Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions

Abstract

In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Graphical abstract

Figure 1.

Key survival outcomes for patients with R/R MCL. Kaplan-Meier plots, with 95% CIs (dashed lines) for PFS (A), OS (B), DOR (C), TTF (D), and 16-week landmark analysis (E) for TTF in responders. Tick marks represent censoring at last follow-up before data cutoff for patients without an event. Note: Patient 2 could not be stringently evaluated by PET until removal of a ureteric stent near site of original disease, with CR by CT/PET formally documented after 2 years on study. For landmark analysis (E), patient 2 was included as a responder at week 16 to reflect the overall clinical assessment at the time. CT, computed tomography.

Figure 2.

Ibrutinib and venetoclax treatment, ETI, disease response, and survival for 23 patients with R/R MCL. Individual patient data are shown in lanes, ordered by duration on study, with key molecular variants detected in corresponding MCL biopsy from each patient at baseline shown to left of the graph. The full molecular data on each MCL sample have previously been fully reported. A black square shows the presence of a pathogenic variant for the indicated genes; for TP53 this includes deletions. Arrows at the end of each lane indicate ongoing treatment on study or ongoing surveillance in ETI. Patient 8 elected to come off study treatment while in MRD-negative CR but declined to enter ETI due the logistic constraints of the surveillance schedule. CR, complete response documented by PET; MRD Neg, minimal residual disease negative on BM by flow cytometry, PD; IB, ibrutinib; IB+V, ibrutinib plus venetoclax; PR, partial response with PET; VEN, venetoclax.