CCCG-ALL2025 LR-B-ALL plan is designed based on the CCCG-ALL2020 plan. This is a clinical trial using 14 days of blinatumomab (Blina-14) as early intensification after induction therapy and 2nd Blina-14 in consolidation therapy in all newly diagnosed provisional low-risk (LR) pediatric acute lymphoblastic leukemia (ALL) patients, regardless of measurable residual diseases (MRD) status. We will compare the efficacy of chemotherapy combined with Blina-14, comparing to CAT+ intensification or historical regimens. Patients with early remission in depth will receive chemo-light late intensification and maintenance therapy afterwards. Early complete remission in depth and maintenance reduction will be determined by next-generation sequencing (Ig-NGS MRD).
Age older than 1 year and younger than 18 years.
Diagnosis of acute lymphoblastic leukemia by bone marrow morphology.
Diagnosis of B-ALL by immunophenotyping.
Low risk group
T-ALL
I/HR B-ALL group
sIgM+
Acute leukemias of ambiguous lineage diagnosed according to WHO or EGIL criteria.
Factorial
Blinatumomab
DrugAll LR-B-ALL patients will be treated with 14 days of blinatumomab (Blina-14) as early intensification to replace CAT+ (historically given in LR-B-AL with MRD19\>0.1% in the 2020 protocol). Additionally, second 14 days of blinatumomab will be given after completion of HDMTX consolidation treatment.
Reinduction-2 omission
DrugReinduction-2 will be omitted for patients with NGS-MRD46\<10\^-6 who have receive the two courses of Blina-14.
Chemo-light Maintenance 2
DrugPatients with FCM-MRD19\<0.01% and IgH rearrangement NGS MRD 46\<10\^-6 will receive chemo-light maintenance-2 with 4 cyles of 8-week course of MTX + 6MP (totally 32 weeks).
Compare 3-year event-free survival (EFS) between patients who receive Blina-14 intensification with this historical controls from CCCG-ALL2015 and CCCG-ALL2000
The primary historical control cohort consists of the patients on the CCCG-ALL2020 trial determined as LR after remission indiction, received 2xHDMTX during consolidation and did not receive Bliniatumomab. As of end of 2024, this cohort contains 1111 patients, with 3-year EFS 0.963 and standard error 0.0087, 95% confidence interval \[0.953,0.980\] . The sample size and power assessment below is based on these data. The primary comparison is between the patients on this trial who are determined as LR after remission induction to the historical cohort described above, on 3-year EFS probability. .Power of the above test procedure is assessed by a simulation study. Historical control is set from the preliminary data as S0=0.963,v0\^2=0.0087\^2. For the current trial total sample size is set to n=2325 with 5 year accrual.LN distribution is chosen for its good assemblance of the EFS functions of the LR cohorts in the historical data.
Estimate event-free survival (EFS) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy
The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 1, 3, 5 years since diagnosis).
Estimate overall survival (OS) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy
The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 1, 3, 5 years since diagnosis).
Estimate cumulative incidence of relapse (CIR) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy
The CIR curve will be estimated by Kalbafleisch-Prentice method, along with 95% confidence intervals.
Compare event-free survival (EFS) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020)
The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 1, 3, 5 years since diagnosis). Standard error will be estimated using the default procedure in R. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of EFS will be performed using two-sided log-rank test. Multivariable regression modeling including trial (CCCGALL-2025 vs. 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Compare the 3-year EFS between patients who received Blina-14 intensification with those who received CAT+ intensification
The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at 3 years since diagnosis. Standard error will be estimated using the default procedure in R. Comparison will be made using the Z-test procedure described in primary endpoint.
Evaluate the significance of the early deep remission rate after Blina-14 intensification by its association with treatment outcomes, especially cumulative incidence of relapse (CIR)
CIR functions of relapse will be estimated by the Kalbafleisch-Prentice method. Associations between deep remission status after blinatumimab treatment and relapse will be analysed using Gray's test or Fine-Gray regression models, as appropriate.
Evaluate toxicities during the immuno-chemo combined therapy in provisional LR-ALL.
Proportions of grade-3 or higher AEs in each treatment phase will be estimated by the sample proportions along with exact 95% confidence intervals. Cumulative incidences of various grade-3 or higher AEs throughout therapy will be estimated by the Kalbafleisch-Prentice method; death, relapse and other events rendering off therapy before completion are regarded as competing risks
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