Updated Response and Safety for Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients with relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) historically have poor outcomes with second-line chemoimmunotherapy (CIT). CR with second line (2L) therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve complete response (CR) with RICE chemotherapy alone. Addition of targeted agents such as Bruton Tyrosine Kinase inhibitors to 2L therapy may improve treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. The goal of this study is to examine the feasibility and efficacy of adding the BTKi, acalabrutinib, to 2L therapy to improve disease response. Here we present primary endpoint data for the fully accrued Cohort A and updated follow-up, safety, and response data for all patients treated on the study.

Study Design and Methods: The primary objective of this phase 2 trial is to evaluate the tolerability, feasibility, and efficacy of combining acalabrutinib with RICE as 2L therapy in R/R DLBCL patients. The two study cohorts are Cohort A: R/R DLBCL patients eligible for autologous HCT and Cohort B: R/R DLBCL patients deemed ineligible for autologous HCT. The study enrolled from 2018 to 2023. The primary endpoint for cohort A is to estimate the CR rate (RECIL 2017 criteria) prior to transplant. The primary endpoint for cohort B was the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy.

Patients in cohort A received 2 cycles of standard RICE CIT in combination with acalabrutinib (RICE-A), 100mg BID day in a 21-day cycle. After 2 cycles of therapy, patients underwent autologous stem cell mobilization and collection followed by a 3^rd cycle of RICE-A. PET-CT (PET3) was performed 14-21 days after C3D1 to assess response. Patients with CR or partial response (PR) after PET3 proceeded to transplant with BEAM conditioning. After hematopoietic recovery, patients received acalabrutinib 100mg BID as consolidation therapy for 12 additional months.

Patients in cohort B received 3 cycles of RICE-A in combination with acalabrutinib 100mg BID for a 21-day cycle followed by PET-CT (PET3) 14-21 days after start of C3D1. Patients without progressive disease at PET3 continued with acalabrutinib consolidation up to 12 additional cycles until disease progression or unacceptable toxicity.

Patients demonstrating progressive disease were withdrawn from study treatment, but their survival outcomes are included in final data analysis.

This trial is currently closed for accrual and additional information can be found on clinicaltrials.gov NCT listing NCT03736616

Results: 32 patients have been enrolled and 31 patients started RICE-A. Median ages were 59 (Cohort A) and 75 (Cohort B). The majority of subjects were ABC/Non-GCB subtype 58% (Cohort A) and 57% (cohort B). The first patient started treatment on 11/27/2019 and the final patient started treatment on 11/21/2023.

27 patients (87%) have completed 3 cycles of RICE-A. One patient (4%) stopped RICE-A due to Adverse effect, 3 patients (11%) stopped RICE-A due to Progressive disease prior to completing Cycle 3.

In cohort A, 23 of 24 pts were response evaluable. ORR was seen in 19 patients (82%), with a 14CRs (60%), 5PRs (22%), 4PDs (17%); (1 patient withdrawn prior to completion of response evaluation period due to SAE – appendicitis). One year estimated PFS was 70%, one year OS was 91%. Median length of follow-up for cohort A is 28 months. Hematologic AEs were observed in 12 patients (1 Grade1/2 and 11 Grade 3/4) all considered study related. Gastrointestinal AEs were observed in 5 patients (4 Grade1/2 and 1 Grade3/4). Treatment related Gastrointestinal AEs were observed in 4 patients (4 Grade 1/2).

Enrollment in Cohort B was closed due to low accrual with emergence of new standard of care therapies. Of 7 patients enrolled, 1 CR, 2 PR, 3 PD were observed. One patient was not response evaluable.

Conclusions: RICE-A was feasible in transplant eligible patients receiving 2L therapy for DLBCL. The observed ORR 82% and CR 60% with a 1 yr. PFS 70%, 1yr OS 91% which exceeded historically reported efficacy for RICE alone. Additionally, the combination has shown to be well tolerated with a toxicity profile expected for its component therapies. Given these results RICE-A may merit further study in R/R DLBCL.