Gilteritinib a New Standard of Care for Relapsed or Refractory AML with FLT3 Mutation

Treatment with gilteritinib (Xospata) significantly improved overall survival (OS) with less toxicity compared with chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) and FLT3 mutation, according to the final results of ADMIRAL, a phase 3 clinical trial presented at the 2019 American Association for Cancer Research meeting.

Patients who received treatment with gilteritinib had improved survival in all subgroups, including those who had a transplant and received gilteritinib as maintenance therapy, said lead investigator Alexander E. Perl, MD, MS, Associate Professor of Medicine, Leukemia Program, Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, who presented the results.

In November 2018, the FDA approved gilteritinib for the treatment of patients with relapsed or refractory AML and FLT3 mutation, based on the results of this study. The median OS was 9.3 months with gilteritinib versus 5.6 months with salvage chemotherapy (P = .007). The rate of complete remission or complete remission with hematologic recovery was 34% with gilteritinib versus 15% with salvage chemotherapy. A much larger percentage of patients in the gilteritinib group continued to allogeneic stem-cell transplant (SCT) versus those who received salvage chemotherapy—26% versus 15%, respectively.

“We have shown that an agent with less toxicity can outperform the general fallback of using standard toxic chemotherapy that requires in-hospital stay. This represents a major change in how we approach patients in the relapsed or refractory setting, because now we are using molecularly targeted therapies in selected patients who can benefit from this approach,” Dr Perl said. “This is a practice-changing study, and we think these findings establish a new standard of care for this patient population,” he added.

Approximately 30% of patients with AML have FLT3 mutations, including internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations.

FLT3-mutated AML is a clinically aggressive phenotype, which confers increased risk for relapse and poor survival. White blood cell counts can double in as few as 24 hours,” Dr Perl told attendees.

“All three currently available FLT3 inhibitors have limitations, including relatively short response duration and development of on-target resistant mutations. Side effects of concern, depending on the specific drug, include hand-foot syndrome, myelosuppression, and QT prolongation. We need an FLT3 inhibitor with less toxicity,” Dr Perl said. “Gilteritinib seems to fulfill these criteria—improved tolerability, no cases of hand-foot syndrome, and limited prolongation of QT interval,” he added.

The phase 3 ADMIRAL study randomized 371 adults with relapsed or refractory FLT3-positive AML in a 2:1 ratio to gilteritinib 120 mg daily or to 2 cycles of salvage chemotherapy (predetermined choice) given until disease progression.

Patients in remission could go on to SCT; patients originally assigned to gilteritinib could go on to maintenance therapy with gilteritinib after recovery from transplant. No crossover was allowed. Previous treatment with the FLT3 inhibitor midostaurin (Rydapt) or with sorafenib (Nexavar) chemotherapy was allowed.

The median age was 62 years; approximately 54% of patients were female; 73% had intermediate risk; 88% had confirmed FLT3 mutations; approximately 82% had received first-line chemotherapy; 12% received previous FLT3 inhibitor tyrosine kinase inhibitor therapy; and 20% had undergone a transplant.

Gilteritinib was reasonably well-tolerated, with relatively few toxicities that required inpatient management. The most frequent treatment-emergent adverse events during the first 30 days of treatment were anemia, increased liver enzymes, and febrile neutropenia. In general, more adverse events were reported with chemotherapy during the first 30 days.

“When looking at safety, keep in mind that the drug exposure to gilteritinib was four times longer than with chemotherapy,” Dr Perl said.

Important New Therapy

Commenting on this study, discussant Tapan M. Kadia, MD, Associate Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, said, “These data suggest that gilteritinib is an important addition to our armamentarium. Remaining questions are how to view these results in an era of front-line FTL3 inhibitor therapy. Most patients will now have prior exposure to FLT3 inhibitors, but in ADMIRAL, only a small subset had prior FLT3 exposure, and the survival benefit is less clear in that subset of patients. It remains to be seen how these results will translate, and there may be a need for combination therapy.”

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