This prospective clinical trial evaluates the effectiveness and safety of "chemotherapy-light" regimen incorporating the third-generation TKI olverembatinib, the bi-specific CD3/CD19 T cell engager blinatumomab, and the BCL-2 selective inhibitor venetoclax for newly diagnosed pediatric/adolescent patients with Ph+ ALL. The CCCG-Ph+ B-ALL-2025 protocol will be modified as following compared to the CCCG-ALL-2020 protocol
Age older than 1 month to younger 18 years.
Newly diagnosed Philadelphia chromosome-positive or BCR::ABL1-positive B-ALL.
Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.
ALL evolved from CML.
Known underlying congenital immunodeficiency or metabolic disease.
Congenital heart disease with cardiac insufficiency.
Gastrointestinal dysfunction or gastrointestinal diseases that may significantly alter the absorption of study drug.
Single group
olverembatinib
DrugAll Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol. Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity. All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase. To decrease the toxicities of high-dose AraC, the dosage will be reduced to 1 g/m2 in the consolidation 2 phase in contrast to 2 g/m2 in 2020 protocol. Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP.
Day 48 end-of-induction measurable residual diseases (MRD48) after induction remission with olverembatinib and blinatumomab, compared to MRD46 of those treated with dasatinib plus chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts .
Primary analysis will be performed by one-sided (Monte-Carlo-) exact chi-square test because the objective calls for testing if the proportion of patients in the \<0.01% Day 48 MRD group is higher than the historical control. The historical control of Day 46 MRD of dasatinib combination with intensive chemotherapy is 80%. It is estimated that VPO+Blinatumomab can increase the negative rate of Day 48 MRD by 10%. a total sample size of 135 provides sufficient power for the planned analyses outlined above if the true D48 MRD negativity probability is 0.90 or higher based on a one-sided alpha of 0.05.
Day 19 measurable residual diseases (MRD19) during induction remission with olverembatinib plus VP (VOP), compared to MRD19 of those treated with dasatinib plus 4-drug chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts
For this objective a one-sided comparison of probabilities and historical control rate of 40% will be made. Let p2 be the probability of achieving negative D19 MRD on the current study, then the one-sided alternative hypothesis H0: p2=40% vs. H1: p2\>40% will be tested. This analysis will be performed by one-sample one-sided exact binomial test, based on a one-sided alpha of 0.025. The historical control is based on the MRD of patients treated on CCCG-ALL-2015.
Event-free survival (EFS) of patients treated with this therapy, in comparison to historical regimens.
The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2, 3 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 (CAMS-Ph+B-ALLRegimen 2025 vs. CCCG-Ph-ALL 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Overall survival (OS) of patients treated with this therapy, in comparison to historical regimens
The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2, 3 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 (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Cumulative incidence of relapse (CIR) of this therapy, in comparison to historical regimens.
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 (CAMS-Ph+B-ALLALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Fine-Gray models.
To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with cumulative incidence of event-free survival (EFS)
Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of OS and EFS will be done by log-trank test, and comparison of CIR will be done by Gray's test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with cumulative incidence of relapse(CIR)
Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The CIR curve will be estimated by Kalbafleisch-Prentice method, along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of CIR will be done by Gray's test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Fine-Gray models(CIR).
To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with overall survival (OS)
Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of OS will be done by log-rank test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models.
Incidence of Grade 3 or higher Treatment-Emergent Adverse Events (TEAE) associated with olverembatinib, venetoclax and blinatumomab, and compared with the historical controls treated with dasatinib plus intensive chemotherapy.
Proportions of grade-3 or higher TEAEs 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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