Effective Risk-Adapted Therapy for Childhood B-Precursor Acute Lymphoblastic Leukemia (ALL) with the Japan Association of Childhood Leukemia Study (JACLS) ALL-97 Protocol.

BACKGROUND: With current intensified chemotherapy, more than 70% of children with acute lymphoblastic leukemia (ALL) are curable. However, prognosis of the patients at higher risk has been unsatisfied. More appropriate risk assignment and innovative treatment is expected to be developed. We conducted a clinical trial of JACLS ALL-97 including multi-agent block therapy followed by hematopoietic stem cell transplantation (SCT) for the selected higher risk patients.

PATIENTS AND METHODS: Between April 1997 and March 2002, 674 patients aged 1 to 15 years with newly diagnosed ALL (excluding mature B-cell ALL) were enrolled on the JACLS ALL-97 protocol. Excluding 75 T-ALL, 26 mixed lineage leukemia other than B-precursor ALL with myeloid markers, 9 acute unclassified leukemia and 1 B-precursor ALL with pretreatment, 563 patients with B-precursor ALL were eligible for this analysis. Treatment group was divided 5 groups according to the modified National Cancer Institute (NCI) workshop criteria. Standard risk (SR) and IR (intermediate risk) divided by WBC10 × 10³ account for NCI-SR. High risk (HR) and ER (extremely high risk) divided by WBC 100 × 10³ account for NCI-HR. The patients with ALL positive for Philadelphia chromosome and for translocation with chromosome11q23 were assigned to the highest risk group F. The patients in complete remission (CR) at day 35 with M2/M3 at the day 14 marrow were assigned to shift higher risk after induction therapy. Treatment of ALL-97 consists of early phase and maintenance phase. Early phase includes induction therapy, consolidation therapy, sanctuary therapy, and re-induction therapy for 19 to 26 weeks dependent on risk group. Early phase in IR/HR protocol is identical to the SR protocol except the addition of two doses of DNR and three doses of CPM. Maintenance phase contains standard MTX and MP with monthly VCR and PSL intensification for SR, and rotational therapy of a set of MTX and MP with a set of VCR, PSL, ASP, and (DNR or CPM) for IR/HR/ER/F. The IR protocol is identical to the HR protocol without cranial irradiation. Treatment duration is 24 months for any risk. The patients assigned ER and F were candidate for allogeneic stem cell transplantation by the end of early phase. Transplant procedures depended on the institute.

RESULTS: Number of patients at each risk was 204 for SR, 158 for IR, 128 for HR, 36 for ER, 27 for Ph+ and 10 for 11q23. Six of them were treated with incorrect risk protocol. Thirty-four patients received SCT in first CR. Following the induction therapy, 550 of 564 patients (97.5%) achieved CR. 23 patients(8 in SR, 9 in IR, 4 in HR and 2 in ER, 4.4% of all) were shift to higher risk due to the findings of day 14 marrow. Five-year overall survival rate (OS) and event-free survival rate (EFS) for all patients was 90.6% and 77.0%, respectively. Five-year EFS for NCI-SR and HR was 81.6% and 67.6%, respectively. According to risk group, 5-year EFS for SR, IR, HR, ER, Ph+ ALL, and ALL with 11q23 were 86.6%, 77.0%, 71.9%, 68.7%, 40.7%, and 70.0%, respectively. 5-year OS for them were 94.0%, 93.9%, 92.1%, 83.8%, 55.6%, and 68.6%, respectively.

CONCLUSIONS: By the risk-adapted therapy in the JACLS ALL-97 trial, high cure rate could be achieved for children with B-precursor ALL.