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Updated: Jan 20, 2026
In Ovo Xenografting of Patient-Derived Acute Lymphoblastic Leukemia (ALL) Cells (PDX-ALL)
Published on: August 1, 2025
Functional precision approach in patients with very high risk acute lymphoblastic leukaemia in India: a single-centre
Jasmeet Sidhu1,2, Arijit Chakraborty2, Parag Das2
1Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, 700160, India.
Insights
Drug response profiling identified effective agents for treating high-risk childhood acute lymphoblastic leukemia (ALL). Integrating venetoclax and bortezomib improved early survival outcomes in very high-risk ALL patients.
Area of Science:
- Pediatric Oncology
- Hematology
- Pharmacology
Background:
- Measurable residual disease (MRD) and high-risk cytogenetics predict relapse in childhood acute lymphoblastic leukemia (ALL).
- Effective risk stratification and targeted therapies are crucial for improving outcomes in pediatric ALL.
Purpose of the Study:
- To analyze outcomes of children with ALL treated with the ICiCLe-ALL-2014 protocol.
- To utilize ex-vivo drug response profiling (DRP) to guide therapy modifications for very high-risk (VHR) ALL patients.
- To evaluate the impact of DRP-guided therapy on event-free survival (EFS) and overall survival (OS).
Main Methods:
- Retrospective analysis of 715 children with ALL treated between August 2013 and May 2023.
- Ex-vivo drug response profiling (DRP) performed on diagnostic or relapsed samples.
- Therapeutic modifications guided by DRP for VHR patients, including the addition of venetoclax and bortezomib.
Main Results:
- 3-year EFS varied significantly across risk categories, with VHR patients having the lowest EFS (38%).
- Persistent MRD was associated with inferior EFS (40.3%).
- DRP identified venetoclax and bortezomib as effective agents; a modified regimen incorporating these drugs showed improved 1.5-year landmark EFS (81.8%) compared to standard therapy (67.7%) in VHR patients.
Conclusions:
- DRP is a valuable tool for identifying effective agents for VHR pediatric ALL.
- The addition of venetoclax and bortezomib to therapy demonstrated improved early survival outcomes and was well-tolerated.
- Prospective evaluation of DRP-guided treatment regimens in VHR ALL is warranted.
Background:
Persistence of measurable residual disease (MRD) and high-risk cytogenetics are established predictors of relapse in childhood acute lymphoblastic leukaemia (ALL).
Methods:
Outcomes of children with ALL treated with the ICiCLe-ALL-2014 protocol at a single centre, between August 2013 and May 2023 were analysed. Co-culture ex-vivo drug response profiling (DRP) was performed on diagnostic or relapsed samples. Patients classified as very high risk (VHR) received DRP guided therapeutic modifications. Event free (EFS) and overall (OS) survival were compared across risk categories.
Findings:
Among 715 patients, at a median 55 (50-58) months, the 3-year EFS for standard-risk, intermediate-risk, high-risk B, T-ALL and VHR were 71% (64%-78%), 67% (58%-75%), 77% (70%-82%), 81% (71%-88%), and 38% (24%-52%) respectively (p < 0.0001). Persistent MRD at end of consolidation was associated with inferior EFS (40.3%, p ≤ 0.0001). Drug sensitivity scores from DRP performed on 112 samples identified panobinostat (median DSS 23.4), venetoclax (20.7), daunorubicin (17.9), selinexor (12.7) and bortezomib (12.1) as effective in VHR or relapsed ALL. From November 2020, 25 VHR patients received a modified treatment block incorporating venetoclax and bortezomib. At 1.5-year, landmark EFS was 81.8% (58%-93%) with the modified regimen vs 67.7% (49-81) with standard therapy (p = 0.0324). Venetoclax sensitivity correlated with MRD clearance (p = 0.0070).
Interpretation:
DRP enabled identification of effective agents for integration into therapy of VHR paediatric ALL. The addition of venetoclax and bortezomib was well tolerated and associated with improved early survival outcomes. These findings support prospective evaluation of DRP-guided treatment regimens in VHR ALL.
Funding:
DBT-Wellcome India Alliance, Tata Consultancy Services.
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