A phase 1b/2a clinical trial testing the AXL inhibitor bemcentinib in older adults with acute myeloid leukemia has produced early survival data that could reshape treatment options for patients who cannot tolerate intensive chemotherapy. The trial is drawing attention because it targets a population where certain genetic subgroups, particularly those carrying TP53 mutations, face survival odds below 5%. If confirmed in larger studies, the results could mark a meaningful shift in how clinicians approach one of the deadliest forms of blood cancer.
Why TP53-Mutated AML Remains So Lethal
Acute myeloid leukemia is not a single disease. Risk varies sharply depending on a patient’s age, fitness level, and the specific genetic mutations driving their cancer. Guidance from the National Cancer Institute emphasizes that AML is stratified into multiple prognostic groups, and that extreme statistics such as survival rates under 5% apply to narrowly defined high-risk subsets rather than to all patients. Among the most treatment-resistant of these is TP53-mutated AML, a subtype in which the tumor suppressor gene TP53 is damaged, allowing leukemia cells to evade standard chemotherapy and accumulate additional genetic lesions.
Even contemporary regimens combining hypomethylating agents with venetoclax, now widely used as frontline therapy for older or unfit patients, have struggled against TP53-mutated disease. A detailed risk analysis of patients treated with such combinations found that only a small fraction of those with TP53 mutations survived beyond two years, with long-term survival in this subgroup falling below 5%. That grim baseline explains why any trial showing meaningful activity in TP53-mutated or otherwise adverse-risk AML immediately attracts scientific interest and cautious optimism.
What the Bemcentinib Trial Found
The bemcentinib trial, reported in Nature Communications, evaluated the oral AXL inhibitor both as a standalone therapy and in combination with low-dose cytarabine in older AML patients considered unfit for intensive induction chemotherapy. Bemcentinib targets AXL, a receptor tyrosine kinase implicated in treatment resistance, immune evasion, and leukemic stem cell survival, providing a biologic rationale for pairing it with low-intensity chemotherapy. The investigators reported objective response rates, duration of response, overall survival, and detailed safety findings across both single-agent and combination cohorts, allowing early comparisons with established low-intensity regimens.
The combination with low-dose cytarabine has drawn particular scrutiny because it attempts to enhance efficacy without substantially increasing toxicity in a frail population. By adding a targeted inhibitor to a long-used chemotherapy backbone, the regimen aims to disarm resistance pathways that typically blunt the impact of low-dose cytarabine alone. According to the peer-reviewed report, the trial documented manageable adverse events and signals of activity in genomically high-risk patients, including those with adverse cytogenetics. However, as a phase 1b/2a study without a randomized control arm, its encouraging survival curves remain hypothesis-generating rather than practice-changing, underscoring the need for larger, controlled trials before bemcentinib can be integrated into treatment guidelines.
Age, Mutations, and Global Patterns in AML
The significance of bemcentinib’s early data becomes clearer when placed in the broader context of how AML biology changes with age. A large collaborative effort by international cooperative groups, described in a cross-continental analysis, mapped age-related shifts in mutation patterns and demonstrated that older adults accumulate a higher burden of adverse-risk genetic alterations. Mutations in genes such as TP53, ASXL1, and RUNX1 were shown to be more prevalent in elderly patients and strongly associated with inferior responses to conventional chemotherapy and shorter survival.
This age-mutation link helps explain why novel agents are being prioritized for older adults with AML. Most diagnoses occur in people over 65, who often present with both biologically aggressive disease and comorbid conditions that limit their ability to tolerate intensive regimens. Subtype-focused research, including work on KMT2A-rearranged leukemia, has reinforced the concept that genetically defined high-risk groups require tailored therapeutic strategies rather than a uniform approach. In this landscape, an oral AXL inhibitor that can be combined with low-intensity chemotherapy offers a potentially attractive option for patients whose age and mutation profile place them at the highest risk of treatment failure.
Competing Approaches and Cautionary Lessons
Bemcentinib is emerging in a crowded field of experimental strategies aimed at adverse-risk AML, many of which build on the venetoclax-based backbones that have become standard for older or unfit patients. One Phase II study evaluated a triplet regimen of azacitidine, venetoclax, and gilteritinib in newly diagnosed adverse-risk AML lacking FLT3 mutations, a population that overlaps biologically with TP53-mutated and other high-risk subsets. That trial was motivated by preclinical evidence that layering additional targeted agents onto venetoclax could deepen remissions and potentially overcome resistance, reflecting a broader trend toward multi-drug combinations in high-risk myeloid malignancies.
However, the field has also learned hard lessons about the limits of promising early-phase data. Magrolimab, an anti-CD47 antibody designed to enhance macrophage-mediated clearance of malignant cells, generated strong enthusiasm after a phase Ib study combining it with azacitidine in higher-risk myelodysplastic syndromes, as described in a peer-reviewed report. That study documented encouraging response rates and a tolerable safety profile, including in patients with TP53 mutations, and it spurred rapid advancement into later-phase trials. Subsequent randomized studies, however, failed to reproduce the magnitude of benefit seen initially, leading to program setbacks and a reassessment of the drug’s role. This experience serves as a cautionary example for bemcentinib, even robust phase 1b signals in genomically adverse AML must be validated in larger, well-controlled trials before clinicians can be confident that early promise will translate into durable benefit.
What This Means for Patients and Next Steps
For older adults currently facing an AML diagnosis, the practical implications of the bemcentinib data are measured but meaningful. Standard-of-care options for patients who are not candidates for intensive induction remain centered on hypomethylating agents, venetoclax-based combinations, and low-dose cytarabine, with allogeneic transplantation reserved for a minority who can tolerate it. Population-level data from the U.S. Surveillance, Epidemiology, and End Results program show that survival declines sharply with age and that many patients over 75 derive only modest benefit from existing regimens, highlighting the unmet need for therapies that are both effective and tolerable in this group. In that context, an oral targeted agent with an acceptable safety profile that can be layered onto low-intensity chemotherapy is an attractive concept, even if it is still years away from routine use.
In the near term, bemcentinib remains an investigational drug that should be accessed, where possible, through clinical trials rather than off-label use. The next critical steps include randomized studies comparing bemcentinib-based combinations against current standards, with prespecified analyses in key molecular subgroups such as TP53-mutated, complex karyotype, and other adverse-risk genotypes. Parallel efforts will need to clarify biomarkers of response and resistance, determine optimal sequencing with other targeted agents, and assess quality-of-life outcomes that matter deeply to older patients. For now, the bemcentinib trial adds to a growing body of evidence that rationally designed, mutation-informed therapies can begin to chip away at the historically dismal prognosis of high-risk AML, while also reminding clinicians and patients that early-phase success is only the first step on a long path toward durable, real-world impact.
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*This article was researched with the help of AI, with human editors creating the final content.
