To the editor,

MCL is a rare, B-cell non-Hodgkin lymphoma with highly heterogeneous clinical presentation and aggressiveness [1,2,3]. Before the use of Bruton’s tyrosine kinase (BTK) inhibitors, therapeutic options for patients with R/R MCL were limited, and their outcomes were generally poor [4,5,6]. Zanubrutinib is a next-generation, highly specific and potent BTK inhibitor [3, 7].Based on two phase I/II studies (BGB-3111-206 and BGB-3111-AU-003) [8, 9], Zanubrutinib was approved in 2019 by the US Food & Drug Administration for the treatment of adult patients with MCL who have received at least one prior therapy.

For this analysis, the patient-level data from BGB-3111-206 and BGB-3111-AU-003 were pooled to further characterize the efficacy profile of zanubrutinib monotherapy in R/R MCL.

A total of 112 patients were included, with 33 from BGB-3111-AU-003 and 79 from BGB-3111-206. The median duration of follow-up in BGB-3111-AU-003 and BGB-3111-206 was 24.7 and 24.9 months, respectively. Across the overall population, the median duration of follow-up was 24.9 months, and the duration of treatment was 20.4 months. Most of the patients had Stage III or IV disease (91%) and low to intermediate MCL International Prognostic Index (MIPI) risk scores (79%). There were 8% with bulky disease and 13% with blastoid variant (Table 1).

Table 1 Baseline covariates in two trials
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Before weighting, there were 41 patients in the second-line group and 71 patients in the later-line group. The second-line group had higher age, body mass index (BMI) and a higher percentage of patients with high MIPI risk scores, and lower percentages of patients with extra nodal disease and blastoid subtype compared with the later-line group. After weighting, all baseline covariates were balanced between the second- and later-line groups (Additional file 1: Table S1).The effective sample sizes were 27 in the second-line group and 59 in the later-line group, with median treatment durations of 22 and 18.8 months, respectively.

Prior treatment regimens included cyclophosphamide/vincristine/doxorubicin/dexamethasone (hyper-CVAD) or hyper-CVAD-like regimens (9% and 19%), lenalidomide (0 and 14%), bortezomib (1% and 10%) and autologous stem cell transplantation (2% and 10%) in second- and later-line therapy groups, respectively. The percentage of patients who received prior bendamustine was low in both groups (4% in second-line and 5% in later-line; Additional file 1: Table S2).

In BGB-3111-AU-003, the ORR was 84.9%, and the CR rate was 24.2%; the median PFS was 16 months, and the median OS was 25.8 months. In BGB-3111-206, the ORR was 84.8%, and the CR rate was 78.5%; the median PFS was 25.8 months, and the median OS was not reached (Additional file 1: Figure S1). The difference in CR rates between the two trials might be due to the different imaging strategies (Additional file 1) and poorer patients’ condition in BGB-3111-AU-003 (Table 1). In the pooled population, the ORR and the CR rate were 84.8% (95% CI: 76.8–90.9%) and 62.5% (95% CI: 52.8–71.5%); the median duration of response(DOR), PFS and OS were 24.9 (95% CI: 19.5-not estimable [NE]), 25.8 (95% CI: 16.8-NE) and 38.2 (95% CI: 29.3-NE) months, respectively (Additional file 1: Figure S2).

After weighting, the ORR (89.4 vs. 85.5%, adjusted OR = 1.5; P = 0.538), DOR (median: NE vs. 23.1 months, adjusted HR = 0.743; P = 0.436), PFS (median: NE vs. 21.1 months, adjusted HR = 0.679; P = 0.235) and OS (median: NE vs. 38.2 months, adjusted HR = 0.449; P = 0.057)were similar but numerically better in the second-line than later-line group (Additional file 1: Figure S3).

In the original population, the rate of treatment discontinuation due to disease progression was 40.2% and due to AEs was 12.5%. Most patients (96.4%) experienced at least one AE, and 50.9% experienced at least one grade ≥ 3 AE. Serious AEs (SAEs) occurred in 33.9% of patients and AE leading to death occurred in 7.1% (congestive heart failure, n = 1; general disorders, n = 2; pneumonia, n = 2; road traffic accident, n = 1; hemorrhagic stroke, n = 1; ischemic stroke, n = 1). The most focused AE of special interest (AESI) were hypertension (11.6%), major hemorrhage (5.4%) and atrial fibrillation/flutter (1.8%). The incidence of grade ≥ 3 atrial fibrillation was 0.89% (Table 2). Detailed information of AEs was presented in Additional file 1: Table S3.

Table 2 Extent of exposure and adverse events before and after weighting
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In conclusion, zanubrutinib is an effective and well-tolerated therapeutic option for R/R MCL. Early treatment with zanubrutinib tends to have better survival profiles.