Risk-Oriented Therapy for Myeloid Leukemia of Down Syndrome: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)
Authors: Taga Takashi , Watanabe Tomoyuki , Kudo Kazuko , Tomizawa Daisuke , Terui Kiminori , Moritake Hiroshi , Kinoshita Akitoshi , Iwamoto Shotaro , Nakayama Hideki , Takahashi Hiroyuki , Shimada Akira , Taki Tomohiko , Toki Tsutomu , Ito Etsuro , Goto Hiroaki , Koh Katsuyoshi , Saito Akiko M. , Horibe Keizo , Nakahata Tatsutoshi , Tawa Akio , Adachi Souichi 
Published: October 2019

Abstract
Introduction: Asmyeloid leukemia in Down syndrome patients (ML-DS) is known to have higher sensitivity against cytotoxic agents, children with ML-DS are treated with less intensive ML-DS-oriented protocol in recent clinical studies. On the basis of results of previous Japanese trials for ML-DS, we have evaluated an efficacy of the risk-oriented therapy in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-D05 study.
Patients and Methods: Between January 2008 and December 2010, seventy-four patients with newly diagnosed ML-DS from 122 hospitals in Japan were enrolled in this study. All patients received induction chemotherapy consisted of pirarubicin (25 mg/m2/d for 2 days), cytarabine (100 mg/m2/d for 7 days), and etoposide (150 mg/m2/d for 3 days). Patients who achieved complete remission (CR) after initial induction therapy were stratified to the Standard Risk (SR) and received four courses of reduced dose intensification therapy. Patients who did not achieve CR were stratified to the High Risk (HR) and received intensfied therapy consisted of continuous and high-dose cytarabine. Prophylaxis for CNS leukemia was not included throughout the therapy.
Results: Out of 74 patients registered in this study, two patients were excluded (one because of uncontrolled cardiac failure, another of non-Down syndrome), and 72 were eligible and were evaluated. Male/Female ratio was 40/32. The median age at diagnosis was 19 months (range, 10 months and 17 years old). Median follow-up period was 3.64 years (range, 0.05 -5.96 years. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and 2 patients to HR. Both of the two HR patients achieved CR but one relapsed. No therapy-related death was observed during intensification therapy. The 3-year event free and overall survival rate was 83.3% ± 4.4% and 87.5% ± 3.9 %, respectively. Age at diagnosis less than 2 years old was significant favorable prognostic factor for relapse (p=0.009). Sex, history of TAM, and chromosomal abnormalities (Normal karyotype or monosomy 7) did not influence the risk of relapse.
Conclusion: This study succeeded the previous Japanese strategy with very low-intensive chemotherapy regimen for ML-DS, and despite the dose reduction of chemotherapeutic agents compared to the previous studies, the overall outcome was good and further dose reduction might be possible for specific subgroups. However, considering that most relapse occurred in the SR group defined by morphological treatment response and that relapsed cases are rarely salvageable, more accurate method for identification of the poor prognostic subgroup is needed.
This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000989.

Disclosures
No relevant conflicts of interest to declare.