ASH 2024 | A Phase II trial of azacitidine, ipilimumab, and nivolumab in previously untreated MDS

In the Phase II trial of azacitidine with ipilimumab, nivolumab, or ipilimumab and nivolumab in previously untreated myelodysplastic syndrome, we enrolled 66 patients with MDS in three separate treatment cohorts. Patients received one of three combinations, azacitidine with ipilimumab, azacitidine with nivolumab, or azacitidine with ipilimumab and nivolumab. We gave azacitidine 75 mg per meter squared for 5 days in 28-day cycles with ipilimumab 3 mg per kg on day 6 or nivolumab 3 mg per kg on day 6 and 20. Patients in the triplet cohort of azacitidine, ipilimumab, and nivolumab received azacitidine for 5 days followed by ipilimumab and nivolumab on day 6. This trial featured a cohort of older adults with a median age of 68 years. Most patients were transfusion dependent and most patients had IPSS-R, very poor risk disease. TP53 mutations were the most common mutation found in this cohort, comprising nearly half of the overall cohort. In this trial, the composite complete remission rate was 40% for AZA-NEVO, 13% for AZA-IPI, and 46% for AZA-IPI-NEVO. The complete remission rates significantly favored AZA-NEVO compared to AZA-IPI. Despite that, there were no significant differences in the overall response rates between cohorts. We noted that normal karyotypes were associated with improved rates of overall response, whereas DNMT3A mutated MDS was associated with reduced overall response rates in patients with elevated blasts. We noted no differences in the median overall survival between cohorts. The overall survival was 22.7 months with azacitidine and ipilimumab, 14.3 months with azacitidine and nivolumab, and 11.8 months with the triplet regimen of azacitidine, ipilimumab, and nivolumab. However, we noticed an interesting phenomenon. The triplet cohort of AZA-IPI-NEVO was associated with a significantly shorter post-transplant overall survival compared to the double cohorts of AZA-IPI and AZA-NEVO. We observed an immunotherapy-related adverse event rate of 44% across all three cohorts. The rate was higher in the triplet combination of AZA-IPI-NEVO compared to AZA-IPI or AZA-NEVO. Strikingly, we observed that the incidence of grade 2 or higher pneumonitis was associated with significantly worse overall survival. And patients who developed pneumonitis tended to be enriched in mutated TP53. So in summary, a triplet approach of AZA-IPI-NEVO failed to improve response or survival compared to AZA-IPI or AZA-NEVO and was associated with higher rates of toxicity and post-transplant mortality.

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