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
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 (
= 25) and HMA-pretreated (
= 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 infiltrate by flow 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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Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses by unleashing T-cells in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells were increased in the bone marrow ...(BM) of pts with AML (Daver et al, ASH 2016). AZA up-regulates PD-1 and interferon-gamma signaling in AML and the up-regulation of PD-1 has been associated with resistance to AZA (Yang et al., Leukemia 2013).
Methods: Pts were eligible for the AZA+Nivo if they had AML and failed prior therapy (R/R AML), had adequate performance status (ECOG ≤ 2), and organ function (cohort 1). The recommended phase 2 dose (RP2D) was established as AZA 75mg/m2 Days 1-7 with Nivo 3mg/kg Day 1 and 14. Courses were repeated approximately every 4-5 weeks indefinitely. 70 relapsed AML pts have been treated and cohort 1 is complete.
Two subsequent cohorts are now enrolling: AZA+Nivo in frontline AML ≥65 years and not suitable for induction therapy (cohort 2), and AZA+Nivo with Ipilimumab in first and second salvage AML (cohort 3).
Responses in all three cohorts included best response within 3 months of therapy initiation.
Results:
Cohort 1:70 R/R AML pts with median age 70 years (range, 22-90), secondary AML (44%), poor risk cytogenetics (34%), median salvage 2 (range, 1-7) have been enrolled. Frequent mutations by baseline next-generation sequencing (NGS) included TP53 (23%), DNMT3A (17%), ASXL1 (16%), TET2 (16%). All pts were evaluable: 15 (22%) achieved complete remission (CR)/complete remission with insufficient recovery of counts (CRi) (4 CR, 11 CRi), 7 (10%) hematologic improvement (HI), 17 (24%) had ≥50% BM blast reduction, 5 (8%) had stable disease >6 months, and 26 (37%) had progression. The response rate did not differ by age ≤65 versus >65 years, was higher in pts with diploid cytogenetics, pts without prior HMA therapy, and pts with ASXL1 mutations (Figure 1A). The 8-week mortality was 7%. The med OS among the CR/CRi patients was 15.3 months (range, 2.29-17.25+), HI pts was 11.9 months (range, 4.67-17.45+), and NR pts was 5.6 months (range, 0.29-16.16). The median OS with Aza+Nivo compares favorably to historical median OS with AZA-based salvage protocols in similar pts at MDACC in all salvage (P=0.004) and more prominently so in first salvage (P<0.001) (Figure 1B). Diploid relapsed AML pts, any salvage (n=25) had an especially improved med OS of 15.3 mo on AZA+Nivo.
Grade 3/4 and Grade 2 immune related adverse events (irAEs) were observed in 8 (12%) and 8 (12%) pts, respectively with median time to onset 6 weeks (range, 4 days - 14 weeks). These responded rapidly to steroids. Common Grade 2-4 irAEs included, in order of incidence, pneumonitis, colitis, nephritis, skin rash, and hypophysitis.
Cohort 2: 10 pts with frontline AML ≥65 years of age have been treated. Median age was 75 (range, 68-82), secondary AML (30%), diploid cytogenetics (60%), and common molecular mutations were NPM1 in 4, IDH1/2 in 4, ASXL1/TP53/EZH2/DNMT3 in 2 pts each. 9 pts enrolled before May 1, 2017 are evaluable for response: 5 CR/CRp (including 2 CR and 3 CRp), 1 PR, 1 stable disease > 6 months, and 2 no response. This cohort is enrolling.
Flow cytometric analysis of bone marrow (BM) samples from cohort 1 pts was performed after 2 and after 4 doses of nivo in 15 CR/CRi and 30 non-responders at baseline. CR/CRi pts had a higher frequency of live CD3+ total T cells (P=0.02) and CD8+ T-cells (P=0.07) compared to non-responders in the baseline BM. Frequency of total T cells and CD8+ T-cell subsets increased progressively after 2 and 4 doses of nivo with increased expression of ICOS (an activation marker) on the CD3+CD4+CD127lo/+Foxp3- T-effector cell subsets in CR/CRi pts. Expression of inhibitory receptor CTLA-4was up-regulated on CD8+ T cells after nivo in both responders and in non-responders. We also performed 36 parameter mass cytometry on BM of 3 CR/CRi and 5 non-responders. Phenograph analysis revealed higher frequency of a CD8+PD1+ T cell cluster (Cluster#13) co-expressing other inhibitory receptors such as BTLA, TIGIT and TIM3 in the non-responders in the baseline BM (Figure 1C).
Conclusion: AZA+nivo produced an encouraging response rate with improved OS compared to historical in relapsed AML with poor risk features. Immune mediated toxicities occur and should be managed with early systemic steroids. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML. Frontline AZA+Nivo and salvage AZA+Nivo+Ipi cohorts are currently enrolling.
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Daver:Jazz: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Incyte Corporation: Honoraria, Research Funding; Immunogen: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Kiromic: Research Funding. Cortes:Teva: Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Pemmaraju:cellectis: Research Funding; roche diagnostics: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. DiNardo:Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Sharma:BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Consetellation: Other: stock; Astra Zeneca: Consultancy; Kite Pharma: Consultancy, Other: stock; EMD Serono: Consultancy; Evelo: Consultancy, Other: stock; Neon: Consultancy, Other: stock; Jounce: Consultancy, Other: stock, Patents & Royalties: Patent licensed to Jounce; Astellas: Consultancy. Kantarjian:ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding.
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