Purpose Although IKZF1 deletion ( IKZF1) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1 to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1 using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1 on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1 frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1 was not used in risk assignment, IKZF1 conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1 conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1 significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1 improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1 significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1 screening significantly improved treatment outcomes in contemporary ALL therapy.

PURPOSE To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines. PATIENTS AND METHODS Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts. RESULTS The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively ( P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% ( P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively ( P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004). CONCLUSION In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.

Vincristine (VCR) is a key drug in the successful multidrug chemotherapy for childhood acute lymphoblastic leukaemia (ALL). However, it remains unclear how VCR pharmacokinetics affects its antileukaemic efficacy. The objective of this study is to explore the VCR pharmacokinetic parameters and intracellular VCR levels in an up-front window of Ma-Spore ALL 2010 (MS2010) study. Methods: We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 BALL and 20 TALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed. Results: There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in BALL , Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR 24h levels (P = .03 and P = .04, respectively). The median VCR 24h intracellular levels were similar among the Nan Jiang, Lingzhi Wang and Xiaoqiang Xiang contributed equally. The authors confirm that the PI for this paper is Allen Eng-Juh Yeoh and he had direct clinical responsibility for patients.