Safety, outcomes and T cell characteristics in patients with relapsed or refractory MDS or CMML treated with atezolizumab in combination with guadecitabine

Casey L O'Connell*, Maria R Baer, Andreas Due Ørskov, Sunil Kumar Saini, Vu H Duong, Patricia Kropf, Jakob Werner Hansen, Denice Tsao-Wei, Hyo Sik Jang, Ashkan Emadi, Staffan Holmberg-Thyden, Jack Cowland, Brett T Brinker, Kristin Horwood, Ryan Burgos, Galen Hostetter, Benjamin A Youngblood, Sine Reker Hadrup, Jean-Pierre Issa, Peter JonesStephen B Baylin, Imran Siddiqi, Kirsten Grønbæk

*Corresponding author af dette arbejde
4 Citationer (Scopus)

Abstract

PURPOSE: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA.

PATIENTS AND METHODS: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival.

RESULTS: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months.

CONCLUSIONS: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind28
Udgave nummer24
Sider (fra-til)5306-5316
Antal sider11
ISSN1078-0432
DOI
StatusUdgivet - 15 dec. 2022

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