Abstract
PURPOSE: Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF).
METHODS: We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape.
RESULTS: IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents.
CONCLUSION: The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.
| Original language | English |
|---|---|
| Pages (from-to) | 3545-3556 |
| Number of pages | 12 |
| Journal | Journal of Clinical Oncology |
| Volume | 41 |
| Issue number | 19 |
| Early online date | 25 Apr 2023 |
| DOIs | |
| Publication status | Published - 1 Jul 2023 |
Bibliographical note
Acknowledgment:The authors would like to thank all the patients who took part in the UKALL trials as well as their families. UKALL2003 was supported by grants from Blood Cancer UK (previously Leukaemia and Lymphoma Research) and the Medical Research Council. UKALL2011 was funded by Cancer Research UK (CRUK). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support toward the establishment of The Francis Crick Institute. The authors are grateful to the Blood Cancer UK Childhood Leukaemia Cell Bank, the Great Ormond Street Haematology Cell Bank, and the Queensland Children’s Tumour Bank for provision of patient samples. The authors acknowledge the input of all the scientists and technicians working in the MRD laboratories. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100, 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Keywords
- Humans
- Young Adult
- Adolescent
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Treatment Outcome
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Hematopoietic Stem Cell Transplantation
- T-Lymphocytes
- Prognosis