Treatment of Patients with Relapsed or Refractory Mantle–Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase

Abstract

Purpose: Mantle-cell lymphoma (MCL) is an incurable mature B-cell neoplasm with high initial response rates followed almost invariably by relapse. Prognosis for patients following relapse is poor, and treatment choices are limited. We evaluated the efficacy and safety of zanubrutinib, an investigational selective Bruton's tyrosine kinase (BTK) inhibitor. Patients and Methods: Patients with relapsed/refractory MCL were enrolled in this ongoing phase II, single-arm, open-label study, and treated with oral zanubrutinib 160 mg twice daily. The primary endpoint is overall response rate (ORR) assessed by an independent review committee (per Lugano 2014 classification); secondary endpoints include duration of response (DOR), time to response, progression-free survival (PFS), and safety. Results: Eighty-six patients (median age, 60.5 years) were enrolled after a median of 2 prior lines of therapy, received ≥1 dose of the study drug, and were evaluable for safety and efficacy. After a median follow-up of 18.4 months, 72 (84%) patients achieved an objective response, with 59 (68.6%) achieving a complete response (CR). Median DOR and PFS were 19.5 and 22.1 months, respectively; 12-month event-free estimates for DOR and PFS are 78% and 76%, respectively. Most common grade ≥3 adverse events (AE) were neutropenia (19.8%) and lung infection/ pneumonia (9.3%). Three patients experienced major bleeding events, and there were no reports of atrial fibrillation. Eight (9.3%) patients discontinued zanubrutinib for AEs. Conclusions: These results demonstrate high and durable ORR and CR rates in patients with relapsed/refractory MCL. Zanubrutinib was generally well tolerated; grade ≥3 BTK inhibitorassociated toxicities (hemorrhage, rash, hypertension, diarrhea, atrial fibrillation) were uncommon.

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

“…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.…”

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

“…Zanubrutinib is a highly specific next-generation BTK inhibitor which is FDA-approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). 33 It binds covalently to Cys481 in the adenosine-triphosphate binding pocket of BTK. 29 Utilizing a structure-activity relationship (SAR)-driven strategy, several key stoichiometric modifications have allowed for increased specificity for BTK, leading to a decreased rate of inhibition of EGFR, HER2, ITK, JAK3, TEC, BMX and BLK.…”

Saudi lymphoma group's clinical practice guidelines for diagnosis, management and follow-up of patients with various types of lymphoma during the Coronavirus Disease 2019 pandemic

“…[ 64 65 66 67 ] However, in patients with symptomatic disease, off-label use of the BTK inhibitors ibrutinib, acalabrutinib or zanubrutinib or the immunomodulatory agent lenalidomide with rituximab could be considered an upfront therapy, if provisional access is approved locally, to avoid hospital visits for intravenous chemotherapy and thus the potential risk of COVID-19. [ 68 69 70 71 ] The Phase 3 randomized STiL and Bright studies have clearly demonstrated that B-R is superior to R-CHOP in terms of progression-free survival, but not in the overall survival. [ 72 73 ] Bendamustine is associated with a reduced risk of myelotoxicity and neutropenic fever but increased risk of lymphopenia.…”

“…Novel chemotherapy-free BTK inhibitors such as ibrutinib, acalabrutinib or zanubrutinib or the immunomodulatory agent lenalidomide plus rituximab (R 2 ) are recommended, minimizing or avoiding visits to the hospital for treatment. [ 68 69 70 71 79 80 ] Young, physically fit patients with a Mantle Cell Lymphoma International Prognostic Index high-risk score with or without TP53 mutations or blastoid/pleomorphic variants can be considered for allogeneic SCT. [ 81 82 ] Finally, for patients unfit for treatment, oral corticosteroids and alkylating agents can be offered for symptom relief.…”