Clinical Biological Characteristics And Prognostic Analysis Of Chronic Lymphocytic Leukemia And Indolent Mantle Cell Lymphom

Background and Objectives:Chronic lymphocytic leukemia(CLL),the most common adult leukemia in Western countries,is 10-20 times less common in China than in Europe.The reason for the difference is not yet clear.At present,the differences in clinical,biological characteristics and prognosis of CLL patients in China and Western countries are not well understood,and the number of cases in the study cohort reported in China is small.Unmutated immunoglobulin heavy chain variable region(IGHV)is an independent adverse prognostic factor for CLL,but the prognostic characteristics of Chinese CLL patients using different IGH-VDJ fragments are not yet clear.Based on a large series of case data,this study explored the clinical and biological characteristics of Chinese patients with CLL,the proportion and efficacy of different treatments,and the real-world survival outcome.The IGHV mutation status,the usage characteristics of IGH-VDJ fragment,the stereotype of B-cell receptor(BCR)and the influence of the above factors on the prognosis were analyzed.This paper aims to explore the causes of different morbidity and clinical characteristics of CLL patients in China and Western countries from the perspective of immunogenetics.Methods:The data of 2005 CLL patients admitted to Blood Diseases Hospital,Chinese Academy of Medical Sciences from February 2000 to December 2020 were retrospectively analyzed.The immunoglobulin sequences of 1223 Chinese CLL patients were collected,and those of 7424 published CLL patients from Europe and the United States(hereinafter referred to as the west)were compared for IGHV gene mutation status,IGH-VDJ gene fragment use and BCR stereotype frequency.Chi-square test or Fisher exact probability method were used to compare the count data between groups.The Maan-Whitney U test was used to compare the measurement data of skewness distribution between groups.Kaplan-Meier method was used to calculate the survival rate,and log-rank test was used to compare the survival rate between groups.Results:Clinical features:The median age of 2005 CLL patients at diagnosis was 61(20-92)years old,nearly 10 years younger than that of western CLL patients.The male to female ratio was 1.8:1,which was similar to that reported in western countries.The proportion of asymptomatic patients who only found abnormal blood routine(49.0%)at diagnosis was lower than that of western countries(70%),and the proportion of Binet B-C stage(69.3%)and Rai medium-high risk stage(78.7%)were higher than that of western CLL patients.Compared with western reports,the proportion of patients with immunophenotypic score≥3(96.2%)at diagnosis was similar,with a higher proportion of positive CD5,CD23,FMC7,a higher proportion of weakly positive CD22,and a lower proportion of positive CD10 by flow cytometry.Biological characteristics:the proportion of RBI deletion(20.9%)detected by immunofluorescence in situ hybridization(FISH)was lower than that of Western countries,the proportions of trisomy 12(20.1%),IgH translocation(16.6%),del(17p)(11.3%)and del(11q)(10.8%)detected by FISH were similar to those reported in Western countries.Treatments and survival outcome:Among 1476 patients with treatment data available,1191(80.7%)were treated,a higher proportion than in Western countries.The time from diagnosis to first treatment(TTFT)was 7.0(95%CI 4.1-9.9)months,which was shorter than reported in Western countries.Among the patients who started treatment,the proportions of first-line conventional chemotherapy,immunochemotherapy and targeted therapy were 69.1%,14.4%and 16.5%,and the overall response rate(ORR)was 68.6%,88.2%and 94.3%,respectively(P<0.001).Median progression free survival(PFS)time was 44.0(95%CI 40.5-47.5)months,5-year PFS rate was 36.8%(95%CI 32.9%-40.7%),and 10-year PFS rate was 13.7%(95%CI 10.0%-17.4%).Median overall survival(OS)was 136.0(95%CI 123.4148.6)months,5-year OS rate was 78.7%(95%CI 76.5%-80.9%),and 10-year OS rate was 53.9%(95%CI 50.2%-57.6%).The PFS and OS of CLL patients receiving first-line immunochemotherapy and targeted therapy were superior to those receiving conventional chemotherapy,and those who achieved partial response(PR)or above after first-line treatment could obtain longer PFS and OS.In 543 relapsed or refractory CLL patients,the ORR of second-line conventional chemotherapy,immunochemotherapy and targeted therapy was 49.5%,60.8%and 85.5%(P<0.001),respectively.The median PFS was 31.0(95%CI 27.4-34.6)months,and the median OS was 84.0(95%CI 75.7-92.3)months.Efficacy and survival of patients treated with first-line FCR and R-CHOP were compared,ORR,median PFS,and median OS were similar between the two cohorts.Interestingly,it was observed in this study that women had longer OS than men.In addition,the median OS for younger patients was nearly 13 years,while that for older patients was less than 10 years.The characteristics of very young CLL patients<40 years old were analyzed and compared with those reported by MD Anderson Cancer Center(MDACC)in the United States.It was found that the very young CLL patients in this study had a higher ratio of Rai high risk stage and shorter TTFT,and the 5-year and 10-year OS rates were lower than those reported by MDACC.Characteristics of IGH-VDJ use and its impact on prognosis:compared with western CLL patients,Chinese patients with CLL had a higher proportion of mutated IGHV(65.8%vs.54.9%,P<0.001),a higher frequent usage of IGHV4 and IGHV7 fragment and a lower frequent usage of IGHV1 fragment.A higher frequent usage of IGHV4-34,IGHV4-39,IGHV4-59,IGHV374 fragments and a lower frequent usage of IGHV1-69,IGHV1-2 and IGHV321 fragments was observed in Chinese CLL patients.IGHD3 fragment was the most commonly used D-region fragment in CLL patients in China and western countries.In addition,IGHD6,IGHD3-10,IGHD6-13,IGHD3-9,IGHD5-12,IGHD2-21 and IGHD5-18 fragments were more frequently used,while IGHD3-3 and IGHD2-2 fragments were less frequently used in Chinese CLL patients.IGHJ4 fragment was the most commonly used fragment in J-region of CLL patients in China and western countries,but the frequency in China was higher than that in western countries.In addition,IGHJ5 fragment was used more frequently and IGHJ6 fragments was used less frequently in Chinese CLL patients than in western CLL patients.In this study,15.3%of CLL patients had stereotyped BCR,and the major stereotyped BCR accounted for 7.4%,both lower than the frequency reported in western countries.In addition,the frequency of subset#8,subset#4 and subset#77 was higher in the Chinese CLL cohort,while the frequency of subset#2 was lower.Consistent with previous reports,the median TTFT,median PFS,and median OS of CLL patients with unmutated IGHV were shorter.CLL patients with heavy chain complementarity determining region 3(HCDR3)sequence amino acid length ≥17 had poor prognosis.Of concern,CLL patients using the IGHV1 fragment had shorter PFS and the result was independent of the IGHV mutation status.The median TTFT of CLL patients using IGHD4 fragment was longer,while the median PFS and median OS were shorter.In addition,whether use of IGHV1-69,IGHD4-17,IGHJ4 and IGHJ6 segments had a statistically significant impact on prognosis.Patients with stereotyped BCR had shorter median PFS and median OS than those without stereotyped BCR,but the difference was not statistically significant.Conclusions:This study is the largest real-world study of CLL patients in China to date.These data can serve as an important baseline for evaluating new therapies and lay the foundation for future clinical studies of CLL in China.Although compared with Western CLL patients,Chinese CLL patients were younger at diagnosis,had advanced clinical stages,a higher proportion of requiring treatment,shorter TTFT,a higher proportion of IGHV mutations,and different usage characteristics of IGHVDJ,overall survival outcomes were similar to those reported in Western studies.At the same time,the study reported the characteristics of IGHV use and its impact on prognosis in the largest series of CLL patients in China,with the number of cases nearly twice that of the largest published cohort.There were differences in the proportion of IGHV mutation,the use frequency of IGH-VDJ gene and the distribution of stereotyped BCR between Chinese and Western CLL patients,suggesting that there may be different antigen exposure in the course of disease in Chinese and Western CLL patients.Background and Objectives:Mantle cell lymphoma(MCL)is a mature B-cell tumor with clinical and biological heterogeneity,mainly in elderly males,often invading the sites besides lymph nodes.It is characterized by both rapid progression of invasive lymphoma and incurability of indolent lymphoma.MCL is mainly divided into two subtypes:classical mantle cell lymphoma(cMCL)and leukemic non-nodal mantle cell lymphoma(nnMCL).nnMCL is rare,and only a few cases have been reported in China.The understanding of nnMCL by clinicians is still insufficient.In this study,the clinical,biological and prognostic characteristics of patients with nnMCL were discussed,and the differences were summarized between nnMCL and cMCL,so as to improve the hematologists’ understanding of the disease.Methods:Clinical data of 14 patients with nnMCL and 238 patients with cMCL were retrospectively analyzed in Blood Diseases Hospital,Chinese Academy of Medical Sciences from November 2000 to October 2020.The clinical,biological and prognostic differences between patients with nnMCL and those with cMCL were compared.The counting data were expressed as n(%)and compared between groups by chi-square test or Fisher exact probability method.The measurement data of skewness distribution were expressed as M(Q1,Q3)and compared between groups by Maan-Whitney U test.Kaplan-Meier method was used to calculate the survival rate,and log-rank test was used to compare the survival rate between groups.Results:Compared with cMCL patients,nnMCL patients had a lower proportion of lymphadenopathy(28.6%versus 90.5%,P<0.001),a lower proportion of B symptoms(0.0%versus 40.5%,P=0.002),higher median WBC and ALC counts(25.8×109/L versus 8.6×109/L,P=0.002),(23.5×109/L versus 2.2×109/L,P<0.001),a lower proportion of anemia(14.3%versus 45.1%,P=0.024),a higher proportion of immunophenotype CD200 expression(57.1%versus 14.6%,P=0.001),a higher proportion of immunophenotype CD23 expression(57.1%versus 13.5%,P<0.001),a lower proportion of immunophenotype CD5,CD38 and SOX11 expression(71.4%versus 97.4%,P=0.001),(28.6%versus 69.6%,P=0.005),(20.0%versus 77.9%,P=0.014).The mutated proportion of immunoglobulin heavy chain variable region(IGHV)was higher(100.0%versus 26.0%,P<0.001).However,there were no significant differences in age,gender,PLT count,mantle cell lymphoma international prognostic index(MIPI)grouping,and proportion of enlarged spleen.Moreover,there were no significant differences in the proportion of P53 gene deletion,ATM gene deletion,RBI gene deletion,chromosome 12 trisomy detected by FISH and complex karyotypes.The time to first treatment(TTFT)for nnMCL patients was 19 months.Among the 14 nnMCL patients,6 patients were still under observation,8 patients were treated.The overall response rate(ORR)was 100%(8/8),including 50%(4/8)with complete response and 50%(4/8)with partial response.The median overall survival and median progression free survival of nnMCL patients were not reached.Conclusions:nnMCL patients have an indolent progression,with higher expression rates of CD23 and CD200,lower expression rates of SOX11,CD5 and CD38.Most patients have IGHV mutations.The prognosis is relatively good,and "watch and wait" approach is an option.