Evaluation of High-Dose Cytarabine Induction Therapy and Flow Cytometric Measurable Residual Disease Monitoring for Children with <em>De Novo</Em> Acute Myeloid Leukemia: A Report from the JPLSG-AML-12 Trial

Tomizawa, Daisuke

Oral and Poster Abstracts
Oral
615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Outcomes and New Treatment Strategies in Genetically Adverse Risk and MRD-positive AML

Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, pediatric, Diseases, neonatal, Therapies, Myeloid Malignancies, Study Population, Human, Minimal Residual Disease

Daisuke Tomizawa, MD, PhD¹, Shiro Tanaka, PhD²^*, Shotaro Iwamoto, MD³^*, Hidefumi Hiramatsu, MD, PhD⁴, Jun Matsubayashi, PhD⁵^*, Daisuke Hasegawa, MD, PhD⁶^*, Hiroshi Moritake, MD, PhD⁷, Daiichiro Hasegawa, MD, PhD⁸, Kiminori Terui, MD, PhD⁹^*, Asahito Hama, MD, PhD¹⁰^*, Shin-ichi Tsujimoto, MD, PhD¹¹^*, Nobutaka Kiyokawa, MD, PhD¹²^*, Hayato Miyachi, MD, PhD¹³^*, Takao Deguchi, MD, PhD^14,15, Yoshiko Hashii, MD, PhD^16,17, Yuka Iijima-Yamashita, PhD¹⁸^*, Tomohiko Taki, MD, PhD¹⁹, Yasushi Noguchi, MD²⁰^*, Kazutoshi Koike, MD²¹^*, Katsuyoshi Koh²²^*, Yuki Yuza, MD, PhD²³^*, Akiko Moriya Saito, MD, PhD¹⁸^*, Keizo Horibe, MD, PhD¹⁸^*, Takashi Taga, MD, PhD²⁴^* and Souichi Adachi, MD, PhD²⁵

¹Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
²Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
³Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
⁴Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
⁵Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Japan
⁶Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
⁷Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
⁸Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
⁹Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
¹⁰Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Nagoya, Japan
¹¹Department of Pediatrics, Yokohama City University, Yokohama, Japan
¹²Department of Pediatric Hematology and Oncology Research, Research Institute, National Center for Child Health and Development, Tokyo, Japan
¹³Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Japan
¹⁴Division of Cancer Immunodiagnostics, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
¹⁵Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, TKY, Japan
¹⁶Department of Immunotherapy, Osaka University Graduate School of Medicine, Muko, KYO, Japan
¹⁷Department of Pediatrics, Osaka International Cancer Institute, Osaka, Japan
¹⁸Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
¹⁹Department or Medical Technology, Kyorin University Faculty of Health Sciences, Tokyo, Japan
²⁰Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan
²¹Ibaraki Children's Hospital, Mito, Japan
²²Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
²³Department of Hematology-Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
²⁴Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan
²⁵Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Background: High-dose cytarabine (HDAC) in initial induction therapy has been tested in several clinical trials both in children and adults with acute myeloid leukemia (AML), however, the trial results are conflicting. In addition, there is growing evidence on significance of measurable residual disease (MRD) monitoring to predict subsequent relapse, but MRD in AML is still challenging in terms of methodology and quality control. In the nationwide clinical trial AML-12 by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), the hematological malignancy subgroup of the Japan Children’s Cancer Group (JCCG), a role of HDAC in initial induction and feasibility and efficacy of central reference laboratory-based flow cytometric MRD (FCM-MRD) monitoring were evaluated in children with AML.

Patients & Methods: JPLSG-AML-12 trial (registered as jRCTs041180128) was designed as a seamless phase II/III trial; because of a safety concern in HDAC induction, children (0-18 years old) with newly diagnosed de novo AML (excluding acute promyelocytic leukemia and AML in Down syndrome patients) registered in selected institutions were randomized to receive either standard ECM (etoposide, standard-dose cytarabine, and mitoxantrone) or experimental HD-ECM (etoposide, HDAC, and mitoxantrone) induction, while patients registered in non-selected institutions were non-randomly allocated to receive standard ECM; in the following phase III part, all the patients were randomized. FCM-MRD were measured at two time points [end of Induction-1 (EOI-1) and end of Induction-2 (EOI-2)] at either of the two central reference laboratories (Mie University or Kyoto University) but was not used to guide subsequent therapies. Following complete remission (CR) evaluation at EOI-2, patients achieving CR were allocated to either of the 3 risk groups and received post-remission chemotherapies; core-binding-factor standard risk (CBF SR), non-CBF SR, or high risk (HR) group. Only HR patients were allocated to receive allogeneic hematopoietic stem cell transplantation in first CR. Primary endpoints of the trial were 3-year EFS and positive FCM-MRD (≥0.1%) rate at EOI-1.

Results: Total 359 eligible patients were registered at 102 institutions between 2014-2018. CR, 3-year EFS, and 3-year OS rates of all patients were 94.0%, 63.1% (95%CI, 57.9-67.9%), and 80.3% (95%CI, 75.8-84.1%), respectively. Among all, 324 patients were randomized (ECM, n=168; HD-ECM, n=156). Median follow-up period of these patients was 50.9 months (range, 0.2 – 84.7 months). No significant difference in outcomes were observed between the 2 arms; CR rates were 94.2% vs. 93.8% (p=0.998), 3-year EFS rates were 64.3% (95%CI, 56.5-71.0%) vs. 61.2% (53.1-68.4%) (p=0.551), 3-year OS rates were 84.4% (95%CI, 78.0-89.1%) vs. 75.3% (95%CI, 67.7-81.4%) (p=0.053), 3-year cumulative incidence of relapse were 28.6% (95%CI, 21.5-36.0%) vs. 30.9% (95%CI, 23.3-38.8%) (p=0.585), and 3-year non-relapse mortality rates were 0.9% (95%CI, 0.1-6.4%) vs. 1.8% (95%CI, 0.4-7.1%) (p=0.832). These outcome parameters were not different within each risk groups as well. FCM-MRD at EOI-1 was evaluated in 135 patients (80.4%) in the ECM arm and 127 patients (81.4%) in the HD-ECM arm; the positive FCM-MRD rates were 21.5% vs. 25.2% (p=0.575). Regarding grade 3 or higher adverse events (AEs) evaluated by CTCAE version 4 during Induction-1, disseminated intravascular coagulation was more frequent in the HD-ECM arm (1.8% vs. 6.4%, p=0.046), but no significant difference was observed for other AEs. Univariable Cox regression analysis for baseline characteristics revealed that the intermediate-risk cytogenetics and positive FLT3-ITD were significantly associated with decreased EFS rate. However, in multivariable analyses for EFS after EOI-1 and EOI-2, FCM-MRD was the sole poor prognostic factor; hazard ratios were 5.24 (95%CI, 3.19-8.63) (p<0.001) at EOI-1 and 5.56 (95%CI, 2.93-10.54) (p<0.001) at EOI-2.

Conclusions: Although HDAC in initial induction did not improve the outcome of children with AML, overall outcomes were comparable to the recently completed pediatric AML trials worldwide. Central reference laboratory-based FCM-MRD measurement was feasible and MRD at both EOI-1 and EOI-2 were the most powerful prognostic factors to predict outcome of children with AML. Therefore, FCM-MRD should be included in future risk stratification for children with AML.

Disclosures: Tomizawa: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hiramatsu: Novartis: Speakers Bureau. Horibe: Novartis Japan: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Speakers Bureau; Amgen Inc: Speakers Bureau; Kyowa Kirin Co.,Ltd.: Consultancy; Pfizer Japan Inc.: Consultancy.

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605 Evaluation of High-Dose Cytarabine Induction Therapy and Flow Cytometric Measurable Residual Disease Monitoring for Children with De Novo Acute Myeloid Leukemia: A Report from the JPLSG-AML-12 Trial