Impact of FLT3-ITD Mutations in Patients with Normal Karyotype Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction : For patients affected by acute myelogenous leukemia (AML) with normal karyotype, the presence of a mutation in FLT3-ITD identifies a subgroup of individuals with poor prognosis for whom allogenic transplantation in first complete remission is indicated; such therapy is not required in patients with mutations in NPM1 or CEPBA. The present study evaluated the impact of mutations in FLT3 on post-allogenic transplantation outcomes in patients with cytogenetically normal AML.

Methods : A total of 68 patients with normal karyotype AML underwent to allogenic stem cell transplantation at our Department from March 2006 to March 2017. Median age was 51 years (range 15-70); there were 45 males and 23 females. The conditioning regimen was TBI or BU based regimen for full-dose transplantations, while TT-FLU-MEL was used in patients undergoing reduced intensity conditioning. Cyclosporine and short-term methotrexate was used as prophylaxis for graft versus host disease (GVHD) for transplantation with an HLA identical family member or unrelated donors. For haploidentical transplants, a post-transplantation infusion of cyclophosphamide (50 mg/kg) was administered at days +3 and +4 followed by mycophenolate mofetil and cyclosporine. All patients were investigated for mutations in the FLT3, NPM1, and CBPA genes.

Results : Conditioning was full-dose in 46 patients, and reduced intensity 17 cases. In 5 patients, a haploidentical transplant was used. 38 patients were transplanted in first complete remission and 20 in second complete remission, while 10 were transplanted with active disease. Overall survival (OS) of the entire cohort was 57% with an event-free survival (EFS) of 54%. The main cause of death was recurrence of disease (n=19); 10 patients died of non-relapse mortality. All patients who were transplanted with active disease died.

Considering the results of molecular characterization, 20 patients had a mutation in FLT3-ITD (FLT3+), while 48 did not (FLT3-). The presence of a mutation in FLT3-ITD was not associated with age, conditioning regimen, or donor type; 80% of FLT3+ patients were in first complete remission compared to 45% of FLT3- patients. OS in the FLT3+ subgroup was 35%, with a relapse rate of 45% (9/20); OS in the FLT3- subgroup was 66%, with a relapse rate of 25% (12/48). There were no differences in OS or EFS in the FLT3- subgroup among those undergoing transplantation during first or second complete remission.

Signs and symptoms of chronic GVDH (cGVHD) were observed in 25 of 55 evaluable patients (37%); of these, 20 patients were FLT3- and 5 were FLT3+. The presence of cGVHD was associated with better survival in FLT3- patients; in fact, 8/21 (38%) patients without signs of cGVHD had relapse compared to 4/20 (20%) with cGVHD (p=0.02). In FLT3+ patients, 4/9 (44%) without cGVHD had relapse vs. 3/5 (60%) of those with cGVHD (p=0.78).

Conclusions : The present data suggest that patients with mutations in FLT3 have a greater risk of relapse than FLT3- patients, although additional studies in larger patient groups are needed. The different impact of cGVDH in OS in the two groups appears to suggest different post-transplant strategies, reserving the use of donor leukocyte infusion for FLT3- patients with relapse or at high risk of relapse, and using FLT3 inhibitors in the subset of FLT3+ patients as they are at high risk.