Successful Reduction of Cranial Irradiation in Children with B Cell Precursor Acute Lymphoblastic Leukemia(ALL) through Four Consecutive ALL Studies: Long-Term Follow-up of ALL in Tokyo Children’s Cancer Study Group (TCCSG) L89-12, 92-13, 95-14 and 99-15 Studies.
Authors: Ogawa Chitose , Ohara Akira , Manabe Atsushi , Kikuchi Akira , Koh Katsuyoshi , Tomizawa Daisuke , Fujimura Junya , Inoue Hiroyasu , Sunami Syosuke , Ishii Eizaburo , Shiohara Masaaki , Mori Tetsuya , Takahashi Hiroyuki , Hayashi Yasuhide , Hanada Ryoji , Tsuchida Masahiro 
Published: October 2019

Abstract
Development of prophylactic cranial irradiation (CRT) has greatly contributed to the improvement of outcome of childhood ALL. However, late complications, including secondary malignant neoplasms, arising from CRT are becoming big problems. Furthermore, the prognosis of the patients with relapse in central nervous system (CNS) after CRT is extremely poor. To eliminate CRT in the treatment for majority of the patients with B-cell precursor (BCP) ALL, we had attempted to reduce the indication of CRT by conducting randomizations in 3 studies. We present here the long-term results of 4 consecutive clinical trials, to assess the effect of reducing the proportion of patients who received CRT on the treatment outcome. Of the 2,116 children with newly diagnosed ALL with 1–18 years of age who were enrolled to the 4 consecutive TCCSG ALL studies between 1989 and 2003, 1845 BCP ALL patients were evaluable: 354 Pts in L89-12 protocol (1989–1992), 291 Pts in L-92-13 (1992–1995), 536 Pts in L95-14 (1995–1999) and 664 Pts in L99-15 (1999–2003). The probability of event-free survival (EFS) and overall survival (OS) were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. The initial status of CNS disease was examined after 7 or 10 days of pre-phase treatment consisted of steroid and/or other drugs. The definition of the CNS status was as follows: CNS positive = CNS-1 with symptomatic CNS disease, CNS-2, CNS -3 and traumatic lumbar puncture (TLP) with leukemic blasts; CNS negative = CNS-1 and TLP without leukemic blasts. In L89-12 study, all but a half of the standard risk group (SR) patients had received CRT. After this study, no CRT was given for the patients in SR. Patients in the intermediate risk group (IR) were randomly assigned into either high-dose methotrexate (HD-MTX) arm or CRT arm in L92-13 study. In L95-14 study, patients with initial leukocyte count exceeding 50,000/ul received CRT, whereas the others were treated with HD-MTX in IR. A part of patients in the high risk group (HR) in L95-14 study proceeded to stem cell transplantation during the first remission. In L99-15 study, only patients with high WBC, more than 100,000/ul, at diagnosis received CRT. Overall, no increase in CNS relapse was observed. The EFS rate and the OS rate at 8 years in L99-15 study were significantly improved compared to those in L89-12 study. Details of the results are shown in the table. By intensifying systemic chemotherapy and intrathecal injections, the proportion of the patients who received CRT in L99-15, which was the last study, was reduced to as small as 4% without increase in CNS relapse. These remaining 4% of the patients who had received CRT included those with CNS-3 disease (= 0.3 %), and they are the ultimate target who needs innovative treatment. In conclusion, we have succeeded to reduce the proportion of the patients with BCP ALL receiving CRT from 79% to 4% in the past 20 years, without compromising the treatment outcome.
Table. Treatment and outcome in each study
L89-12 L92-13 L95-14 L99-15 LP: lumbar puncture, IT: intrathecal injection, *randomization, **Pts with WBC higher than 50,000/ul at diagnosis received CRT. ***Pts with WBC higher than 100,000/ul at diagnosis received CRT. Rate of CNS positive 2.0% 3.4% 1.3% 2.1% Date of 1st LP/IT Day8 Day8 Day11 Day8 Rate of Pts receiving CRT 79% 36% 23% 4% Dose of CRT 18Gy 1y:12Gy, 2-18y: 18Gy 1y:12Gy, 2–18y: 18Gy 1–6y:12Gy, 7–18y: 18Gy CNS directed therapy SR*: A; HD-MTX 9g B; CRT IR: CRT HR: CRT SR: HD-MTX 6g IR*: A; HDMTX 6g B; CRT HR: CRT SR: HD-MTX 9g IR**:A;MTX9g B;CRT HR: CRT SR: HD-MTX 9g IR***: HD-MTX 9g (*HD-or LD-Ara-C) HR***: HD-MTX 6g Rate of Pts receiving SCT 0% 0% 15% 8% 8y-EFS 65+/−3% 55+/−3% 76+/−2% 74+/−2% 8y-OS 76+/−2% 79+/−2% 84+/−2% 86+/−2% Rate of BM relapse 25.6% 31.1% 17.6% 18.7% Rate of Isolated CNS relapse 2.6% 0.72% 1.2% 1.5% Rate of all CNS relapse 3.2% 1.4% 1.7% 3.2%