Abstract
Background: Preclinically blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. PD-1 positive CD8 T-cells are increased in the bone marrow (BM) of patients (pts) with relapsed AML (Williams P et al., Cancer 2018). PD1 inhibition alone however had limited clinical activity in AML (Berger et al, Clin Cancer Res 2008). AZA up-regulates PD-1 and PD-L1 in AML and the up-regulation of these genes has been associated with emergence of resistance to AZA (Yang et al., Leukemia 2013).
Methods: Pts were eligible for the AZA+Nivo (cohort 1) if they had relapsed/refractory AML (R/R AML), ECOG ≤ 2, and adequate organ function. 70 R/R AML pts were treated. This cohort is closed.
A subsequent cohort of AZA+Nivo+Ipi was opened (cohort 2), with the same eligibility criteria. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule. This double CPI dosing was based on lung and melanoma dosing.
Results: Cohort 1 of 70 R/R AML pts treated with Aza+Nivo (Daver et al., Cancer Discovery 2018). Response rates and OS were superior to contemporary historic HMA-based clinical trial controls at MDACC (Table 1), with most significant OS improvement in patients with low pretherapy BM blasts (<20% BM blasts) and early salvage (Salvage 1). Similar features predict for response to blinatumomab (Topp M et al., Lancet Oncology 2015) and CART (Park J et al, NEJM 2018) in relapsed B-ALL, and to Macrogenics CD3xCd123 bispecific Ab in R/R AML (Uy G et al, ASH 2018), suggesting progressive T-cell exhaustion with multiple relapses may be a major hindrance to successful T-cell based therapies. Responders (Rs) to AZA+Nivo had a higher frequency of pretherapy BMA CD3+ cells compared with non-responders (NRs) (optimal CD3+ cutoff 13.2%). In addition to quantitative T-cell infiltration we interrogated the functionality of pretherapy sorted BM T-cells in Rs versus NRs using Isoplexis 32-plex, single cell, stimulated T-cell, cytokine response panel (Daver N et al, LBA AACR 2019). The pretherapy BM T-cell polyfunctional strength index (PSI) defined as the percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines, was dramatically different between Rs and NRs, especially for CD4 cells (p=0.0317) (Figure 1A). All CR/CRi pts, and none of the NR pts, had pretherapy PSI>10 with a statistically significant OS difference for PSI< vs > 10 (p= 0.0018) (Figure1B), suggesting this may be a more specific biomarker to prospectively select pts for T-cell therapy based trials. RNAseq and nanostring analysis on baseline R vs NR sample will be presented at the meeting.
Cohort 2 of 31 R/R AML pts treated with Aza+Nivo+Ipi with median (med) age 71 years (26-86), secondary AML (49%), ELN unfavorable cytogenetics (65%), TP53 (38%), med salvage 2 (range, 1-4). 54% pts previously treated with HMA based therapies. 4 pts had prior alloSCT (med time from alloSCT 13 monts). 24 pts are evaluable, 7 too early. CR/CRi was noted in 9 (36%), additionally 2 (8%) had HI maintained >6 months, 4 (16%) stable disease (SD) (defined as absence of CR, CRi, PR, MLFS; with stable disease on treatment for at least 6 months), and 10 (40%) were NRs. The 4-week and 8-week mortality were 0 and 8%, respectively. In all salvage setting the med OS in Aza+Ipi+Nivo versus Aza+Nivo versus contemporary historical HMA-based clinical trial in R/R AML at MDACC, were 10.5, 6.4, and 4.6 months, respectively (P =0.0025) (Figure 1C). This median OS with Aza+Ipi+Nivo compares favorably even to DAC10+venetoclax in R/R AML (med OS: 7.1 months) reported from our center at ASH 2019. The 1-year OS in R/R AML pts with AZA+Nivo+Ipi was very encouraging at 45%. Grade 3/4 immune mediated toxicities were observed in 6 pts (25%), including rash, pneumonitis, and colitis. One pt required ICU stay but no deaths were attributed to immune toxicity. Other grade >2 toxicities were as expected for R/R AML population and were mostly infections/febrile neutropenia, and electrolyte disturbance.
Conclusion: The CR/CRi rates and OS with Aza+Nivo+Ipi are encouraging, with median OS of >10 months in R/R high-risk AML, and the study is enrolling. PSI on pretherapy BM CD4 T-cells from pts treated with Aza+Nivo almost completely segregated Rs vs NRs (p=0.0317). This suggests a very significant and hitherto underappreciated immune diversity in AML and a critical need for biomarker based trials (as we are doing with molecular therapies) with immunotherapies in AML.
Disclosures
Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Ablynx: Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Calithera: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Pemmaraju:incyte: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. DiNardo:celgene: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; medimmune: Honoraria. Cortes:Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Allison:BMS: Consultancy, Honoraria, Research Funding. Sharma:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Ariad: Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.