Myeloablative single-unit cord blood transplantation overcomes the negative prognostic impact of FLT3-ITD in adult acute myeloid leukemia

Abstract

Genetic mutation is one of the most powerful prognostic factors for adult patients with acute myeloid leukemia (AML). The FMS-like tyrosine kinase 3 (FLT3) gene mutations, including internal tandem duplication (FLT3-ITD) and point mutation involving the tyrosine kinase domain (FLT3-TKD), are frequently observed in patients with AML, particularly in the cytogenetically normal karyotype. The FLT3-ITD mutation is associated with a poor prognostic factor in patients with AML mainly because of high relapse rates when chemotherapy is used alone. Several recent studies have shown a beneficial effect of allogeneic hematopoietic cell transplantation (HCT) over conventional chemotherapy in AML patients with FLT3-ITD [1,2]. Therefore, allogeneic HCT should be considered in FLT3ITDþ AML during early disease course. Cord blood transplantation (CBT) is an acceptable alternative to unrelated allogeneic HCT for patients without human leukocyte antigen (HLA)-matched related or unrelated donors. The rapid availability of a graft source for HCT is one of the most attractive benefits of using cord blood. However, the efficacy of CBT for FLT3-ITDþ AML patients has been limited [3,4]. In the present study, we retrospectively analyzed the results of myeloablative single-unit CBT in adult patients with FLT3-ITDþ and FLT3-ITD AML and clarified whether FLT3-ITD remains a prognostic factor in CBT. This retrospective study included adult patients who received single-unit CBT as a first myeloablative allogeneic HCT at our institute between May 2007 and June 2018, and who had AML with information available on their FLT3-ITD status. In total, 49 patients were eligible for this study. The intensified myeloablative conditioning (MAC) regimen included total body irradiation (TBI) 12 Gy, cyclophosphamide (CY) 120mg/kg, and high-dose cytosine arabinoside (Ara-C) 12 g/m with granulocyte colonystimulating factor (G-CSF) for patients younger than 59 years and those without comorbidity [5]. The reducedtoxicity MAC regimen included TBI 4 Gy, intravenous busulfan 9.6mg/kg, fludarabine 180mg/m, and highdose Ara-C 12 g/m with G-CSF for patients older than 60 years or those with comorbidity [6]. No patients received FLT3 tyrosine kinase inhibitors (TKIs) after CBT for maintenance therapy or treatment of relapse because TKIs were not commercially available for FLT3þ AML in Japan during the study period. This retrospective study was approved by the institutional review board of The Institute of Medical Science, The University of Tokyo (2984-B0302). The probabilities of overall survival (OS) and diseasefree survival (DFS) were estimated according to the Kaplan–Meier method, and the groups were compared using the log-rank test. The rates of relapse, non-relapse mortality (NRM), and neutrophil engraftment were estimated based on a cumulative incidence method to accommodate competing risks, and the groups were compared using Gray’s test. A multivariate analysis was performed with either a Cox proportional hazard model for overall mortality or a Fine and Gray proportional hazards model for relapse using these factors: FLT3-ITD status (positive versus negative), age (<50 versus 50 years), recipient cytomegalovirus (CMV) serostatus (positive versus negative), cytogenetics defined according to the National Comprehensive Cancer Network criteria for AML (better/intermediate versus poor), disease status at CBT (CR1 versus other than CR1), cryopreserved cord blood total nucleated cells (<2.5 versus 2.5 10/kg), and HLA disparities (<2 versus 2 locus). All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [7], a graphical user interface for R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). p Values of <.05 were considered to be significant. The characteristics of patients are shown in Table 1. There were no significant differences between patients with or without FLT3-ITD, except that the proportion of