Patients with relapsed or refractory acute myeloid leukemia (AML) face some of the most challenging outcomes in hematologic oncology. Once the disease returns or fails to respond to initial treatment, long-term survival drops sharply, and therapeutic options are limited.
Now, results from the RELAX trial, published in The Lancet Haematology, suggest that combining the BCL-2 inhibitor venetoclax with intensive chemotherapy could significantly improve remission rates and help more patients reach potentially curative stem cell transplantation.
The multicenter Phase I/II study, conducted across hospitals in Germany, evaluated a regimen combining venetoclax with high-dose cytarabine and mitoxantrone (HAM) in adults with relapsed or refractory AML.
A persistent therapeutic challenge
Standard salvage chemotherapy regimens such as HAM have historically produced limited responses in this patient population. As the study authors note, “complete remission rates achieved with conventional intensive salvage chemotherapies alone … are low (40–50%), and corresponding overall survival is generally short.”
These limited outcomes have driven intense research into targeted therapies and combination regimens that can improve response rates while maintaining tolerable toxicity.
Venetoclax, a BCL-2 inhibitor that promotes apoptosis in leukemia cells, has already transformed treatment for newly diagnosed AML patients who are not eligible for intensive chemotherapy. Researchers have increasingly explored whether it could also enhance the effectiveness of more aggressive regimens.
The RELAX trial was designed to answer that question.
Testing a new combination
The study enrolled 55 patients aged 18 to 75 years with relapsed or refractory AML who were considered medically fit for intensive chemotherapy. Patients received venetoclax alongside the HAM regimen, with venetoclax administered orally for 14 days in each cycle while cytarabine and mitoxantrone were given intravenously.
The trial used a dose-escalation design in Phase I to determine safety and dosing, followed by a Phase II expansion focused on efficacy.
The results were encouraging.
The regimen achieved a composite complete remission rate of 75%, substantially higher than historical outcomes for HAM chemotherapy alone.
Importantly, the improved response translated into meaningful downstream outcomes: Many patients who achieved remission were able to proceed to allogeneic hematopoietic cell transplantation, which remains the only potentially curative therapy for many AML patients.
According to the authors, the combination “appeared to be safe in this setting and showed promising activity … inducing high remission rates, thus enabling transition to allogeneic HCT.”
Survival outcomes and genetic insights
With a median follow-up of approximately 30.8 months, the investigators reported a 24-month overall survival rate of 56%.
Median overall survival had not yet been reached at the time of analysis, suggesting potentially durable responses in a subset of patients.
Exploratory analyses also revealed that genetic features influenced outcomes. Patients with TP53 alterations or complex karyotypes had worse survival, whereas mutations in genes such as NPM1, IDH1, or IDH2 were associated with numerically longer survival.
Although these analyses were not prespecified, they highlight how molecular stratification could eventually guide treatment decisions for AML patients receiving combination regimens.
Positioning the regimen in the AML landscape
Over the past decade, venetoclax has become a cornerstone therapy in AML, particularly in combination with hypomethylating agents or low-dose cytarabine for older or unfit patients.
However, its role alongside intensive chemotherapy remains an active area of research.
Previous trials combining venetoclax with other chemotherapy backbones—such as FLAG-IDA or CPX-351—have shown response rates between 39% and 64%.
The RELAX results suggest that adding venetoclax to HAM may achieve comparable or higher remission rates in the relapsed AML setting.
The investigators conclude that “combining intensive chemotherapy regimens with venetoclax seems to be a promising bridge to allogeneic transplantation, together inducing deep and durable remissions.”
Toward a potential new standard
Although the RELAX trial was relatively small and single-arm, its findings could influence future salvage treatment strategies for AML.
Relapsed AML patients often require rapid disease control to qualify for stem cell transplantation. A regimen capable of inducing remission in a larger proportion of patients could therefore significantly improve long-term survival prospects.
Further studies will be needed to validate the results in larger randomized trials and to determine how best to integrate the HAM-venetoclax regimen with other targeted therapies, such as FLT3 or IDH inhibitors.
For now, the RELAX study provides strong evidence that combining targeted apoptosis-inducing therapy with established chemotherapy backbones may offer a new pathway to improve outcomes for patients with aggressive leukemia.
