FLT3 Mutations Are Prevalent and Are Significantly Associated with Induction Death In Pediatric Acute Promyelocytic Leukemia, a Report From the Children's Oncology Group

Abstract 753

Mutations of the FLT3 gene (FLT3/ITD and FLT3/ALM) are common in AML and the presence of FLT3/ITD is associated with poor outcome in de novo AML. Although the prevalence of FLT3 mutations has been documented in acute promyelocytic leukemia (APL), the prognostic significance of FLT3 mutations in pediatric patients with APL has not been well characterized. We screened specimens from 119 children with APL for the presence of FLT3 mutations and correlated the mutations with clinical characteristics and outcome. Prevalence of FLT3 mutations was determined in specimens from 119 APL patients treated on pediatric cooperative group protocols (CCG 9710, CCG 2911, CCG 2891, N=96) or per institutional standard therapies (N=23). Of the 119 patients evaluated, FLT3/ITD was detected in 33 patients (28%) and FLT3/ALM in an additional 15 patients (13%) with a combined prevalence of 41%. These abnormalities of the FLT3 gene appear to be mutually exclusive in APL patients as no patient had both FTL3/ITD and FLT3/ALM. For the 16 patients with FLT3/ALM, one patient sample had a 6 base pair deletion involving part of the Eco RV site and all others had a single base pair substitution resulting in a missense mutation of amino acid D835 (8 patients with D835Y, 2 patients each with D835H, D835E and D835A and one patient with D835V). In pediatric AML, the ITD allelic ratio (ITD-AR) has been shown to have prognostic significance, and patients with ITD-AR >0.4 demonstrate a worse prognostic outcome than those with ITD-AR <0.4 or wild type FLT3. For the 34 APL patients with FLT/ITD the average ITD-AR was 0.56 with range from 0.03 to 2.42. Sixty-three percent of the FLT3/ITD APL patients had an ITD-AR greater than 0.4 which is similar to the rate of high ITD-AR reported in pediatric non-APL AML patients with FLT3/ITD (67%).

Presence of FLT3 mutations was correlated with clinical characteristics and outcome in 50 patients treated on the intergroup APL study CCG-9710 which treated patients on contemporary ATRA based chemotherapy. Of the patients treated on C9710, 12 had FLT3/ITD (24%) and 9 had FLT3/ALM (18%) for a combined prevalence of 42%. Of those with FLT3 mutations, 70% had elevated diagnostic WBC (>10,000cells/uL) compared to 26% of those without FLT3 mutations (p=0.0068). Conversely, of those with elevated WBC, 67% had FLT3 mutations. Remission induction rate at the end of one course of therapy was assessed in patients with and without FLT3 mutations. Ninety-three percent of the patients without FLT3 mutations achieved a complete remission compared to a CR rate of 60% in those with FLT3 mutations (p=0.0137). Patients with FLT3/ITD and FLT3/ALM had similar remission induction rates (55% and 67%, respectively). Early death in the first 30 days of induction therapy occurred in 7 patients (14%), all in patients with high diagnostic WBC. All patients with early death had a FLT3 mutation, 4 with FLT3/ITD and 3 with FLT3/ALM. Induction death rate in those with and without FLT3 mutations was 33% and 0%, respectively (p=0.0015). Among patients with high diagnostic WBC, the induction death rate in those with and without FLT3 mutations was 50% and 0%, respectively (p=0.0468). Overall survival (OS) for those with FLT3 mutations was 66.7% compared to 82.7% in wild type FLT3 patients (p=0.3273). Event-free survival at 5 years from diagnosis for patients with and without FLT3 mutations was 47.6% and 62.1%, respectively (p=0.4670).

Presence of a FLT3 mutation was highly correlated with elevated white blood cell count at diagnosis. Pediatric APL patients with FLT3 mutations have a significantly higher risk of death during induction. Within the group of patients with high diagnostic WBC, all induction deaths occurred in patients with FLT3 mutations. This resulted in a lower rate of complete remission and worse overall survival and event free survival in patients with FLT3 mutations. The prevalence of FLT3 mutations in pediatric APL provides evidence for further evaluation of FLT3 inhibitors in the treatment of pediatric APL. Due to the association of FLT3 mutations with induction death, FLT3 inhibitors should be evaluated as a therapeutic option early in the course of APL treatment.