Gilteritinib and chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial

Key Points

• •The SKIPPER trial found that pediatric patients with FLT3-ITD AML responded well to gilteritinib + FLAG, with a manageable safety profile.
• •Although sample size was small due to recruitment challenges, data support further evaluation of gilteritinib in pediatric FLT3-ITD AML.

Visual Abstract

Abstract

Fms-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) occurs in ∼15% of pediatric patients with acute myeloid leukemia (AML) and is associated with a high relapse risk with conventional chemotherapy. Gilteritinib is a selective, next-generation FLT3 inhibitor (FLT3i) approved for adults with relapsed/refractory FLT3–mutated AML, but pediatric-specific data remain limited. The multinational phase 1/2 SKIPPER study evaluated gilteritinib combined with fludarabine and cytarabine chemotherapy and granulocyte colony-stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3-ITD AML. Nine patients, aged 8 to 15 years, were enrolled in phase 1 of the study between 2020 and 2023. Recruitment challenges, including disease rarity, off-label FLT3i availability, and competing trials, led to study termination after phase 1. The composite complete remission rate in the study population was 66.7% (95% confidence interval, 29.9-92.5). The 2-year event-free and overall survival probabilities were 41.7% and 55.6%, respectively. Treatment-emergent adverse events, most commonly reversible hepatic enzyme elevations and cytopenias, were consistent with known toxicity profiles of gilteritinib and FLAG. Pharmacokinetic parameters were comparable to those of adults, and pharmacodynamic plasma inhibitory activity assays confirmed sustained FLT3 inhibition. No dose-limiting toxicities were observed, and the recommended phase 2 dose of gilteritinib was established at 2 mg/kg per day for patients aged ≥2 years. The gilteritinib and FLAG regimen had manageable safety, induced high remission rates, and enabled allogeneic hematopoietic stem cell transplant for several patients. Although limited by a small sample size, these findings support further evaluation of gilteritinib in pediatric patients with FLT3-mutated AML, particularly in frontline settings. This trial was registered at www.ClinicalTrials.gov as NCT04240002.

Introduction

Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children and adolescents/young adults, accounting for ∼20% of all pediatric acute leukemia cases.^1,2 Despite improvements in survival outcomes for children with newly diagnosed AML over the past decade with current overall survival (OS) rates of 65% to 70%, the long-term prognosis of patients with relapsed/refractory disease remains poor due to suboptimal response to most salvage therapies.^3,4

AML is a genetically heterogeneous malignancy driven by numerous cytomolecular fusions and mutations.^5,6 Internal tandem duplication (ITD) within the juxtamembrane domain of the fms-like tyrosine kinase 3 (FLT3) gene occurs in ∼25% of adults and 15% of children with AML and are associated with high rates of relapse in patients treated with conventional chemotherapy.^2,7

The prognostic impact of FLT3-ITD within pediatric AML depends on accompanying genetic alterations, including oncogenic fusions (eg, NUP98::NSD1) and molecular alterations (eg, WT1 or NPM1 mutations).^8,9 Pediatric patients with AML harboring FLT3-ITD mutations without favorable co-occurring molecular alterations (eg, NPM1 mutations) are high risk due to historically poor outcomes with conventional multiagent chemotherapy alone.^2,10 These patients typically proceed to allogeneic hematopoietic stem cell transplant (HSCT), ideally performed in a measurable residual disease (MRD)-negative first complete remission (CR), following induction and/or consolidation/intensification chemotherapy.^2,11,12

Various FLT3 inhibitor (FLT3i) drugs, administered as monotherapy or in combination with chemotherapy, have induced high rates of remission in adult patients with relapsed or newly diagnosed FLT3-mutated AML.13, 14, 15, 16, 17, 18, 19 The selective, second-generation FLT3i gilteritinib is approved in >60 countries and regions, including the United States and European Union, for treatment of adult patients with relapsed/refractory FLT3-mutated AML,^20,21 but it is not licensed for children. Midostaurin monotherapy and quizartinib plus chemotherapy have shown promising response rates in children with relapsed/refractory FLT3-ITD AML,^22,23 and the addition of sorafenib to chemotherapy for pediatric patients with newly diagnosed FLT3-ITD AML markedly improved outcomes in the recent Children’s Oncology Group (COG) AAML1031 clinical trial compared with historic data with chemotherapy alone.²⁴ Based on these promising results, the COG AAML1831 clinical trial is currently evaluating the addition of gilteritinib to chemotherapy for the treatment of pediatric patients with newly diagnosed AML harboring FLT3-ITD or FLT3 tyrosine kinase domain mutations (ClinicalTrials.gov identifier: NCT04293562).^25,26

The phase 1/2 SKIPPER study aimed to examine the safety and clinical activity of gilteritinib in combination with fludarabine and cytarabine chemotherapy and granulocyte colony–stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3-ITD AML.

Materials and methods

Ethics

This study was conducted in accordance with ethical principles derived from international guidelines, including the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and other applicable laws and regulations. The protocol and any amendments were reviewed and approved by institutional review boards and/or independent ethics committees before study initiation. Written informed consent was provided by each patient or their parents/legal parent/guardian before the initiation of any study-related procedures.

Study design

SKIPPER (ClinicalTrials.gov identifier: NCT04240002) was a multinational, open-label, single-arm, phase 1/2 dose escalation and expansion study (supplemental Figure 1). In phase 1, a starting gilteritinib dose of 2 mg/kg per day (maximum of 120 mg; dose level 1) was selected for patients aged ≥2 years based on physiologically based pharmacokinetic (PK) modeling predicting drug exposures similar to those in adults (Astellas, unpublished data, 2025). Patients aged <2 years were planned to receive gilteritinib at 1 mg/kg per day (dose level 1) due to theoretical concerns about potential drug toxicities.

Eligibility criteria

Eligible patients were aged from 6 months to <21 years and had FLT3-ITD AML refractory to frontline induction therapy or in first hematologic relapse, assessed by the principal investigator in accordance with recent studies.³ Patients who did not attain CR after 2 courses of remission induction chemotherapy were considered to have refractory disease and were eligible for the study. Previous FLT3i therapy was allowed. All patients must have recovered from acute toxic effects of previous therapy. If relevant, ≥90 days must have elapsed from the previous HSCT, and patients with previous transplants were required to be free of graft-versus-host disease before chemotherapy initiation on the SKIPPER study.

Patients with active central nervous system leukemia, uncontrolled or significant cardiovascular disease, and/or an active malignant tumor other than AML were excluded. Concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol, as well as coadministration of strong inducers of cytochrome P450 3A/P-gp medications, were not allowed.

Study end points

The primary end point for the phase 1 component was determination of the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) of gilteritinib in combination with FLAG. The primary end points for the phase 2 component were CR and composite CR (CRc) rates after 2 treatment cycles.

Secondary study end points included pharmacodynamic (PD) inhibition of phosphorylated FLT3 (pFLT3) measured by plasma inhibitory activity (PIA) assays, gilteritinib plasma concentration, PK parameters of gilteritinib, safety, tolerability, and toxicity of gilteritinib in combination with FLAG, event-free survival (EFS) rate, OS rate, and molecular MRD response. MRD negativity was defined as FLT3-ITD to total FLT3 sequencing reads of <10⁻⁴. Safety analyses included all patients who received ≥1 dose of the treatment regimen. These analyses consisted of data summaries of adverse events, dose-limiting toxicities (DLTs), and other safety parameters.

PDs

PIA assays were conducted to determine pFLT3 inhibition relative to baseline FLT3 levels using methods previously described.^27,28 Inhibition of pFLT3 protein in ≥7 out of 9 treated subjects was considered necessary to identify the biologic activity of gilteritinib at each tested dose.²⁹

Statistical analyses

Efficacy analyses (CRc, CR, OS, and EFS) and PIA assay data were summarized using descriptive statistics. Survival curves and medians for time-to-event variables, as well as EFS and OS rates, were estimated using the Kaplan-Meier method and were reported with corresponding 95% confidence intervals (CI).

Results

Patient baseline characteristics and treatment exposure

Between 4 September 2020 and 6 July 2023, 9 children or adolescents/young adults with relapsed/refractory FLT3-ITD AML were enrolled in phase 1 of the study at 6 of 25 initiated centers in Europe, the United Kingdom, or the United States (Table 1). Due to a slower-than-anticipated rate of patient accrual, attributed to the general rarity of relapsed/refractory FLT3-ITD AML in children and the off-label pediatric use of FLT3i in some countries, the trial was terminated early before phase 2. Notably, this study closure was not related to any safety or efficacy issues.

Table 1.

Patient characteristics and previous therapy history of SKIPPER study subjects

	Patients (N = 9)
Age, median (range), y	13 (8-15)
Male, n (%)	6 (66.7)
White, n (%)	9 (100)
Previous lines of treatment, n (%)
1	7 (77.8)
2	1 (11.1)
3	1 (11.1)
Previous FLT3i exposure, n (%)
Gilteritinib	1 (11.1)
Midostaurin	2 (22.2)
Sorafenib	5 (55.6)
Relapsed/refractory status, n (%)
Relapsed	3 (33.3)
Refractory	6 (66.7)
Previous allogeneic HSCT, n (%)∗	2 (22.2)
Gilteritinib/FLAG cycles, n (%)
Cycle 1 only	6 (66.7)
Cycles 1 and 2	3 (33.3)
DLT evaluable, n (%)†	8 (88.9)

^∗Further details are provided in supplemental Table 1.

^†One patient was not evaluable for DLT due to an FLT3-ITD refractory ETP-ALL diagnosis during the study period: at enrollment, the patient was diagnosed at the referring center with FLT3-ITD refractory AML and met eligibility criteria based on local pathology. After treatment initiation, central laboratory testing indicated findings more consistent with ETP-ALL; this represented reclassification based on central review, not lineage switch during therapy.

The median (range) age of phase 1 patients was 13 years (8-15), all patients were White (100%), and most were male (66.7%). No patients were enrolled in the cohort aged <2 years, consistent with the epidemiology of FLT3-ITD AML.

Three patients (33.3%) were in relapse and 6 patients (66.7%) had refractory disease. Eight patients (88.9%) had received previous FLT3i (gilteritinib, n = 1; midostaurin, n = 2; sorafenib, n = 5) in earlier lines of therapy. Two patients (22.2%) had undergone prior allogeneic HSCT at 41.1 months and 21.4 months from initial diagnosis, respectively, before study enrollment (supplemental Table 1).

Four patients (44.4%) discontinued SKIPPER study treatment due to progressive disease. One patient (11.1%) with an initial refractory FLT3-ITD AML diagnosis was ultimately deemed inevaluable for DLT assessment due to a revised FLT3-ITD early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) diagnosis after treatment initiation, which represented reclassification based on central review and not lineage switch during therapy.

Six patients (66.7%) received 1 cycle and 3 patients (33.3%) received 2 cycles of gilteritinib and FLAG. Three of the 9 patients also received gilteritinib monotherapy maintenance treatment after on-study chemotherapy completion and/or allogeneic HSCT. Two patients (22.2%) completed the protocol-defined duration of maintenance therapy (24 cycles of 28 days per cycle of gilteritinib monotherapy after gilteritinib/FLAG cycle 2 completion or after HSCT), whereas 1 patient (11.1%) discontinued after 18 days of maintenance due to increased alanine aminotransferase (ALT) serum levels.

Efficacy

Three of 9 patients (33.3%) had the best overall response (BOR) of CR, and an additional 3 patients (33.3%) achieved CR with incomplete hematologic recovery (CRi), including the patient with FLT3-ITD ETP-ALL (Table 2; Figure 1). The CRc rate was estimated at 66.7% (95% CI, 29.9-92.5). The median duration of CR was not estimable, with observed durations ranging from 55 to 849 days.

Table 2.

BOR of pediatric patients treated with gilteritinib and FLAG on the SKIPPER study

BOR	Patients (n = 9)
CR	3 (33.3)
CRi	3 (33.3)
Treatment failure	3 (33.3)

The number and percentage of patients are shown (n [%]). Percentages may not sum to 100%.

Figure 1.

Swimmer plot of pediatric patients treated with gilteritinib and FLAG in the SKIPPER study. More detailed data for the complete study period (upper panel) are depicted through day 400 in the lower panel. For patients who did not achieve remission during induction, the event date for treatment failure is the enrollment date (day 0). ^aAt enrollment, 1 patient was diagnosed with FLT3-ITD refractory AML at the referring center and met study eligibility criteria based on local pathology. After treatment initiation, central laboratory testing indicated a diagnosis of ETP-ALL, which represented reclassification based on central review, not lineage switch during therapy. NR, no response.

EFS and OS

The estimated 2-year EFS and OS probabilities were 41.7% (95% CI, 10.9-70.8) and 55.6% (95% CI, 20.4-80.5), respectively (Table 3). EFS and OS for individual patients are presented in Figure 1.

Table 3.

Outcomes of pediatric patients treated with gilteritinib and FLAG in the SKIPPER study

	Patients (n = 9)
EFS
Events, n (%)	5 (55.6)
Relapse	2 (22.2)
Treatment failure	3 (33.3)
Death	0
Censored, n (%)∗	4 (44.4)
Duration of EFS, median (range), d†	123 (1-908)‡
EFS rate at 2 y, % (95% CI)§	41.7 (10.9-70.8)
OS
Death, n (%)	4 (44.4)‖
Censored, n (%)¶	5 (55.6)
Duration of OS, median (range), mo∗	NE (4.8-45.0)‡
OS rate at 2 y, % (95% CI)†	55.6 (20.4-80.5)

NE, not estimable.

^∗EFS was defined as the time from the date of enrollment until the date of documented relapse (excluding relapse after partial response), treatment failure, or death from any cause, whichever occurred first. For a patient who was not known to have had a relapse, treatment failure, or death event, EFS was censored, and the event date was the date of the last relapse-free disease assessment. Patients were not censored at HSCT.

^†Based on Kaplan-Meier estimate.

^‡The upper end of the range was determined by a patient censored at the last follow-up.

^§EFS and OS rates and 95% CIs were estimated using the Kaplan-Meier method and Greenwood formula.

^‖Causes of death: progressive deterioration of the neurological picture and cardiovascular function (n = 1); acute respiratory distress syndrome (n = 1); progression of disease (n = 2).

^¶OS was defined as the time from the date of enrollment until the date of death from any cause. For a patient who was not known to have died by the end of study follow-up, OS was censored at the date of last contact.

MRD status and rates of subsequent HSCT

Five of the study patients achieved CRc, 4 of whom (80.0%) had molecular MRD negativity at ≥1 postbaseline time point. BOR among this cohort was CR (n = 3) or CRi (n = 1). The other patient with CRc and MRD positivity achieved a BOR of CRi. A sixth patient achieved CRc as BOR, but experienced subsequent rapid relapse and was ultimately classified by the investigator as a nonresponder. The patient with FLT3-ITD ETP-ALL did not achieve MRD negativity and had only 1 postbaseline MRD time point assessed.

Four of 9 patients (44.4% [95% CI, 13.7-78.8]) proceeded to on-treatment allogeneic HSCT, 3 of whom were in gilteritinib and FLAG-induced remission before transplant and remained in post-HSCT remission through the date of last on-study evaluation (11 March 2025). Pre-HSCT MRD assessments were available for 2 of these 3 patients, both of whom were MRD-negative before transplant. No evaluable pre-HSCT MRD data were available for the third patient; however, multiple serial post-HSCT MRD assessments were performed before the study closure, all of which were negative. The fourth patient, who did not achieve CR with study chemotherapy, proceeded nevertheless to on-study HSCT; the child subsequently experienced disease progression shortly after transplantation and died of AML-associated complications. The patient with FLT3-ITD ETP-ALL underwent off-study HSCT and was alive at last follow-up. The HSCT rates and outcomes for individual patients are presented in Figure 1.

Safety

All 9 patients experienced treatment-related treatment-emergent adverse events (TEAEs), including increased ALT (66.7%) and aspartate aminotransferase serum levels (55.6%), nausea (44.4%), and vomiting (44.4%; Table 4). Grade ≥3 TEAEs were reported in all patients; the most common were anemia (55.6%), increased ALT (55.6%), febrile neutropenia (44.4%), and decreased platelet count (33.3%). In addition, 2 patients (22.2%) experienced grade 3 or 4 thrombocytopenia. TEAEs leading to treatment discontinuation were reported in 1 patient (11.1%); this event of increased ALT was considered to be treatment-related. No events of QT prolongation, posterior reversible encephalopathy syndrome, differentiation syndrome, or gastrointestinal bleeding, which are known, previously reported side effects of gilteritinib³⁰ were observed. No DLTs or deaths due to treatment-related TEAEs were reported.

Table 4.

TEAEs in pediatric patients treated with gilteritinib and FLAG in the SKIPPER study

n (%)	Patients (n = 9)∗
Most common TEAEs†(≥2 patients)
ALT increased	6 (66.7)
AST increased	5 (55.6)
Nausea	4 (44.4)
Vomiting	4 (44.4)
Pyrexia	3 (33.3)
Anemia	3 (33.3)
Febrile neutropenia	2 (22.2)
Thrombocytopenia	2 (22.2)
Lymphocyte count decreased	2 (22.2)
Platelet count decreased	2 (22.2)
Most common grade ≥3 TEAEs (≥2 patients)
ALT increased	5 (55.6)
Anemia	5 (55.6)
Febrile neutropenia	4 (44.4)
Platelet count decreased	3 (33.3)
Thrombocytopenia	2 (22.2)
Nausea	2 (22.2)
AST increased	2 (22.2)
Blood bilirubin increased	2 (22.2)
Blood creatine phosphokinase increased	2 (22.2)
Lymphocyte count decreased	2 (22.2)
Hypoxia	2 (22.2)
Sepsis	2 (22.2)
Device-related infection	2 (22.2)
Serious TEAEs‡	7 (77.8)
Treatment-related deaths	0

AST, aspartate aminotransferase.

^∗One patient was not evaluable for DLT due to an FLT3-ITD refractory ETP-ALL diagnosis during the study period: at enrollment, the patient was diagnosed at the referring center with FLT3-ITD refractory AML and met eligibility criteria based on local pathology. After treatment initiation, central laboratory testing indicated findings more consistent with ETP-ALL; this represented reclassification based on central review, not lineage switch during therapy.

^†A reasonable possibility that the event may have been caused by the study intervention as assessed by the investigator.

^‡Includes serious AEs upgraded according to the sponsor’s medical review process, if any upgrade was done.

PK and PD

Comparison of pediatric and adult patients with relapsed/refractory AML showed similar PK between children dosed at 2 mg/kg per day and adults dosed at 80 mg/day (Astellas, unpublished data, January 2026), with mean steady-state C_trough values of 225.3 and 220.0 ng/mL, respectively.

The median PD pFLT3 inhibition across all patients at each trough time point was >90%, as measured serially by PIA assays (Figure 2). In 4 patients, biological activity was confirmed by achieving >90% PIA inhibition at the required number of time points.

Figure 2.

Baseline-corrected FLT3 plasma inhibitory activity (PIA) during SKIPPER protocol therapy. PIA as compared with baseline sampling was summarized at each time point (days 8, 15, and 21 of cycles 1 and 2) by dose levels. Per protocol, a dose of gilteritinib was considered biologically active based on PIA assessment (>90% PIA inhibition in ≥3 of 4 trough time points after 2 induction cycles, or in 2 of 2 trough time points for patients who received only 1 induction cycle) and/or based on a patient achieving CR. Two patients who received 2 cycles achieved >90% PIA inhibition at all 4 time points, and 2 patients who only received 1 cycle achieved >90% PIA inhibition at 2 time points. C, cycle; D, day.

Based on clinical activity, efficacy, and safety results, the study committee confirmed the RP2D of gilteritinib as 2 mg/kg per day for pediatric patients aged ≥2 years.

Discussion

Gilteritinib in combination with FLAG chemotherapy had a manageable safety profile in pediatric patients with relapsed/refractory AML with a toxicity profile consistent with the delivery of myelosuppressive chemotherapy. Gilteritinib 2 mg/kg per day dosing was identified as the RP2D for children aged ≥2 years treated in phase 1 of the SKIPPER study, which is also the dose used in combination with multiagent chemotherapy in the ongoing frontline COG AAML1831 clinical trial (ClinicalTrials.gov identifier: NCT04293562).^25,26

Importantly, two-thirds of children achieved CRc with the SKIPPER regimen, which was transplant-enabling for several patients. Similar response rates have been described in small phase 1 pediatric-specific studies of midostaurin monotherapy (CR, 56%) or quizartinib in combination with chemotherapy (CRc, 42.9%) in children with relapsed/refractory FLT3-mutant AML.^22,23 A report of 8 pediatric patients with FLT3-ITD AML treated with gilteritinib at 2 mg/kg per day, either as consolidation therapy or in the relapsed/refractory setting, also reported a CR rate of 63%. Four of these patients (50%) subsequently underwent HSCT, concordant with the transplant rates of the present study.³¹ Although gilteritinib has demonstrated OS benefits in adult patients with relapsed/refractory FLT3-ITD AML,³² published data in the pediatric setting are scarce. Direct OS comparisons between pediatric and adult patients, given their baseline differences and including those associated with recurrent molecular lesions, are thereby of limited interpretive value in this context. Given the historically poor outcomes of patients with relapsed FLT3-ITD AML,³ the achievement of a second CRc and successful consolidation with first- or second-line HSCT in nearly half of the patients in the SKIPPER study is clinically meaningful.

Important findings from the present pediatric study were the observed lack of new toxicities and a lower incidence of key AEs that have been previously reported in adults receiving gilteritinib. The most common grade ≥3 TEAEs reported were hepatic and hematologic, which were reversible with supportive care. Although elevated liver enzymes are common AEs of gilteritinib,³⁰ severe pancytopenia (eg, anemia, thrombocytopenia) and febrile neutropenia are common AEs associated with the FLAG chemotherapy backbone.^17,33 The most common treatment-related TEAEs were elevated liver enzymes and gastrointestinal symptoms, both of which have previously been associated with gilteritinib.^17,30,32 Mild to moderate liver enzyme elevation is a generally reversible AE of gilteritinib, which can be managed with dose modifications or a temporary dose interruption.³⁴ Clinically significant ALT and aspartate aminotransferase serum level elevations were observed in some patients, all of whom had additional potential confounding factors, including liver graft-versus-host disease, concomitant medications, such as antifungal prophylaxis, and preexisting transaminitis related to previous therapy.³⁵ Notably, no events of QT prolongation, posterior reversible encephalopathy syndrome, or differentiation syndrome (previously identified as gilteritinib-specific AEs in adult patients^30,32) were reported in this study. Although the small sample size limits definitive conclusions, the reported tolerability profile of gilteritinib with intensive cytotoxic chemotherapy supports further pediatric use and study.

Despite the fact that the study was open at 25 international centers for >3 years, recruitment of patients was challenging and slower than predicted. Although the historical relapse risk of patients with FLT3-ITD AML before the introduction of FLT3i was high, FLT3-ITD mutations are less common in children than in adults and thus comprised a small patient population that was potentially eligible for the SKIPPER study. Enrollment was further limited by differential access to salvage therapies across global regions and the inability of many patients and families to travel long distances to the participating study centers. During the SKIPPER study period, the frontline MyeChild-01 phase 3 trial in the United Kingdom and Europe (ClinicalTrials.gov identifier: NCT02724163) enrolled >500 children with newly diagnosed AML and importantly reported 2-year EFS and OS rates of 68% and 78%, respectively, in children with high-risk pediatric AML subtypes, including FLT3-ITD.³⁶ These excellent outcomes potentially reduced the incidence of relapsed/refractory FLT3-ITD AML during subsequent years. Similarly, the addition of sorafenib to frontline chemotherapy for children with newly diagnosed FLT3-ITD AML in the COG AAML1031 study significantly improved outcomes for pediatric patients with FLT3-ITD AML,²⁴ likely contributing to fewer relapses in this patient population across North America, Australia, and New Zealand. Since 2020, gilteritinib has also been studied in combination with multi-agent chemotherapy in children and adolescents/young adults with newly diagnosed FLT3-mutant AML in the successor COG AAML1831 trial (ClinicalTrials.gov identifier: NCT04293562),^25,26 potentially further reducing gilteritinib use in the relapsed/refractory setting. Finally, recruitment was certainly hindered by relatively easy access to off-label gilteritinib use for children in the United States and Europe following US Food and Drug Administration and European Medicines Agency approval of this FLT3i for adults in 2018 and 2019, respectively.20, 21 These regulatory approvals anecdotally facilitated physician prescribing of gilteritinib for children outside of a clinical trial (S.K. Tasian, written communication, December 2025), thereby likely reducing the incentive for site participation and SKIPPER study enrollment. Such barriers are not uncommon in pediatric oncology, particularly for rare molecularly-defined cancer subtypes, and often lead to prolonged timelines or underpowered studies.³⁷

The clear safety and preliminary efficacy results of the SKIPPER relapsed/refractory study provide important context that will surely be augmented by emerging data from ongoing frontline trials, including the COG AAML1831 trial. Based on analogous data demonstrating higher response rates with FLT3i in the de novo vs relapse setting,13, 14, 15, 16, 17 it is similarly plausible that pediatric patients with newly diagnosed AML will preferentially benefit from gilteritinib- or other FLT3i-based frontline therapies. Ultimately, these collaborative international efforts will continue to optimize treatment strategies, reduce relapse rates, and improve long-term survival of pediatric patients with FLT3-ITD AML.

Conflict-of-interest disclosure: P.C. reports departmental funding from the Association of the British Pharmaceutical Industry; received payment or honoraria from Sobi for lectures and presentations on an unrelated clinical topic; support for travel expenses from the British Society for Hematology (for Special Interest Group meetings and teaching), Health Care Research Wales, and the Resuscitation Council UK; served on an advisory board for Sobi in an unrelated clinical topic; and serves in a leadership role as Chair and Vice Chair of the Pediatric Special Interest Group, as Chair of a guideline writing group for the British Society for Hematology, and as Specialty Lead for child health research for Health Care Research Wales. N.H., D.D., A.H., J.H., S.G., and T.B. are employees of Astellas Pharma Inc. S.K.T. reports research funding from Incyte and Kura Oncology; serves or has served on scientific advisory boards for Aleta Biotherapeutics, Amgen, Ascentage, AstraZeneca, C-Further/LifeArc, Jazz Pharmaceuticals, Kura Oncology, Novartis, and Syndax; and reports travel support from Amgen and Jazz Pharmaceuticals. F.L. reports speakers' bureau fees from Amgen, Bristol Myers Squibb, Gilead, Jazz Pharmaceuticals, Medac, Miltenyi, Neovii, Novartis, Sanofi, and Sobi; served on advisory boards for Amgen, Neovii, Novartis, Sanofi, and Vertex Pharmaceuticals; served as president of the Italian Higher Health Council (the technical scientific advisory body to the Ministry of Health) from February 2019 until March 2025; and served as coordinator of the Technical Scientific Committee for the COVID-19 pandemic from March 2021 to March 2022. The remaining authors declare no competing financial interests.