Ruxolitinib Plus Venetoclax Demonstrates Safe but Limited Clinical Activity in Relapsed/Refractory AML

Key Clinical Summary:

• Design/Population: Results from a multicenter, phase 1 trial evaluated ruxolitinib plus venetoclax in 30 heavily pretreated adult patients with relapsed/refractory acute myeloid leukemia. The study evaluated dose escalation, safety, preliminary efficacy, and correlative biomarkers for ruxolitinib plus venetoclax. 
• Key Outcomes: The regimen was well tolerated with no dose-limiting toxicities and produced a 20% clinical response rate and a 10% composite complete remission rate. Median overall survival was 3.7 months, although exceptional long-term responses were observed in a small subset of patients.
• Clinical Relevance: Ruxolitinib plus venetoclax may offer benefit for selected patients, but overall efficacy was modest. CD56 expression and PI3K/AKT pathway activity may help guide future biomarker-driven treatment strategies and deserve further validation.

Results from a multicenter, phase 1 trial demonstrated that ruxolitinib plus venetoclax is well tolerated but shows modest clinical activity among heavily pretreated adult patients with relapsed/refractory acute myeloid leukemia (AML). 

“Preclinical testing by our group and others showed that treatment with [ruxolitinib] increased sensitivity to [venetoclax] in ex vivo drug assays performed on primary AML samples,” stated Uma Borate, MBBS, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, and co-authors. This suggests “that [ruxolitinib plus venetoclax] combination therapy may have novel applicability in treating AML.” 

In this study, researchers enrolled 30 heavily pretreated patients with relapsed/refractory AML after failure of ≤1 line of prior induction therapy or hypomethylating agent (HMA) exposed, induction-ineligible AML to receive escalating doses of ruxolitinib and venetoclax. Primary end points included maximum tolerated dose and safety. Key secondary end points included response, clinical benefit, event-free survival (EFS), and overall survival (OS). Exploratory molecular analyses assessed biomarkers associated with response and resistance. 

At analysis, the maximum tolerated dose was 400 mg of daily venetoclax and 30 mg of twice daily ruxolitinib. This regimen was well tolerated with no dose-limiting toxicities, and median treatment duration was 55 days. 

The most frequently reported grade ≥3 hematologic adverse events included thrombocytopenia (50%), anemia (40%), neutropenia (37%), and febrile neutropenia (33%). The most frequently reported grade ≥3 non-hematologic treatment-emergent adverse events, occurring in ≥2 patients, included lung infection (17%), sepsis (10%), hypotension (10%), hypoxia (10%), fatigue (7%), hypokalemia (7%), abdominal pain (7%), acute kidney injury (7%), bacteremia (7%), and neck pain (7%). Six deaths were reported, including 2 due to sepsis and neutropenic pneumonia considered potentially venetoclax related. 

Over the first 2 treatment cycles, the clinical response rate was 20%. Composite complete remission rate was 10%, and the clinical benefit rate was 63%. At a median follow-up of 50 months, median EFS was 1.8 months, and median OS was 3.7 months, with 23% of patients alive at 1 year. There were 2 long-term responders, including 1 patient with prior HMA plus venetoclax failure who achieved complete remission and remained on treatment for more than 4 years.

Exploratory molecular analyses suggested that responders had higher baseline expression of PI3K/AKT pathway genes, including PIK3R3, FGF2, and PDGFA. Expression of NCAM1/CD56 on leukemic blasts was associated with lower odds of response (odds ratio [OR], 0.09; P = 0.039) and shorter OS (hazard ratio [HR], 2.35; P = 0.048). Additional predictors of poor survival included TP53 mutations (HR, 6.37; 95% CI, 1.96 to 20.74; P = 0.002) and complex karyotype (HR, 4.26; 95% CI, 1.55 to 11.67; P = 0.005). 

Mass cytometry analyses in a subset of patients suggested that nonresponders had upregulation of pCREB and persistence of metabolic programs associated with mitochondrial activity and fatty acid oxidation.

“The combination of [ruxolitinib plus venetoclax] in [relapsed/refractory] or in HMA-exposed, intensive chemo-ineligible secondary AML is well-tolerated with moderate efficacy,” concluded Dr Borate et al. 

“The prognostic role of pre-treatment CD56 blast expression and early on treatment pCREB upregulation as predictors of resistance to this combination is under further investigation… and validation in a larger cohort of [venetoclax]-treated patients is needed to assess the reliability and prognostic value of these potential molecular targets,” they added. 

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