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Clin Cancer Res. 2018 Aug 1;24(15):3519-3527. doi: 10.1158/1078-0432.CCR-17-3763. Epub 2018 May 1.

A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure.

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Section of Hematology, Department of Medicine, and the Smilow Cancer Center at Yale University, New Haven, Connecticut.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington.
Lineberger Comprehensive Cancer Center at University of North Carolina, Raleigh, North Carolina.
Duke Cancer Institute, Durham, North Carolina.
Columbia University Medical Center, New York, New York.
Texas Oncology at Baylor University Medical Center, Dallas, Texas.
Siteman Cancer Center at Washington University, St. Louis, Missouri.
Cancer Therapy Evaluation Program, NIH, Bethesda, Maryland.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Contributed equally


Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2-4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/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 3 mg/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 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519-27. ©2018 AACR.

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