomic profile. Bruton tyrosine kinase (BTK) inhibitors are a new option to treat patients with WM. Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors.

Waldenström macroglobulinemia zanubrutinib Bruton tyrosine kinase inhibitor

1. Introduction

Waldenström macroglobulinemia (WM) is a rare, incurable, non-Hodgkin B-cell lymphoma caused by the malignant accumulation of lymphoplasmacytic lymphoma cells in bone marrow and other organs, which secrete a monoclonal immunoglobulin M paraprotein [1][2]. In the US and Europe, the incidence of WM is 3 to 4 cases annually per million people [2][3][4]. It is more common in White men over 60 years of age [2][3][5]. Common symptoms of WM include serum hyperviscosity, B symptoms, bleeding, and anemia; however, approximately a quarter of patients are asymptomatic at the time of diagnosis [4][6]. The anemia associated with WM is attributed to insufficient erythropoiesis due to bone marrow infiltration and low iron levels [6][7]. Additionally, precipitation of immunoglobulin M can cause peripheral neuropathy, cryoglobulinemia, and cold agglutinin syndrome [6]. Rare features of WM include malignant pleural effusions [8], renal disease [9], and central nervous system involvement [10].
Recurring somatic mutations have been observed in patients with WM [11]. The MYD88 innate immune signal transduction adaptor (MYD88) L265P mutation, detected in approximately 90% of patients with WM [12], mediates the activation of nuclear factor κB via interleukin-1 receptor-associated kinase 1 and Bruton tyrosine kinase (BTK), which promotes the survival of WM cells [13]. C-X-C motif chemokine receptor 4 (CXCR4) mutations are also present in up to 40% of patients with WM [14]; mutations in CXCR4 promote sustained activation of the 2 kinase signaling pathways involved in survival (serine/threonine-protein kinase Akt and extracellular signal-regulated kinase). CXCR4 mutations occur subclonally in patients who have MYD88 mutations. The presence of CXCR4 mutations has been associated with higher serum immunoglobulin M levels and an increased risk of hyperviscosity [15].
Selection of a treatment regimen for WM includes a review of treatment efficacy and safety, but patient-specific factors, such as a patient’s mutational profile, comorbidities, and preference must also be considered [16]. Rituximab-based treatments are common for WM, particularly for treatment-naive (TN) disease. Some patients with WM will eventually experience disease progression and need a new treatment regimen or may be poor candidates for certain treatment regimens. This is particularly relevant in light of data showing that patients with B-cell malignancies, such as chronic lymphocytic leukemia (CLL), are at a high risk of death if they require inpatient admission for symptomatic coronavirus disease 2019 (COVID-19) [17], and they have a poor response to COVID-19 vaccination [18]. For these patients, it may be better to avoid treatment regimens that are administered in a clinic or hospital setting where exposure to the disease could occur.
Covalent BTK inhibitors are a newer option for the treatment of WM [1]. BTK is involved in the signaling cascade for B-cell malignancies downstream of the B-cell antigen receptor and is essential for the development and function of B cells [19]. Inhibition of BTK has shown to induce apoptosis in WM cells, and when inhibited in combination with interleukin-1 receptor-associated kinase 1 and 4, improved inhibition of nuclear factor κB signaling occurred along with WM cell death [13].
Three orally administered covalent BTK inhibitors are approved by the US Food and Drug Administration (FDA) as treatment options for B-cell malignancies: ibrutinib, acalabrutinib, and zanubrutinib [20][21][22]. Ibrutinib is a first-generation BTK inhibitor administered once daily and was the first BTK inhibitor to receive FDA approval for the treatment of WM [22]. Ibrutinib is also approved to treat mantle cell lymphoma (MCL) in patients who have had at least 1 prior treatment, CLL/small lymphocytic lymphoma (SLL), marginal zone lymphoma in patients who require systemic therapy and have had 1 prior anti-CD20-based therapy, and chronic graft versus host disease after failure of a systemic therapy. Ibrutinib induces high response rates in patients with WM, with an overall response rate (ORR) as high as 100% (n = 30) observed in patients with TN WM [23] and 90.5% (n = 63) in patients with relapsed/refractory (R/R) disease [24]. However, ibrutinib also has well-described off-target effects, including atrial fibrillation, hypertension, and hemorrhage [24][25], and evidence shows that some patients with WM require a dose reduction (~20%; n = 95 and 15) [26][27] or treatment discontinuation (31% [n = 25], 68% of which were due to treatment-related toxicities) [27]. The discontinuation rate of ibrutinib in patients with CLL in real-world settings has a wide range, from 16% (of 1497 patients) to 50% (of 447 patients) [28][29][30].
Acalabrutinib is a second-generation BTK inhibitor administered twice daily [20] and has fewer off-target effects compared with ibrutinib [31]. Acalabrutinib is FDA approved to treat MCL in patients who have received at least 1 prior therapy and CLL/SLL [20]; it also has a high ORR in patients with both TN (93% [95% CI, 66–100%]; n = 14) and R/R (93% [95% CI, 86–98%]; n = 92) WM [32]. Discontinuation remained a problem though, with 50% of patients with TN disease and 25% of patients with R/R disease having discontinued treatment due to any cause during the study. Adverse events led to discontinuation in 7% of patients (n = 106). Grade 3/4 atrial fibrillation occurred in only 1 patient (1%), and grade 3/4 bleeding occurred in 3 (3%). A direct comparison with other BTK inhibitors in WM has not yet been performed [32], although a randomized trial comparing acalabrutinib (n = 268) to ibrutinib (n = 265) in patients with R/R CLL showed that acalabrutinib had a better adverse effect profile than ibrutinib [33].
Zanubrutinib is a next-generation BTK inhibitor administered once or twice daily [21]. It was designed to have fewer off-target effects [34] and is approved by the FDA for the treatment of patients with MCL who have received prior therapy and patients with R/R marginal zone lymphoma who have had at least 1 anti-CD20–based treatment [21]. Zanubrutinib is also approved by the FDA for use in WM [35].

2. Zanubrutinib Safety and Efficacy

A pooled safety analysis assessed treatment-emergent adverse events (TEAEs) and treatment-limiting toxicities of zanubrutinib in patients with B-cell malignancies (n = 779) [36]. Most patients (98%) experienced TEAEs, with 66% reporting at least 1 TEAE that was grade ≥ 3, including 37% with treatment-related events. Nonhematologic TEAEs (incidence ≥ 15%) included upper respiratory tract infection (39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (15%), and fatigue (15%). Hematologic AEs were reported as AEs of interest and included bleeding or bruising (55%), treatment-emergent neutropenia (36%), thrombocytopenia (21%), and anemia (18%). At least 1 serious AE was reported in 46% of patients, including 17% that were treatment related. Serious AEs included pneumonia (11%); cellulitis, sepsis, urinary tract infection, upper respiratory tract infection, and pyrexia (2% each); and febrile neutropenia (1%). One or more dose reductions occurred in 8% of patients; common TEAEs that led to a dose reduction were neutropenia, diarrhea, and pneumonia (1% each). The most common cause of treatment discontinuation was progressive disease (27%). TEAEs led to treatment discontinuation in 10% of patients; almost half of the TEAEs were treatment related, including pneumonia (2%) and hemorrhage (1%).
In patients with WM in the pooled safety analysis, the discontinuation rate due to TEAEs was 10%, and infections were common (80%), with 8 patients having 1 or more opportunistic infections, including 1 death [36]. Over half (54%) of the patients with WM reported bleeding events, and major hemorrhages occurred in 6% of patients. Neutropenia and thrombocytopenia occurred in 32% and 15% of patients with WM, respectively.
In a phase 1/2 study of zanubrutinib in patients with TN (n = 24) or R/R WM (n = 53), the ORR was 96% at follow-up (median, 36 and 23.5 months for patients with R/R and TN WM, respectively) with 73% of patients remaining on treatment [37]. The estimated 3-year progression-free survival (PFS) rate was 80.5%, with a 3-year overall survival (OS) rate of 85%. AEs led to treatment discontinuation in 13% of patients; 1 patient discontinued treatment due to a treatment-related AE. AEs of interest included contusion (32.5%), neutropenia (19%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%).
The phase 3 ASPEN trial compared the use of zanubrutinib with ibrutinib in patients with WM who had the MYD88L265P mutation (TN, n = 37; R/R, n = 164) [38] and assessed response to zanubrutinib in MYD88WT patients (TN, n = 5; R/R, n = 23) [39]. No patients achieved a complete response (CR). In patients with the MYD88L265P mutation, 29 (28%) who received zanubrutinib and 19 (19%) who received ibrutinib achieved a very good partial response (VGPR); however, these results were not significantly different. Major response rates (MRRs) were 77% and 78%, respectively [38]. The most common AEs (reported in >20% of patients in any treatment arm) were diarrhea (ibrutinib, 32%; zanubrutinib, 21%), upper respiratory tract infection (ibrutinib, 29%; zanubrutinib, 24%), contusion (ibrutinib, 24%; zanubrutinib, 13%), muscle spasm (ibrutinib, 24%; zanubrutinib, 10%), and neutropenia (ibrutinib, 13%; zanubrutinib, 29%). At follow-up (median, 18 months) in patients with MYD88WT, 7 patients (27%) achieved a VGPR, and 50% had a major response; the estimated PFS and OS rates at 18 months were 68% and 88%, respectively [39].

Recent Developments

In a long-term follow-up (median, 43 months) to the ASPEN study, the CR combined with VGPR rate in patients with the MYD88 mutation who received zanubrutinib (n = 102) or ibrutinib (n = 99) was 36% and 22%, respectively, and 31% in patients without the mutation who received zanubrutinib (n = 28) [40]. Similar safety outcomes were observed between patients with and without the MYD88 mutation who received zanubrutinib. Combined CR and VGPR rates were lower in patients with both the MYD88 and CXCR4 mutations than in those with the MYD88 mutation and wild-type CXCR4 treated with zanubrutinib (28% and 45%, respectively) or ibrutinib (5% and 21%, respectively), with the rates in both groups being higher for patients treated with zanubrutinib.
A phase 2 trial of zanubrutinib in Chinese patients with R/R WM (n = 44) had efficacy findings similar to those in the initial ASPEN analysis [41]. The MRR in patients with MYD88L265P and MYD88WT WM were 73% and 50%, respectively, at the median follow-up time of 33 months. Frequent TEAEs that were grade ≥ 3 included decreased neutrophil count (31.8%), decreased platelet count (20.5%), and pneumonia (20.5%), and no cases of atrial fibrillation/flutter occurred. Together, these data suggest that zanubrutinib can induce durable responses in Chinese patients with R/R WM and that it has an acceptable tolerability profile.
A matching-adjusted indirect comparison of zanubrutinib and rituximab-based chemoimmunotherapy from 2 single-arm studies showed that zanubrutinib resulted in better patient outcomes than either bendamustine-rituximab (BR) (zanubrutinib post-matching, n = 50; BR, n = 71) or dexamethasone-rituximab-cyclophosphamide (DRC) (zanubrutinib post-matching, n = 53; DRC, n = 72) [42]. Zanubrutinib resulted in longer PFS and OS compared with both BR (post-matching hazard ratio [95% CI], 0.37 [0.15–0.91] and 0.29 [0.10–0.85], respectively) and dexamethasone-rituximab-cyclophosphamide (post-matching hazard ratio [95% CI], 0.35 [0.14–0.86] and 0.47 [0.14–1.62], respectively), although treatment with zanubrutinib was also associated with a higher incidence of neutropenia post matching (14.3%) compared with dexamethasone-rituximab-cyclophosphamide (9.7%; post-matching risk ratio [95% CI], 1.47 [0.58–3.74]). A lower incidence of neutropenia (17.5%) and pneumonia (1.5%) also occurred with zanubrutinib than BR (35% and 6%; risk ratio [95% CI], 0.50 [0.27–0.91] and 0.26 [0.03–2.28], respectively). These data suggest that zanubrutinib may improve treatment efficacy over traditional chemoimmunotherapy approaches.
Bing-Neel syndrome is a rare complication of WM seen in approximately 1% of patients that occurs when lymphoplasmacytic lymphoma cells enter the central nervous system, causing neurological symptoms [10]. There is no standardized treatment for Bing-Neel syndrome, and therapeutic options are limited to agents that can penetrate the blood–brain barrier. The efficacy of ibrutinib in Bing-Neel syndrome has been reported in a handful of cases [43][44][45][46] and a retrospective multicenter study of 28 patients, which reported improvement in symptomatic and radiologic results in 85% and 60% of patients, respectively, with a 5-year Bing-Neel syndrome survival rate of 86% (95% CI, 63–95%) [47]. One case report has described zanubrutinib use in Bing-Neel syndrome. A 75-year-old woman who developed Bing-Neel syndrome experienced small symptomatic improvements after 12 cycles of high-dose methotrexate, but no improvement was observed on magnetic resonance imaging scans [48]. Treatment with zanubrutinib improved her symptoms, and magnetic resonance imaging scans showed complete resolution of contrast-enhancing lesions in the cervical and thoracic cord and reduced contrast in the intradural lumbar nerve roots. After 15 months of zanubrutinib treatment, the patient had maintained a VGPR. More research on the efficacy of zanubrutinib in Bing-Neel syndrome is warranted.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Javier Muñoz
,
Jonas Paludo
,
Shayna Sarosiek
,
Jorge J. Castillo
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Revisions: 2 times (View History)
Update Date: 08 Nov 2022
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