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1448 Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Non-Biological therapies, Chemotherapy, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Emmanuel Almanza Huante, MD, MDN1, Hagop Kantarjian, MD2, Kelly S. Chien, MD1, Courtney D. DiNardo, MD, MSCE1, Nicholas Short, MD3, Abhishek Maiti, MBBS4, Guillermo Montalban-Bravo, MD1, Naval Daver, MD1, Jitesh D. Kawedia, BPharm5*, Kayleigh Bowie, BSN, RN6*, Sherry A. Pierce, BSN, BA1*, Farhad Ravandi, MD1, Marina Konopleva, MD7*, Guillermo Garcia-Manero, MD8 and Tapan M. Kadia, MD9

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas Health Science Center At Houston, Houston, TX
5Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, The University of Texas. MD Anderson Cancer Center, Houston, TX
7Hematology/Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY
8Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
9Department of Leukemia, MD Anderson Cancer Center, Houston, TX


Treated secondary AML (TS-AML), arising after prior HMA-treated MDS, is associated with very poor prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-8 months). E-selectin ligand is highly expressed on AML blasts in the leukemic microenvironment and may be a marker of cell survival and resistance to chemotherapy. Exposure of leukemic blasts to HMAs has been shown to increase their expression of E-selectin ligand. Uproleselan is an E-selectin antagonist that overcomes resistance to chemotherapy in AML (Barbier, Nat Commun 2020).

We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance and improve outcomes in this difficult subset.


This is Phase Ib/II clinical trial (NCT04848974) to evaluate the safety, tolerability, and explore the 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 a fixed dose of 800mg intravenously [IV]) added to IV CLAD 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 a previously treated myeloid neoplasm. Presence of the E-selectin ligand was assessed using Flow Cytometry (FC).


10 pts have been treated, with 9 pts currently evaluable: 6 (67%) were male and the median age was 68 years (range, 58-80); at the start of therapy, the median bone marrow blasts were 33% (1-78%), median WBC was 2.2x109/L (0.6-20.1), median platelets were 18x109/L (4-305), and median creatinine was 0.98mg/dL (0.67-1.52). Pts had received a median of 1 (1-2) treatments prior to AML transformation. Prior diagnoses were: therapy-related Myelodysplastic Syndrome (t-MDS), Chronic Myelomonocytic Leukemia (CMML), MDS and MDS/MPN in 3 (33%), 3 (33%), 2 (22%) and 1 (11%) respectively; all had received HMA, 5 (56%) additionally had Ven and 3 (33%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable features by ELN 2017. The most frequent mutations were:SXL1, TP53 and TET2 in 4 pts each (44%), SRSF2 and NRAS in 3 patients each (33%) and SETBP1, RUNX1 and EZH2 in 2 patients each (22%). 6 pts were evaluable for E-selectin ligand expression; the median expression was 59% (42%-95%) and median MFI was 20.5 (13-262). The most common SAEs were ≥ grade 3 neutropenic fever (70%), (including 2 grade 5 events), grade 3 bleeding (10%), and grade 2 thrombosis (5%) (Table 1). There were no dose-limiting toxicities observed on dose levels -1 or 1. Two pts treated on dose level -1 die during the study follow-up due to sepsis within the first 4-weeks during induction. Median time to 0.5x109/L neutrophil and 50x109/L platelets recovery was 29 (17-39) and 38 (33-48) days respectively. The median follow-up is 4+ months. 8 pts were evaluable for response at the time of analysis. The ORR was 62% (5/8), including 2 (25%) PR, 1 (13%) CRi, 1 (13%) CRp and 1 (13%) MLFS. There was a reduction in BM blasts in 6 pts (75%) (Figure 1). 5 pts were taken off protocol due to progression, 2 for death, 1 for allogeneic SCT and 1 continued onto maintenance in remission. The one pt who achieved negative MRD, underwent SCT and is still alive. Median OS and EFS were 4.7 and 1.3 months respectively; 4-month RFS (CRi, CRp, and MLFS) was 67%. The median cycles received was 1 (1-3), median cycles at which the best response was achieved was 1 (1-2). The 4-month OS were 100% and 60% among responders vs. non-responders, respectively (p=0.27), and the 4-month EFS were 50% and 0% respectively (p=0.01). The ORR was 40% (2/5) (p=0.85) and 33% (1/3) (p=0.85) among pts who had prior Ven exposure or prior SCT, respectively.


The combination of Cladribine + LDAC with Uproleselan was overall well tolerated with few treatment-related AEs. The combination produced an ORR of 62% in a high-risk, refractory population whose prognosis is very dismal. The relationship of E-selectin ligand expression, response to treatment, and outcomes is being analyzed.

Disclosures: Kantarjian: Daiichi-Sankyo: Consultancy, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Jazz Pharmaceuticals: Research Funding; ImmunoGen: Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. DiNardo: ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria; Astex: Research Funding; Gilead: Honoraria; LOXO: Research Funding; Novartis: Honoraria; Astellas: Honoraria; Foghorn: Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Research Funding; Cleave: Research Funding. Short: Astellas: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Stemline Therapeutics: Research Funding; Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding. Daver: Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Ravandi: Amgen: Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Xencor: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Garcia-Manero: Acceleron Pharma: Consultancy; Gilead Sciences: Research Funding; Aprea: Honoraria; Novartis: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Curis: Honoraria, Research Funding. Kadia: Pfizer: Research Funding; Genfleet: Research Funding; Servier: Consultancy; JAZZ: Consultancy, Research Funding; cellenkos: Research Funding; PinotBio: Consultancy; Iterion: Research Funding; Amgen: Research Funding; Delta-Fly: Research Funding; Novartis: Consultancy; Ascentage: Research Funding; AstraZeneca: Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Glycomimetics: Research Funding; Astex: Honoraria; Agios: Consultancy; Abbvie: Consultancy, Research Funding; cyclacel: Research Funding; Regeneron: Research Funding.

*signifies non-member of ASH