Rapid Readouts: Ibrutinib Plus Rituximab and Venetoclax Followed by Risk-Stratified Chemoimmunotherapy in Young Patients With Previously Untreated MCL

Expert perspectives on the phase II clinical trial assessing IRV triplet therapy in young patients with previously untreated mantle cell lymphoma to help minimize chemotherapy exposure.

Preetesh Jain, MD, PhD, discusses data from the following study:

  • Ibrutinib plus rituximab and venetoclax followed by risk-stratified observation or short-course R-hyper-CVAD [rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone]–methotrexate in young patients with previously untreated mantle cell lymphoma: phase 2 WINDOW-2 clinical trial. (Blood. 2020;136:35-36)
    • The objective of this study is to report results in young patients with previously untreated mantle cell lymphoma treated with IRV [ibrutinib, rituximab, venetoclax] followed by observation or short-course R-hyper-CVAD–methotrexate.
    • IRV is a chemotherapy-free combination option.
    • 50 patients were enrolled to receive IR [ibrutinib, rituximab] induction for an initial 4 cycles, restaging at cycle 4, then IRV for up to 8 cycles. Patients were then risk-stratified (high, moderate, or low) to receive R-hyper-CVAD–methotrexate consolidation or observation, followed by 2 years of IRV maintenance.
    • Safety and efficacy outcomes were assessed in the population:
      • Overall response rate (ORR) was assessed at 96% with a complete response in 92% before consolidation.
      • Best ORR after consolidation in medium- and high-risk patients was 96%.
      • The median number of cycles of IRV to reach best response was 8.
      • Grade 3/4 toxicities with initial IRV were 3% mucositis and 10% each with myelosuppression, fatigue, myalgia, and rashes.
      • Grade 3 atrial flutter developed in 1 patient with initial IRV, while none had bleeding or bruising.
      • Among 35 patients who received consolidation, grade 3/4 toxicities were 46% neutropenia, 30% anemia, and 40% thrombocytopenia.
    • Conclusions:
      • IRV induced unprecedented efficacy before chemotherapy consolidation.
      • Thirteen patients (26%) came off study: 5 for adverse events, 3 for on-study deaths, 2 for patient choice, 2 lost to follow-up, and 1 for disease progression.
      • Overall, 5 patients died (3 on trial and 2 off, 1 from progressive disease and another from COVID-19).
      • WINDOW-2 suggests that patients with low-risk mantle cell lymphoma may not need chemotherapy, but further follow-up is warranted.
      • Further studies on predictors of response, minimal residual disease, and clonal evolution are ongoing.