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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.

Author information

1
Section of Hematology, Department of Medicine, and the Smilow Cancer Center at Yale University, New Haven, Connecticut.
2
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
3
Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington.
4
Lineberger Comprehensive Cancer Center at University of North Carolina, Raleigh, North Carolina.
5
Duke Cancer Institute, Durham, North Carolina.
6
Columbia University Medical Center, New York, New York.
7
Texas Oncology at Baylor University Medical Center, Dallas, Texas.
8
Siteman Cancer Center at Washington University, St. Louis, Missouri.
9
Cancer Therapy Evaluation Program, NIH, Bethesda, Maryland.
10
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. bdsmith@jhmi.edu.
#
Contributed equally

Abstract

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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