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905 Results of a Phase 2, Open-Label Study of Idarubicin (I), Cytarabine (A) and Nivolumab (Nivo) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Immunotherapy
Hematology Disease Topics & Pathways:
Biological, AML, Diseases, Therapies, Biological Processes, checkpoint inhibitors, MDS, Clinically relevant, Myeloid Malignancies, immune mechanism
Monday, December 3, 2018: 5:30 PM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Rita Assi, MD1*, Hagop M. Kantarjian, MD2, Naval G. Daver, MD3, Guillermo Garcia-Manero, MD3, Christopher B. Benton, MD4, Philip A. Thompson, MBBS3, Gautam Borthakur, MD3, Tapan M. Kadia, MD5, Yesid Alvarado, MD2,3, Elias J. Jabbour, MD 3, Marina Y. Konopleva, MD, PhD3, Koichi Takahashi, MD6, Steven M. Kornblau, MD4, Courtney D. DiNardo, MD, MSc7, Zeev E. Estrov, MD3, Wilmer Flores8*, Sreyashi Basu, PhD9*, James P Allison, PhD9*, Padmanee Sharma, MD, PhD9*, Sherry A. Pierce, BSN, BA3*, Allison Pike, RN3*, Jorge E. Cortes, MD3 and Farhad Ravandi, MBBS3

1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
6Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
7Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
8Leukemia, University of Texas - MD Anderson Cancer Center, Houston, TX
9Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The combination of an anthracycline and cytarabine has remained a standard of care induction regimen for newly diagnosed AML pts for more than 40 years. PD-1 positive CD8+ T-cells are increased in bone marrow (BM) of AML pts and blocking PD-1/PD-L1 pathways enhances anti-leukemia effect of cytotoxic chemotherapy by increasing CD8+ T-cells in murine models. Addition of Nivo to IA induction may prolong event-free, relapse-free and overall survival (EFS, RFS, OS; respectively). We report on updated feasibility and efficacy data.

Methods: Pts aged 18-65 yrs with newly diagnosed AML (≥20% blasts by WHO criteria) and high risk MDS (≥10% blasts) were eligible if they had adequate performance status (ECOG ≤2) and organ function. Treatment included 1-2 induction cycles of (A) 1.5 g/m2 over 24 hours (days 1-4) and (I) 12 mg/m2 (days 1-3). Nivo 3 mg/kg was started on day 24±2 and continued every 2 weeks for up to a yr. For pts achieving complete response (CR) or CR with incomplete count recovery (CRi), up to 5 consolidation cycles of attenuated dose I+A was given. Eligible pts received allogeneic stem cell transplant (alloSCT) at any time during or after consolidation.

Results: 3 AML pts were treated at a run-in phase with Nivo 1 mg/kg without drug-related toxicity. Subsequently, 41 pts were treated as above. Median (med) age was 54 yrs (range, 26-66) with 42 AML (32 de novo, 7 secondary, 3 therapy-related) and 2 high risk MDS. 19 pts had adverse ELN genetic risk with 8 TP53 mutations (Fig 1A).

All pts were evaluable for response: 34 (77%) achieved CR/CRi (28 CR, 6 CRi) and 18/34 (53%) had undetectable MRD by flow cytometry (FC) following induction. Med number of cycles to response was 1 (range 1-2) and med number of total cycles received was 2 (range, 1-6). Counting maintenance schedule, med number of Nivo doses was 2 (range, 0-25) and 15 pts (34%) received ≥4 doses; 4 pts did not receive Nivo: insurance issues (n=2), early death (n=1) and rapid disease progression (n=1). The 4- and 8-week mortality was 5%. At med follow-up of 17.25 mos (range 0.5-30.4), med OS was 18.54 mos (range, 0.5-30.4) and med RFS for the 34 CR/CRi pts was 18.5 mos (range 1.7-25.6); med EFS was not reached (range 0.5-13.7). When compared to a contemporary cohort of pts treated with I+A alone, there is a trend of improvement of OS at a short follow-up duration (med 18.54 vs 13.2 mos; p=0.2).

Six pts had grade 3/4 immune-related toxicities with rash (n=2), colitis (n=2), transaminitis and pancreatitis (n=1; each). Grade 3/4 cholecystitis was possibly attributed to Nivo in 1 pt. 18 (41%) pts proceeded to alloSCT. Donor source was matched related in 3, matched unrelated in 12 and haplo-identical in 3 pts. Conditioning regimen was Fludarabine+busulfan-based in 12, and fludarabine+melphalan in 6 pts. 13 (72%) pts developed graft versus host disease (GVHD)(grades I/II in 8, III/IV in 5), which responded to treatment in 8 (Fig 1B).

Multicolor FC studies were conducted on baseline (prior to 1st Nivo dose) and on-treatment BM aspirate and peripheral blood to assess T-cell repertoire and expression of co-stimulatory receptors and ligands on T-cells and leukemic blasts, respectively. Baseline BM was evaluated on 19 responders and 5 non-responders. Pts who achieved CR/CRi had a trend to higher frequency of live CD3+ total T cell infiltrate compared to non-responders in baseline BM aspirates (Fig 1C). We evaluated expression of immune markers on T cell subsets: CD4 T effectors [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T regulatory: CD3+CD4+CD127-Foxp3+, and CD8 T cells. At baseline, BM of non-responders had significantly higher percentage of CD4 Teff co-expressing PD1/TIM3 (p<0.05) (Fig 1D) and trend towards higher percentage of CD4 Teff cells co-expressing PD1/LAG3 compared to responders (data not shown). TIM3/LAG3 co-expression on PD1+ T cells has been linked to an exhausted immune phenotype in AML. Using Cytof mass cytometry, we quantified leukemic progenitor cells and T-cells and demonstrated clearance of progenitors and reconstitution of T-cells in pts achieving CR.

Conclusion: Addition of Nivo to (I+A) induction is feasible and safe in younger AML pts. Post-transplant severe GVHD is not significantly increased and is manageable. CD4+ T-effector cells display exhausted phenotype in non-responders that can be potentially reversed. Studies with earlier initiation of checkpoint inhibitor therapy are planned

Disclosures: Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. Daver: Incyte: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy, Research Funding; Alexion: Consultancy; Otsuka: Consultancy; BMS: Consultancy, Research Funding; ARIAD: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Research Funding; ImmunoGen: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Research Funding; Novartis: Consultancy, Research Funding; Kiromic: Research Funding. Thompson: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia: Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding. Jabbour: Spectrum: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy. Konopleva: Stemline Therapeutics: Research Funding. Takahashi: Symbio Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Agios: Consultancy. DiNardo: Bayer: Honoraria; Celgene: Consultancy; Syros: Honoraria; Agios: Consultancy; Abbvie: Consultancy; Medimmune: Honoraria; Karyopharm: Honoraria; Jazz: Honoraria. Cortes: Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ravandi: Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Seattle Genetics: Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Orsenix: Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau.

*signifies non-member of ASH