AUTHORS
Daisuke Hasegawa, MD, Shiro Tanaka2, Kiminori Terui3, Tsutomu Toki4, Shotaro Iwamoto, MD,PhD5, Hidefumi Hiramatsu, MD,PhD6, Takao Deguchi, MD, PhD7, Tomohiko Taki8, Asahito Hama9, Hideto Iwafuchi10, Kentaro Nakashima11, Shin-Ichi Tsujimoto, MD,PhD12, Shota Kato, MD, PhD13, Yuki Arakawa14, Yuki Yuza15, Utako Oba16, Etsuro Ito, MD, PhD17, Akiko Saito18, Katsuyoshi Koh19, Souichi Adachi, MD,PhD20, Daisuke Tomizawa, MD, PhD21, Hiroshi Moritake, MD,PhD22, Takashi Taga, MD,PhD23
AFFILIATIONS
1 St. Luke's International Hospital, Tokyo, Japan
2 Kyushu University Hospital, Fukuoka, Japan
3 Hirosaki University Graduate School of Medicine, Hirosaki, Japan
4 Hirosaki University Graduate School of Medicine, Hirosaki, Japan
5 Mie University Graduate School of Medicine, Tsu, Japan
6 Kindai University Faculty of Medicine, Sakai, Japan
7 National Center for Child Health and Development, Tokyo, Japan
8 Kyorin University Faculty of Health Sciences, Mitaka, Japan
9 Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
10 Shizuoka Children’s Hospital, Shizuoka, Japan
11 Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
12 Yokohama City University Graduate School of Medicine, Yokohama, Japan
13 the University of Tokyo Graduate School of Medicine, Tokyo, Japan
14 Saitama Children’s Medical Center, Saitama, Japan
15 Tokyo Metropolitan Children’s Medical Center, Fuchu, Japan
16 Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
17 Hirosaki University Graduate School of Medicine, Hirosaki, Japan
18 NHO Nagoya Medical Center, Nagoya, Japan
19 Saitama Children’s Medical Center, Saitama, Japan
20 Kyoto University Graduate School of Medicine, Kyoto, Japan
21 National Center for Child Health and Development, Tokyo, Japan
22 University of Miyazaki Faculty of Medicine, Miyazaki, Japan
23 Shiga University of Medical Science, Otsu, Japan
ABSTRACT
Background
Myeloid leukemia of Down syndrome (ML-DS) has achieved excellent outcomes with reduced-intensity chemotherapy that balances the marked chemosensitivity of leukemic blasts with the increased vulnerability of patients with DS to treatment-related toxicity. However, the prognosis of relapsed/refractory ML-DS remains dismal. Consequently, recent treatment strategies have shifted from further treatment de-escalation toward intensification within acceptable toxicity limits to prevent relapse. In contrast, the Japan Children’s Cancer Group (JCCG) has pursued a different strategy: while intensifying therapy for selected high-risk patients, it has focused on identifying the majority of patients who may safely benefit from further treatment reduction through refined risk stratification. In the nationwide single-arm, phase II AML-D16 trial, we sought to optimize treatment for ML-DS using a risk-stratification approach incorporating age at diagnosis, GATA1 mutation status determined by Sanger sequencing, and morphological response and flow cytometry-based measurable residual disease (FCM-MRD), both assessed at the end of induction (EOI).
Methods
AML-D16 enrolled patients with newly diagnosed ML-DS between July 2019 and June 2022. Patients younger than 4 years with a GATA1 mutation who achieved complete remission (CR) with EOI FCM-MRD <0.05% were classified as the low-risk (LR) group and received four courses of reduced-intensity, standard-dose cytarabine-based chemotherapy (cytarabine 100 mg/m2 administered as a 1-hour intravenous infusion). Patients with an inadequate response to initial induction therapy received intensified post-induction chemotherapy including high-dose cytarabine. Among patients who achieved CR, those with EOI FCM-MRD ≥0.05% were classified as the MRD-high-risk (MHR) group and received six courses of therapy, including four intensified courses. Patients who failed to achieve CR were classified as the HR group and received six courses of therapy, including five intensified courses. All remaining patients were assigned to the standard-risk (SR) group and received five courses of reduced-intensity chemotherapy. The primary endpoint was 3-year event-free survival (EFS) in the LR group.
Results
A total of 87 patients were enrolled, and one was excluded following withdrawal of consent. Among the 86 patients in the full analysis set, the median age at diagnosis was 1 year (range, 0–11), 84 (97.7%) were younger than 4 years, 52 (60.5%) had a history of transient abnormal myelopoiesis, and 73 (84.9%) harbored GATA1mutations. Based on the predefined risk stratification, 63 patients (73%) were assigned to the LR group, 15 (17%) to the SR group, 5 (6%) to the MHR group, and 3 (3%) to the HR group. After a median follow-up of 48.4 months, the 3-year EFS, overall survival (OS), and cumulative incidence of relapse (CIR) for the entire cohort were 94.1% [95% confidence interval (CI), 86.4–97.5%], 95.3% (95% CI, 88.0–98.2%), and 5.9% (95% CI, 2.5–13.6%), respectively. Importantly, patients in the LR group (73% of the cohort) were successfully treated with further reduced-intensity chemotherapy, achieving a 3-year EFS of 96.8% (95% CI, 87.9–99.2%), OS of 96.8% (95% CI, 87.7–99.2%), and CIR of only 3.2% (95% CI, 0.8–12.1%). The corresponding 3-year EFS/OS/CIR rates were 85.7%/93.3%/14.3% in the SR group, and 80.0%/80.0%/20.0% in the MHR group. All three HR patients subsequently achieved CR after two additional courses of intensive chemotherapy and remain in continuous CR. Grade ≥3 adverse events consisted mainly of hematological toxicities and febrile neutropenia, and no treatment-related deaths occurred.
Discussion
Risk-stratified therapy in the AML-D16 trial enabled safe treatment de-escalation in the LR group, comprising 73% of the cohort, while maintaining an excellent 3-year EFS of 96.8%. Patients with poor response to induction therapy also achieved encouraging outcomes following treatment intensification. Overall, treatment outcomes were superior to those observed in the preceding AML-D11 trial and other previous reported studies. These findings demonstrate that refined prospective risk stratification can simultaneously identify the majority of children who can safely receive further treatment de-escalation and the small subset who benefit from treatment intensification, thereby optimizing therapy and improving outcomes in ML-DS.
DISCLOSURES
Daisuke Hasegawa, MD: Chugai Pharmaceutical Co., Ltd. - Honoraria; Sanofi - Honoraria; Astellas Pharma Inc. - Honoraria; Nippon Shinyaku Co., Ltd. - Honoraria; Novo Nordisk Pharma Ltd. - Honoraria; CSL Behring K.K. - Honoraria; Otsuka Pharmaceutical Co., Ltd. - Honoraria