Gilteritinib as post-HCT maintenance for FLT3-ITD AML: Yay or nay?

The BMT CTN* 1506 (MORPHO) trial narrowly missed its primary outcome, but it did show that the potent oral FLT3 inhibitor gilteritinib conferred benefit for a subset of individuals with FLT3-ITD** acute myeloid leukaemia (AML).

“[Our study failed to] achieve its primary endpoint of relapse-free survival (RFS) at the primary analysis, but gilteritinib appeared to have a clear benefit for 50 percent of patients with detectable MRD*** pre- or post HCT^# compared with those without detectable MRD,” said Dr Mark Levis from Johns Hopkins University School of Medicine, Baltimore, Maryland, US, at EHA 2023.

The hazard ratio (HR) for RFS was 0.679, with a two-sided p-value of 0.0518. “This did not meet the study’s primary or prespecified level of statistical significance of 0.05,” said Levis.

“[On subgroup analysis,] we would have predicted that gilteritinib would not be associated with benefit but in fact, it was,” Levis continued. The effect of gilteritinib was more pronounced among those with MRD 10^-6 detectable at pre- or post-HCT (HR, 0.515; p=0.0065) than those without (HR, 1.213; p=0.575). “This means that if you have MRD, you benefit from gilteritinib, as it improved MRD eradication for patients with detectable MRD. If you do not have MRD, the benefit is unclear.”

 

RFS by region

There was also greater separation of survival curves between arms in North American patients (HR, 0.397; p=0.0022) compared with those from Europe (HR, 1.424; p=0.3537) and Asia (HR, 0.807; p=0.5801). [EHA 2023, abstract LB2711]

“The curves for the three different regions looked strikingly different. In North America, it looked exactly as we would have predicted, but we were surprised seeing Europe and Asia showing no clear benefit,” explained Levis.

Regional differences could have driven the divergent results and confounded any potential benefit, he noted. In North America, patients went to transplant sooner, had more chemo pre-transplant, and were more likely to be on FLT3 inhibitor pre-HCT. Whereas in Asia-Pacific, patients were 10 years younger, tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.

Other regional differences to be taken into context were the number of prior treatment cycles, time to transplant, and azole use. “There were clear practice patterns that were becoming evident amongst the different regions,” he said. “We are going to be looking at [these differences] very closely … to try to explain this better, but this was a rather fascinating finding.”

 

Safety, tolerability

The incidences of treatment-emergent acute GVHD^## (grade II–IV) were similar between the gilteritinib and placebo arms (18 percent vs 20 percent), but there was a modest increase in chronic GVHD with the former vs the latter (52 percent vs 42 percent).

The most common drug-related grade ≥3 treatment-emergent AEs with gilteritinib vs placebo were reductions in neutrophil (25 percent vs 8 percent) and platelet counts (15 percent vs 6 percent), as well as anaemia (6 percent vs 2 percent).

There were higher rates of drug interruption (18 percent vs 7 percent) and treatment withdrawal (15 percent vs 8 percent) with gilteritinib vs placebo.

 

High relapse risk

Patients with FLT3-ITD AML have a high risk of relapse, especially if they have MRD prior to transplant. “Having MRD is bad,” Levis stressed. “The detection of MRD pre-transplant is highly predictive of the outcome post-transplant.”

FLT3 inhibitors are mostly administered as post-HCT maintenance to reduce risk of relapse, but this is based on sorafenib trials that included patients salvaged with FLT3 inhibitors pre-transplant. “Uncertainly exists regarding the broad applicability of these results,” Levis pointed out.

To determine the potential of gilteritinib as post-HCT maintenance, Levis and team randomized 356 participants to gilteritinib 120 mg daily or placebo, who were followed for 24 months. About 40 percent of participants were from North America, a quarter from Europe, and a third from Asia-Pacific. Sixty percent of participants had FLT3 inhibitor use pre-HCT.

In sum, the findings underline the correlation between MRD and survival in post-HCT therapy in this subset of AML patients.

“[While] the study did not meet its primary endpoint … I think this was a successful study. We learned how to use this drug and in whom and, in fact, it fit with the pretest hypothesis,” Levis concluded. “[Gilterinib] should be standard of care for FLT3-ITD AML patients who are MRD-positive pre- or post-HCT.”

“The decision to use this drug in any patient should be balanced against the potential for toxicity,” Levis added.