A multi-center Phase 1 trial of ipilimumab in myelodysplastic syndrome patients following hypomethylating agent failure

Purpose: After failure of hypomethylating agents (HMAs), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options. Experimental Design: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with high-risk MDS that have failed HMAs. Patients received monotherapy at 2 dose-levels (DL; 3 and 10mg/kg) with an induction and a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria. We also performed immunologic assays and T-cell receptor sequencing on serial samples. Results: Twenty-nine patients from 7 centers were enrolled. In initial DL1 (3mg) 3 of 6 patients experiencing grade 2-4 immune-related adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. On DL2, 4 of 5 patients experienced grade 2 or higher IRAE thus DL1 (3mg/kg) was expanded with no grade 2-4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95%CI, 240-671+). Patients who achieved PSD or mCR had significantly higher frequency of T-cells expressing ICOS (Inducible T-Cell CO-Stimulator). Conclusions:Our findings suggest that ipilimumab dosed at 3mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as monotherapy. Increased frequency of ICOS-expressing T-cells might predict clinical benefit.

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