Clinical Challenges: FLT3 Inhibitors After Allo-Transplant in AML

Relapse after allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) is an extremely risky clinical setting, and physicians are eager to prevent it. As new research comes in, hematologists say FLT3 inhibitors appear to provide some benefit for the right patients.

“We think that providing additional anti-leukemia therapy after a transplant will reduce the risk of relapse, particularly during the early post-transplant period when a graft-versus-leukemia effect may not yet be present,” Andrew Brunner, MD, of Massachusetts General Hospital in Boston, told MedPage Today. “These targeted drugs can be helpful in preventing relapse, and most of the time we can find a dose that is tolerable for 1 to 2 years after the transplant.”

An estimated 40% of patients with AML relapse after undergoing allogeneic HCT. “Relapse generally results from residual malignant cells that survived the conditioning regimen and are not eliminated by the graft-versus-leukemia effect,” said Amany Keruakous, MD, MS, of Augusta University in Georgia, in an interview. “The median time to relapse after HCT is approximately 7 months, with most relapses occurring within 2 years. The outcomes are dismal, with only 15% of patients achieving a subsequent complete hematologic remission, and only 4% of patients who relapsed within 6 months being alive at 3 years post-HCT.”

For maintenance in this population, several specialists recommended the use of FLT3 inhibitors in appropriate patients. “There are an increasing number of highly effective FLT3 inhibitors out there, and most patients can find one that is tolerable and can be continued in the maintenance setting,” Keruakous said. “We are waiting on further data, but so far we do have some randomized data suggesting these drugs reduce the risk of relapse after a transplant.”

FLT3 inhibitors “should be recommended in FLT3-positive AML patients except for patients with active, acute graft-versus-host disease,” she said. “Maintenance should be initiated as soon as possible after disease evaluation, provided adequate hematologic reconstitution.”

Sorafenib (Nexavar), a multitargeted tyrosine kinase inhibitor (TKI) that also inhibits FLT3, and the FLT3 inhibitor midostaurin (Rydapt) “have the most robust evidence thus far despite variability in clinical trials’ results and inclusion criteria, limited data by small sample size, and decreased accrual,” Keruakous said. “There is a noticeable trend that FLT3 inhibitors after HCT play a role in disease control and improve the patient’s outcomes compared to the historical trends.”

In the SORMAIN trial, published in 2020, researchers randomly assigned 83 adults with FLT3 internal tandem duplication (ITD)-positive AML to 2 years of sorafenib or placebo after HCT. At 2 years, those on sorafenib saw improved relapse-free survival compared to those assigned placebo (85.0% vs 53.3%, respectively; P=0.002) as well as better overall survival (90.5% vs 66.2%; P=0.007). The greatest benefit with the TKI appeared to be in patients with undetectable minimal residual disease (MRD) prior to HCT as well as those with detectable MRD after HCT, the researchers noted.

As for midostaurin, the phase II RADIUS trial randomized 60 patients with FLT3-ITD-positive AML to receive the drug for 12 months or to standard of care following HCT. At 18 months, relapse-free survival was 89% in the midostaurin arm and 76% in the control arm (HR 0.46, 95% CI 0.12-1.86, P=0.27). While not a significant difference, the study authors concluded that midostaurin “may be a viable option to reduce the risk of relapse in some patients.”

What’s the best way to decide which drug is appropriate? “Consider the type of FLT3 mutation that your patient has and whether the drug you choose will sufficiently inhibit it,” recommended Amir Fathi, MD, also of Massachusetts General Hospital, in an interview. “Sorafenib, for example, is not very effective against the TKB variant of FLT3.”

For her part, Keruakous said “sorafenib could be considered the preferred option in the absence of other clinical trials. The recommended sorafenib dose for maintenance in MRD patients is 200 mg BID and should be transiently discontinued if graft-versus-host disease requires systemic treatment. The recommended midostaurin dose is 50 mg BID. Maintenance duration is not established, but a minimum of 2 years is recommended, depending on tolerance.”

The drugs can cause myelosuppression, hand-foot syndrome, rash, nausea, diarrhea, and cardiac toxicities, Keruakous said. “Keep in mind that both FLT3 inhibitors have potential drug interactions, especially with immunosuppressants, that might need a dose adjustment. Additionally, they both cause QT-prolongation and require close monitoring of EKGs.”

Cost can also be a challenge. Neither sorafenib nor midostaurin is FDA approved for maintenance in AML after HCT. “These are quite expensive agents that could be around $9,000 for a month supply,” Keruakous said. “But generally, these agents are approved by insurers. If not, there are coupons and patient assistance programs that help our patients.”