Continued and posttransplant gilteritinib maintenance therapy was associated with sustained remission, led to better long-term survival than salvage chemotherapy, and featured an acceptable side effect profile over two years in patients with relapsed or refractory FLT3-mutation-positive (FLT3+) acute myeloid leukemia (AML), according to study results published in Blood.
The study, conducted by Alexander Perl, MD, of the University of Pennsylvania in Philadelphia, and colleagues, was a post hoc analysis of data from the phase III ADMIRAL trial. The analysis focused on data from two years after the primary analysis to examine the long-term efficacy and safety of gilteritinib in patients with relapsed or refractory FLT3+ AML.
Patients in the ADMIRAL study were adults with confirmed FLT3+ AML who were either in their first relapse following complete remission with initial induction therapy or who were refractory to their initial induction treatment. Study participants were randomly assigned to receive either gilteritinib 120 mg/day (n=247) or preselected high- or low-intensity salvage chemotherapy (n=124).
The median survival follow-up at the time of the analysis was 37.1 months. Deaths were reported for 203 patients in the gilteritinib group and 97 patients in the salvage chemotherapy group. Sixteen patients in the gilteritinib arm were still on therapy at the time of data cutoff. The median overall survival (OS) was significantly longer in the gilteritinib arm versus the chemotherapy group (9.3 vs. 5.6 months, respectively; hazard ratio = 0.665; 95% CI 0.518-0.853; two-sided p=0.0013). Additionally, the two-year estimated survival rates were 20.6% for gilteritinib (95% CI 15.8-26.0) and 14.2% for salvage chemotherapy (95% CI 8.3-21.6).
In the gilteritinib group, the two-year cumulative incidence of relapse following complete composite remission was 75.7%. The complete composite remission rate was defined as the sum of patients who achieved complete remission (CR), CR with incomplete hematologic recovery, and CR with incomplete platelet recovery. Relapses rarely occurred after 18 months of study enrollment. A total of 49 patients assigned to gilteritinib and 14 patients assigned to salvage chemotherapy were still alive beyond two years. In addition, 26 patients in the gilteritinib arm were alive without relapse for more than two years, and 18 of these individuals underwent allogeneic hematopoietic stem cell transplantation during the study, while 16 remained on their assigned treatment following transplant.
Increased levels of alanine aminotransferase and aspartate aminotransferase were the most common adverse events (AEs) of interest during the first and second year of gilteritinib therapy. Approximately 5.7% of patients (n=14) in the gilteritinib arm experienced an AE of interest in the first year of treatment that persisted into the second year. Additionally, 14.2% of patients experienced AEs of interest that led to dose reductions during the first year of treatment with gilteritinib. Four patients experienced AEs of interest that led to dose reductions during the second year of therapy.
There were no new significant safety signals associated with gilteritinib in the second year of treatment; however, the investigators pointed to a small risk of late-occurring cardiac events, liver dysfunction, and gastrointestinal events during this period. Additionally, while the AEs of interest in this analysis occurred more frequently in the gilteritinib group relative to salvage chemotherapy, the researchers stated that this finding “does not necessarily suggest that gilteritinib was more toxic,” given that the short duration of the administered chemotherapy likely “confounds direct comparison during follow-up.”
According to the researchers, the findings from the study provide “the first evidence that [an] FLT3 inhibitor administered in the salvage setting can afford an ongoing and absolute survival benefit over” salvage chemotherapy in patients with relapsed or refractory FLT3+ AML.
Limitations of the study included the small number of patients who were assessed for pretransplant and posttransplant outcomes as well as the lack of a second randomization period and a placebo arm, the latter of which, according to the researchers, precluded quantification of “the utility of posttransplant gilteritinib or comparisons with no posttransplant maintenance therapy.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Perl AE, Larson RA, Podoltsev NA, et al. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial [published online ahead of print, 2022 Jan 26]. Blood. doi: 10.1182/blood.2021011583.
