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Adult T‐cell leukaemia/lymphoma and the trouble with TP53

Adult T-cell leukaemia/lymphoma (ATL) remains a highly aggressive T-cell malignancy with no major improvement in the overall survival of patients since first reported 40 years ago. Despite clinical trials of a variety of novel agents including chemotherapy intensification, the median overall survival of those with aggressive subtypes remains 6–9 months. In acute and lymphoma subtypes treatment with either chemotherapy or zidovudine with interferon alpha is not usually curative and the typical disease course is characterised by early chemotherapy-resistant relapse, malignant hypercalcaemia and frequent opportunistic infections that can preclude potentially curative allogeneic transplantation. ATL is a clinically heterogeneous disorder with a variety of presentations according to clinical subtype (skin, leukaemic, nodal, lung or central nervous system presentations, etc.), and with varying responses to treatment. For example, zidovudine with interferon or mogamulizumab may be relatively effective in leukaemic disease, but less so in patients with any significant lymphadenopathy. Several clinical parameters including age, performance status, and biochemical markers have been suggested to predict clinical course. In chronic leukaemic disease the presence of any one of raised urea, lactate dehydrogenase (LDH) or a reduced albumin is associated with an inferior prognosis (‘chronic unfavourable’ subtype), but prognostic scores in aggressive disease have not yet identified biological groups of patients that clearly do not benefit from risks of transplantation. There is clear and urgent clinical need to develop novel treatment strategies underpinned by understanding the molecular disease. Whilst human T-cell lymphotropic virus type 1 (HTLV-1) is the hallmark of ATL, the fact that relatively few carriers develop malignancy, and that a long latency period is required prior to malignant presentation, suggest that HTLV-1 infection itself is not sufficient for disease transformation and abnormal ATL-like clonal expansions containing driver mutations may circulate in the peripheral blood of asymptomatic carriers for years prior to the development of malignancy. Kataoka et al. delineated the genomic landscape and reported that aggressive subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequency of TP53 and IRF4 mutations, and many copy number alterations, including PD-L1 amplifications and CDKN2A deletions. A molecular profile typically seen in aggressive disease (IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions) significantly predicted a poor prognosis when it was observed in indolent ATL, suggesting a subset of patients that might benefit from earlier intensified therapy or, extrapolating from B-cell non-Hodgkin lymphoma (NHL) observations, incorporating lenalidomide which may overcome the poor prognosis conferred by IRF4 mutations. The results reported here by Sakamoto and colleagues are tremendously exciting since for the first time the impact of abnormal TP53 on clinical outcomes has been revealed in a sizeable cohort of patients (n = 177) treated in Japan with standard clinical protocols. This builds upon their previous report that activating mutations in CCR4 are associated with better responses to mogamulizumab. Here, the authors report that abnormalities in TP53 were observed frequently (37 9% of cohort) and were associated with really poor survival, and this cannot be overcome by allogeneic transplantation. Of the total cohort, those with abnormal TP53 had a median overall survival of just one year compared with 6 7 years in those without TP53 abnormalities. The type of abnormality may also be important — TP53 copy number variants (CNVs) alone had a significantly worse overall survival than those with TP53 single nucleotide variants/insertions or deletions (SNVs/Indels) +/ CNVs (0 8 vs 1 0 year). Patients younger than 70 years were planned to receive an allogeneic transplant, and those with abnormalities in TP53 Correspondence: Lucy B. M. Cook, Department of Haematology and National Centre for Human Retrovirology, Imperial College Healthcare NHS Trust, 2nd Floor Catherine Lewis Centre, Hammersmith Hospital, London W12 OHS, UK. E-mail: l.cook@imperial.ac.uk commentary