The Lancet regional health. Southeast Asia · 2026
Functional precision approach in patients with very high risk acute lymphoblastic leukaemia in India: a single-centre cohort study.
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Sidhu Jasmeet, Chakraborty Arijit, Das Parag, Steffen Fabio D, Kundu Subhajit, Basu Sangramjit, Tarafdar Bhaswati, Dey Tanima, Kar Abhirupa, Biswas Mousumi, Das Ankita, Sivadasan Naveen, Dasgupta Pritha, Ghara Niharendu, Bornhauser Beat, Bourquin Jean-Pierre, Krishnan Shekhar, Saha Vaskar
Аннотация
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.
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.