From the Journals

Ibrutinib-MTX-rituximab combo shows promise in CNS lymphoma



The three-drug combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab showed positive safety and clinical outcomes in patients with recurrent/refractory primary/secondary CNS lymphoma, according to results from a phase 1b trial.

Ibrutinib has already shown single-agent activity in recurrent/refractory CNS lymphoma, Christian Grommes, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, wrote in Blood. “The primary objective was to determine the maximum tolerated dose of ibrutinib in combination with HD-MTX alone and ibrutinib in combination with HD-MTX and rituximab.”

With respect to ibrutinib dosing, the initial cohort was started at 560 mg daily, which was increased to 840 mg daily in successive cohorts using a 3+3 design. HD-MTX was administered every 2 weeks at 3.5 g/m2 for a total of eight infusions, or four cycles, with each cycle lasting of 28 days.

After no dose-limiting adverse effects were seen with the ibrutinib-MTX combination, the researchers added rituximab at 500 mg/m2 every 2 weeks, for a total of eight infusions, which completed the induction phase. The three-agent induction therapy was followed by daily ibrutinib monotherapy, which was maintained until discontinuation caused by malignancy progression, intolerable adverse events, or death.

“To minimize the risk of adverse events, we held ibrutinib on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after MTX clearance,” they wrote.

After analysis, Dr. Grommes and his colleagues reported that no dose-limiting or grade 5 toxicities were detected. At a median follow-up of 19.7 months, they saw an 80% overall response rate in study patients treated with combination therapy. The median progression free survival for all 15 patients was 9.2 months and the median overall survival was not reached, with 11 of 15 patients alive.

The researchers proposed an 840-mg dose of ibrutinib for future studies.

The most frequent adverse events were lymphopenia, thrombocytopenia, anemia, and transaminase elevations. No fungal infections were seen during the study.

The researchers noted that two key limitations of the study were the nonrandomized design and small sample size. As a result, they reported that the degree of ibrutinib-specific activity in the three-drug combination remains unknown.

The study was supported by grant funding from Pharmacyclics to Memorial Sloan Kettering. The authors reported financial ties to AstraZeneca, Bristol-Myers Squibb, BTH, Kite Pharma, Pfizer, and others.

SOURCE: Grommes C et al. Blood. 2019;133(5):436-45.

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