MCL Survival Likely Affected by Reason for Acalabrutinib Discontinuation

Outcomes for patients with mantle cell lymphoma (MCL) who stop using acalabrutinib may differ depending on the reason for discontinuation and if they are eligible for other therapies, according to researchers in The American Journal of Hematology.

Published literature notes that 51% of patients have discontinued use of acalabrutinib, but does not detail their outcomes, management, and mutation profiles. Patients whose MCL progresses while using acalabrutinib have limited treatment options, and their survival rates after discontinuing ibrutinib, another MCL therapy, are limited to 3 to 10 months, calling into questions whether patients ceasing acalabrutinib will have the same results.

Investigators said that their results show that, “unlike postibrutinib outcomes in relapsed MCL, patients who fail acalabrutinib have better outcomes.”

The present researchers sought to establish what happens after treatment stoppage by looking at 21 patients with relapsed MCL who cease acalabrutinib treatment. Whole exome sequencing (WES) was conducted for 9 patients, amounting to 10 samples. Four of the samples were collected prediscontinuation and 6 were collected post discontinuation.

Among the 21 patients, 15 (71%) stopped acalabrutinib treatment due to disease progression and 6 (28%) stopped due to intolerance. The median number of treatments prior to starting acalabrutinib was 2. All patients had received at last 1 line of chemo-immunotherapy and were treatment-naïve to ibrutinib.

Patients were on acalabrutinib for a median 8.3 months (range, 1-50) and had a median 8 cycles of treatment (range, 1-53). Those who discontinued treatment because of disease progression received acalabrutinib for a median 8.3 months (range, 1-50) compared with a median 9.4 months (range, 4-31) among those who stopped due to intolerance.

Best outcomes among the patients consisted of complete remission (n = 13), becoming primary refractory (n = 5), and partial remission (n = 3). After cessation, the median follow-up period was 38 months and the median survival rate was 24.3 months (P = .02).

Patients who stopped treatment because of medication intolerance were not eligible to receive subsequent MCL treatment, leading to a poorer survival rate after discontinuation than patients who were eligible for other treatment options. Five of the 6 patients who stopped acalabrutinib because of intolerance died.

Among the 15 patients who progressed on acalabrutinib, 14 went on to receive other therapies, with 7 getting ibrutinib. Of these 7 patients, 4 received either single-agent ibrutinib or ibrutinib plus rituximab, 2 received carfilzomib, and 1 received ibrutinib plus bendamustine-rituximab.

Six patients who transitioned to nonacalabrutinib therapies received chemo-immunotherapy with bortezomib or lenalidomide-based therapies, and 1 was lost to follow-up.

Furthermore, 6 of the 14 patients receiving subsequent therapies were enrolled in a clinical trial on the use of chimeric antigen receptor (CAR) T-cell therapy. All achieved complete remission. In addition, patients who received CAR T had a longer median survival (not reached) compared with those who did not receive CAR T (15.5 months; P = .007).

In the WES samples, investigators did not detect any mutations or copy number alterations of genes that had previously been associated with ibrutinib resistance in chronic lymphocytic leukemia.

The authors identified the small patient cohort and limited molecular data as the main limitations of their research. Additionally, they could not confirm the efficacy of venetoclax because only 1 patient in the study received it and did not respond; this was despite 2 retrospective studies having shown promising results for venetoclax use in patients who have discontinued ibrutinib. Therefore, the authors recommended that future studies evaluate venetoclax efficacy, either as a monotherapy or in combination, in patients whose disease progresses on acalabrutinib.

“Larger patient cohorts to study the molecular mechanisms of acalabrutinib-resistant MCL are required. Clinical trials and CAR T therapies should be considered for MCL patients who progress on acalabrutinib,” noted the authors.

Reference

Jain P, Zhang S, OK CY, et al. Outcomes of relapsed mantle cell lymphoma patients after discontinuing acalabrutinib. Am J Hematol. Published online January 25, 2021. doi:10.1002/ajh.26109