Pursuing a Gentler Path to Treat—and Potentially Cure—Acute Myeloid Leukemia
Key Findings
- Intensive induction chemotherapy (IC) has been the standard upfront treatment for acute myeloid leukemia (AML) for over five decades
- Although IC leads to suboptimal long-term outcomes in most patients, no alternative treatment regimen to date has proven to be superior in terms of both tolerability and efficacy
- The PARADIGM study found that a novel combination therapy, azacitidine and venetoclax, outperformed IC in newly diagnosed AML patients who have historically been considered fit enough to receive intensive therapy
Intensive induction chemotherapy (IC) has been the standard upfront treatment for acute myeloid leukemia (AML) for over five decades. Although IC leads to suboptimal long-term outcomes in most patients, no alternative treatment regimen to date has been shown to be superior in terms of both safety and efficacy.
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PARADIGM is a phase II randomized multicenter study comparing traditional IC to a novel combination therapy, azacitidine and venetoclax (aza-ven), in newly diagnosed AML patients who have historically been considered fit enough to receive intensive therapy.
The trial enrolled 172 adults with AML who were functionally fit and eligible for IC. Patients with core binding factors, FLT3 mutations, or NPM1 mutations (only under age 60), in whom newer approved targeted therapies would have made randomization difficult, were excluded.
"As a result, a sizable minority of AML patients were not eligible for the study," notes Amir Fathi, MD, director of the Center for Leukemia at Mass General Brigham Cancer Institute, who led the design and conduct of the study.
The researchers found that aza-ven clearly outperformed IC in those patients enrolled on study.
"Aza-ven is a gentler and better-tolerated therapy associated with improved event-free survival (EFS), higher composite remission rates, better quality of life, less hospitalization, and less impactful infection and bleeding complications," Dr. Fathi says. "In addition, a higher proportion of patients who received aza-ven proceeded to a potentially curative stem cell transplant."
Study findings could spark a significant shift in the management of AML.
VIALE-A Trial Serves As Precursor
Since a pivotal 1973 paper, intensive IC—typically with cytarabine and anthracyclines—has been the standard of care for newly diagnosed AML. This regimen is commonly known as "7+3," in reference to the week-long continuous IV administration of cytarabine combined with daunorubicin or idarubicin on days 1 to 3.
The many drawbacks of IC include a heightened risk of bleeding, infections, malnutrition, systolic dysfunction, secondary cancer, and other complications and side effects. In addition, IC is not curative and may prevent the remission that is necessary for the patient to progress to stem cell transplant. It is also associated with longer hospitalizations, higher bed utilization, and other factors that raise healthcare costs.
VIALE-A, a phase III trial, showed that aza-ven improved survival and remission rates versus azacitidine alone in older patients. The results made an impression on Dr. Fathi and others in the field.
"We thought that if aza-ven is so well-tolerated, producing such good outcomes, and taking so many of these older patients to transplant, why are we keeping it away from patients who are younger and may also benefit from better-tolerated therapies?" Dr. Fathi says. "Why are we putting these younger patients through all this and only reserving this gentler treatment for older patients? That had a lot to do with how we designed our study."
Study Meets Primary Endpoint
Participants were randomly assigned to receive aza-ven (n=86) or conventional IC (n=86). The study met its primary endpoint, EFS (median EFS was 14.6 months for aza-ven versus 6.15 months for IC). Among other key metrics, aza-ven also outperformed IC in terms of:
- 60-day mortality (0% vs. 4.7%)
- Admission to ICU (0% vs. 10%)
- Overall response (88% vs. 62%)
- Composite complete response (78% vs. 54%)
- Progression to transplant (61% vs. 40%)
"Considering the activity, safety, tolerability, quality of life, and various key healthcare-utilization metrics," Dr. Fathi concludes, "these data support the use of aza-ven in traditionally induction-eligible, potentially transplant-eligible patients with intermediate- or adverse-risk, FLT-wildtype AML."
Dr. Fathi and his colleagues are preparing more data from PARADIGM focused on measurable residual disease and depth of response. They are also conducting further analyses comparing costs, healthcare burden, and other factors that may affect treatment decisions for this patient population.