Beyond conVENtional 7+3 in acute myeloid leukemia

In this issue of Blood, Mantzaris et al report the results of a phase 1b study of venetoclax in combination with 7+3 induction chemotherapy for newly diagnosed acute myeloid leukemia (AML).¹ This study shows that venetoclax can be safely combined with standard cytarabine and daunorubicin in adult patients with newly diagnosed AML, with rates of adverse events that are generally comparable to what would be expected with 7+3 alone. High rates of measurable residual disease (MRD)-negative responses were observed, and efficacy is being further evaluated in an ongoing expansion phase.

For fit patients with newly diagnosed AML, intensive chemotherapy (IC) has been the standard of care for decades. The commonly used 7+3 regimen, consisting of a continuous infusion of cytarabine for 7 days in combination with a daily dose of an anthracycline for the first 3 days, was initially reported in 1973.² Over 50 years later, 7+3 has endured as the preferred initial induction regimen at many institutions. Although there have been improvements such as the addition of gemtuzumab ozogamicin for core-binding factor AML and FLT3 inhibitors for AML with a FLT3 mutation, IC has remained the standard of care for younger, fit patients with AML.

The BCL-2 inhibitor venetoclax, given in combination with a hypomethylating agent (HMA), has transformed the management of newly diagnosed AML in patients who are older or are otherwise not fit for IC.³ Multiple recent and ongoing studies are now evaluating venetoclax as a part of initial therapy for fit patients with newly diagnosed AML. Two major approaches are being studied. The first is to combine venetoclax with standard frontline IC regimens. The other is to evaluate lower-intensity venetoclax regimens in carefully selected younger patients, such as those who would not be predicted to do well with IC due to antecedent myelodysplastic syndrome or adverse risk disease biology and in whom a consolidative allogeneic transplant is planned.

Recent studies have shown safety and high rates of responses when venetoclax is combined with the intensive induction regimens FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) and CLIA (cladribine, idarubicin, and cytarabine).^4-7 In a study of FLAG-Ida with venetoclax in adults with newly diagnosed AML, the composite complete remission (CR) rate was 89%, with 93% achieving MRD negativity by multiparameter flow cytometry.^4,5 The only previously published study of venetoclax with the 7+3 regimen is a study by Wang et al where the venetoclax was given on days 6 through 11 with standard daunorubicin and cytarabine. The study enrolled 33 adults ≤60 years old with newly diagnosed de novo AML and found a composite CR rate of 91% (97% MRD⁻).

Mantzaris et al present the results from the first US-based study of venetoclax in combination with 7+3 (https://clinicaltrials.gov/ identifier NCT05342584). This was a phase 1b trial designed to assess the safety and optimal duration of venetoclax when given in combination with standard cytarabine and daunorubicin. The study included adults between 18 and 75 years old with newly diagnosed AML. Venetoclax was given at 400 mg daily (following the initial 3-day ramp-up) at escalating durations (8, 11, and 14 days) in a 3+3 design. The study included 34 patients at a median age of 59 years (range 27-71 years).

The addition of venetoclax to 7+3 was well tolerated at all durations, and no dose-limiting toxicities occurred. Common adverse events were generally comparable to what would be expected with 7+3 alone and included neutropenic fever (100%), sepsis or bacteremia (29%), and lung infections (18%). There was, however, a relatively high incidence of neutropenic enterocolitis reported (23.5%). Notably, the 60-day mortality was 0%. The composite CR rate was 85%, with an MRD negativity rate of 86%. The median overall survival, event-free survival, and duration of response have not yet been reached after a median follow-up of 9.6 months.

Overall, these results demonstrate safety when venetoclax is combined with 7+3. This study, which is currently in an expansion phase to further evaluate efficacy, included a diverse patient population (63% of participants were nonwhite) and adds to the literature showing that venetoclax is promising in combination with IC, supporting ongoing investigation of this approach.

Although combining IC with venetoclax generally appears safe and response rates reported in early phase studies are high, it is also likely that selected younger, fit patients may benefit from a lower-intensity induction regimen. In theory, treatment with venetoclax and an HMA could have lower toxicity and potentially allow for patients to have more time out of the hospital, although careful patient selection to exclude patients with favorable-risk AML is critical since patients will require a consolidative transplant. Xie et al published a study of venetoclax with decitabine for initial induction in younger adults with adverse risk AML.⁸ Of note, patients who responded subsequently received high-dose cytarabine consolidation, and eligible patients were also offered transplant. The study included 42 patients, with 81% achieving CR. Another study of venetoclax with azacitidine for initial therapy in adults ≤59 years with intermediate- and adverse-risk AML was recently presented and showed an overall response rate of 61%, which compared favorably to matched historic controls who received IC.⁹ 

Overall, the integration of venetoclax into frontline therapy for fit adults with AML is promising. How this will fit with the incorporation of FLT3 inhibitors and other mutation-selective therapies such as menin inhibitors is likely to continue to evolve. Ongoing randomized trials comparing azacitidine and venetoclax vs IC regimens (NCT04801797, NCT05554393) may provide additional data that further inform frontline therapy choice.

Conflict-of-interest disclosure: C.M.M. has served on an advisory board for Syndax Pharmaceuticals and on a safety monitoring committee for Kura Oncology.