Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy.
Eunice S WangPau MontesinosMark D MindenJe Hwan LeeMichael HeuserTomoki NaoeWen-Chien ChouKamel LaribiJordi EsteveJessica K AltmanViolaine HavelangeAnne-Marie WatsonCarlo B Gambacorti-PasseriniElżbieta PatkowskaShufang LiuRuishan WuNisha PhiliposeJason E HillStanley C GillElizabeth Shima RichRamon V TiuPublished in: Blood (2022)
Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- newly diagnosed
- allogeneic hematopoietic stem cell transplantation
- open label
- free survival
- end stage renal disease
- phase iii
- epidermal growth factor receptor
- ejection fraction
- stem cells
- chronic kidney disease
- study protocol
- physical activity
- squamous cell carcinoma
- double blind
- prognostic factors
- peritoneal dialysis
- cross sectional
- bone marrow
- placebo controlled