Three-Year Update of the Phase 2 ABT-199 (Venetoclax) and Ibrutinib in Mantle-Cell Lymphoma (AIM) Study

The phase 2 ABT-199 (Venetoclax) and Ibrutinib in Mantle-Cell Lymphoma (AIM) trial in patients with poor-prognosis mantle-cell lymphoma (MCL) showed that the combination of the Bruton’s tyrosine kinase inhibitor ibrutinib and the BCL-2 inhibitor venetoclax resulted in a 16-week complete remission rate (CRR) of 62%, overall response rate of 71%, flow minimal residual disease (MRD)-negative rate of 67%, and allele-specific oligonucleotide–polymerase chain reaction MRD-negative rate of 37%. With median follow-up 15.9 months, median progression-free survival, duration of response (DOR), time to progression (TTP), and overall survival had not been reached. At the 2019 ASH annual meeting, these results were updated with an additional 21.6 months of follow-up, and outcomes of patients who electively interrupted treatment were reported.

The AIM study enrolled 24 patients with relapsed/refractory MCL or who were treatment naïve but were inappropriate for, or refused, chemotherapy. Patients were treated with ibrutinib 560 mg daily for 4 weeks, followed by weekly ramp-up of venetoclax to 400 mg daily. Per initial plan, patients were to continue both drugs until progressive disease (PD) or unacceptable toxicity. However, a later amendment allowed patients to electively interrupt both drugs if MRD-negative complete remission was reached; these patients were closely monitored by peripheral blood flow MRD testing and regular computed tomography scans, and were allowed to recommence both study drugs at MRD recrudescence or clinical progression.

The median age of study participants was 68 years (range, 47-81), and the median number of previous treatments was 2 (range, 0-6); 50% of patients harbored TP53 aberrations. In the current analysis, at median follow-up of 37.5 months (range, 1.4-45.3), the median DOR and TTP had not been reached; 30-month DOR was estimated to be 74%, and 30-month TTP was estimated to be 60%. In the TP53-aberrant cohort (n = 12), the CRR was 50% (95% confidence interval [CI], 21-79) with and without positron emission tomography (PET), 58% (95% CI, 28-85) without PET, and 50% (95% CI, 21-79) with PET. Of the 6 responders with TP53-aberrant MCL, the DOR was 12+, 24+, 26+, 35+, 36+, and 38+ months from study commencement.

The most common adverse events (AEs) occurring in ≥20% of patients included diarrhea; fatigue; nausea and vomiting; bleeding, bruising, or postoperative hemorrhage; musculoskeletal or connective tissue pain; neutropenia; anemia; and thrombocytopenia. Serious AEs included diarrhea, tumor lysis syndrome, atrial fibrillation, pyrexia, pleural effusion, cardiac failure, and soft tissue infection. A total of 13 deaths were reported; 8 were due to PD, 2 were due to infection, and 1 each were due to cardiac failure, glioblastoma, and graft-versus-host disease after an allograft that occurred after PD on trial.

After a median of 18.5 months (range, 18-33) of therapy, 5 patients with MRD-negative, PET-confirmed complete remission electively interrupted treatment. Of these, 1 patient had radiologic progression after 7 months, whereas 4 remained free of clinical or MRD progression after 6, 13, 17, and 18 months off therapy, respectively.

Based on the results of the 3-year update of the phase 2 AIM study, the investigators concluded that ibrutinib + venetoclax therapy was effective in patients with MCL, and that treatment interruption was feasible for patients in MRD-negative complete remissions.

Handunnetti SM, et al. ASH Abstract 756. Session 623.

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