Background: Despite recent advances in the therapeutic armamentarium for AML, outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20%. Multiple immune aberrations in AML lead to immune suppression, exhaustion, and senescence. Programmed Death-1 (PD-1), a co-inhibitory receptor (IR) on immune cells, suppresses immune activation and is exploited by leukemic cells to evade immune surveillance. PD-1 and other IRs are up-regulated during disease progression. We hypothesized that pembrolizumab, a monoclonal antibody targeting PD-1, after HiDAC would stimulate a T-cell mediated anti-leukemic immune response. Methods: Eligibility for this study included R/R AML 18-70 years, ECOG PS 0-1 and adequate organ function. Treatment consisted of HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; >60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14. The primary objective of this study was to estimate the overall complete remission (CR + CRi) rate. Secondary objectives included assessment of safety, durability of CR, overall survival (OS) and biomarker correlates of response. Overall responders were eligible to receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (alloSCT) was permissible before or after maintenance phase. Results: Thirty-seven pts were enrolled and evaluable (Table 1). Sixteen (43%) pts had refractory disease and 16 (43%) pts had relapsed AML with CR1 duration <1 year. Excluding electrolyte abnormalities, the most common pembrolizumab-related toxicities were febrile neutropenia (57%), ALT elevation (43%; Grade >3: n=1), AST elevation (32%; Grade >3: n=1), fatigue (27%), alkaline phosphatase elevation (24%), and maculopapular rash (19%; Grade >3: n=2). Grade >3 immune-related adverse events (iRAE) were rare (maculopapular rash: n=2, AST/ALT increase: n=2, right upper quadrant pain with lymphocytic infiltrate in liver: n=1) and self-limiting. Five (14%) pts required steroid administration for grade 2 hyperbilirubinemia (n=1), grade 3 ALT elevation (n=1), grade 3 AST elevation with liver biopsy revealing no evidence of iRAE (n=1), grade 3 bilirubin subsequently deemed to be a delayed hemolytic transfusion reaction (n=1), and grade 3 systolic dysfunction without evidence of myocarditis by endomyocardial biopsy or cardiac MRI (n=1). Sixty-day mortality was 3% (1/37) due to progressive AML. Median time to full neutrophil (>1x109/L) and platelet (>100x109/L) recovery was 32 and 31 days, respectively. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% [29%,63%] and 38% [22%,55%], respectively, meeting the primary endpoint of the study. Notably, 13/28 (46%) pts receiving HiDAC + pembrolizumab as their first salvage regimen achieved CR/CRi. Two pts refractory to HiDAC (administered within past 6 months) achieved CR including one pt who was refractory to HiDAC salvage 1 month prior to enrollment and ultimately achieved CR without evidence of minimal residual disease. Nine (24%) pts received an alloSCT. There were no instances of Grade >3 acute GVHD or veno-occlusive disease post-alloSCT. Nine (24%) pts received maintenance phase pembrolizumab (median # of cycles = 3; range: 1-12) for CR (n=8) or PR (n=1). Seven out of 9 pts relapsed/progressed after maintenance phase. Median follow-up among survivors, and median OS, event-free survival and disease-free survival was 7.8 months, 8.9 months [6.0,13.1], 6.9 months [4.2,11.5], and 5.7 months [1.9,7.3], respectively. Conclusions: Pembrolizumab can be safely administered after HiDAC salvage in R/R AML. Severe iRAE's were uncommon despite administration after cytotoxic chemotherapy. The addition of pembrolizumab to HiDAC led to an encouraging overall CR rate meeting the primary endpoint of the study. Immunogenomic biomarker analyses consisting of B cell receptor amplicon sequencing, RNA-seq of blasts and CD8+ T cells, CD8+ T cell receptor repertoire, whole exome sequencing and flow cytometry analyses are ongoing to determine predictors of response. These results warrant further investigation of IR blockade and other immunomodulatory therapeutic strategies after intensive cytotoxic chemotherapy in AML. Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; AsystBio Laboratories: Consultancy; Pfizer: Honoraria; Tolero: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria; AbbVie: Honoraria. Vincent:Pharmacyclics: Research Funding; Merck: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy. Coombs:Dedham Group: Consultancy; Covance: Consultancy; Cowen & Co.: Consultancy; Octopharma: Honoraria; H3 Biomedicine: Honoraria; Loxo: Honoraria; Pharmacyclics: Honoraria; Medscape: Honoraria. Webster:Pfizer: Consultancy; Amgen: Consultancy; Genentech: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Smith:Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Agios: Consultancy. Levis:Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Serody:Merck: Research Funding; GlaxoSmithKline: Research Funding. Gojo:Amphivena: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Pembrolizumab is investigational for AML.

Berlin-Frankfurt-M€ unster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and alltrans retinoid acid.

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Background: Outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Programmed Death-1 (PD-1), an inhibitory receptor on T and B cells, suppresses immune activation. We hypothesized that administration of pembrolizumab, a monoclonal antibody targeting PD-1, after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML. Methods: We are conducting a multicenter phase II study of HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; ≥60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 in R/R AML pts 18-70 years. The primary objective of this study is to estimate the overall complete remission (CR + CRi) rate. Overall responders can receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (SCT) is permissible before or after maintenance phase. Results: To date, 26 pts are evaluable for safety and response (Table 1). Grade ≥3 immune-related adverse events have been rare and self-limiting. The overall CR rate is 35%. Of the 9 CR pts, 5 (56%) had no evidence of minimal residual disease (MRD) by standard monitoring. Notably, 2/3 primary refractory pts with inv(3) cytogenetics achieved CR and underwent SCT. Additionally, 1 pt with relapsed AML with most recent treatment refractory to HiDAC salvage achieved CR with no evidence of MRD. Five pts received maintenance pembrolizumab: 3 relapsed (median duration of CR = 2.8 months; range: 2-5.7 months), 1 proceeded to SCT after 2 cycles, and 1 initially achieved a partial remission (PR) and had stable disease for 12 cycles of maintenance pembrolizumab before progressing. Four pts received a SCT in CR (n=3) and morphologic leukemia free state (MLFS) (n=1). Grade II acute graft-versus host disease (GVHD) and moderate chronic GVHD was seen in 2/4 (50%) pts, respectively. With a median follow up of 10.8 months to date, median overall survival is 10.5 months (range: 1.8-20.8 months). We performed B cell receptor amplicon sequencing, T cell receptor (TCR) amplicon sequencing from CD8+ T cells, and RNA-seq from enriched blasts and non-blast fractions in bone marrow (BM) from 3 CR and 3 non-responders (NR) prior to HiDAC. From the BM blast enriched fraction, expression of innate immune genes such as NLRP12, C3, S100A9, S100A12 and CD14 correlated with response. Gene Set Enrichment Analysis (GSEA) demonstrated that CR correlated with expression of genes in the Toll Pathway, Lysosome pathway, and adaptive immune system while NRs were associated with expression of the PAR1 and GATA3 pathways. From the non-blast BM population, CR correlated with expression of cell-cycle genes such as CCNE1, CCNB2, E2F2, KIF18B and CDKN3. Not surprisingly, GSEA revealed that expression of cell cycle pathways correlated with response. CR correlated with increased expression of B cell metagenes and the inverse IPRES signature in the non-blast BM fraction. As previously reported, there was a significant increase in peripheral blood (PB) TCR diversity in CR pts. CR was also significantly associated with the abundance and richness of the non-blast BM fraction of the B cell heavy and both light chains suggesting that a broader immune response at baseline may be critical for response to HiDAC and pembrolizumab. Finally, CR correlated with increased expression of CD300E, CCR7, CCR4, CCR8 and CCL7 in PB CD8+ T cells suggesting that migration of monocytes, T and B cells is associated with response. Conclusions: Our findings demonstrate that pembrolizumab is well tolerated after HiDAC in an ongoing study in R/R AML. An encouraging response rate has been seen in a high-risk patient population without apparent additive toxicity post-SCT. Our RNA-seq and amplicon sequencing data indicate that biomarkers of response are present prior to therapy. Increased expression of innate immune genes expressed by leukemic blasts and cell cycle genes by the non-blast fraction correlated with response to therapy. Additionally, CR was associated with increased measures of B and T cell diversity and immune cell migration. Further immunogenomic biomarker correlates are ongoing to determine predictors of response to pembrolizumab after HiDAC in R/R AML. Disclosures Zeidner: Tolero: Honoraria, Other: Travel Fees, Research Funding; Asystbio Laboratories: Consultancy; Merck: Research Funding; Takeda: Other: Travel fees, Research Funding; Rafael Pharmaceuticals: Other: Travel Fees; Celgene: Honoraria. Vincent:Merck: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Coombs:Incyte: Other: Travel fees; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Serody:Merck: Research Funding.

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