Newly-diagnosed Low Risk Pediatric B-cell ALL Protocol

Phase 3RecruitingNCT06882057

Institute of Hematology & Blood Diseases Hospital, China3,000 enrolled

Overview

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).

1. All 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). 2. Two courses of HD-MTX will be administered as consolidation phase, maintaining the same dose of 3 g/m². 3. Second 14 days of blinatumomab will be given after completion of HDMTX consolidation treatment . 4. Adding IgH rearrangement NGS MRD as an evaluation indicator. Reinduction-2 will be omitted for patients with NGS-MRD46\<10-6 who have receive the second course of Blina-14. (Reinduction-2 should be given regardless of NGS-MRD 46 status in patients who did not receive the second course of binatumomab). 5. A total of four repeating courses will be applied in Maintenance 1 (in contrast to 5 courses in 2020 protocol). Additionally, one-week rest period will be implemented after each course to ensure safety and optimal efficacy. 6. Patients 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). The other patients with higher levels of MRD by FCM MRD or NGS MRD will receive maintenance-2 with 9 cycles of 8-week course of MTX + 6MP for a total of 72 weeks (same as CCCG-ALL2020) 7. Bone Marrow Aspiration Assessment (BMA): One additional bone marrow puncture at the end of 1st Blina-14 course (Day60 MRD) will be performed at early intensification phase. This results in a total of 4 BMAs in the CCCG2025-LR protocol, in contrast to 3 BMAs in 2020 protocol. 8. Triple Intrathecal Therapy (TIT)：In the HDMTX consolidation phase, there will be two TITs in contrast to four treatments in the CCCG2020 protocol. To compensate for this reduction, two additional TIT treatments will be administrated before the 1st and 2nd Blina-14 courses. Additionally, two intrathecal treatments will be added during Reinduction 1 and Reinduction 2 to further enhance CNS control. Meanwhile, one TIT will be reduced in the Maintenance-1 phase compared to 2020 protocol. This results in a total of 16 or 17 TITs, depending on whether the second Blina-14 course is applied This is similar to the CCCG2020, where 16 or 17 TITs are administrated depending on whether CAT+ was given). 9. Adding pharmacotyping study for LR B-ALL. 10. Treatment duration: The treatment duration for the CCCG-LR-ALL-2020 protocol is 121/124 weeks (depending on if CAT+ was given). In the CCCG-LR-ALL-2025 protocol: * For patients with NGS MRD46 ≥10-6, the total treatment duration is 123 weeks. Key changes include: 2 weeks of Blina-14 replacing 3 weeks of CAT+, 2 courses of HDMTX reduction (4 weeks), and an additional 2 weeks for the 2nd blina-14 course added following HDMTX; * For patients with MRD19≥ 0.01% and NGS MRD46 \< 10-6 who subsequently receive 2nd Blina-14, Reinduction-2 is omitted, shortening the total duration by 3 weeks. (120 weeks in total). If the 2nd Blina-14 is not administrated, Reinduction -2 will still be included, resulting in a total duration of 121 weeks. * For patients with MRD19 \< 0.01% and NGS MRD46 \< 10-6, who subsequently receive 2nd Blina-14, both the Reinduction-2 (3 weeks) and the subsequent 5 cycles of Maintenance-2 (40 weeks) are omitted. This results in a total treatment duration of 80 weeks (81 weeks if 2nd Blina-14 is not applied).

Eligibility

Sex: ALLMin age: 1 YearMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Must meet all items below: 1. Age older than 1 year and younger than 18 years. 2. Diagnosis of acute lymphoblastic leukemia by bone marrow morphology. 3. Diagnosis of B-ALL by immunophenotyping. 4. Low risk group Exclusion Criteria: Should be excluded in the presence of any item below: 1. T-ALL 2. I/HR B-ALL group 3. sIgM+ 4. Acute leukemias of ambiguous lineage diagnosed according to WHO or EGIL criteria. 5. Philadelphia chromosome positive ALL (Ph-ALL) 6. ALL evolved from chronic myeloid leukemia (CML). 7. Down's syndrome, or major congenital or hereditary disease with organ dysfunction 8. Secondary leukemia 9. Known underlying congenital immunodeficiency or metabolic disease 10. Congenital heart disease with cardiac insufficiency. 11. Glucocorticoid treatment for ≥14 days, or ABL kinase inhibitors for \> 7 days within one month before enrollment, or any chemotherapy or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression)

Outcomes

Primary Outcomes

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.

Time frame: The expected study duration is approximately 5 years.

Secondary Outcomes

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).