Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
adult, Research, clinical trials, Clinical Research, Combination therapy, Therapies, Human, Study Population
This Phase Ib/II clinical trial (NCT04848974) evaluate the safety, tolerability, and efficacy of Uproleselan added to Cladribine and LDAC. A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at fixed dose of 800mg intravenously [IV]). Induction and reinduction if required, included IV uproleselan twice a day from day 1-12; consolidation was given same days but once a day if patients(pts) achieved response (complete response[CR] with incomplete hematological recovery [CRi] or morphologic leukemia-free state [MLFS]). CLAD was IV for 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1 respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1 respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles, pts aged ≥18 years with a diagnosis of ts-AML with adequate organ function, who have not received therapy for their AML were enrolled. ts-AML is defined as AML arising from previously treated myeloid neoplasm. Presence of the e-selectin was assessed as exploratory analysis.
20 pts have been treated, 18 pts evaluable: 14 (70%) male, median age was 72 yrs (range, 58-86); at the start of therapy, the median bone marrow blasts were 26.5% (20-82%), median WBC was 2.1x109/L (0.6-26.4), and median platelets were 26x109/L (4-667). Pts had received a median of 1 (1-6) treatments prior to AML transformation. Prior diagnoses were: Chronic Myelomonocytic Leukemia (CMML), MDS, and MDS/MPN in 3 (25%), 14 (70%), and 1 (5%) respectively; all had received HMA, 11 (55%) additionally had received Ven, and 5 (25%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable cytogenetics by ELN 2022. The most frequent mutations were: TET2, TP53, RUNX1 and SRSF2 in 9 (45%), 7 (35%), 6 (30%) and 6 (30%) pts respectively. 18 pts were evaluable for e-selectin; median plasmatic concentration was 26.2ng/mL (15.3-131 ng/mL).
Most common AEs were grade(gr) ≥3 neutropenic fever (13 pts, 65%; including 2 gr 5 events), gr 3 bleeding (10%) and gr 2 thrombosis (5%). There were no dose-limiting toxicities observed on dose levels -1 or 1. The chosen dose level was 1 as described above. 2/3 pts who received dose level -1 died during the study follow-up due to sepsis in the first 4-week after induction. Median time to 0.5x109/L neutrophil and 50x109/L platelets recovery was 30 (17-52) and 38 (20-69) days, respectively.
The response rates were 2 (11%) CRi, 1 (6%) CRp, and 4 (22%) MLFS. There was a reduction in BM blasts in 13 pts (72%) (Figure 1). The ORR was 50%(5/10) (p=0.60) and 20% (1/5) (p=0.06) among pts who had prior Ven exposure or prior SCT, respectively. The median cycles received was 1.5 (1-4), median cycles at which the best response was achieved was 1 (1-2). 12 pts were taken off protocol due to progression, 3 for death, 3 for allogeneic SCT and 1 continued in remission. The pt who achieved negative MRD-negative by flow cytometry underwent SCT and is still alive. The median follow-up is 8.1 months. Median OS and EFS were 5.3 and 1.4 months respectively; 4-month RFS (CRi, CRp and MLFS) was 30% (Fig 2). In the univariate analysis by Cox regression for plasmatic E-selectin concentration the HR for OS was 1.016 (95% CI 1.002-1.031).
Ts-AML, progressing from previously treated antecedent myeloid disorders, is associated with low rates of remission and poor OS. Uproleselan combined with Cladribine + LDAC was well-tolerated with minimal therapy-related AEs – allowing a safe approach to marrow blast reduction and disease control in preparation for a potential allogeneic SCT. We are currently determining the relationship of plasmatic e-selectin concentration and response to treatment.
Disclosures: Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. DiNardo: Notable Labs: Honoraria; Novartis: Honoraria; ImmuniOnc: Honoraria; Servier: Honoraria; Fogham: Honoraria; BMS: Honoraria; Takeda: Honoraria; AbbVie/Genentech: Honoraria; Astellas: Honoraria; Schrödinger: Consultancy. Short: Amgen: Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Stemline therapeutics: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Maiti: Celgene: Research Funding; Lin BioScience: Research Funding. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Ravandi: Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Biomea fusion: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Kadia: Pinotb-Bio: Consultancy; Amgen, Inc.: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; AstraZeneca: Research Funding; Astellas Pharma Global Development: Research Funding; Ascentage Pharma Group: Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy; Cellenkos Inc.: Research Funding; Agios: Consultancy; Cyclacel: Research Funding; Celgene: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Cure: Speakers Bureau; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Genzyme: Honoraria; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; GenFleet Therapeutics: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Janssen Research and Development: Research Funding; Liberum: Consultancy; Novartis: Consultancy; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding; Astex: Honoraria.