Risk-Adjusted Therapy of Acute Lymphoblastic Leukemia Can Optimize the Indication of Stem Cell Transplantation and Cranial Irradiation: Results of Japan Association Childhood Leukemia Study Group (JACLS) Protocol ALL-02
Authors: Hasegawa Daiichiro , Imamura Toshihiko , Yagi Keiko , Takahashi Yoshihiro , Usami Ikuya , Suenobu So-ichi , Shinichiro Nishimura , Suzuki Nobuhiro , Hashii Yoshiko , Deguchi Takao , Saito Akiko M. , Kato Koji , Kosaka Yoshiyuki , Komada Yoshihiro , Iguchi Akihiro , Kawasaki Hirohide , Hori Hiroki , Sato Atsushi , Kudo Tooru , Nakahata Tatsutoshi , Oda Megumi , Hara Junichi , Horibe Keizo 
Published: October 2019

Abstract
BACKGROUND: The trial JACLS ALL-02 for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in unfavorable-risk groups by treatment intensification. These aims were pursued through a refined stratification strategy using white blood cell count, age, immunophenotype, unfavorable genetic aberrations, and treatment response providing an excellent discrimination of risk groups.
PATIENTS AND METHODS: Between April 2002 and March 2008, 1252 children with newly diagnosed de novo ALL with 1-18 years of age were enrolled to JACLS ALL-02 trial. Ph+ALL, mature B-ALL, and NK-leukemia were excluded. Patients with BCP-ALL were stratified into 3 groups: standard-risk (SR), high-risk (HR), extremely high-risk (ER), based on initial prednisolone (PSL) response and the modified National Cancer Institute(NCI) workshop criteria. Prednisolone poor response (PPR) was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate. PSL good responders (PGR; < 1,000 blasts/microL) were divided into SR and HR according to the modified NCI workshop criteria by WBC 10K and age 10, and received conventional therapy. BCP-ALL with PPR (≥ 1,000 blasts/microL) or t(4;11), and acute mixed lineage leukemia/ acute unclassified leukemia were assigned to ER and received intensified post-induction therapy . Patients with T-ALL were treated by a specific protocol that was different from the protocol used for BCP-ALL. Bone marrow response was also evaluated in aspiration smears on day 15 and 33 of induction treatment, and those who had slow early bone marrow response, defined as an M3 marrow on day 15 or M2/3 marrow on day33, shifted to the higher risk and received augmented post-induction therapy. Cranial irradiation was restricted to patients with initial central nerve system involvement or T-ALL with high WBC (≥10K) at diagnosis. Alternatively, protracted TIT was given during induction, intensification and maintenance depending on the risk group (12 doses in SR/T and 15 in HR/ER). Slow early responders who had an M3 marrow on day 15 in ER/T or M2/3 marrow on day33 in any risk, underwent to stem cell transplantation (SCT). PPRs without slow early bone marrow response underwent to SCT only if a matched sibling donor was available. The probability of event-free survival (EFS) and overall survival were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. All statistical analyses were done according to intent-to treat methods.
RESULTS: Estimated 4-year EFS and OS for all 1252 patients was 83.7% (SE=1.1) and 90.3% (SE=0.89), slightly better in EFS than the former study (ALL-97; 79.3%, SE=1.7, p=0.054). The SR group (N=457, 37%) achieved excellent 4-year EFS of 90.4% (95%CI: 87.2, 92.7) and 4-year OS 97.3% (95.3, 98.5); in SR without slow early bone marrow response, patients with hyperdiploid and triple trisomy showed excellent 4-year EFS/OS of 100%. In the HR group (N=542, 43%), the estimated 4-year EFS and 4-year OS were 84.9% (81.5, 87.7) and 89.3% (86.3, 91.6), respectively; older age (≥ 6 years) was predictive for inferior OS (hazard ratio=1.14, p<0.0001), and ETV6-RUNX1 was predictive for favorable OS (HR=0.182, p<0.03). In the ER group (N=139, 11%), intensification of consolidation treatment using high-dose dexamethasone and AML-oriented agents led to considerable improvement yielding a 4-year EFS of 74.1% (66.0, 80.6) and a 4-year OS of 87.0 (80.2, 91.6). In T group (N=107, 8%), the dose reduction of L-asparaginase and anthracyclines compared with the ALL-97 resulted in inferior outcome in 4-year EFS 65.1% (54.9, 73.6), but not in 4-year OS 83.2% (74.6, 89.1), although the incidence of pancreatitis decreased. In non-T-ALL, The 5-year cumulative risk of an isolated and total CNS relapse was lower in ALL-02 than in ALL-97 (isolated CNS relapse: 0.8% vs 2.7%, p=0.017, total CNS relapse: 1.4% vs 4.5%, p=0.01). The proportion of CRT and SCT were 2%, 8% in ALL-02 respectively, whereas 31%, 11% in ALL-97 respectively.
CONCLUSIONS: Refined stratification and risk-adjusted therapy in the JACLS ALL-02 trial can bring about the abolition of prophylactic CRT in non-T ALL and the optimized indication of SCT without compromising the treatment results.

Disclosures
No relevant conflicts of interest to declare.