PF493 TP53 STATUS IN MANTLE CELL LYMPHOMA (MCL) ‐ A 10 YEAR SINGLE CENTER EXPERIENCE

Abstract

Background:Mantle Cell Lymphoma (MCL) is a rare sub‐type of B‐cell non‐Hodgkin lymphoma (NHL), with variable course. Most of patients with this disease has an aggressive clinical course and poor prognosis. MCL is responsive to a variety of initial therapies, but relatively short‐term remissions are achieved with conventional chemotherapy regimens. The median duration of remission in most trials using standard chemo‐immunotherapy is 1.5–3 years and the median overall survival (OS) is 3–6 years. TP53 mutation confers a dismal prognosis in MCL with a median survival of 1.3 years.Aims:The aim of this study was to further investigate the mutation profile and prognostic impact of TP53 mutations in our cohort of 29 MCL patients over the study period (2006–2016). In addition, to correlate the TP53 mutational status with p53 expression by immuno‐histochemistry (IHC).Methods:We analysed 32 tumour DNA samples (including 2 samples at relapsed disease) for evidence of TP53 disruption using p53 expression (>30% cut off for positivity) on IHC, Sanger sequencing (SS) (exon 4–10) and next generation sequencing (NGS) if indicated.Results:The median age at diagnosis was 65 years (range, 36–88 years), with predominately male patients (72%). Nineteen (59%) samples were nodal including 4(12%) samples with blastoid variant morphology, while the remaining,13 biopsies (41%) were extra‐nodal. Three (10%) patients had multiple samples, one was from a separate involved site at initial presentation and 2 samples were taken at disease relapse. The proliferation index (Ki67) expression was high (>30%) in 4 (14%), low in the remainder (76%) and un‐available in 3 (10%) samples. Immunoglobulin variable heavy chain genes (IGHV) mutation status were analyzed in 22 samples, 13 (59%) patients had mutated IGHV whilst the remaining 9 (41%) with unmutated IGHV genes. A deleterious TP53 mutation was detected in 6 (21%) samples, of which all (100%) of these mutant sample showed positive p53 expression on IHC confirming the strong correlation of p53 expression and mutional status. The total number of deaths over the study period were 11 (38%), lymphoma related death (disease progression) were accounted in 5 (45%) patients. Of these, 4 (80%) patients were harbouring deleterious TP53 mutations. While the reminder 6 (55%) deaths were either un‐treated patients due to extreme age (3 patients = 10%) or non‐lymphoma related death (3 patients = 10%). The median OS and PFS for the entire cohort were 6.5 and 3 years respectively. As expected, OS was significantly shorter among MCL cases with high MIPI score than among MCL cases with low MIPI score (median 4.3 years vs unreached, P = 0.03, log rank test). Most of MCL patients harbouring TP53 mutations have aggressive disease course with multiple relapses and lymphoma related deaths (80%). In sub‐set analysis, the impact of TP53 mutation was clearly apparent on patient survival, the OS was only 4 years in TP53 mutated disease and was not reached in the wild‐type TP53 cohort (P value = 0.007, long rank test). These findings confirm the dismal outcome of MCL patients harbouring TP53 mutations as reported in literature.Summary/Conclusion:Our data confirmed the dismal outcome of MCL in presences of TP53 disruption and the strong correlation between p53 expression and the mutation status, of which will be incorporated in our routine initial histological assessment. We intend to expand this project nationally to overcome the sample size limitations and advocating upfront use of novel therapies in TP53‐disrupted disease in larger clinical trials.image