Abstract
Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.
Highlights
Current treatments for high-grade paediatric B-cell non-Hodgkin lymphoma (B-NHL) in resource-rich countries are extremely effective, with over 93% of children being cured [1,2,3,4,5]
In keeping with previously published clinical trial cohorts [4, 41], the 89 FAB/ LMB96-treated cases in the present study demonstrated a median age of 8 years, a male predominance of 3.4:1, a predominance (67%) of Burkitt lymphoma, a majority of high stage (III/IV) patients (73%), bone marrow disease in 18% and CNS disease in 6% of cases
Stratification of the low/intermediate-risk group identified an high-risk B-NHL has resulted in ≥93% event-free survival (EFS) in inferior outcome for patients with any TP53 abnormality but this all risk groups [5]
Summary
Current treatments for high-grade paediatric B-cell non-Hodgkin lymphoma (B-NHL) in resource-rich countries are extremely effective, with over 93% of children being cured [1,2,3,4,5]. Following the recent demonstration of the benefit of the anti-CD20 monoclonal antibody rituximab, these same rates of cure are achieved even in patients presenting with established highrisk clinical features (high lactate dehydrogenase (LDH), bone marrow (BM) and/or central nervous system (CNS) disease) [5] This success, has required the use of intensive multiagent chemo-immunotherapy regimens, associated with significant, predominantly acute, toxicity such as infection and mucositis as well as a small risk of long-term neurological side effects and second malignancy [6,7,8]. A more comprehensive understanding of the biological drivers of therapy resistance is essential to support the development of more effective and less toxic targeted therapies for this group of patients [15]
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