Are you ready for it? VEN-HMA for younger patients with AML Free

In this issue of Blood, Lu et al report results from a randomized clinical trial comparing outcomes of newly diagnosed younger patients with acute myeloid leukemia (AML) treated with venetoclax-decitabine (VEN-DEC) vs idarubicin-cytarabine (IA-12) induction and found noninferior response rates and superior safety with VEN-DEC.¹ Anthracycline-cytarabine induction has been the mainstay of AML treatment for over 50 years,² and the VIALE-A trial established the combination of venetoclax plus hypomethylating agent (VEN-HMA) as a new standard of care for older and unfit patients.³ Retrospective studies compared outcomes between the 2 approaches and demonstrated the feasibility and efficacy of VEN-HMA in younger patients,^4-6 but, until this report, prospective, randomized data were lacking.

This phase 2b trial randomized 188 patients, 18 to 59 years of age, to 1 of 2 induction regimens: VEN-DEC (28 days of venetoclax plus 5 days of decitabine) or IA-12 (3 days of idarubicin and 7 days of cytarabine). Patients had de novo AML and included all European Leukemia Network risk groups. The primary end point was composite complete remission (CRc, complete remission + complete remission with incomplete count recovery) and was assessed after induction. Secondary end points included incidence of grade 3 or higher infections, duration of severe myelosuppression, event-free survival and overall survival, and rates of measurable residual disease negativity by multiparameter flow cytometry. Analysis of efficacy across molecular subgroups was exploratory.

After randomized induction, all patients were treated with high-dose cytarabine consolidation for 1 to 4 cycles. Allogeneic stem cell transplant (SCT) was recommended for patients with intermediate/poor risk disease and favorable risk AML with high relapse risk as determined by the treating investigator.

The study met its primary end point, which was noninferiority of VEN-DEC to IA-12. CRc rates were 89% in the VEN-DEC group and 79% in the IA-12 group, with the majority on both arms achieving remission after 1 cycle of induction. Measurable residual disease negativity was similar between groups, at 80% with VEN-DEC and 76% with IA-12, and there was similar median time to response in each arm. Analyses of CRc rates favored VEN-DEC in certain AML subtypes, including adverse risk patients (CRc rate 91% for VEN-DEC vs 42% for IA-12) and patients with U2AF1 mutations (100% vs 14%). In contrast, patients with RUNX1::RUNX1T1 rearrangement had higher CRc rates to IA-12 (88%) vs VEN-DEC (44%). When looking at outcomes for secondary safety end points, the incidence of grade 3 or higher treatment-related adverse events was less with VEN-DEC (20%) vs IA-12 (42%), with lower rates of febrile neutropenia with VEN-DEC (43% vs 69%) and grade 3 documented infections (32% vs 67%). Rates of hematologic toxicities were similar between the arms. The duration of grade 4 thrombocytopenia was shorter with IA-12 (19 days vs 23 days), and the duration of grade 4 neutropenia was shorter with VEN-DEC (13 days vs 19 days).

The authors are to be commended for conducting this randomized trial of a lower intensity induction in younger patients with newly diagnosed AML. The findings show noninferiority in CRc rates across the entire trial, with improved safety seen with VEN-DEC. In standard practice, patients would continue with VEN-HMA as consolidation/maintenance and not be switched to higher intensity therapy. The efficacy results from smaller patient subsets will need additional validation before prompting a change to clinical practice. The trial highlights the need for continued investigation of VEN-HMA for younger and fit patients so we can better understand which patients may benefit from this regimen as compared with traditional anthracycline-cytarabine induction. In addition, many centers do not have complete next generation sequencing data available at the time of initial therapy decision. These data showing differential induction response rates in specific AML subgroups underscore the need to have rapid, readily available, and complete diagnostic testing for patients with AML to inform up-front treatment decision as a standard of care.

A critical question that comes up when using VEN-HMA based treatment is: What is the optimal duration of therapy? For older and unfit patients, VEN-HMA is continued until disease relapse or toxicities preclude further treatment, with limited, but encouraging data on VEN-HMA discontinuation.^7,8 For younger patients not going to SCT who may be cured with an intensive induction/consolidation approach, the optimal duration of VEN-HMA therapy for cure is unknown. A strategy such as this one, using VEN-DEC as initial induction to limit early toxicity followed by therapy intensification in consolidation to further eradicate residual disease, is worthy of additional exploration. This approach may have particular benefit in those patients with intermediate and adverse-risk disease who are planned for SCT, especially if response rates are similar but toxicities are lower with VEN-DEC.

The authors underscore the need for larger, randomized studies of these 2 induction approaches, especially because the benefits to each induction strategy vary among AML subgroups, and larger patient numbers are needed to validate the findings. Ongoing randomized clinical trials in the United States are designed to answer this question. A multicenter, randomized trial of intensive induction chemotherapy vs VEN-HMA will enroll 172 patients ≥18 years of age (NCT04801797). Notably, the study excludes patients with core binding factor and FLT3-mutated AML. The National Cancer Institute–sponsored MyeloMATCH portfolio of trials has 2 trials in patients 18 to 59 years of age, which are testing various induction strategies, including anthracycline-cytarabine and VEN-HMA, in intermediate-risk AML (NCT05554393) and high-risk AML (NCT05554406). The MyeloMATCH studies are expected to enroll 153 and 335 patients, respectively.

As we look to combine targeted agents, such as isocitrate dehydrogenase inhibitors or menin inhibitors, with either an anthracycline-cytarabine or VEN-HMA, we will need to examine combinations based on disease biology and not those based on age alone for choice of backbone therapy. Data from these ongoing studies suggest that just because someone is younger and fit for induction chemotherapy, it may not be the most efficacious regimen, depending on the characteristics of their leukemia. Going forward, the availability of rapid complete diagnostic testing and data predicting which AML subtypes respond better to which induction strategy may finally usher in an era of truly personalized medicine for patients with AML.

Conflict-of-interest disclosure: T.L.L. has done consulting work for Servier, Syndax, and Jazz Pharmaceuticals.