Enhanced antileukemic activity of momelotinib in combination with venetoclax and azacitidine compared to gilteritinib-based combination Free

Acute myeloid leukemia (AML) is highly heterogeneous and the most common form of acute leukemia in adults. Despite extensive genomic insights, conventional chemotherapies, specifically anthracyclinesand cytarabine, have remained the cornerstone of treatment for the past four decades. The post-genomic era, marked by the advent of targeted therapies, has not yet resulted in the anticipated improvement in treatment outcomes. In particular, the efficacy of first-generation FLT3 inhibitors was hampered by limited target engagement and suboptimal bioavailability. The second-generation FLT3 inhibitors were designed to overcome these limitations and have demonstrated superior responses compared to their predecessors, but acquired resistance remains a significant challenge. Treatment response and the duration of remission are closely associated with levels of minimal residual disease (MRD). For instance, patients with notable MRD relapse within a short duration while those with low or undetectable MRD exhibit prolonged remission. MRD is largely comprised of leukemia stem cells (LSCs), which are generally refractory to TKI treatment and serve as a reservoir to develop resistance. Elevated apoptotic threshold from overexpressed hematopoietic cytokines through activation of the MAPK and JAK-STAT signaling pathways poses a significant challenge leading to treatment refractoriness. Consistently, relapsed AML patients frequently acquire mutations in the RAS-MAPK and JAK-STAT pathways, supporting the notion that cytokine-driven signaling is a key mechanism underlying treatment failure. Elimination of these refractory cells is essential for durable remission. Recent clinical evaluation of gilteritinib in combination with venetoclax and azacitidine exhibited superior remission than the venetoclax and azacytidine combination. However, responses were not durable with most patients relapsing within 6-12 months. As relapsed AML patients consistently acquire mutations in the RAS-MAPK and JAK-STAT pathways and overcoming this treatment resistance will likely require combination strategies that target reactivation of these key survival pathways, we reasoned that inhibition of multiple pro-inflammatory cytokine signaling pathways in combination with venetoclax and azacitidine could be more a more effective AML therapy. As proof of this concept, momelotinib, a JAK1 and JAK2 inhibitor with activity against several other proinflammatory and pro-tumorigenic signaling pathways including ACVR1, FLT3, IRAK1, IKKa/b/e, and ROCK2, has been shown to be more effective in suppressing the leukemic progression compared to gilteritinib alone. Here we show that momelotinib in combination with venetoclax and azacitidine exerts synergistic cytotoxic response in both FLT3 wild-type and mutant AML cells. In contrast, selective inhibitors of JAK-STAT (ruxolitinib) or FLT3 (gilteritinib or quizartinib) alone failed to demonstrate comparable synergy, highlighting the distinct polypharmacological profile of momelotinib in mediating the cytotoxic response. Importantly, the combination of momelotinib with venetoclax and azacitidine exhibited prolonged survival and enhanced leukemic clearance in AML PDX mouse models compared to the same gilteritinib-based combination. Notably, while the efficacy of gilteritinib-based regimens was restricted to FLT3-mutant AML, the momelotinib combination demonstrated activity across both FLT3 mutant and FLT3 wild-type contexts. Altogether these preclinical data support clinical evaluation of momelotinib in combination with venetoclax and azacitidine as a potential effective treatment in AML.