Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome

被引：53

作者：

Chien, Kelly S. ^{[1
]}

Kim, Kunhwa ^{[1
]}

Nogueras-Gonzalez, Graciela M. ^{[2
]}

Borthakur, Gautam ^{[1
]}

Naqvi, Kiran ^{[1
]}

Daver, Naval G. ^{[1
]}

Montalban-Bravo, Guillermo ^{[1
]}

Cortes, Jorge E. ^{[1
]}

DiNardo, Courtney D. ^{[1
]}

Jabbour, Elias ^{[1
]}

Alvarado, Yesid ^{[1
]}

Andreeff, Michael ^{[1
]}

Bose, Prithviraj ^{[1
]}

Jain, Nitin ^{[1
]}

Kadia, Tapan M. ^{[1
]}

Huang, Xuelin ^{[2
]}

Sheppard, Kimberly B. ^{[1
]}

Klingner-Winton, Cheri ^{[1
]}

Pierce, Sherry A. ^{[1
]}

Dong, Xiao Qin ^{[1
]}

Soltysiak, Kelly A. ^{[1
]}

Kantarjian, Hagop M. ^{[1
]}

Garcia-Manero, Guillermo ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

来源：

BRITISH JOURNAL OF HAEMATOLOGY | 2021年 / 195卷 / 03期

关键词：

myelodysplastic syndromes; azacitidine; pembrolizumab; hypomethylating agent failure; immunotherapy; SCORING SYSTEM; LEUKEMIA; EFFICACY; OUTCOMES; STRATEGY; FAILURE; CARE; MDS;

D O I：

10.1111/bjh.17689

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 center dot 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 center dot 0 months, the mOS was 5 center dot 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.

引用

页码：378 / 387

页数：10

共 28 条

[1] Phase Ib Study of the Anti-TIM-3 Antibody MBG453 in Combination with Decitabine in Patients with High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) [J].

Borate, Uma ;

Esteve, Jordi ;

Porkka, Kimmo ;

Knapper, Steve ;

Vey, Norbert ;

Scholl, Sebastian ;

Garcia-Manero, Guillermo ;

Wermke, Martin ;

Janssen, Jeroen ;

Traer, Elie ;

Chua, Chong Chyn ;

Narayan, Rupa ;

Tovar, Natalia ;

Kontro, Mika ;

Ottmann, Oliver ;

Sun, Haiying ;

Longmire, Tyler ;

Szpakowski, Sebastian ;

Liao, Serena ;

Patel, Anuradha ;

Rinne, Mikael L. ;

Brunner, Andrew ;

Wei, Andrew H. .

BLOOD, 2019, 134

[2] Molecular mechanisms of T cell co-stimulation and co-inhibition [J].

Chen, Lieping ;

Flies, Dallas B. .

NATURE REVIEWS IMMUNOLOGY, 2013, 13 (04) :227-242

[3] Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia [J].

Cheson, Bruce D. ;

Greenberg, Peter L. ;

Bennett, John M. ;

Lowenberg, Bob ;

Wijermans, Pierre W. ;

Nimer, Stephen D. ;

Pinto, Antonio ;

Beran, Miloslav ;

de Witte, Theo M. ;

Stone, Richard M. ;

Mittelman, Moshe ;

Sanz, Guillermo F. ;

Gore, Steven D. ;

Schiffer, Charles A. ;

Kantarjian, Hagop .

BLOOD, 2006, 108 (02) :419-425

[4] Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study [J].

Daver, Naval ;

Garcia-Manero, Guillermo ;

Basu, Sreyashi ;

Boddu, Prajwal C. ;

Alfayez, Mansour ;

Cortes, Jorge E. ;

Konopleva, Marina ;

Ravandi-Kashani, Farhad ;

Jabbour, Elias ;

Kadia, Tapan ;

Nogueras-Gonzalez, Graciela M. ;

Ning, Jing ;

Pemmaraju, Naveen ;

DiNardo, Courtney D. ;

Andreeff, Michael ;

Pierce, Sherry A. ;

Gordon, Tauna ;

Kornblau, Steven M. ;

Flores, Wilmer ;

Alhamal, Zainab ;

Bueso-Ramos, Carlos ;

Jorgensen, Jeffrey L. ;

Patel, Keyur P. ;

Blando, Jorge ;

Allison, James P. ;

Sharma, Padmanee ;

Kantarjian, Hagop .

CANCER DISCOVERY, 2019, 9 (03) :370-383

[5] Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study [J].

Fenaux, Pierre ;

Mufti, Ghulam J. ;

Hellstrom-Lindberg, Eva ;

Santini, Valeria ;

Finelli, Carlo ;

Giagounidis, Aristoteles ;

Schoch, Robert ;

Gattermann, Norbert ;

Sanz, Guillermo ;

List, Alan ;

Gore, Steven D. ;

Seymour, John F. ;

Bennett, John M. ;

Byrd, John ;

Backstrom, Jay ;

Zimmerman, Linda ;

McKenzie, David ;

Beach, C. L. ;

Silverman, Lewis R. .

LANCET ONCOLOGY, 2009, 10 (03) :223-232

[6] A Phase II Study of Nivolumab or Ipilimumab with or without Azacitidine for Patients with Myelodysplastic Syndrome (MDS) [J].

Garcia-Manero, Guillermo ;

Sasaki, Koji ;

Montalban-Bravo, Guillermo ;

Daver, Naval G. ;

Jabbour, Elias J. ;

Alvarado, Yesid ;

DiNardo, Courtney D. ;

Ravandi, Farhad ;

Borthakur, Gautam ;

Bose, Prithviraj ;

Pemmaraju, Naveen ;

Naqvi, Kiran ;

Cortes, Jorge E. ;

Kadia, Tapan M. ;

Konopleva, Marina Y. ;

Colla, Simona ;

Yang, Hui ;

Rausch, Caitlin R. ;

Gasior, Yvonne ;

Bueso-Ramos, Carlos E. ;

Kanagal-Shamanna, Rashmi ;

Patel, Keyur P. ;

Kantarjian, Hagop M. .

BLOOD, 2018, 132

[7] Pembrolizumab, a PD-1 Inhibitor, in Patients with Myelodysplastic Syndrome (MDS) after Failure of Hypomethylating Agent Treatment [J].

Garcia-Manero, Guillermo ;

Tallman, Martin S. ;

Martinelli, Giovanni ;

Ribrag, Vincent ;

Yang, Hui ;

Balakumaran, Arun ;

Chlosta, Sabine ;

Zhang, Yayan ;

Smith, B. Douglas .

BLOOD, 2016, 128 (22)

[8] Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial [J].

Garcia-Manero, Guillermo ;

Fenaux, Pierre ;

Al-Kali, Aref ;

Baer, Maria R. ;

Sekeres, Mikkael A. ;

Roboz, Gail J. ;

Gaidano, Gianluca ;

Scott, Bart L. ;

Greenberg, Peter ;

Platzbecker, Uwe ;

Steensma, David P. ;

Kambhampati, Suman ;

Kreuzer, Karl-Anton ;

Godley, Lucy A. ;

Atallah, Ehab ;

Collins, Robert, Jr. ;

Kantarjian, Hagop ;

Jabbour, Elias ;

Wilhelm, Francois E. ;

Azarnia, Nozar ;

Silverman, Lewis R. .

LANCET ONCOLOGY, 2016, 17 (04) :496-508

[9] International scoring system for evaluating prognosis in myelodysplastic syndromes [J].

Greenberg, P ;

Cox, C ;

LeBeau, MM ;

Fenaux, P ;

Morel, P ;

Sanz, G ;

Sanz, M ;

Vallespi, T ;

Hamblin, T ;

Oscier, D ;

Ohyashiki, K ;

Toyama, K ;

Aul, C ;

Mufti, G ;

Bennett, J .

BLOOD, 1997, 89 (06) :2079-2088

[10] Revised International Prognostic Scoring System for Myelodysplastic Syndromes [J].

Greenberg, Peter L. ;

Tuechler, Heinz ;

Schanz, Julie ;

Sanz, Guillermo ;

Garcia-Manero, Guillermo ;

Sole, Francesc ;

Bennett, John M. ;

Bowen, David ;

Fenaux, Pierre ;

Dreyfus, Francois ;

Kantarjian, Hagop ;

Kuendgen, Andrea ;

Levis, Alessandro ;

Malcovati, Luca ;

Cazzola, Mario ;

Cermak, Jaroslav ;

Fonatsch, Christa ;

Le Beau, Michelle M. ;

Slovak, Marilyn L. ;

Krieger, Otto ;

Luebbert, Michael ;

Maciejewski, Jaroslaw ;

Magalhaes, Silvia M. M. ;

Miyazaki, Yasushi ;

Pfeilstoecker, Michael ;

Sekeres, Mikkael ;

Sperr, Wolfgang R. ;

Stauder, Reinhard ;

Tauro, Sudhir ;

Valent, Peter ;

Vallespi, Teresa ;

van de Loosdrecht, Arjan A. ;

Germing, Ulrich ;

Haase, Detlef .

BLOOD, 2012, 120 (12) :2454-2465

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