NEJM Data Highlight Gilteritinib Survival Benefit in FLT3+ AML

Gilteritinib demonstrated a higher remission rate and a statistically significant improvement in overall survival compared with salvage chemotherapy in patients with relapsed/refractory acute myeloid leukemia who harbor a FLT3 mutation.

Alexander Perl, MD

Gilteritinib (Xospata) demonstrated a higher remission rate and a statistically significant improvement in overall survival (OS) compared with salvage chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML) who harbor a FLT3 mutation, according to findings from the phase III ADMIRAL trial that have now been published in the New England Journal of Medicine (NEJM).1

Additional data that were published in NEJM also showcased a median event-free survival (EFS) of 2.8 months in the gilteritinib arm compared with 0.7 months in the chemotherapy group (HR, 0.79; 95% CI, 0.58-1.09), which was not found to be a significant difference. Moreover, complete remission (CR) with either full or partial (CRh) hematologic recovery was 34.0% and 15.3% with gilteritinib and chemotherapy, respectively (risk difference, 18.6 percentage points; 95% CI, 9.8-27.4). The CR rates were 21.1% versus 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8-18.4).

Furthermore, in an analysis that was adjusted for therapy duration, grade ≥3 adverse events (AEs) and serious AEs were less frequent in the gilteritinib arm than in those who received chemotherapy. The most common grade ≥3 AEs with gilteritinib included febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

“These data show that in a very high-risk leukemia population, single-agent FLT3-targeted therapy leads to superior clinical outcomes compared to salvage chemotherapy,” principal investigator Alexander Perl, MD, associate professor of Hematology Oncology in the Abramson Cancer Center at the University of Pennsylvania, stated in a press release.2 “This is an important result for patients who previously had quite limited treatment options.”

Gilteritinib was initially approved by the FDA in this setting in November 2018; the decision was based on an interim analysis of data from the ADMIRAL trial, which included CR/CRh, duration of CR/CRh, and rate of conversion from transfusion dependence to transfusion independence.3

In May 2019, the FDA approved a supplemental new drug application to update the label for gilteritinib to include final analysis data from the ADMIRAL, which demonstrated an improvement in OS with the FLT3 inhibitor versus salvage chemotherapy in adult patients with relapsed/refractory FLT3-mutant AML.4 At a median follow-up for OS of 17.8 months, the median OS in patients who were treated with gilteritinib was 9.3 months (95% CI, 7.7-10.7) compared with 5.6 months (95% CI, 4.7-7.3) in those who received salvage chemotherapy. This translated to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.49-0.83; two-sided P <.001), which was reported in the NEJM article.

In the international, phase III ADMIRAL study, 371 adult patients with FLT3-mutant relapsed/refractory AML were randomized 2:1 to receive gilteritinib at 120 mg daily (n = 247) or salvage chemotherapy (n = 124). Patients in both arms then underwent hematopoietic stem cell transplantation (HSCT), but only patients in the gilteritinib arm then resumed treatment with the FLT3 inhibitor; crossover was not permitted. Additionally, salvage chemotherapy was selected prior to randomization and could be one of the following regimens: mitoxantrone, etoposide, and cytarabine; fludarabine, cytarabine, idarubicin, and G-CSF; low-dose cytarabine; and azacitidine.

To be eligible for enrollment, patients with AML must have also harbored a FLT3-ITD or FLT3-TKD mutation, a mean of triplicate Fridericia-corrected QT interval <450 milliseconds at screening based on central reading, and be refractory to induction chemotherapy or in untreated first relapse.

Baseline characteristics were comparable between arms. Overall, the median age was 62 (range, 19-85) and 54% of patients were female. The majority of patients had intermediate-risk cytogenetics (73%) and 88% of patients had FLT3-ITD mutations. Additionally, 20% of patients had underwent prior HSCT, and 82% had received upfront intensive chemotherapy. Thirty-nine percent of patients had primary refractory AML without HSCT and 27% relapsed ≤6 months after composite complete remission (CRc). The most common co-mutated genes were NPM1 (46.6%) and DNMT3A (31.0%).

The coprimary endpoints were OS and CR/CRh rate; secondary endpoints were EFS, CR rate, leukemia-free survival, duration of remission, CRc rate, transplantation rate, brief fatigue inventory, CRh rate, transfusion conversion rate, and transfusion maintenance rate.

The survival benefit with gilteritinib was observed across multiple subgroups, including cohorts of patients who received high- (HR, 0.66; 95% CI, 0.47-0.93) and low-intensity chemotherapy (HR, 0.56; 95% CI, 0.38-0.84). Patients in the high FLT3-ITD allelic ratio subgroup had a median OS of 7.1 months on gilteritinib and 4.3 months on chemotherapy (HR, 0.49; 95% CI, 0.34-0.71). In those who had primary refractory AML, the median OS was 10.4 months and 6.9 months, respectively (HR, 0.99; 95% CI, 0.63-1.55).

A total 25.5% of patients on gilteritinib compared with 15.3% on chemotherapy underwent transplant; however, the OS advantage for the FLT3 inhibitor was maintained when survival data were censored at the time of transplant (HR, 0.58; 95% CI, 0.43-0.76).

The authors noted that because the CRc rate was 4% in patients who had low-intensity chemotherapy, the EFS in the chemotherapy group was largely derived from those who received high-intensity chemotherapy. Additionally, because relapse events were defined on the basis of central review of bone marrow biopsy specimens, most patients who responded to high-intensity chemotherapy and entered long-term follow-up had data censored for EFS at 1 to 2 months following randomization; this limited the efficacy of the protocol-defined EFS analysis. Therefore, the investigators performed a prespecified sensitivity analysis of EFS that included investigator-reported events during the long-term follow-up period, which included the initiation of new antileukemic therapy. These results showed an EFS of 2.3 months with gilteritinib and 0.7 months with chemotherapy (HR, 0.50; 95% CI, 0.39-0.64).

Although it could not be evaluated in the chemotherapy arm due to censoring, the median duration of CR with full or partial hematologic recovery was 11.0 months with gilteritinib. Following an increase in dosing for gilteritinib to 200 mg (n = 78), the CR rate was 9.0%; in those who decreased their dose to 80 mg (n = 58) , the CR rate was 24.1%.

When excluding remissions that occurred following transplant on ADMIRAL, the percentage of CR with full or partial hematologic recovery rate was 26.3% with gilteritinib group and 15.3% with chemotherapy (risk difference, 10.9 percentage points; 95% CI, 2.4-19.5). In patients with primary refractory AML, the percentage of patients who had CR with full or partial hematologic recovery was 32% in the gilteritinib group and 21% in those who received chemotherapy.

A total 79.8% of patients on gilteritinib were transfusion-dependent at randomization, and 34.5% of these patients became transfusion-independent.

Regarding safety, according to the NEJM article, the median duration of gilteritinib and chemotherapy exposure was 18 weeks. The most common serious AEs that were potentially related to gilteritinib were febrile neutropenia (9.3%), increase in alanine aminotransferase level (ALT; 4.5%), and increase in the aspartate aminotransferase level (AST; 4.1%). Treatment-related AEs leading to discontinuation of gilteritinib occurred in 11.0% of patients; the most common events were elevated AST (1.6%), elevated ALT (1.2%), and pneumonia (1.2%).

Of 355 patients in the safety population, there were 170 (69.1%) deaths with gilteritinib and 81 (74.3%) in the chemotherapy arm. In the intent-to-treat population, the 30- and 60-day mortality rate with gilteritinib was 2.0% and 7.7%, respectively, and 10.2% and 19.0% with chemotherapy, respectively. The most common fatal AEs that were considered to be treatment related in the gilteritinib arm were pneumonia (1.2%), large intestine perforation (0.8%), and septic shock (0.8%); the most common fatal AEs with chemotherapy were sepsis (1.8%) and respiratory failure (1.8%).

“The detailed findings from our phase III ADMIRAL trial further validate that Xospata is a significant addition to the treatments available for people with FLT3 mutation—positive relapsed or refractory AML,” Andrew Krivoshik, MD, PhD, senior vice president and Oncology Therapeutic Area Head at Astellas, the developer of gilteritinib, stated in the press release. “We are especially pleased to see the results published in the New England Journal of Medicine, which is widely regarded as one of the most prestigious scientific medical journals.”


  1. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Eng J Med. 2019;381:1728-1740. doi: DOI: 10.1056/NEJMoa1902688.
  2. New England Journal of Medicine Publishes Results from Astellas’ Phase 3 ADMIRAL Trial of XOSPATA® (gilteritinib) in Adult Patients with FLT3 Mutation Positive Relapsed/Refractory Acute Myeloid Leukemia. Astellas Pharma. Published October 31, 2019. Accessed November 1, 2019.
  3. FDA Prescribing Information: XOSPATA® (gilteritinib) tablets, for oral use. Accessed November 28, 2018.
  4. U.S. FDA Approves Supplemental New Drug Application Adding Overall Survival Data for XOSPATA® (gilteritinib). Astellas Pharma. Published May 30, 2019. Accessed May 30, 2019.