7-Year Data Show Feasibility of Elective Treatment Interruption of Venetoclax/Ibrutinib in R/R MCL

Mantle Cell Lymphoma | Image Credit: © LASZLO – stock.adobe.com

Treatment with venetoclax (Venclexta) plus ibrutinib (Imbruvica) demonstrated long-term durable responses with acceptable toxicity in patients with relapsed/refractory mantle cell lymphoma (MCL), and maintained disease control following elective treatment interruptions (ETI) was feasible in this patient population, according to 7-year follow-up in the phase 2 AIM trial (NCT02471391) published in Blood.1

Findings showed that complete responses (CRs) were achieved in 17 of 23 evaluable patients at a median of 4 months (range, 4-24). At a median follow-up of 88 months (range, 1.6-95), the median duration of response (DOR) was 81 months (95% CI, 22-not evaluable [NE]). Among the 17 patients to achieve a CR, 4 died in remission on therapy, 3 experienced disease progression on continuous therapy, 2 remained in CR on continuous therapy, and 8 opted for ETI.

The median time on study treatment before ETI was 23 months (range, 18-61), and the median time in remission on ETI was 58 months (95% CI, 37-79). Disease progression was reported in 4 patients on ETI; 3 patients resumed venetoclax/ibrutinib treatment, of which 2 rapidly re-achieved CR and 1 had disease progression.

“Now, with more than 7 years of follow-up, these data indicate that venetoclax/ibrutinib provides long-term benefit for some patients with relapsed/refractory MCL,” lead study author Sasanka M. Handunnetti, MBBS, PhD, and coauthors wrote in the publication. “Here, we have provided, to our knowledge, the first exploration of ETI in patients treated with venetoclax/ibrutinib achieved minimal residual disease [MRD]–negative CR with a median duration of ETI of 58 months.”

Handunnetti is an academic researcher in the Department of Haematology at the Peter MacCallum Cancer Centre, Royal Melbourne Hospital in Australia, and Princess Alexandra Hospital in Brisbane, Australia.

AIM Background, Design, and Patient Characteristics

The open-label, single-group, phase 2 study evaluated venetoclax/ibrutinib in patients with relapsed/refractory MCL or previously untreated MCL who were not candidates for chemoimmunotherapy. Patients needed to have a neutrophil count of at least 750 mm3; a platelet count of at least 50,000 mm3; a creatinine clearance of at least 50 mL per minute; and an ECOG performance score of 0 to 2.2

Patients (n = 24) were treated with oral ibrutinib monotherapy at 560 mg daily for the first 4 weeks of treatment. At week 5, oral venetoclax was introduced according to a dosing schedule starting at 50 mg and increased weekly in a step-up approach at 100 mg daily, 200 mg daily, and finally 400 mg daily, based on the recommended dose for treating chronic lymphocytic leukemia at the conception of the study. The recommended phase 2 dose in MCL was reported to be 800 mg daily after week 16 if a CR did not occur.

The previously reported primary end point was CR rate at 16 weeks; the current exploratory aim of the study was time-to-treatment failure (TTF).1,2

Patients with relapsed/refractory MCL were enrolled on the study between July 2015 and September 2016, of which 23 patients were previously treated with a median of 2 lines of therapy (range, 1-6).2 The median age was 68 years (range, 47-81); nearly half of patients had present TP53 aberrations (48%), and some had an NF-κB pathway mutation (26%).

Additional Efficacy Data

The 7-year TTF rate in patients treated with venetoclax/ibrutinib was 39% (95% CI, 20%-58%), with a median TTF of 28 months (95% CI, 13-NE). In patients who responded at week 16, the 7-year TTF rate was 68% (95% CI, 39%-86%).1

The median progression-free survival (PFS) was 28 months (95% CI, 13-82) with an estimated 7-year PFS rate of 30% (95% CI, 14%-49%). The median overall survival (OS) was 32 months (95% CI, 15-NE) with an estimated 7-year OS rate of 43% (95% CI, 23%-62%).

In patients with TP53 aberrations (n = 11), median PFS was 5 months. Five of these patients achieved responses; 2 had respective DORs of 9 and 37 months, and 3 had ongoing responses with durations of 84, 86, and 87 months, respectively; 2 of these ongoing responses were achieved in patients who restarted venetoclax/ibrutinib after relapse during ETI.

“Although the number of patients electing to enter ETI in this study [was] small, the data establish the proof-of-principle for durable disease control with ETI in deep remission and that patients could respond rapidly to retreatment after disease progression on ETI,” study authors wrote. “We are now exploring 2 limited duration target-agent combination regimens in response-adapted treatment of relapsed/refractory MCL in the [phase 2] AIM2 clinical trial [NCT05864742].”

Safety Data

Of the 24 total patients in the study, 15 died, including 9 due to disease progression. In patients with active disease, 2 deaths were infection-related. Non–MCL-related deaths occurred during ongoing CRs in 4 patients, with 3 due to secondary malignancies including metastatic small cell lung cancer, therapy-related myelodysplastic syndrome that became acute myeloid leukemia, and glioblastoma multiforme; 1 patient died due to cardiac failure.

Safety beyond 56 weeks was evaluated, looking specifically at grade 3 or greater adverse effects (AEs) and serious AEs. Notably, no new cases of cardiac toxicity were reported. The most common grade 3 or greater and serious AEs included diarrhea (n = 3), lung infection (n = 2), infectious enterocolitis (n = 1), urosepsis (n = 1), sinusitis (n = 1), and febrile neutropenia (n = 1).

References

1. Handunnetti SM, Anderson MA, Burbury K, et al. Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions. Blood. 2024;144(8):867-872. doi:10.1182/blood.2023023388
2. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi:10.1056/NEJMoa1715519