Ruxolitinib Plus Venetoclax Demonstrates Favorable Safety and Modest Clinical Activity in Relapsed or Refractory Acute Myeloid Leukemia

Clinical Summary:

• Design/Population: This multicenter, phase 1 dose-escalation trial evaluated ruxolitinib plus venetoclax in 30 adults with heavily pretreated relapsed or refractory acute myeloid leukemia (AML), assessing safety, preliminary efficacy, and exploratory biomarker analyses.

• Key Outcomes: The combination was well tolerated, with no dose-limiting toxicities observed. Clinical responses occurred in 20% of patients, including a 10% composite complete remission rate, while exploratory analyses identified potential molecular markers associated with treatment response and resistance.

• Clinical Relevance: These findings support the feasibility of combining ruxolitinib with venetoclax in relapsed or refractory AML and provide a rationale for biomarker-driven studies to identify patients most likely to benefit.

Results from a multicenter phase 1 trial demonstrated that ruxolitinib plus venetoclax was well tolerated and produced modest clinical activity in heavily pretreated adults with relapsed or refractory acute myeloid leukemia (AML), while exploratory analyses identified potential biomarkers associated with treatment response.

"The primary goal of AML induction chemotherapy is to achieve complete remission... however, 20% to 40% of patients do not achieve remission with standard cytotoxic induction, and 50% to 70% of patients with first [complete response] experience relapse within 3 years," stated Uma Borate, MBBS, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, and coauthors. "Preclinical testing... suggest that [ruxolitinib plus venetoclax] combination therapy may have novel applicability in treating AML." 

In this dose-escalation study, 30 adult patients with relapsed or refractory AML received escalating doses of ruxolitinib plus venetoclax following failure of prior induction therapy or after exposure to hypomethylating agent–based therapy. The primary end points were maximum tolerated dose and safety. Secondary end points included response, clinical benefit, event-free survival (EFS), overall survival (OS), and exploratory biomarker analyses.

The maximum tolerated dose was established as 400 mg of once daily venetoclax plus 30 mg of twice daily ruxolitinib. No dose-limiting toxicities were observed, and the median treatment duration was 55 days.

The most common grade ≥3 hematologic adverse events included thrombocytopenia (50%), anemia (40%), neutropenia (37%), and febrile neutropenia (33%). Common grade ≥3 non-hematologic adverse events included lung infection (17%), sepsis (10%), hypotension (10%), hypoxia (10%), and acute kidney injury (7%). Six deaths occurred during the study, including 2 attributed to sepsis and neutropenic pneumonia considered potentially related to venetoclax.

During the first 2 treatment cycles, the clinical response rate was 20%, including a composite complete remission rate of 10%. The clinical benefit rate was 63%. After a median follow-up of 50 months, median EFS was 1.8 months and median OS was 3.7 months. Two patients experienced durable long-term responses, including one patient previously treated with hypomethylating agent plus venetoclax who remained in complete remission on study treatment for more than 4 years.

Exploratory molecular analyses demonstrated that responders had higher baseline expression of PI3K/AKT pathway genes, including PIK3R3, FGF2, PDGFA. Expression of NCAM1/CD56 on leukemic blasts was associated with a lower likelihood of response (odds ratio [OR], 0.09; P = .039) and shorter OS (hazard ratio [HR], 2.35; P = .048). TP53 mutations and complex karyotype were also independently associated with inferior survival. Mass cytometry analyses further suggested that persistent activation of pCREB signaling and mitochondrial metabolic programs characterized treatment-resistant disease.

"The novel, all-oral combination of [ruxolitinib plus venetoclax] for patients with [relapsed or refractory] AML was well tolerated with no [dose-limiting toxicities]," concluded Dr Borate et al. "The prognostic role of pretreatment CD56 blast expression and early on-treatment pCREB upregulation as predictors of resistance to this combination is under further investigation."

Source:

Borate U, Tognon CE, Madanat YF, et al. Results of a phase 1 trial testing ruxolitinib + venetoclax in relapsed/refractory acute myeloid leukemia patients. Blood Neoplasia. Published online: February 5, 2026. doi: 10.1016/j.bneo.2026.100205