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Past, Present and Future of Uproleselan, A New Anti-Leukemia Drug

Hillard M. Lazarus1*, Jay N. Lozier2

Acute Myeloid Leukemia (AML) therapy has improved over
decades, yet patients continue to die from persistent or recurrent
disease, as well as complications of therapy. 2024 estimated new
cases and deaths in the United States (US) were 20,800 and
11,220, respectively [1]. Five-year survival from 2014-2020 was
31.9% [2]. Over time, survival has improved due to better
supportive care, new anti-leukemia drugs, and advances in
management of chemotherapy toxicity. Yet cytotoxic therapies
induce remissions and prolong survival at the cost of potentially
fatal organ damage, immune dysfunction, and marrow
suppression. Hence, new conventional therapy agents have not
significantly improved outcomes, except for all-trans retinoic acid
and arsenic trioxide in acute promyelocytic leukemia [3].
Importantly, increasing numbers of patients are receiving
allogeneic Hematopoietic Cell Transplantation (HCT), the
treatment with highest probability of cure, partly due to
emergence of haploidentical HCT [4,5]. The E-selectin
antagonist uproleselan introduces a promising new mechanism
with potential for AML therapy. E-selectin is an endothelial cell
surface mediator of cellular adhesion. Selectin glycoproteins
mediate binding to cell surface carbohydrates on leukocytes [6],
such as the E-selectin binding ligand, sialyl Lewisx [7]. Three
homologous selectins are distinguished by their cells of origin: E-
selectin in endothelial cells, P-selectin in platelets, and L-selectin
in lymphocytes [8]