Ibrutinib in combination with rituximab, methotrexate (MTX), vincristine, and procarbazine (R-MPV/i) for newly diagnosed primary CNS lymphoma (PCNSL) Free

Background: The R-MVP regimen results in a 66% complete response rate (CRR) in newly diagnosed PCNSL. The Bruton's tyrosine kinase inhibitor ibrutinib showed single-agent activity in recurrent PCNSL. This phase 2 trial explored the combination of ibrutinib and R-MVP in newly diagnosed PCNSL.

Methods: Eligible patients had newly diagnosed PCNSL, age≥18, ECOG≤2, and normal end-organ function. Treatment was administered over four 28-day cycles. Rituximab 500mg/m² was given on Day 0+14, MTX 3.5g/m² Day 1+15, vincristine 1.4mg/m² Day 1+15 cycles 1-2, and procarbazine 100mg/m²/day Day 1-7 of each cycle. Ibrutinib 560mg/day was given Days 5-14 and 19-28 each cycle. Enrollment was allowed after 1-2 prior doses of methotrexate. The primary endpoint was CRR at end of induction The combination was considers promising if CRR (CR+CRu (if>95% reduction)) reached 80% (24 out of 30 patients) (90% power with a significance of 0.05). Secondary endpoints included safety and tolerability, median progression-free survival (PFS), and overall survival (OS)Consolidation was determined by the investigator.

Results: Accrual is complete (n=30, median age 69 [range 41-79], median ECOG=1). 25 patients completed R-MPV/i, 1 withdrew consent after 2 R-MVP/i cycles and 4 are still receiving treatment. A CR was achieved in 25 and a PR in 1 for a CRR of 25/30 (83%) thus far. Treatment was well tolerated with 23 of 26 (88%) receiving 8 doses of MTX, 2 (8%) 7 doses and 1 (4%) 5 doses. No grade 5 toxicity was observed. Seven patients experiences 13 grade 4 toxicities (lymphopenia (n=3), neutropenia (n=4), thrombocytopenia (n=3) white cell count decrease (n=3)). The most common toxicities were thrombocytopenia, anemia, lymphopenia and liver enzyme elevations. None of the patients developed Aspergillus or Pneumocystis injections. No refractory disease was observed thus far. For the 25 completing R-MVP/i, 16 received Ara-C consolidation, 7 ASCT, and 1 rituximab maintenance. At a median follow up of 24 months (range 1-47), the median PFS and OS was not reached with a 2-year and 3-year PFS of 83.2%.

Conclusions: R-MPV/i induction regimen was well tolerated and resulted in improved complete response rates. The study met the primary endpoint of achieving a CRR of >80% after completion of R-MVP/i.