Hematopoietic Stem-Cell Transplantation in Children with Refractory Acute Myeloid Leukemia
Authors: Okamoto Yasuhiro , Kudo Kazuko , Tabuchi Ken , Tomizawa Daisuke , Taga Takashi , Goto Hiroaki , Yabe Hiromasa , Nakazawa Yozo , Koh Katsuyoshi , Ikegame Kazuhiro , Yoshida Nao , Uchida Naoyuki , Watanabe Kenichiro , Koga Yuuki , Inoue Masami , Kato Koji , Atsuta Yoshiko , Ishida Hiroyuki 
Published: October 2019

Abstract
Purpose
It is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute myeloid leukemia (AML). Despite being refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study demonstrated that age less than 10 years was a factor of good prognosis; however, the details in children remain unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory AML.
Patients and Methods
The data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. A total of 417 patients with AML younger than 21 years old at the time of HSCT between January 2001 and December 2015 who had blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative and reduced-intensity conditioning regimens were analyzed. Patients with AML were classified according to a previous report, which was based on the Eastern Cooperative Oncology Group/Southwest Oncology Group classification as good (inv16, t[8;21], t[15;17]), poor (5/del[5q], 7/del[7q], inv[3q], abn11q, 20q or 21q, del[9q], t[6;9], t[9;22], abn17p, and complex karyotype defined as 3 or more abnormalities), or intermediate (other and normal karyotypes) risk. Myeloablative conditioning was defined as total body irradiation (TBI) of >8 Gy and the administration of 8 mg/kg of busulfan (BU), >140 mg/m2 of melphalan, or >10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented.
Results
The median follow-up time of survivors was 1052 days (range 60-4399). The median age was 13 years. Twenty-three percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS ≥90. The rate of pre-HSCT fungal infection was 12%. Fifty-two percent of patients had more than 25% marrow blasts at the time of HSCT. At the time of HSCT, 36%, 47%, and 17% of patients exhibited primary induction failure, first relapse, and second or additional relapse, respectively. Eighty-nine percent of patients had neutrophils and 70% exhibited platelet recovery by day 100. Three hundred and fourteen patients died. The causes of death were leukemia progression (58%), followed by graft-versus-host disease (GVHD) (11%) and graft failure (10%). The 3-year OS rate was 23% (95% confidence interval (CI) 19-28). Grade ≥2 acute GVHD did not affect OS. Patients with chronic GVHD had better 3-year OS (47%, 95% CI 36-57%) compared to that in patients without chronic GVHD (22%, 95% CI 16-28%) (p = 0.001) (Figure 1). Low PS, greater than 25% marrow blasts, the presence of blasts in blood at the time of transplantation, French-American-British subgroup other than M1 or M2, transplant from a male donor, and a history of transplantation were adverse pre-HSCT variables (Table 1). Patients with 0 (n = 24), 1-2 (n = 175), 3-4 (n = 188), and 5-6 (n = 30) variables had 52% (95% CI 30-71%), 30% (95% CI 23-37%), 17% (95% CI 12-23%), and 0% 3-year OS, respectively (p < 0.001) (Figure 2).
Discussion
Some patients with refractory pediatric AML achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs.

Disclosures
No relevant conflicts of interest to declare.