Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up

Trotman, Judith; Opat, Stephen; Gottlieb, David; Simpson, David; Marlton, Paula; Cull, Gavin; Muñoz, Javier; Tedeschi, Alessandra; Roberts, Andrew W.; Seymour, John F.; Atwal, Siminder; Yu, Yanhao; Novotny, William; Holmgren, Eric; Tan, Ziwen; Hilger, James; Huang, Jane; Tam, Constantine S.

doi:10.1182/blood.2020006449

Cited by 92 publications

(101 citation statements)

References 27 publications

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“…An oral dose of the 320-mg QD dosage regimen in addition to the 160-mg BID dose may provide patients and caregivers with additional dosing flexibility and the potential for increased drug adherence. Choosing the optimal schedule to promote adherence in patients (especially in elderly patients) is an important consideration, given that the median age in clinical studies of zanubrutinib is approximately 65 years [23]. The blue open circles reflect the observed events in zanubrutinib-treated patients.…”

Section: Discussionmentioning

confidence: 99%

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma

Ou¹,

Tang²,

Novotny³

et al. 2021

Leukemia & Lymphoma

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This report summarizes a totality-of-evidence approach supporting recommendation of a 320mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

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Section: Discussionmentioning

confidence: 99%

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma

Ou¹,

Tang²,

Novotny³

et al. 2021

Leukemia & Lymphoma

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“…However, bleeding is still observed using acalabrutinib at variable frequencies, any-grade 26-58% and major bleeding 1-5% (Byrd et al, 2020b;Ghia et al, 2020;Owen et al, 2020;Sharman et al, 2020;Sun et al, 2020). This is also the case for zanubrutinib (Guo et al, 2019), where 4.4-66% of any-grade and 0.3-2.2% of major bleedings were observed in treated patients (Song et al, 2020;Tam et al, 2020a;Trotman et al, 2020;Xu et al, 2020). In addition, as mentioned, data from a cellular assay for TEC phosphorylation suggest that zanubrutinib is less prone to interfere with TEC as compared to ibrutinib (Guo et al, 2019).…”

Section: Increased Risk For Bleedings Under Btki Treatmentmentioning

confidence: 92%

“…Bleedings caused by ibrutinib cannot only be associated with inhibition of both BTK and TEC, since this AE has also been found after treatment with more selective BTKis, such as acalabrutinib and zanubrutinib ( Byrd et al, 2020b ; Ghia et al, 2020 ; Owen et al, 2020 ; Sharman et al, 2020 ; Song et al, 2020 ; Sun et al, 2020 ; Tam et al, 2020a ; Trotman et al, 2020 ; Xu et al, 2020 ). In vitro experiments in human platelets showed that acalabrutinib does not inhibit TEC ( Byrd et al, 2016 ; Nicolson et al, 2018 ), which would suggest a reduced number of cases with bleeding.…”

Section: Increased Risk For Bleedings Under Btki Treatmentmentioning

confidence: 99%

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

167

171

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The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

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“…At a dose of 160 milligrams twice daily 77 patients achieved an overall response rate of 95.9% with a ≥ VGPR rate at 24 months of 43.8%. Three year progression‐free survival was 80.5% 143 . A randomized phase three trial of this drug versus ibrutinib failed to meet its primary endpoint of a significantly higher ≥VGPR rate.…”

Section: Managementmentioning

confidence: 99%

“…One patient developed myelodysplastic syndrome 6 months after bendamustine initiation (1.4%). 129 In an East German lymphoma Study group trial 293 patients received bendamustine plus rituximab. The overall response rate was 91.4% The 5-year survival is estimated to be 78%, two therapy related myeloid neoplasms were seen (0.7%).…”

Section: Novel Agent Based Therapymentioning

confidence: 99%

Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management

Gertz

2021

American J Hematol

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Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients. Risk Stratification: Age, hemoglobin level, platelet count, β 2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Risk-Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection. PATIENT A 55-year-old male was found to have an IgM monoclonal gammopathy in January 2001. He was observed until November 2006 when his IgM level climbed to 9135 mg/dL. He was treated with rituximab, bortezomib and dexamethasone for 4 months. Treatment was interrupted due to neuropathy, but the IgM level fell to 1150 mg/dL. He was observed until April 2011. At the time of progression his IgM was 11 500 mg/dL and he was treated with single agent rituximab. At that time he was found to have acquired von Willebrand disease. Rituximab failed to produce a minor response so he was placed on a trial of bendamustine, lenalidomide and rituximab. His response lasted less than 1 year. In 2014 he was placed on an experimental trial of oprozomib. This resulted in a response of 5 years duration. At relapse in August of 2019 he was placed on a trial of ixazomib and ibrutinib. Ixazomib was poorly tolerated due to diarrhea and he continued on ibrutinib alone. He has now been on ibrutinib 15 months and has achieved a very good partial response.

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Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up

Cited by 92 publications

References 27 publications

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma

Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management

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