The Significance Of TP53 Mutation In Mature B Cell Lymphomas

Background and Objectives Tumor suppressor gene TP53 is the most frequently mutated gene across all cancer types.TP53 mutations are detected in more than half of patients with solid tumors.There are obvious homogeneity and heterogeneity in TP53 mutation of the effect on the prognosis of patients with solid tumors,which include the type of mutation and hotspot of mutation.However,there is no systematic study on TP53 mutation in B-cell lymphomas.This study aims to explore the significance of TP53 mutation in B-cell lymphomas.Methods We performed a retrospective analysis of data from mature B cell lymphomas identified at the Institute of Hematology&Blood Diseases Hospital,Tianjin.A total of 1858 patients with newly diagnosed B-cell lymphoma were enrolled according to the 2016 World Health Organization lymphoid tumors classification between 2010 and 2022.TP53 mutations were examined by second-generation sequencing technology(NGS)in all patients.There were 1483 patients with B-cell chronic lymphoproliferative disease(BCLPD)and 375 patients with aggressive B-cell lymphoma.The mutation frequency and mutation type distribution of the TP53 gene were described for all the patients.And we analyzed the correlation between TP53 mutation and genome stability.In addition,we compared the overall response rate(ORR)to front-line treatment,complete response rate(CRR),overall survival(OS),and progression-free survival(PFS)of different mutations to illuminate the heterogeneity of mutations.Results There were 306 patients with TP53 mutation among the 1858 patients,with a mutation frequency of 16.5%.The mutation frequency of TP53 was 24.8%in aggressive B cell lymphoma,and 14.4%in patients with BCLPD.There was a marked difference in mutation frequency between the two groups.The mutation frequency in aggressive B cell lymphoma was significantly higher than that in BCLPD(p<0.001).In mature B-cell lymphoma,TP53 mutation mainly occurs in exons 5-8,the and most common type of mutation is missense.In BCLPD,the most common hotspot mutations in the p53 protein include 248,273,282,245,175,and 179,all of which are in the DNA binding domain.Compared with the patients without TP53 mutation,patients with TP53 mutation had a higher proportion karyotype abnormality(59.9%vs 39.9%),chromosome 17p13 deletion(56.7%vs 3.7%),chromosome 13q14 deletion(23.4%vs 11%).Patients with TP53 mutation had significantly shorter overall survival(OS)(3-year OS rate of 63.8%vs 90.7%,p<0.001)and progression-free survival(PFS)(3-year PFS rate of 51.6%vs 80.7%,p<0.001).Notably different effects on patients’ prognosis were observed for mutation in the same domain.For example,patients with mutations the of p53 protein at 273,175,179,and 220 have a worse prognosis than patients with mutations of the other sites at the DNA binding domain.These patients manifested with lower treatment response rates(CRR,8.7%vs 30.8%,p=0.041)and short survival time(3-year OS rate 43.6%vs 67.2%,p=0.0031;3-year PFS rates were 32.0%vs 54.7%,respectively,p=0.003).In addition,patients with mutations located in exons 2 and 5 have a poor prognosis.For aggressive B cell lymphoma,the most common mutations at p53 protein are 248,175,282,245 and 273 of p53 protein,which are also located in the DNA binding domain.The proportion of chromosome 17p13 deletion in patients with TP53 mutation was significantly higher than that in patients without TP53 mutation(50.6%vs 11.1%).Besides,the proportion of complex karyotypes in patients with TP53 mutation was higher than that in patients without TP53 mutation(25.9%vs 9.3%,p=0.058),but there was no statistical difference.Patients with mutations at exons 5 and 10 tended to have longer survival than patients with mutations at other exons but still had a poorer prognosis than wild-type patients.Patients with mutations at 245,282,161 and 196 showed a tendency of decrease in CRR(CRR 20.0%vs 50.0%,p=0.180).Compared to patients with mutations at other sites,these patients had significant shorter PFS(median PFS of 4.8 months vs 19.8 months,respectively,p=0.021)and OS(median OS of 12.3 months vs 42.8 months,respectively,p=0.047).Conclusion Based on the clinical data of mature B-cell lymphoma,we noted that for patients with BCLPD and aggressive B cell lymphoma,The frequency and characteristic distribution of TP53 mutation revealed the differences of TP53 mutation in different disease types.Also for diseases with similar clinical characteristics,the heterogeneity of the effects of different sites and exons on response rates to the front-line treatment and survival was identified.Even if the mutation in the same domain,the effect of different sites on prognosis is different.We identified p53 protein mutation sites with worse prognosis in patients with BCLPD and aggressive B-cell lymphoma,including hot spot mutations and mutation sites that are rare in clinical practice,which had a certain guiding significance for clinical prognosis and treatment selection.Background and Objectives Follicular lymphoma(FL)is a common mature indolent B-cell lymphoma,and it is incurable.Patients with FL often experience recurrent relapses and unfortunately,the response duration and survival time shorten after each relapse.Therefore,the target of the treatment of FL is to postpone the relapses,prolong survival,and improve the quality of life.Currently,the front-line treatment for patients with newly diagnosed FL is immunochemotherapy.After the end of induction therapy,two-year’s rituximab maintenance is of consideration for patients who respond to the induction.Rituximab maintenance(RM)prolongs the progression-free survival(PFS)of responding patients with follicular lymphoma(FL).FL is a heterogeneous disease.Follicular Lymphoma International Prognostic Index(FLIPI)is the most commonly used risk stratification system in clinic.Although several studies showed that RM prolonged PFS in FL,the maintenance efficacy in different risk groups is still confusing.This study aimed to describe the characteristics of newly diagnosed FL,analyze the response to front-line treatment,and explore if the FLIPI could be the indication for patients with FL to benefit from RM the most.Methods We retrospectively enrolled the newly diagnosed patients with FL at Institute of Hematology and Blood Disease Hospital between 2013 and 2019.These patients received standard 4-8 cycles of immunochemotherapy.Efficiency was evaluated 1 month after the end of induction therapy.Their physician’s recommendation and personal decision determined patients who achieved remission.Some patients continued RM every 3 months(RM group),while others continued observation(control group).Kaplan-Meier method was used to fit the survival curves of PFS and OS,and comparison between groups was performed by log-rank test.Results A total of 173 newly diagnosed patients with FL were enrolled in this study.The median age was 47 years,and the proportion of male patients was 45.7%.There were 90.1%of patients who had Ann Arbor Ⅲ-Ⅳ disease.Bone marrow involvement was observed in 67.1%of patients.The proportion of FLIPI low-risk,intermediate-risk,and high-risk were 26.6%,47.4%,and 26%,respectively.After a median follow-up of 39 months,neither median overall survival(OS)nor PFS was reached for the entire population.The PFS was significantly prolonged in the RM group compared to the control group(median PFS NA vs 83.1 months,P=.00027).When the population was divided into the 3 FLIPI risk groups,the PFS differed significantly(4-year PFS rates,97.5%vs 88.8%vs 72.3%,P=.01)according to group.There was no significant difference in PFS for FLIPI low-risk patients with RM compared to the control group(4-year PFS rates,100%vs 93.8%,P=.23).However,the PFS of the RM group was significantly prolonged for FLIPI intermediate-risk(4-year PFS rates,100%vs 70.3%,P=.00077)and high-risk patients(4-year PFS rates,86.7%vs 57.1%,P=.023).Conclusion These data suggest that patients with FL achieved good response and long survival with immunotherapy.FLIPI had prognostic value in the Rituximab era.In addition,standard RM significantly prolongs the PFS of patients assigned to intermediate-and high-risk FLIPI groups but not to lowrisk FLIPI group and is pending larger-scale studies to validate.