Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Abstract

Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142).

Fig. 1. Forrest plot of response rate according to demographic features.

The center black dot in each row represents the response rate, and the line with vertical whiskers show 95% confidence interval. The 95% confidence intervals were calculated using the Blythe-Still-Casella method. A two-sided Fisher’s exact test was used to compare the response rates between the groups, without adjusting for multiple comparisons. Source data are provided as a Source Data file. CI confidence interval, GCB germinal center B-cell type, IPI International Prognostic Index, LDH lactate dehydrogenase, nGCB non-germinal center B-cell type, Prev. Tx number of previous treatment lines, ULN upper limit of normal.

Fig. 2. Duration of response and survival.

a Swimmer plot of patients enrolled in the trial. Each row represents a patient and the length of each bar represents the time from treatment initiation. b Kaplan-Meier survival curve for progression free survival. c Kaplan-Meier survival curve for overall survival. The cross marks on the Kaplan-Meier curves depict the censored data. Source data are provided as a Source Data file. CR complete response, OS overall survival, PFS progression-free survival, PR partial response, SD stable disease, PD progressive disease, NE not evaluable.

Fig. 3. Results of targeted gene next-generation sequencing, classification, and outcome according to mutation status.

Landscape plot of next generation sequencing results. The genes related to each LymphGen subtype are annotated in the left. There were seven patients whose data on the BCL2, BCL6, and MYC rearrangements were not available, which are marked with dark gray color. Source data are provided as a Source Data file. CR complete remission, DLBCL diffuse large B-cell lymphoma, FL follicular lymphoma, GCB germinal center B-cell type, NE not evaluable, PD progressive disease, PFS progression free survival, PR partial response, SD stable disease.