Post-Allogeneic Hematopoietic Cell Transplant Gilteritinib Maintenance Demonstrates Benefit for Patients With AML With Detectable FLT3-ITD MRD

Patients with acute myeloid leukemia (AML) harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) with measurable residual disease (MRD) detectable in the peri-allogeneic hematopoietic cell transplantation (HCT) period derived benefits from post-transplant gilteritinib, whereas those without detectable MRD did not, according to a recent randomized trial. This data serves to highlight how MRD can be used to guide the treatment strategy for patients with AML undergoing HCT.

For patients with induction standards for FLT3-ITD AML who are undergoing HCT in first remission, previous research has examined if the benefits of maintenance therapy with FLT3 inhibition outweigh the risks of toxicity.

“Despite the risk of post-HCT relapse, at least half of patients with [FLT3]-ITD AML transplanted in first remission are cured without further treatment, which means that many patients treated with post-HCT [FLT3] inhibition are subjected to an unnecessary therapy,” Mark J Levis, MD, PhD, Johns Hopkins University, Baltimore, Maryland and colleagues explained.

Investigators included 356 patients in this trial who were randomly assigned post-HCT to receive gilteritinib or placebo treatment. The primary end point was RFS, which was assessed by a blinded end point review committee (BERC). Overall survival (OS) was a key secondary objective.

Results demonstrated that, despite RFS measuring higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% confidence interval [CI], 0.459 to 1.005]; 2-sided P = .0518). However, 50.5% of patients had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Patients without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575).

Overall, these data show that the improvement in RFS conferred by gilteritinib treatment over placebo did not reach the predetermined level of significance. However, as measured in secondary analysis and consistent with the pretrial hypothesis, participants with FLT3-ITD AML who undergo HCT in first remission with peri-HCT detectable FLT3-ITD MRD benefit from post-HCT gilteritinib. Patients in deep remissions did not benefit from maintenance gilteritinib therapy and were therefore exposed unnecessarily to its potential toxicity. Among the 270 participants who survived at data cutoff, the median follow-up was 43.8 months.

Trial efficacy was examined, and investigators determined the 2-year RFS rate by BERC (95% CI) was 77.2% (CI, 70.1 to 82.8) for patients who received gilteritinib and 69.9% (CI, 62.4 to 76.2) for those who received placebo. Of the 47 participants who relapsed in the placebo arm, 20 (42.6%) were treated with a FLT3 inhibitor (gilteritinib-13, quizartinib-4, sorafenib-3) following relapse.

Safety measurements concluded that treatment-emergent grade 2 to 4 acute graft-versus-host disease (GVHD) occurred in 33 of 178 (18.5%) patients on gilteritinib versus 36 of 177 (20.3%) patients on placebo (P = .6157). Treatment-emergent chronic GVHD occurred in 93 of 178 (52.2%) patients who received gilteritinib treatment versus 75 of 177 (42.4%) who received placebo (P = .181). Treatment-emergent adverse events ≥grade 3 occurred in 146 of 178 (82%) participants on gilteritinib compared with 94 of 177 (53.1%) on placebo. The study authors noted that both treatment-emergent myelosuppression and infection were more common in the gilteritinib arm compared with placebo, and myelosuppression was the most common reason for early withdrawal from study treatment.

“In summary, we found that post-HCT maintenance with gilteritinib does confer a benefit for patients with [FLT3]-ITD AML, but only for those with peri-HCT FLT3-ITD MRD,” the investigators concluded. “At the same time, we have validated the utility of FLT3-ITD mutations as useful markers of MRD with clear implications for intervention.”

“Post-transplant gilteritinib maintenance represents a significant therapeutic advance in patients allografted for FLT3-ITD AML who have evidence of peri-transplant MRD. MRD-negative patients derive no benefit from gilteritinib maintenance but instead may be exposed to unnecessary toxicity,” Journal of Clinical Oncology associate editor Charles Craddock, MD, PhD added.

Source:

Levis M, Hamadani M, Logan B, et al. Gilteritinib as post-transplant maintenance for acute myeloid leukemia with internal tandem duplication mutation of FLT3. JCO 0, JCO.23.02474. doi: 10.1200/JCO.23.02474