Reduced-Intensity Allogeneic HSCT for Children and Adolescents/Young Adults with CML: A Study from the Adult and Pediatric CML Working Group of the Japan Society for Hematopoietic Cell Transplantation
Authors: Shimada Hiroyuki , Tanizawa Akihiko , Kondo Takeshi , Muramatsu Hideki , Yasui Masahiro , Tojo Arinobu , Nagamura-Inoue Tokiko , Eto Tetsuya , Igarashi Aiko , Kanamori Heiwa , Sato Maho , Noguchi Maiko , Ichinohe Tatsuo , Inoue Masami , Kato Koji , Atsuta Yoshiko , Ohashi Kazuteru 
Published: October 2019

Abstract
Background: The introduction of tyrosine kinase inhibitor (TKI) has reduced the indications for allogeneic hematopoietic stem cell transplants (HSCT) in patients with chronic myeloid leukemia (CML). In children and adolescents/young adults (AYA), however, the long-term side effects of TKI and financial burden could become a future issue. Thus, the role of HSCT with reduced intensity conditioning (RIC) as an alternative to TKI especially in the first chronic phase (CP1) should be defined for children and AYA with CML. However, less is well-known about the efficacy of RIC regimens on children and AYA with CML, in chronic phase (CP) as well as advanced phase.
Aims: To describe the long-term outcomes of children and AYA with all phases of CML treated with a RIC HSCT and to define potential prognostic factors for outcome.
Patients and Methods: We retrospectively analyzed 3796 patients with CML using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation and included children and AYA under 30 years old at HSCT who underwent allo-HSCT between 2001 and 2014 and received TKI before HSCT. The myeloablative conditioning regimen was defined as TBI ≥ 8 Gy, busulfan > 8mg/kg, or melphalan > 180 mg/m2.
Result: The characteristics of patients are summarized in Table 1. RIC was selected preferentially in patients with better status. The median follow-up of survivors was 64 months (3 - 171 months). There was no significant difference in 5-year overall survival (OS) among CP (124 cases), accelerated phase (AP) (23 cases) and blastic phase (BP) (53 cases) at diagnosis, 83%, 71% and 73%, respectively. In CP at diagnosis, 5-year OS was significantly higher in CP1 (89 cases) at HSCT than in CP2≤/AP/BP (35 cases) (89% versus 66%, p = 0.0004), and in CP1 at HSCT, there was no difference in 5-year OS between myeloablative conditioning (MAC) (58 cases) and RIC (31 cases) (both 89%) (Figure 1). However, 5-year OS in RIC was significantly higher in children (0-14 years old, 23 cases) than in AYA (15-29 years old, 8 cases) (95% versus 75%, p = 0.0495). Two of eight AYA patients with CP1 died after RIC HSCT due to grade IV acute GVHD-related complications without disease relapse, suggesting that the indications for RIC in AYA with CP1 should be carefully judged. In AP/BP at diagnosis, 5-year OS was significantly higher in the second chronic phase (CP2) (48 cases) at HSCT than in the third chronic phase (CP3)≤/AP/BP (28 cases) (82% versus 56%, p = 0.0073). However, the rate of major cytogenetic response (MCyR) at HSCT was significantly higher in CP2 than in CP3≤/AP/BP, and when focusing only on MCyR at HSCT in AP/BP at diagnosis, there was no difference in 5-year OS between CP2 at HSCT (40 cases) and CP3≤/AP/BP (13 cases) (83% versus 78%). On condition of MCyR at HSCT in AP/BP at diagnosis, regardless of the phase at HSCT, there was no difference in 5-year OS between MAC (46 cases) and RIC (7 cases: 2 in children and 5 in AYA) (79% versus 100%) (Figure 2), suggesting that even in AP/BP at diagnosis, RIC could be indicated for the patients with good response to TKI. On multivariate analysis, disease phase at HSCT and time from diagnosis to HSCT were independent predictors of OS in CP at diagnosis (Table 2), and cytogenetic response at HSCT and stem cell source in AP/BP at diagnosis (Table 3). There was no significant difference of OS between MAC and RIC.
Conclusion: In HSCT for CML after TKI administration, the indications for RIC in children under 15 years old with CP1 are appropriate. In RIC HSCT for AYA patients under 30 years old with CP1, caution should be exercised in transplant-related mortality rather than disease progression. Furthermore, even in AP/BP at diagnosis, RIC could be indicated for children and AYA patients with MCyR at HSCT.

Disclosures
Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis.: Honoraria.