TY - JOUR
T1 - Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/ refractory acute myeloid leukemia
T2 - A nonrandomized, open-label, phase II study
AU - Daver, Naval
AU - Garcia-Manero, Guillermo
AU - Basu, Sreyashi
AU - Boddu, Prajwal C.
AU - Alfayez, Mansour
AU - Cortes, Jorge E.
AU - Konopleva, Marina
AU - Ravandi-Kashani, Farhad
AU - Jabbour, Elias
AU - Kadia, Tapan
AU - Nogueras-Gonzalez, Graciela M.
AU - Ning, Jing
AU - Pemmaraju, Naveen
AU - Dinardo, Courtney D.
AU - Andreeff, Michael
AU - Pierce, Sherry A.
AU - Gordon, Tauna
AU - Kornblau, Steven M.
AU - Flores, Wilmer
AU - Alhamal, Zainab
AU - Bueso-Ramos, Carlos
AU - Jorgensen, Jeffrey L.
AU - Patel, Keyur P.
AU - Blando, Jorge
AU - Allison, James P.
AU - Sharma, Padmanee
AU - Kantarjian, Hagop
N1 - Funding Information:
N. Daver reports receiving commercial research grants from Bristol-Myers Squibb, Pfizer, Incyte, Servier, AbbVie, NOHLA Therapeutics, Glycomimetics, Daiichi-Sankyo, and Kiromics and is a consultant/advisory board member for Bristol-Myers Squibb, AbbVie, Incyte, Agios, Astellas, Daiichi-Sankyo, Pfizer, Novartis, and Jazz. J.E. Cortes is a consultant/advisory board member for Bristol-Myers Squibb. F. Ravandi-Kashani reports receiving a commercial research grant from Bristol-Myers Squibb. T.M. Kadia reports receiving commercial research support from Bristol-Myers Squibb, Pfizer, Celgene, Jazz, and Amgen and is a consultant/advisory board member for Jazz, Novartis, Genentech, Amgen, Takeda, and AbbVie. N. Pem-maraju reports receiving commercial research support from Novartis, Stemline, Cellectis, AbbVie, Daiichi-Sankyo, Plexxikon, and Samus and is a consultant/advisory board member for Celgene, Stemline, and Incyte. C.D. DiNardo is a consultant/advisory board member for AbbVie, Agios, Bayer, Celgene, Karyopharm, MedImmune, Syros, and Jazz. J.P. Allison reports receiving commercial research grants from Astellas Pharma US Inc., Bristol-Myers Squibb Company, and AbbVie; has ownership interest (including stock, patents, etc.) in Jounce Therapeutics, Neon Therapeutics, ImaginAb, Amgen, BioAtla, Apricity, Polaris, Marker Therapeutics, Codiak Biosciences, Forty Seven, Tvardi Therapeutics, and TapImmune; and is a consultant/ advisory board member for Jounce Therapeutics, Neon Therapeutics, Marker Therapeutics, Polaris, Amgen, Apricity, BioAtla, Forty Seven, Tvardi Therapeutics, TapImmune, ImaginAb, and Codiak Biosciences. P. Sharma has ownership interest (including stock, patents, etc.) in Jounce Therapeutics, Constellation, Polaris, Imagi-nAb, Forty-Seven, Apricity Health, and BioAtla and is a consultant/ advisory board member for Jounce Therapeutics, Forty-Seven, Pieris, Oncolytics, ImaginAb, Polaris, Bristol-Myers Squibb, and BioAtla. H. Kantarjian has received honoraria from the speakers bureaus of AbbVie, Actinium, Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported by Bristol-Myers Squibb, the MD Anderson Cancer Centre Leukemia Support Grant CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Dick Clark Immunotherapy Research Fund, and the MD Anderson Moon Shots Program.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m 2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4 + Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3 + bone marrow infi ltrate by fl ow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.
AB - Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m 2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4 + Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3 + bone marrow infi ltrate by fl ow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.
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U2 - 10.1158/2159-8290.CD-18-0774
DO - 10.1158/2159-8290.CD-18-0774
M3 - Article
C2 - 30409776
AN - SCOPUS:85063596016
VL - 9
SP - 370
EP - 383
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 3
ER -