Breakthrough treatment choice for Acute Myeloid Leukemia in pediatric and adult patients: Revumenib, an oral selective inhibitor of KMTA2Ar.

Abstract

Acute myeloid leukemia (AML) represents the predominant manifestation of acute leukemia in the adult population, whereas in children, it ranks second in terms of frequency. It is characterized by genetic mutations and epigenetic dysregulation resulting in a heterogeneous population of malignant cells with blocked differentiation resulting in increased proliferation and self-renewal activity . Every year 20,000 new cases of AML are diagnosed in the United States, whereas the global burden of the disease is believed to range between 119,000 to 352,000 cases per annum. NPM1 gene mutations are the most encountered genetic aberrations in acute myeloid leukemia (AML), being detectable in about one-third of adult AML and 50– 60% of AML patients with normal karyotype. The mutant NPM1 is directly involved in promoting increased expression of homeobox (HOX) genes, which are necessary for maintaining the leukemic cells in undifferentiated state. Recent studies have shown the importance of MLL1Menin interaction in AML with mutated nucleophosmin 1 (NPM1c). MLL1 (also known as lysine methyltransferase 2A [KMT2A]) is located on chromosome 11q23, but chromosomal translocation (MLL1-rearrangement [MLL1-r]) is observed in 5%–10% of acute leukemia cases (AML and ALL) in adults and children. This leads to the expression of chimeric MLL1 fusion proteins (ML-FP) that drive leukemic gene expression and proliferation and prevent hematopoietic differentiation, consequently giving rise to a particularly aggressive subtype of leukemia with an unfavorable outcome. Chromosomal rearrangements involving KMT2A gene are prevalent in neonates with acute leukemia, and affects 75% of newborns with ALL. Research findings suggest that this crucial molecular alternation takes place antenatally, leading to leukemia during the infantile period. Although induction therapy achieves complete remission (CR) in 60–80% cases, no targeted therapies have specifically been approved for acute leukemia with KMT2A rearrangement (KMT2Ar) or mutated NPM1currently. Unfortunately, the median survival is relatively brief at 8.5 months with 2-year and 5-year Overall Survival (OS) rates just 32% and 24%, respectively. Furthermore, existing research has suggested that circRNAs are capable of playing a role in the post-transcriptional regulation of AML by binding miRNAs, activating downstream signaling cascades, and regulating the expression of related genes, closely correlated with a wide variety of processes of AML. AML has a poor prognosis and a considerable tendency to relapse therefore, the need for effective treatment is undeniable.