A triplet, chemotherapy-free regimen consisting of ibrutinib, rituximab, and venetoclax (IRV) followed by a risk-stratified short course of R-Hyper-CVAD with methotrexate and cytarabine (R-HCVAD/MTX-ARA-C) as consolidation, and IRV maintenance was safe and significantly improved outcomes across all risk groups in young patients with previously untreated mantle cell lymphoma (MCL).
The results were presented during the 17th International Conference on Malignant Lymphoma in Lugano, Switzerland, by Luhua (Michael) Wang, MD, of the University of Texas MD Anderson Cancer Center, and colleagues.
The single-arm, phase II WINDOW-2 trial enrolled 50 previously untreated patients with a median age of 58 years (range, 35–65) from a single institution. The patients underwent an induction treatment consisting of ibrutinib plus rituximab, followed by the addition of dose ramp-up venetoclax 400 mg starting at cycle five.
Patients were stratified into three risk groups: high, moderate, and low risk (each including 21, 18, and 11 patients, respectively) using baseline data. Patients were assigned to receive R-HCVAD/MTX-ARA-C as consolidation in the second part of the study (four cycles, two cycles, or no chemotherapy for high-, medium-, and low- risk patients, respectively).
Patients with high-risk features were defined as those with Ki-67 ≥50%, mutations in TP53, NSD2, or NOTCH genes, a tumor diameter of >5 cm, or blastoid/pleomorphic histology.
After consolidation, all patients received two years of IRV maintenance. The primary objective was to assess complete recovery (CR) rates after IRV induction.
Of the 50 patients, 48 received the triplet. Two patients were unable to start venetoclax due to progression on ibrutinib plus rituximab and an on-study death prior to venetoclax. The best response to IRV was 100% with a CR rate of 100%. The median number of triplet IRV cycles to reach the best response was eight cycles (range, two to 12).
With a median follow up of 41 months (range, 25–50), the median PFS and OS were not reached (the three-year PFS and OS rates were 85% and 86%, respectively). The median PFS and OS were not significantly different between patients with high and low Ki-67, or with and without TP53 aberrations, or among patients in low-, medium-, or high-risk categories. Twenty-seven patients (54%) discontinued the study for various reasons: 20 due to adverse events, nine related to COVID-19, 11 unrelated to COVID-19, three due to death, and four based on patient choice.
“Chemotherapy-free induction with IRV induced deep responses,” the authors concluded, noting that no patients relapsed regardless of risk category. “Patients with low-risk MCL may not need chemotherapy,” they added.
Wang ML, Lee HJ, Fetooh A, et al. Ibrutinib-rituximab and venetoclax (IRV) followed by risk-stratified R-HYPERCVAD/MTX in young patients with untreated MANTLE CELL LYMPHOMA—phase-II WINDOW-2 trial. Abstract #099. Presented at the 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland.