San Diego, California—Immune checkpoint inhibitors demonstrate significant activity in myelodysplastic syndrome with an acceptable toxicity profile, according to results from a recent phase 2 trial presented by Guillermo Garcia-Manero, MD, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, at the 2018 ASH Annual Meeting.

“Myeloid cells express PD-1 and CTL-A. The expression of these molecules is activated by treatment with a hypomethylating agent (HMA) both in cell lines and patient samples,” according to Dr Garcia-Manero and colleagues who hypothesized that treatment with immune checkpoint inhibitors blocking CTL-A or PD-1 could have activity in front-line and relapsed myelodysplastic syndrome (MDS) with or without azacitidine.

The exploratory phase 2 trial treated a total of 76 patients between November 2015 and August 2017. Patients were divided into two groups—front-line and HMA-failure. Front-line patients were treated in 2 cohort: azacitidine plus nivolumab and azacitidine plus ipilimumab. HMA-failure patients were also treated in 2 cohorts: single agent nivolumab and single-agent ipilimumab. HMA-failure patients were first treated with single-agent immune checkpoint inhibitors and after 6 cycles azacitidine was allowed to test the concept of resensitization.

Nivolumab was administered at a dose of 3 mg/kg on days 1 and 15 every 4-week cycle and ipilimumab at 3 mg/kg on day 1 every 3-week cycle. Azacitidine was used at the standard dose. When combined with azacitidine, nivolumab was administered on days 6 and 20 every 4-week cycle and ipilimumab on day 6 every 4-week cycle.

A total of 41 patients were treated in the front-line group and 35 in the HMA failure group. The median age of patients was 71 years. 20 patients were treated with azacitidine plus nivolumab, 21 were treated with azacitidine plus ipilimumab, 15 were treated with single-agent nivolumab, and 20 were treated with single-agent ipilimumab.

Overall response was observed in 15 of 20 patients treated with azacitidine plus nivolumab, 15 of 21 patients treated with azacitidine plus ipilimumab, 2 of 15 patients treated with single-agent nivolumab, and 7 of 20 patients treated with single-agent ipilimumab. CR/CRp was observed in 10 patients, 8 patients, 0 patients, and 3 patients treated with azacitidine plus nivolumab, azacitidine plus ipilimumab, nivolumab, and ipilimumab, respectively.

The median cycle received was 4 cycles. Among 37 patients with response, the median cycle to response was 3 cycles. At a median follow-up of 20 months, the median overall survival were 12 months among patients treated with azacitidine plus nivolumab, not reached among patients treated with azacitidine plus ipilimumab, 8 months among patients treated with single-agent nivolumab, and 8 months among patients treated with single-agent ipilimumab.

Event-free survival were 10 months, not reached, 7 months, 6 months with azacitidine plus nivolumab, azacitidine plus ipilimumab, nivolumab, and ipilimumab, respectively. Survival rates at 1 year were 50%, 68%, 25%, and 45%, respectively.

The median event-free survival were 16 months and 7 months in the frontline and HMA-failure cohort, respectively (p=0.096); the median overall survival were 17 months and 8 months in the frontline and HMA failure cohort, respectively (p=0.030).

Observed toxicities were skin rash, 26 (11%); fatigue, 22 (9%); pain, 16 (7%); infection, 14 (6%); febrile neutropenia, 13 (5%); pruritus, 14 (6%); diarrhea, 11 (5%); constipation, 9 (4%); nausea, 10 (4%), ALT elevations, 8 (3%); anorexia, 7 (3%); cough, 7 (3%). Early mortality was observed in 1 patient (1%).

“The incorporation of ICPI [immune checkpoint inhibitors] is feasible in MDS,” Dr Garcia-Manero and colleagues concluded.

“These agents have significant activity as single agents and in combination in MDS with an acceptable toxicity profile and significant response and survival outcomes, particularly with ipilimumab,” they added.

They emphasized that further randomized studies are needed to test the use of immune checkpoint inhibitors in MDS.—Janelle Bradley

Garcia-Manero G, Sasaki K, Montalban-Bravo, G, et al. A Phase II Study of Nivolumab or Ipilimumab with or without Azacitidine for Patients with Myelodysplastic Syndrome (MDS). Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 465.