TOPLINE:

In patients with core-binding factor acute myeloid leukemia (CBF-AML), the addition of the TKI dasatinib to intensive chemotherapy followed by a 12-month maintenance phase with the drug did not improve event-free survival (EFS) or overall survival in a phase 3 trial. The dasatinib regimen was also associated with a higher incidence of serious adverse events. 

METHODOLOGY:

• CBF-AML with t(8;21) or inv(16)/t(16;16) often harbors activating KIT mutations or high KIT expression, both of which are associated with worse outcomes. Preclinical data and early-phase trials suggested that dasatinib inhibits KIT and may enhance chemotherapy efficacy.
• Researchers conducted a randomized phase 3 trial evaluating the addition of dasatinib to intensive induction and consolidation chemotherapy. The intention-to-treat population included 202 patients with newly diagnosed CBF-AML eligible for intensive chemotherapy (median age, 48.9 years); 58 patients (28.7%) harbored KIT mutations.
• Participants were randomly assigned to receive either standard intensive chemotherapy (n = 102; daunorubicin plus cytarabine induction followed by high-dose cytarabine consolidation) or the same chemotherapy regimen plus dasatinib (n = 100) followed by 12 months of dasatinib maintenance therapy.
• The primary outcome was EFS, defined as the time from randomization to treatment failure. Secondary outcomes included overall survival and relapse-free survival. Median follow-up duration was 63.4 months.

TAKEAWAY:

• Overall, EFS did not differ significantly between the treatment arms (hazard ratio [HR], 0.92; P = .66). Median EFS was numerically longer with dasatinib (16.6 months) than with standard therapy (13.3 months), and 4‑year EFS rates were 44% and 41%, respectively.
• Similarly, overall survival (HR, 0.93; P = .79) and relapse-free survival (HR, 0.82; P = .31) were not significantly different between the arms. The 4‑year overall survival rate in the standard arm vs treatment arm was 76% vs 78%, and relapse-free survival rate was 42% vs 49%.
• Subgroup analyses according to KIT mutation status, CBF-AML subtype, age group, and sex showed no significant differences in EFS, overall survival, or relapse-free survival between the treatment arms. However, in multivariable analysis, the presence of a KIT mutation was associated with worse EFS (HR, 1.94), overall survival (HR, 1.75), and relapse-free survival (HR, 2.15), and a higher white blood cell count was associated with worse EFS (HR, 2.02) and relapse-free survival (HR, 2.21).
• Serious adverse events were more frequent in the dasatinib arm than in the standard therapy arm, occurring in 64% vs 36% of patients, and 41% of serious adverse events in the dasatinib arm were related to the treatment. The most common were pneumonia/pneumonitis, sepsis, febrile neutropenia, and pyrexia. Adverse events of grade ≥ 3 were more frequent with dasatinib vs standard therapy and included colitis (8% vs 1% of patients), acute kidney injury (4% vs 0%), and atrial fibrillation (4% vs 0%).

IN PRACTICE:

“Dasatinib combined with [intensive chemotherapy] had no beneficial effect on outcome parameters,” and “was associated with an increase in toxicity,” the authors of the study wrote, concluding that “the use of dasatinib for patients with CBF‑AML cannot be recommended in clinical practice.”

SOURCE:

The study, led by Hartmut Döhner, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany, was published online in Blood.

LIMITATIONS:

The limitations were not explicitly detailed in the source document, but the open-label design may have introduced bias as both patients and clinicians were aware of treatment assignments. The study was conducted exclusively in Germany and Austria, which may limit generalizability to other populations and healthcare settings. 

DISCLOSURES:

This study received partial financial support from Bristol Myers Squibb, which also provided dasatinib free of charge. Döhner disclosed an advisory role with AbbVie, Otsuka, Pfizer, Servier, and Syndax; research funding to the institution from AbbVie, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; and travel support from AbbVie and Servier. Several other authors declared receiving grants or honoraria and having other ties with various sources, including Bristol Myers Squibb, AbbVie, Astellas, BeiGene, and others. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.