FLT3 Mutation Status is a Predictor of Early Death in Pediatric Acute Promyelocytic Leukemia: A Report From The Children's Oncology Group

• Authors: Matthew A. Kutny, Fred Hutchinson Cancer Research Center; Barry K. Moser, Duke University; Kristina Laumann, Mayo Clinic; James H. Feusner, Children's Hospital and Research Center Oakland; Alan Gamis, Children's Mercy Hospital; John Gregory, Goryeb Children's Hospital; Richard A. Larson, University of Chicago; Bayard L. Powell, Wake Forest University; Wendy Stock, University of Chicago; Cheryl L. Willman, University of New Mexico; William G Woods, Emory University; Soheil Meshinchi, Fred Hutchinson Cancer Research Center
• Journal Title: Pediatric Blood and Cancer
• Volume: Volume 59, Number 4
• Publisher: Wiley: 12 months | 2012-10-01, Pages 662-667
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/pbc.24122
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Hematology; Pediatrics; acute promyelocytic leukemia; APL; FLT3 mutation; pediatric; ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; PML/RAR-ALPHA; GENE; SUBTYPES; IMPACT; ASSOCIATION; PROGNOSIS; PATHWAYS; SURVIVAL

Abstract

Background: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). Procedure: Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n=50). Results: Forty-two of the 104 patients (40%) had either FLT3/ITD (n=28, 27%) or FLT3/ALM (n=15, 14%). Median diagnostic WBC count was 23,400cells/μl vs. 3,600cells/μl for those with and without FLT3/Mut (P<0.001), and similar results for the cohort of 50 patients treated on C9710 (P<0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P=0.004), microgranular variant histology (P=0.035), and a lower remission rate (P=0.009). In patients who received ATRA (C9710 or CCG-2911, n=58), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P=0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P=0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. Conclusions: FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.