Phase III Data Support Use of Gilteritinib in Relapsed or Refractory FLT3-Mutated AML

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Treatment with gilteritinib, an oral type 1, FLT inhibitor, significantly improved overall survival compared with chemotherapy in patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML), according to the final results of the phase III ADMIRAL trial.1 The longest survival for patients receiving transplants after gilteritinib was seen among those who restarted gilteritinib as maintenance. There was a consistent trend of improved survival across the vast majority of subgroups treated. The treatment was reported to be tolerable and less toxic than chemotherapy.

The median overall survival was 9.3 months with gilteritinib vs 5.6 months with salvage chemotherapy (P = .007). Gilteritinib treatment almost doubled the percentage of patients who achieved complete remission or complete remission with partal hematologic recovery compared with salvage chemotherapy: 34% vs 15%. More patients treated with gilteritinib were able to go on to allogeneic stem cell transplant (the only possible curative treatment) than treated with salvage chemotherapy (26% vs 15%, respectively).

Gilteritinib is now approved by the U.S. Food and Drug Administration for the treatment of adults with relapsed or refractory FLT3-positive AML, based on response rates from an interim analysis of the ADMIRAL trial. The data presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR) represent the final analysis of the ADMIRAL trial, including the comparison between gilteritinib and chemotherapy.

Single-agent gilteritinib improved both response and survival in patients with FLT3-mutated relapsed or refractory AML. This represents a major change in how we approach patients in the relapsed or refractory setting.
— Alexander E. Perl, MD

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“Single-agent gilteritinib improved both response and survival in patients with FLT3-mutated relapsed or refractory AML. 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,” stated lead author Alexander E. Perl, MD, Associate Professor of Medicine at the University of Pennsylvania’s Abramson Cancer Center, Philadelphia.

“We have shown that an agent with less toxicity [ie, gilteritinib] can outperform the general fallback of using standard toxic chemotherapy, which requires an in-hospital stay. This is a practice-changing study, and we think these findings establish a new standard of care for this patient population,” Dr. Perl stated. “It is important to screen patients with AML for FLT3 mutations.”


About 70% of patients with AML achieve remission from induction chemotherapy, and between 40% and 70% will relapse; another 40% are refractory to induction chemotherapy. Relapsed or refractory AML is associated with a short survival and poor response to salvage chemotherapy. “After decades of study, there is still no standard regimen for relapsed or refractory AML,” said Dr. Perl.

About 30% of patients with AML have FLT3 mutations, including internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations. “This is a clinically aggressive phenotype, which confers an increased risk for relapse and poor survival. White blood cell counts can double in as few as 24 hours,” Dr. Perl added.

Gilteritinib is active against both FLT3-ITD and FLT3–TKD D835 mutations, the latter of which can emerge during therapy with other FLT3 inhibitors and confer drug resistance that leads to a short response duration. Early studies have shown it has single-agent activity and 120 mg/d was chosen as the starting dose for further lines of investigation in AML.

Overcoming Limitations of FLT3 Inhibitors

Gilteritinib is a novel oral type 1 FLT3 inhibitor that appears to overcome the shortcomings of other FLT3 inhibitors such as midostaurin, sorafenib, and quizartinib. Some of these other agents are multitargeted and therefore tend to have more off-target toxicities, such as nausea, diarrhea, and hand-foot syndrome.

“FLT3 is low-hanging fruit, but it has taken a long time to develop FLT3 inhibitors,” Dr. Perl said. “All currently available FLT3 inhibitors have limitations, including a relatively short response duration and development of on-target resistant mutations. Depending on the specific drug, the side effects of concern include hand-foot syndrome, myelosuppression, and QT prolongation. We wanted a potent FLT3 inhibitor with less toxicity. Gilteritinib seems to fulfill these criteria—improved tolerability, no cases of hand-foot syndrome, and limited prolongation of QT interval.”

Study Details

The ADMIRAL trial randomly assigned 371 adults with relapsed or refractory FLT3-positive AML in a 2:1 ratio to receive gilteritinib at 120 mg/d or salvage chemotherapy. Prior to randomization, the investigators selected the choice of up to two cycles of high-intensity chemotherapy (mitoxantrone, etoposide, and cytarabine [MEC] or fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor [FLAG-IDA]) or low-intensity chemotherapy (low-dose cytarabine or azacitidine), which was given until disease progression.

Patients who were in remission could go on to hematopoietic stem cell transplant; patients originally assigned to gilteritinib could go on to maintenance therapy with gilteritinib following recovery from transplant. No crossover was allowed. Patients enrolled in the trial could have had prior midostaurin or sorafenib.

Data From ADMIRAL Trial in AML

  • The FLT3-inhibitor gilteritinib significantly improved overall survival, overall response rates, and complete response rates compared with chemotherapy in patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML); all subgroups seemed to benefit.
  • Gilteritinib was associated with lower rates of toxicity than chemotherapy.
  • Many experts believe gilteritinib may represent a new standard of care for relapsed or refractory FLT3-mutated AML, and all patients with AML should be screened for this and other mutations.

Co-primary endpoints were overall survival as well as complete response and complete response with partial hematologic recovery. Although there were two primary endpoints, response was examined only in the gilteritinib arm and was used for regulatory submission only—it did not affect the study conduct. The study enrolled fully and was analyzed once a prespecified number of enrolled patients had met a survival endpoint (ie, data were analyzed only after 258 enrolled patients had died). The median age of patients was 62 years; about 54% were female; 73% had intermediate-risk disease; 88% had confirmed FLT3 mutations; about 82% had upfront chemotherapy; 12% had prior FLT3 tyrosine kinase inhibitor therapy; and 20% had undergone prior stem cell transplant.

“The duration of therapy was substantially longer in the gilteritinib arm vs chemotherapy: 11 months vs 1.8 months. More patients treated with gilteritinib went on to transplant: 26% vs 15%, respectively,” reported Dr. Perl.

Key Trial Findings

Overall survival was significantly longer with gilteritinib: median of 9.3 months vs 5.6 months, respectively (P = .0007). The 12-month overall survival rate was 37% vs 17%, respectively.

“Subgroup analysis showed a general trend for improved outcomes in nearly all subtypes. Drilling down into the data, at least as much benefit was observed with gilteritinib in females as in males, which is not seen with all FLT3 inhibitors. Prior FLT3 inhibitor treatment also favored gilteritinib, but with a wide confidence interval because of the small number of patients,” Dr. Perl continued. “The drug also appears to be active in patients with FLT3-TKD mutations, but again, there were small numbers of patients.”

“The survival benefit of gilteritinib appeared to be predominantly attributable to better outcomes among relapsed, rather than refractory, patients, but again, we have to be cautious about interpretation because of the small sample sizes of various subsets,” added Dr. Perl. “The relative contribution of transplant to gilteritinib’s advantages over chemotherapy seems to be small. The survival of transplant recipients who restarted gilteritinib was superior to those who did not receive posttransplant gilteritinib.”


Gilteritinib was reported to be tolerable, with relatively few toxicities that required in-patient 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, toxicity was higher 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,” he said. 

DISCLOSURE: The ADMIRAL trial was funded by Astellas. Dr. Perl has received honoraria from AbbVie, Actinium Pharmaceuticals, Agios, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, NewLink Genetics, and Takeda; consulting fees from Astellas, Daiichi Sankyo, Arog Pharmaceuticals, and AbbVie; and institutional funding from Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, Daiichi Sankyo, Fujifilm Pharmaceuticals, and Novartis.


1. Perl AE, Martinelli G, Cortes JE, et al: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia: Results from the phase III ADMIRAL trial. 2019 AACR Annual Meeting. Abstract CT184. Presented April 2, 2019.

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