TY - JOUR
T1 - Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome
AU - Chien, Kelly S.
AU - Kim, Kunhwa
AU - Nogueras-Gonzalez, Graciela M.
AU - Borthakur, Gautam
AU - Naqvi, Kiran
AU - Daver, Naval G.
AU - Montalban-Bravo, Guillermo
AU - Cortes, Jorge E.
AU - DiNardo, Courtney D.
AU - Jabbour, Elias
AU - Alvarado, Yesid
AU - Andreeff, Michael
AU - Bose, Prithviraj
AU - Jain, Nitin
AU - Kadia, Tapan M.
AU - Huang, Xuelin
AU - Sheppard, Kimberly B.
AU - Klingner-Winton, Cheri
AU - Pierce, Sherry A.
AU - Dong, Xiao Qin
AU - Soltysiak, Kelly A.
AU - Kantarjian, Hagop M.
AU - Garcia-Manero, Guillermo
N1 - Funding Information:
This research was funded by Merck & Co. (Kenilworth, NJ, USA). This work was also supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672, the University of Texas MD Anderson MDS/AML Moon Shot, and the MDS Clinical Research Consortium, which is funded by the Edward P. Evans Foundation.
Publisher Copyright:
© 2021 British Society for Haematology and John Wiley & Sons Ltd.
PY - 2021/11
Y1 - 2021/11
N2 - Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.
AB - Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.
KW - azacitidine
KW - hypomethylating agent failure
KW - immunotherapy
KW - myelodysplastic syndromes
KW - pembrolizumab
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U2 - 10.1111/bjh.17689
DO - 10.1111/bjh.17689
M3 - Article
C2 - 34340254
AN - SCOPUS:85111670323
SN - 0007-1048
VL - 195
SP - 378
EP - 387
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -