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4244 Delayed Intensification Including Venetoclax and Bortezomib Prolongs Survival in Very High Risk Acute Lymphoblastic Leukaemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Jasmeet Sidhu, MD1,2,3*, Arijit Chakraborty4*, Parag Das4*, Manash Pratim Gogoi4*, Tanima Dey4*, Fabio D. Steffen, PhD5*, Sangramjit Basu4*, Debdutta Ganguli4*, Debjani Ghosh1*, Niharendu Ghara6*, Subhajit Kundu4*, Abhirupa Kar4*, Beat Bornhauser, PhD5*, Jean-Pierre Bourquin, MD, PhD7, Vaskar Saha, PhD, FRCP, FRCPath1,3,8* and Shekhar Krishnan1,3,8*

1Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India
2University Children’s Hospital, Zurich, Switzerland
3Tata Translational Cancer Research Center, Tata Medical Center, Kolkata, India
4Tata Translational Cancer Research Center, Kolkata, India
5Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
6Department of Paediatric Haematology and Oncology, Tata Medical Center, Zurich, India
7Department of Oncology and Children’s Research Center, University Children's Hospital Zurich, Zurich, Switzerland
8Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health,, University of Manchester, Manchester, United Kingdom

Modern multi-drug risk-stratified response-adapted chemotherapy protocols lead to >85% cure rates in childhood acute lymphoblastic leukaemia (ALL). Between 2013-2022, 707 children (0-18 years) with acute lymphoblastic leukaemia (ALL) treated systematically on the ICiCLe-ALL-14 risk-adapted protocol achieved a 3-year event-free survival (EFS) of 73% (95% confidence interval, CI 69-77). A very high risk (VHR) subgroup (N = 107) was identified with poor outcome (3-year EFS, 38% [95% CI 25-51]). This included patients with induction failure, persistent minimal residual disease (MRD) and/or select high risk cytogenetic subtypes (BCR::ABL1, other ABL-class fusion ALL, TCF3::HLF, low hypodiploidy, IKZF1plus with high end-induction MRD, KMT2A-rearranged infant ALL).

Co-culture based high-throughput drug response profiling (DRP) was performed to identify alternate chemotherapeutic drugs for these VHR patients. Primary ALL blasts extracted by density centrifugation, were seeded on immortalized human bone marrow stromal cells and treated with a 14-drug panel: prednisolone; vincristine (VCR), daunorubicin; asparaginase (ASNase), bortezomib (BZM), venetoclax (VEN), panobinostat (PNB), mitoxantrone, cyclophosphamide, cytarabine, selinexor, dasatinib, 6-thioguanine and idarubicin. Seventy-four patients (25 VHR, 37 high-risk, 7 intermediate-risk, and 5 standard-risk,) were analysed. Venetoclax, BZM and PNB were identified as active agents (IC50 <100nM for VEN and PNB, <10nM for BZM) in 71%, 42% and 75% of VHR samples, respectively.

Based on drug-sensitivity patterns of VHR ALL, a pilot study was initiated to prospectively evaluate the addition of VEN and BZM in the frontline delayed intensification (DI) phase of VHR ALL patients (N=24) after informed consent (Figure 1). Response was assessed before and after VHR-DI in 46% (11/24) patients. Good response, i.e. decrease in MRD ≥ 1 log after VHR-DI, was noted in 82% (9/11) patients. Landmark analysis comparing survival of patients (from start of DI) treated on standard DI versus VHR-DI showed significant improvement in 2-year EFS from 54% (95% CI 40-66) to 76% (95% CI 51-89) (p=0.037, log-rank test). Overall, VHR-DI was tolerated well. No significant difference was noted in grade 4 and 5 toxicities (Common Terminology Criteria for Adverse Events v4.0) between standard DI and VHR-DI (p= 0.053 & p=0.988 respectively, chi-square test). Fever-neutropenia and sepsis were the most frequent toxicities with VHR-DI.

To identify potential mechanisms of resistance in poor-responders, transcriptome analysis was performed on diagnostic blast cells from VHR patients with good (N=5) or poor (N=5) response to VHR-DI and compared with highly sensitive SR patients (N=5). Upregulation of oxidative phosphorylation and ubiquitin-mediated proteolysis were found in good responders while non-responders showed upregulation of amino acid metabolic and RNA splicing pathways.

In conclusion, drug response profiling identifies alternative combination therapies for VHR ALL. Our pilot study provides proof-of-concept of effectiveness and tolerability of inclusion of VEN and BZM in the post-induction treatment of patients with poor-response disease.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH