Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/ refractory acute myeloid leukemia: A nonrandomized, open-label, phase II study

Naval Daver, Guillermo Garcia-Manero, Sreyashi Basu, Prajwal C. Boddu, Mansour Alfayez, Jorge E. Cortes, Marina Konopleva, Farhad Ravandi-Kashani, Elias Jabbour, Tapan Kadia, Graciela M. Nogueras-Gonzalez, Jing Ning, Naveen Pemmaraju, Courtney D. Dinardo, Michael Andreeff, Sherry A. Pierce, Tauna Gordon, Steven M. Kornblau, Wilmer Flores, Zainab AlhamalCarlos Bueso-Ramos, Jeffrey L. Jorgensen, Keyur P. Patel, Jorge Blando, James P. Allison, Padmanee Sharma, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)370-383
Number of pages14
JournalCancer Discovery
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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Azacitidine
Acute Myeloid Leukemia
Biomarkers
Safety
Bone Marrow
Eragrostis
nivolumab
Patient Selection
Flow Cytometry
Up-Regulation
Therapeutics
Survival Rate

ASJC Scopus subject areas

  • Oncology

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Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/ refractory acute myeloid leukemia : A nonrandomized, open-label, phase II study. / 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.

In: Cancer Discovery, Vol. 9, No. 3, 01.03.2019, p. 370-383.

Research output: Contribution to journalArticle

Daver, N, Garcia-Manero, G, Basu, S, Boddu, PC, Alfayez, M, Cortes, JE, Konopleva, M, Ravandi-Kashani, F, Jabbour, E, Kadia, T, Nogueras-Gonzalez, GM, Ning, J, Pemmaraju, N, Dinardo, CD, Andreeff, M, Pierce, SA, Gordon, T, Kornblau, SM, Flores, W, Alhamal, Z, Bueso-Ramos, C, Jorgensen, JL, Patel, KP, Blando, J, Allison, JP, Sharma, P & Kantarjian, H 2019, 'Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/ refractory acute myeloid leukemia: A nonrandomized, open-label, phase II study', Cancer Discovery, vol. 9, no. 3, pp. 370-383. https://doi.org/10.1158/2159-8290.CD-18-0774
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. / Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/ refractory acute myeloid leukemia : A nonrandomized, open-label, phase II study. In: Cancer Discovery. 2019 ; Vol. 9, No. 3. pp. 370-383.
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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

PY - 2019/3/1

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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.

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