Clinical Features And Prognosis Of 167 Cases Of Chronic Lymphocytic Leukemia

[Objective]To investigate the clinical features of patients with chronic lymphocytic leukemia（CLL）and the adverse prognostic factors affecting overall survival（OS）and treatment free survival（TFS）,we performed the study.And we further explored the risk factors and the incidence of progression free survival 2（PFS2）<5 years in CLL.We constructed nomogram of overall survival（OS）and Treatment free survival（TFS）for CLL patients to facilitate clinicians and patients to predict the disease.[Methods]The clinical and laboratory examination data of the newly diagnosed and newly treated CLL patients admitted to our center from 2009.09 to 2019.10 were retrospectively analyzed.The effects of clinical features and laboratory test features on prognosis were analyzed,and the difference in survival rate of patients in each group was detected by log-rank method,independent risk factors of OS and TFS were analyzed by COX regression,and a logistics regression model was established to screen out independent prognostic factors affecting PFS2<5 years.The COX regression risk model was constructed by including the one-factor analysis of variables of p<0.1 in R language,the prediction model of OS and TFS was visualized by the nomogram,and the accuracy of the prediction model was evaluated by C index,calibration curve and ROC curve.[Result]1.Clinical features:median age of onset was 62（（36-86）years old,male:female ratio of 1.57.Clinical stage at the initial diagnosis was mainly Rai I-IV,accounting for 149 cases（89.2%）,Laboratory examination:Absolute Lymphocyte Count（ALC）>50×109/L at the initial diagnosis was 44 cases（26.3%）.136 cases detected β2 microglobulin（β2-microglobulin,β2-MG）,of which 62（37.1%）were significantly elevated（>3.5 mg/L）.90 patients had a complete modified Glasgow Scores（mGPS）score,of which 0 score accounted for 54（60.0%）,1 to 2 scores were 36（40.0%）.24（14.4%）patients had immunoglobulin heavy chain variable（IGHV）mutation status detection,including 9 cases of unmutated state（37.5%）,mutant state of 15 cases（62.5%）.123 patients had complete fluorescence in situ hybridization（FISH）data,37 cases（30.1%）with 13q deletion（13q-）,others included trisomy 12（+12）21.1%and 17p deletion（17p-）（9.8%）and llq deletion（11q-）（16.3%）.51 patients were treated with rituximab regimens,including 13 cases under RFC regimen,4 cases with RCHOP regimen,25 cases with RCOP regimen,and 9 cases with R combined cell therapy.While other 47 patients without rituximab regimen were calculated,including 27 cases with FC regimen,19 cases with COP regimen,and 1 VP regimen,1 case treated with BTK inhibitors.41 patients without treatment indications took watch and wait regimen.And 18 cases took chlorambucil monotherapy.9 cases refused treatment.In the second-line treatment,the treatment regimen was mainly BTK inhibitor and immunochemotherapy regimen,with 14 patients using BTK inhibitor regimen and 23 patients using immunochemotherapy regimen at the same time.2.OS analysis:Median follow-up was 83.91 months,and the median OS of 167 patients was 91.53 months（65.777-117.28）,of which patients with PFS2<5 years had a significant poor OS by 2.73 years（95%CI 2.03-3.43）vs 10.22 years（95%CI 8.5011.95）,p<0.001）.Univariate analysis:llq-（P<0.001）,chromosomal complex karyotype（p<0.001）,age（>65 years）（p=0.017）,Rai stage（stage Ⅰ-Ⅳ）（p=0.008）,HBV infection（p=0.028）,ALC（>50×109/L）（p=0.008）,mGPS score>1（p<0.001）,β2-MG>3.5 mg/L（p=0.002）,PFS2<5 years（p<0.001）.Multivariate analysis:PFS2<5 years（p<0.001,HR=32.208（95%confidence interval:11.933-86.934））,Rai stage Ⅰ-Ⅳ（p=0.018,HR=2.321（95%CI 1.153-4.673））,ALC>50×l09/L（p=0.017,HR=2.295（95%CI 1.161-4.540））,17p-（p=0.038,HR=2.537（95%CI 1.051-6.123））are the independent adverse factors of OS.3.TFS analysis:median TFS 10.224 months,univariate analysis showed Rai stage ⅠⅣ（p=0.002）,mGPS score>1 point（p=0.002）,β2-MG>3.5 mg/L（p=0.001）.And risk factors that would have clinical significance（stages Ⅰ-Ⅳ（p=0.002）,mGPS scores≥1（p=0.002）,β2-MG>3.5 mg/L（p=0.001））were included in the COX multivariate regression analysis and showed that β2-MG>3.5 mg/L（p=0.002,HR=2.226（95%CI 1.332-3.719））was independent prognostic adverse factors affecting TFS.4.Nomogram:OS:The variables of p<0.1 for univariate analysis and the variables with clinical significance for OS in CLL patients were included,and finally PFS2<5 years,age>65 years,Rai Ⅰ-Ⅳ,ALC>50×109/L,17p-were included in the multifactor COX regression analysis and a nomogram for predicting OS was established.To evaluate the accuracy of the predictive model by C-index,calibration curve,and ROC curve.The BOOTstrapping verification method was used to internally test.The results show that the C index of the model is 0.857（95%CI:0.771～0.943）,and the area under the ROC curve is about 0.953,which has good differentiation and accuracy.The calibration curve shows good consistency in this study.TFS:The variables of p<0.1 in univariate analysis and the variables with clinical significance for TFS in patients with CLL were included.And finally the five factors of Rai Ⅰ-Ⅳ,β2-MG>3.5,and mGPS were included in the multivariate COX regression analysis and nomogram for predicting TFS was established.To evaluate the accuracy of the predictive model by C-index,calibration curve,and ROC curve.The BOOTstrapping verification method was used to internally test.The results show that the C index of the model is 0.712（95%CI:0.536-0.888）,and the area under the ROC curve is about 0.753,which has good differentiation and accuracy.The calibration curve shows good consistency in this study.5.PFS2 risk factors:50 patients had secondary progression within 5 years,accounting for about 29.9%.Further analysing the clinical characterization analysis of patients with PFS2<5 years,we found that 11q-（p=0.041,4.916（1.071-22.560））17p-（p=0.018,OR=7.000（95%CI:（1.391-35.222）））was independent risk factors for PFS2 by logistics regression models.[Conclusion]1.These findings suggest that our cohort of CLL patients were younger and high-risk at diagnosis,and the treatment is mainly immunochemotherapy,and the OS was consistent with other report.2.In the era of immunochemotherapy,cytogenetic changes（17p-,11q-）are still the main risk factors of CLL patients;3.Multiple progressions is of great significance for the prognosis of CLL,and the OS of patients who undergo two progressions within 5 years was significantly shortened;4.β2-MG is an independent prognostic factor for TFS;5.Nomogram is a visual prediction model,convenient and fast,worthy of clinical promotion.