Editor's Note: In the treatment of acute myeloid leukemia (AML), the FLT3 mutation is one of the most common genetic abnormalities (accounting for approximately 30%), and the evolution of its treatment strategies has always been a focus of clinical attention. Although the first-generation FLT3 inhibitor midostaurin and the second-generation inhibitor quizartinib have been approved for first-line treatment, direct head-to-head data for the second-generation inhibitor gilteritinib versus midostaurin in the context of first-line intensive chemotherapy were previously a blank.At the recent European Hematology Association (EHA) Annual Meeting, Professor Marc Raaijmakers from the Erasmus University Medical Center (Erasmus MC) in the Netherlands, representing HOVON, AMLSG, and Astellas, grandly announced the results of the Phase 3 HOVON 156/AMLSG 28-18/PASHA trial. This study directly compared the efficacy and safety of gilteritinib versus midostaurin combined with intensive chemotherapy for the first-line treatment of FLT3-mutated AML. This journal has specially compiled the core highlights of the conference for our readers.
01 Background and Challenges: Iteration of FLT3 Inhibitors and Unmet Needs
FLT3 mutations, primarily including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are significant factors for poor prognosis in AML. Currently, the standard first-line treatment is intensive chemotherapy combined with an FLT3 inhibitor. The first-generation inhibitor midostaurin established its position in the RATIFY study, while the second-generation inhibitor gilteritinib demonstrated stronger selectivity and higher single-agent response rates in relapsed/refractory (R/R) FLT3-mutated AML. However, in newly diagnosed patients, is a second-generation inhibitor superior to a first-generation one? Can stronger target inhibition translate directly into prolonged overall survival (OS)? The PASHA study aimed to answer this key clinical question through a head-to-head comparison.
02 Study Design: Phase 3 Head-to-Head Randomized Controlled Trial
The PASHA trial is a multicenter, open-label, Phase 3 randomized controlled clinical study conducted in 13 countries. • Enrolled Population: Patients aged ≥18 years with newly diagnosed FLT3-ITD or FLT3-TKD mutated AML. • Randomization: Patients were randomized 1:1 to either the gilteritinib group or the midostaurin group. • Treatment Regimen: o Induction Therapy: 2 courses of intensive chemotherapy (standard 7+3 regimen) combined with gilteritinib (120mg/d) or midostaurin (50mg bid). o Consolidation Therapy: Including high-dose cytarabine (HiDAC) chemotherapy, autologous transplant, or allogeneic hematopoietic stem cell transplant (Allo-SCT). o Maintenance Therapy: Continuous single-agent maintenance with gilteritinib or midostaurin for up to 12 cycles (approximately 1 year). • Endpoint Settings: The primary endpoint was overall survival (OS); key secondary endpoints included event-free survival (EFS), complete remission (CR) rate after induction, modified EFS (mEFS), relapse-free survival (RFS), and safety. A total of 5,499 patients with AML/MDS-EB2 were screened, and 768 patients with FLT3-mutated AML were finally randomized. Baseline characteristics were balanced between the two groups. The median age was 59 years, approximately 80% had FLT3-ITD mutations, and according to ELN 2017 risk stratification, most were intermediate or high-risk patients.
03 Core Data Interpretation: Equality of Primary Endpoint OS and Benefits in Secondary Endpoints 1. Overall Survival (OS): No significant difference observed
Data from a median follow-up of 43.2 months showed that the OS curves for the gilteritinib and midostaurin groups basically overlapped. Median OS was not reached in either group, and the 4-year OS rates were 59% and 60%, respectively. Subgroup analysis showed no statistical difference in OS between the two groups regardless of age (<60 or ≥60 years) or mutation type (ITD or TKD).
2. Induction Remission Rate: Highly consistent
CR rates assessed by investigators according to ELN 2017 criteria were 78.9% for the gilteritinib group and 83.3% for the midostaurin group, showing comparable performance. Notably, a slightly higher proportion of morphologic leukemia-free state (MLFS) was observed in the gilteritinib group.
3. EFS and RFS: Gilteritinib demonstrates stronger biological activity
Unlike the overlapping OS, gilteritinib showed advantages in indicators reflecting anti-leukemia efficacy: • EFS (defined as time from randomization to failure to achieve CR, relapse, or death): The gilteritinib group showed a superior trend with a hazard ratio (HR) of 0.83. • RFS (relapse-free survival after CR): The gilteritinib group was significantly superior to the midostaurin group, with an HR of 0.68. • Relapse Rate: The relapse rate was 35.9% in the midostaurin group compared to only 21.5% in the gilteritinib group. This significant difference suggests that gilteritinib has stronger biological activity in clearing residual lesions and preventing early relapse.
04 In-depth Analysis: Why did lower relapse rates not translate into better OS?
In the PASHA study, a seemingly contradictory phenomenon appeared: the gilteritinib group had fewer relapses and longer RFS, but the final OS was equal to that of the midostaurin group. Professor Marc Raaijmakers conducted an in-depth analysis of survival data after relapse, revealing the potential underlying logic: • Salvage Success Rate after Relapse: The 2-year survival rate after relapse in the midostaurin group was significantly higher than in the gilteritinib group (37% vs. 17%). • “Cross-over” Effect: Among patients who relapsed in the midostaurin group, 50% subsequently received gilteritinib as salvage therapy; additionally, the proportion of Allo-SCT after relapse was higher in the midostaurin group. • Conclusion: After failure of first-line midostaurin, the second-generation inhibitor gilteritinib can serve as an excellent “safety net,” making up for the disadvantage of the first-line treatment; conversely, after failure of first-line gilteritinib, subsequent salvage methods of equal intensity are lacking.
05 Safety Analysis: Hematologic Toxicity and Infection Challenges
Regarding safety, gilteritinib combined with intensive chemotherapy brought more severe challenges: • Serious Adverse Events (SAEs): The incidence of SAEs was higher in the gilteritinib group (68% vs. 59%), primarily manifested as infectious complications. • Early Mortality: 30-day (5.5% vs. 3.1%) and 60-day (8.9% vs. 6.0%) mortality rates in the gilteritinib group were both slightly higher than in the midostaurin group, with deaths mostly related to infection. • Delayed Hematologic Recovery: After the first course of induction therapy, the median neutrophil recovery time (ANC > 1.0 × 10⁹/L) in the gilteritinib group was significantly longer than in the midostaurin group (33 days vs. 28 days), and platelet recovery time was also delayed (31 days vs. 27 days). This aggravation of myelosuppression explains the increased risk of infection.
06 Conclusion and Clinical Outlook: The Trade-off of Individualized Choice
As the world’s first Phase 3 study to directly compare first- and second-generation FLT3 inhibitors in combination with first-line intensive chemotherapy, the HOVON 156/AMLSG 28-18/PASHA study provides multi-dimensional academic reflections.
Professor Marc Raaijmakers concluded:
- Although the PASHA study did not reach a difference in the primary endpoint of OS, gilteritinib’s performance in reducing relapse risk (RFS) and prolonging EFS proved its powerful anti-tumor activity.
- The increased hematologic toxicity and infection risk in the gilteritinib group, along with the increased difficulty of rescue after relapse, were the primary reasons offsetting its OS benefit.
- Clinical Implications: For newly diagnosed patients with FLT3-mutated AML, midostaurin combined with intensive chemotherapy remains a robust first-line choice. While gilteritinib has not fully replaced midostaurin’s first-line status, its potential to reduce relapse in specific populations cannot be ignored. Future studies should further explore how to release the survival benefit potential of second-generation inhibitors through dose adjustment or regimen optimization (such as reducing toxicity during the induction phase).
Expert Introduction Professor Marc Raaijmakers
Professor of Hematology at the Erasmus MC Cancer Institute, Erasmus University Medical Center. Dedicated to researching the bone marrow microenvironment and genetic evolution of acute myeloid leukemia and myelodysplastic syndromes, he has deep international influence in the design and implementation of clinical trials for FLT3-mutated AML.
