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 language | English (US) |
|---|---|
| Pages (from-to) | 370-383 |
| Number of pages | 14 |
| Journal | Cancer Discovery |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=85063596016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063596016&partnerID=8YFLogxK
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 -