Treatment Protocol
Our treatment protocol was adopted from the St. Jude Total XV therapy with minor modifications [5, 6]. Remission induction therapy began with prednisone, vincristine, daunorubicin, and asparaginase. Patients with ≥ 1% MRD on day 15 received three additional doses of asparaginase. The second part of Induction therapy consisted of cyclophosphamide, mercaptopurine and cytarabine. Upon hematopoietic recovery (between days 43 and 46), MRD was assessed, and consolidation therapy initiated.
After induction, patients were stratified into three risk groups (low, intermediate, high) and two protocol arms (low-risk and intermediate/high-risk). The consolidation phase of 8 weeks consisted of a 24-hr IV infusion of methotrexate at a dose of 2.5 g/m2 for low-risk patients and 5 g/m2 for intermediate- /high-risk individuals every 2 weeks for four doses in combination with 6-MP 50 mg/m2 orally once daily. The continuation phase consisted of 120 weeks for females and 146 weeks for males. A more intensive therapy termed “reinduction” was given for both risk groups. Reinduction I and II phases last for 3 weeks each and occur at weeks 7–9 and 17–19, respectively, during continuation therapy. Low-risk patients received nine doses of IM asparaginase (ASP) at 10,000 units/m2/dose in combination with dexamethasone 8 mg/m2/day for 2 weeks in each reinduction phase. Intermediate-/high-risk patients received an intensive once weekly IM ASP treatment of 25,000 units/m2/dose for the first 20 weeks of continuation in combination with once monthly dexamethasone pulses of 12 mg/m2/day over 5 days. During reinduction phases (weeks 7–9 and 17–19), intermediate-/high-risk patients receive twice-monthly dexamethasone pulses at the same dose over 7 days; between 2015 and 2017, dexamethasone doses were decreased from 12mg/m2/dose to 8mg/m2/dose for intermediate/high risk patients and from 8mg/m2/dose to 6mg/m2/dose for low risk patients.
In case of allergy to Escherichia coli (E. coli ) ASP, Erwinia-derived ASP was used at a dose of 20,000 units/m2 three times weekly to replace the 10,000 units/m2 of E. coli ASP during induction and reinductions 1 and 2 for low risk patients and 30,000 units/m2/dose twice weekly instead of e once weekly 25,000 units/m2 ofE. coli ASP for Int/high risk patients. In case of allergy to both products, we used pegylated ASP at a dose of 2,500 units/m2 once every other week. Low-risk patients are those aged 1– 9.9 years with precursor B-cell ALL and presenting white blood count of less than 50,000/𝜇 l, DNA index of ≥ 1.16 or t (12, 21). Low-risk patients must not have extramedullary disease, t (1, 19), or mixed- lineage leukemia (MLL) rearrangement. High-risk patients are those with t (9, 22) or failure of induction (> 1% of leukemic lymphoblasts at remission date). Intermediate-risk patients are all T-cell patients and precursor B-cell patients who do not meet the low-risk criteria [4].