Clinical Outcomes of Acute Promyelocytic Leukemia (APL) Patients According to FLT3 Mutation Status
Authors: Singh Harshabad , Werner Lillian , DeAngelo Daniel J , Amrein Philip C. , Wadleigh Martha , Ballen Karen K , Fox Edward , Galinsky Ilene , Neuberg Donna , Stone Richard M , Attar Eyal C 
Published: October 2019

Abstract
Abstract 2689

Introduction:
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by promyelocytes in the blood and bone marrow, coagulopathy, and characteristic translocation between chromosomes 15q22 and 17q21. Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase receptor (FLT3) are found in approximately 30% of patients with APL. While cytogenetically normal AML patients with ITD mutations (especially with high ratio of mutant: WT allele) have a poorer prognosis due to high relapse rate, the prognostic value of ITD in APL is debated. We analyzed the clinical outcome of patients with APL to determine the relationship between FLT3 receptor status and prognosis.

Materials and Methods:
We conducted a retrospective analysis of all adult APL patients < age 60 who were newly diagnosed and tested for FLT3R mutations at Massachusetts General Hospital and Dana-Farber Cancer Institute/Brigham and Women's Hospital between 2002 and 2008. Patient characteristics, complete remission (CR) rates, disease free survival (DFS), and overall survival (OS) were assessed by medical record review under an IRB-approved protocol. CR, DFS and OS were defined according to standard criteria. Kaplan-Meier method was used to estimate median DFS and OS and log-rank p-values were presented. We assessed the associations of clinical characteristics and the type of mutation patients had using Kruskal-Wallis tests. A p-value less than 0.05 was interpreted as statistically significant.

Results and Discussion:
We identified a total of 26 patients with APL for whom FLT3 mutation status was known. There were 13 patients with wtFLT3, 9 with ITD (1 also had TKD), and the remaining 4 had an isolated TKD mutation. Of the 13 patients with wt FLT3APL, 4 had prior chemotherapy and/or radiation. No patients in the FLT3ITD APL or FLT3TKD APL groups had prior chemotherapy or radiation. As we had only 4 patients had an isolated FLT3TKD mutation, we restricted our analyses to patients who had either wt FLT3 or FLT3ITD+/− TKD.
Of the wtFLT3 APL patients, 9/13 were enrolled and treated on CALGB 9710. Of the remaining 4 patients, two were treated according to the PETHEMA regimen, one with a history of breast cancer and significant anthracycline exposure was treated with ATRA and AsO3, and the last patient died before therapy could be initiated. Of the 9 patients with FLT3ITD APL, 5 were treated on CALGB 9710, 2 were treated according to 9710 but off protocol, and 2 with the PETHEMA regimen.
Baseline clinical characteristics were similar between the two groups including CR rates [92 (12/13) versus 100% (9/9) for wt and ITD, respectively]. Patients with the ITD had a lower fibrinogen at presentation than those with wt (103 vs. 235 mg/dl, p=.04). While patients with ITD appeared to have a higher WBC, it was not statistically significant (p=.1). However, patients with ITD had an inferior DFS compared to wt (Figure 1) (p=.01) while there was no significant difference in OS between the two groups (p=.39).
Of the 5 patients with ITD who relapsed, 3 received AsO3 reinduction and autologous SCT, 1 with CNS recurrence received myeloablative allogeneic SCT, and the fifth died in relapse without treatment.
The observation that FLT3ITD APL patients have a reduced DFS raises the possibility that APL therapy may be improved for this group of patients, possibly by incorporating FLT3 inhibitors.

Disclosures:
DeAngelo: Deminimus: Consultancy. Stone:Novartis: Consultancy.