Recent studies have demonstrated that the disruption of signal regulatory protein alpha (SIRPα)-CD47 interaction results in the preferential phagocytosis of AML cells over normal human hematopoietic cells by macrophages (16, 17). This notion creates a therapeutic opening for agents that disrupt SIRPα-CD47 interactions, which may allow for the preferential clearance of leukemic cells over their normal counterparts.

CD47 has long been known to act as a “marker of self” on red blood cells and platelets, regulating their timely clearance by macrophages (18). It is therefore not surprising that cancer cells have exploited this mechanism of self-recognition to evade immunosurveillance. In line with this notion, elevated expression levels of CD47 constitute an adverse prognostic factor for AML patients. Currently, there are several anti-CD47 monoclonal blocking antibodies that are being tested in clinical trials involving patients with myeloid dysplastic syndrome or AML (19-21). The novel anti-CD47 antibody magrolimab demonstrated significant antileukemic activity when combined with azacitidine for the frontline treatment of AML and myeloid dysplastic syndrome, with high response rates and prolonged survival and duration of response, both in TP53-mutant and wild-type populations (22, 23). In a phase 1b trial of magrolimab with azacytidine in newly diagnosed patients with AML, objective responses were noted in 65% of patients, with negative measurable residual disease in 37% (22, 24).

Because of the relatively restricted tissue expression pattern of SIRPα, SIRPα antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed; binds to multiple other ligands, including integrins and thrombospondin; and governs several processes in both normal and malignant tissues. To maximize their utility in enhancing antitumor immunity, SIRPα antagonists must block the interaction of CD47 with SIRPα while minimizing SIRPα signaling. SIRPα consists of an extracellular N-terminal domain composed of 3 immunoglobulin-like domains and a cytoplasmic domain, which has 2 tyrosine phosphorylation sites and 4 immunoreceptor tyrosine inhibitory motifs (25, 26). Binding of CD47 to N-terminal of SIRPα on phagocytic cells induces a phosphorylation reaction of the immunoreceptor tyrosine inhibitory motif (27). This activates protein tyrosine phosphatases Src homology region 2 (SH2) domain-containing phosphatases 1 and 2. Subsequently, dephosphorylation of immunoreceptor tyrosine activation motifs prevents contractile engulfment by the macrophages and sends a “do not eat me” signal to the innate immune system, a new signal that cancers seem to use to evade detection and destruction (17, 28, 29).

FMS-like tyrosine kinase 3 (FLT3) is a transmembrane receptor tyrosine kinase that is normally expressed on hematopoietic stem cells and plays an important role in their differentiation. FLT3 mutations are frequent in AML, occurring in up to 30% of patients.

The most common type of FLT3 mutation is an internal tandem duplication (ITD) (10). Patients with FLT3-ITD-mutated AML have an extremely poor prognosis, with shorter overall survival and higher relapse rates compared to patients who do not carry this mutation (10, 11). Given the importance of FLT3 mutations in disease progression and overall outcomes in AML patients, several targeted therapeutic strategies have been deployed to improve outcomes for patients with FLT3-mutated AML. Tyrosine kinase inhibitors (TKIs) have been extensively investigated in previous and ongoing clinical trials for this subset of AML patients, and the FDA-approved TKIs midostaurin and gilteritinib have been incorporated into the standard treatment regimens (12). However, the bone marrow (BM) microenvironment has been reported to contribute to FLT3 inhibitor resistance, which results in persistence of BM disease (8). Several signaling pathways and downstream targets have been implicated in FLT3-mutated AML disease progression, relapse, and resistance to TKIs. These include but are not limited to PI3K, MAPK, and STAT5 (10, 13). Siddhi Therapeutics is developing small-molecule inhibitors to target FLT3 in AML.