Clinical Lymphoma, Myeloma & Leukemia, Vol.21, Suppl.1 - September 2021

Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2021 S350 state. Total serum soluble TIM-3 was measured, and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 2 7 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted. Results: Sabatolimab PK was similar for patients with solid tumors (n=252) and higher-risk MDS and AML (n=155); no drug–drug interactions were observed for any combinations. Among sabatolimab+HMA regimens, sabatolimab 400 mg Q2W had the highest Ctrough at steady-state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady-state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM (>95% in  95% of patients with higher-risk MDS/AML), suggesting similarly high levels of TIM-3 engagement. There was no relationship between steady-state Cmax or Cavg quartiles and the incidence of treatment-related AEs. Exposure-efficacy analysis showed no clear relationship between steady-state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). Sabatolimab+HMA was safe and well-tolerated, with a low discontinuation rate due to AEs (3.4% [4/116]). Rates of most common grade  3 treatment-emergent AEs did not appear to be dose-dependent. Co n clusio n s: Sabatolimab 400 mg Q2Wwas predicted to have the highest steady-state Ctrough and TIM-3 occupancy rate when combined with HMA; 800 mg was predicted to be an equivalent dosing regimen. No clear relationship was seen between sabatolimab dose or steady-state exposure and safety/efficacy. These results support the clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens. Keywords: MDS, AML, pharmacokinetics, safety MDS-420 Sabatolimab Plus Hypomethylating Agents (HMAs) in Patients with High-/ Very High-risk Myelodysplastic Syndrome (HR/vHR-MDS) and Newly Diagnosed Acute Myeloid Leukemia (ND-AML): Subgroup Analysis of a Phase 1 Study Guillermo Garcia-Manero 1 *, Andrew H. Wei 2 , Kimmo Porkka 3 , Steve Knapper 4 , Elie Traer 5 , Sebastian Scholl 6 , Norbert Vey 7 , Martin Wermke 8 , Jeroen Janssen 9 , Rupa Narayan 10 , Sun Loo 11 , Natalia Tovar 12 , Mika Kontro 3 , Oliver Ottmann 4 , Purushotham Naidu 13 , Elena Orlando 14 , Nidhi Patel 14 , Jessica Makofske 14 , Fei Ma 13 , Na Zhang 14 , Anisa Mohammed 13 , Mikael L. Rinne 14 , Uma Borate 5 , Andrew M. Brunner 10 1 MD Anderson Cancer Center, Houston, TX, USA, 2 The Alfred Hospital and Monash University, Melbourne, Australia, 3 Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland, 4 Cardiff University, Cardiff, UK, 5 Oregon Health & Science University, Portland, OR, USA, 6 University Hospital Jena, Jena, Germany, 7 Institut Paoli-Calmettes, Marseille, France, 8 University Hospital Dresden, Dresden, Germany, 9 Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands, 10 Massachusetts General Hospital, Boston, MA, USA, 11 The Alfred Hospital, Melbourne, Victoria, Australia, 12 Hospital Clínic, Barcelona, Spain, 13 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 14 Novartis Institutes for BioMedical Research, Cambridge, MA, USA Co n text: Sabatolimab (MBG453) is an investigational immuno- myeloid therapy targeting TIM-3, an immune regulator expressed on immune and myeloid leukemic cells and blasts, but not on normal hematopoietic stem cells. Early phase 1b study (NCT03066648) results showed sabatolimab+HMA treatment had promising and durable activity in MDS/AML. Objecti v e: To further explore safety/ tolerability and efficacy in patient subgroups, as well as biomarkers with sabatolimab+HMA. D esig n : Study design/eligibility criteria have been reported. HMA-naïve patients with HR/vHR-MDS and ND-AML and ineligible for intensive chemotherapy received sabatolimab (1–2 infusions/month) + decitabine or azacitidine. Primary objectives: safety/tolerability. Secondary objectives: PK and preliminary efficacy. Data cutoff was 22 September 2020; updated data will be presented. Results: Of 89 patients with HR/vHR- MDS (n=41) and ND-AML (n=48), 36 (40%) had sabatolimab dose interruption, 1 (1%) had dose reduction, 2 (2%) had dose interruption and reduction, 5 (6%) discontinued, and 3 (3%) had dose interruption and discontinued. Four discontinuations were due to AEs and 4 due to death. Twenty-two patients had grade 4 neutropenia/thrombocytopenia at baseline: 4 (18%) had dose interruption, 2 (9%) discontinued, and 1 (5%) had dose interruption and discontinued. In analyses of remission rates (CR+mCR/CRi+PR) by baseline factors, response was independent of bone marrow blast burden in patients with HR/vHR-MDS or ND-AML. Remission rates were similar in patients age  7 5 and 65– 7 4 years: 50% (6/12) and 65% (11/1 7 ) with HR/vHR-MDS and 42% (8/19) for both groups with ND-AML. Response durability in patients age  7 5 and 65– 7 4 years was encouraging: an estimated 83% and 86%, respectively, with HR/vHR-MDS remained in remission after 6 months. In patients with TP53 mutation or  1 mutation conferring European LeukemiaNet (ELN) high risk, remission rates were 55% (6/11; 4/6 in remission >200 days) and 59% (13/22; 8/13 in remission >200 days), respectively, for HR/ vHR-MDS. Durability and remission rates for ND-AML will be presented. Biomarker analyses identified differential expression of IL- 1  in sabatolimab+HMA responders vs nonresponders; expression levels were inversely correlated with remission. Co n clusio n s: Sabatolimab+HMA showed favorable tolerability in MDS/AML, including in patients with grade 4 cytopenias at baseline. Promising remission rates were observed across patient subgroups. This supports development of sabatolimab+HMA in the STIMULUS trial program of MDS/AML. Keywords: MDS, acute myeloid leukemia, clinical trial, immunotherapy, myelodysplasia MDS-426 Cardiovascular Disease and Marrow Vascular Markers in Patients with Myeloid Malignancies Gabriela Sanchez-Petitto 1,2 *, Michael Kallen 3 , Madhurima Koka 3 , Olga Goloubeva 4 , Jack Masur 2 ,