Acute Lymphoblastic Leukemia ALL, B Cell Acute Lymphoblastic Leukemia (B-ALL), Childhood Leukemia, Acute Lymphoblastic
Conditions
Keywords
blinatumomab, chemo-light
Brief summary
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).
Detailed description
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).
Interventions
DRUGBlinatumomab
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). Additionally, second 14 days of blinatumomab will be given after completion of HDMTX consolidation treatment.
DRUGReinduction-2 omission
Reinduction-2 will be omitted for patients with NGS-MRD46\<10\^-6 who have receive the two courses of Blina-14.
DRUGChemo-light Maintenance 2
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).
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 expected study duration is approximately 5 years. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare event-free survival (EFS) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) | Approximately 6.5 years. | 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 event-free survival (EFS) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. | Approximately 6.5 years | 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. Comparisons of EFS will be performed using two-sided log-rank test. Multivariable regression modeling including known prognostic factors as main effects may also be performed, using the Cox models. |
| Compare overall survival (OS) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. | Approximately 6.5 years | 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). Standard error will be estimated using the default procedure in R. Comparisons of OS will be performed using two-sided log-rank test. Multivariable regression modeling including known prognostic factors as main effects may also be performed, using the Cox models. |
| Compare cumulative incidence of relapse (CIR) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. | Approximately 6.5 years | CIR functions of relapse will be estimated by the Kalbafleisch-Prentice method. Comparisons of CIR will be performed by Gray's test. Multivariable regression modeling including known prognostic factors as main effects may also be performed, using the Fine-Gray models. |
| 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 | Approximately 6.5 years. | 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 | Approximately 6.5 years. | 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 | Approximately 6.5 years. | The CIR curve will be estimated by Kalbafleisch-Prentice method, along with 95% confidence intervals. |
| Compare overall survival (OS) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) | Approximately 6.5 years. | 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). Comparison of OS functions will be conducted using the two-sided log-rank test. 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 OS 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 cumulative incidence of relapse (CIR) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) | Approximately 6.5 years. | CIR functions of relapse will be estimated by the Kalbafleisch-Prentice method. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of CIR will be performed by Gray's 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 Fine-Gray models. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate toxicities during the immuno-chemo combined therapy in provisional LR-ALL. | Up to 30 days after last dose of study treatment | 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 |
| 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) | Approximately 6.5 years. | 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. |
| Compare the 3-year EFS between patients who received Blina-14 intensification with those who received CAT+ intensification | Approximately 3.5 years | 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. |
Countries
China, Hong Kong
Contacts
Primary ContactXiaofan Zhu, MD
Backup ContactJingliao Zhang, MD
Outcome results
None listed