The Outcome Of Allogeneic Hematopoietic Cell Transplantation In Children With FLT3/ITD-Positive Acute Myelogenous Leukemia
Authors: Schechter Tal , Gassas Adam , Chen Heidi , Pollard Jessica A. , Meshinchi Soheil , Irina Zaidman , Hitzler Johann K. , Abdelhaleem Mohamed M. , Ho Richard H. , Domm Jennifer , Woolfrey Ann E. , Frangoul Haydar A 
Published: October 2019

Abstract
FLT3 is a receptor tyrosine kinase expressed on hematopoietic progenitors that regulates hematopoietic development. FLT3 internal tandem duplication (FLT3/ITD) is a somatic mutations whose presence is associated with poor outcome in adults and children with AML. In children with FLT3/ITD who have high allelic ratio (ITD-AR), the progression free survival is estimated to be <20%. Hematopoietic stem-cell transplantation (HSCT) has been a recommended therapeutic option for children who are positive for FLT3. There is limited data on the post transplant outcome for children with FLT3/ITD.
We conducted a retrospective study to determine the outcome for all children with FLT3/ITD positive AML who underwent allogeneic HSCT in 4 pediatric centers. Data was collected and analyzed to identify the potential risk factors for overall survival (OS) and event-free survival (EFS). The association with OS and EFS was evaluated by Cox proportional hazard regression with results reported using hazard ratio (95% CI). The survival curve and cumulative incidence were calculated using the Kaplan-Meier method.
Between March 2007 and June of 2012, 29 AML patients with FLT3/ITD received HSCT. Median age at HSCT was10.2 years (range 4.5-21.9), 16 were males, and 26 were in first complete remission (CR), 2 with refractory disease and 1 in second CR. Among those with minimal residual disease testing, it was present in 3 (12%) patients in 1stCR. FLT3-ITD allelic ratio at the time of diagnosis was available in 25 patients and among those patient 14 (56%) the ratio was >0.4 (range 0.03-15.99). Eleven patients (38%) received stem-cells from HLA identical siblings while in 18 (62%) an alternative donors stem-cell was utilized (mismatched related donor (n=2), unrelated donor (n=7) or cord blood (n=9)). Eighteen patients (62%) received a total body irradiation (TBI) based preparative regimen while 11 (38%) received a busulfan-based regimen. Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor and mycophenolate for recipients of cord blood HSCT and calcineurin inhibitor plus methotrexate for the rest. Three (10%) patients experienced primary graft failure following cord blood HSCT. All 3 patients received a second graft that resulted in sustained engraftment. The cumulative incidence of neutrophil engraftment at day 42 was 89.6%. Sixteen (55%) patients developed grade 2-4 GVHD and 11 (38%) developed chronic GVHD (6 with severe and 5 mild). None of the patients experienced transplant related mortality. Eleven (38%) patients experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% with 95% CI (20.4%, 54.9%). At 2-years the probability of EFS and OS was 65.3% with 95% CI (45.1%, 79.6%) and 82.2% with 95% CI (58.5%, 91.3%) respectively. Using univariable analysis there was no difference between the EFS of patients who received related donors versus alternative donors, (HR 2.64 (0.79-8.76) p=0.1) and those with residual disease at the time of transplant versus those in complete remission (HR 0.88(0.19-4.09, p=0.8). Patients with higher FLT3/ITD ration at diagnosis had significantly worse EFS (HR 1.42 (1.04-1.93) p=0.03). The use of TBI in the preparative regimen was associated with superior EFS and OS (HR 0.29 (0.08-0.99), p =0.04) and (HR 0.07 (0.01-0.62), p= 0.002) respectively.
In conclusion the use of allogeneic HSCT is associated with improved EFS and OS in children with FLT3/ITD positive AML compared to what has been reported in those treated with chemotherapy alone.

Disclosures:
No relevant conflicts of interest to declare.