Impact Of Diagnosis-to-Treatment-Interval And Treatment-Delay-Time On Outcomes Of Patients With Diffuse Large B-cell Lymphoma

Objective:Diffuse Large B-cell Lymphoma(DLBCL)is the most common subtype of aggressive lymphoma,and there are many factors affecting the prognosis of patients.The purpose of this study was to evaluate the impact of diagnosis-to-treatment interval(DTI)and the treatment-delay-time(TDT)of the following cycles of chemotherapy on disease progression and survival in patients with newly-diagnosed DLBCL.Methods:We retrospectively analyzed patients who were newly diagnosed with DLBCL in the Department of Hematology and Oncology(Affiliated Hospital of North Sichuan Medical College)from December 2013 to December 2019.Patients who received rituximab combined with cyclophosphamide,doxorubicin,vincristine,prednisone/dexamethasone(R-CHOP)or R-CHOP-like chemotherapy for at least 1 cycle with complete clinical and pathological information were initially included and those with received emergent tumor-reducing treatment were excluded.Ultimately,a total of 267 patients were included in the final analysis.Patients were follow-up for disease progression and death.According to the patient’s status of disease progression and DTI(the time interval between the pathological diagnosis and the start of chemotherapy),TDTc2(the delayed time for initiating the second cycle of chemotherapy),TDTAVG(the average delayed time of the second,third and fourth cycle of chemotherapy),ROC curve analysis were performed to preliminarily determine the predictive value of DTI,TDTc2 and TDTAVG on the outcome of patients.According to the optimal cut-off value of ROC curve,patients were divided into two groups.Kaplan-Meier method was used to perform the progression-free survival(PFS)and overall survival(OS)analysis,and log-rank test was used to compare the difference between groups.Cox proportional hazard regression model was adopted to determine the risk factors affecting PFS and OS rate.Results:Part ⅠPFS-1 and OS-1 were defined as the time from diagnosis to disease progression or loss of follow-up,and death of any cause or loss of follow-up,respectively;PFS-2 and OS-2 were defined as the duration from diagnosis to disease progression or loss of follow-up,and death of any cause or loss of follow-up,respectively.1.Until December 2021,of all the 267 patients in this cohort,a total of 57 patients achieved complete remission,188 patients achieved partial remission,4 patients had stable disease,and 18 patients had their disease progression.2.Until December 2021,the median follow-up time(since diagnosis)was 34 months(2-96 months),and the median PFS and OS were both not reached,with a 3-year PFS was 65.6%and a 5-year OS was 72.2%.The median follow-up time(since the first chemotherapy)was 32 months(2-96 months),and the median PFS was 76 months,median OS-2 was not reached,with 3-year PFS of 62.1%and 5-year OS of 69.0%,respectively.3.According to the optimal cut-off value for PFS-1 determined by ROC analysis,patients were divided into DTI≤10 days and DTI>10 days groups.According to the optimal cut-off value for PFS-2 determined by ROC analysis,patients were divided into DTI≤8 days and DTI>8 days groups.Chi-square test was performed to compare the baseline characteristics,and there was no significant difference between the two groups.4.Survival analysis showed that DTI≤10 days group had significantly better PFS and OS than DTI>10 days group(median PFS-1:not reached vs.56 months;3-year PFS:75.3%vs.59.8%;P=0.0037);(median OS-1:not reached;5-year OS:85.4%vs.68.5%;P=0.0300).DTI ≤8 days group had significantly better PFS and OS than DTI>8 days group,(median PFS-1:not reached vs.50 months;3-year PFS:77.0%vs.55.3%;P=0.0007);(median OS-1:not reached;5-year OS:83.9%vs.63.3%;P=0.0580).5.Univariate analysis identified that age,Ann Arbor stage,ECOG score,lactate dehydrogenase(LDH),the number of extranodal lesions,primary extranodal and DTI were risk factors affecting PFS-1.Age,Ann Arbor stage,ECOG score,the number of extranodal lesions and DTI were risk factors affecting OS-1 in DLBCL patients.Age,gender,Ann Arbor stage,with B symptoms,ECOG score,LDH,the number of extranodal lesions,primary extranodal,DTI,TDT,2 and TDTAVG were risk factors affecting PFS-2 in DLBCL patients;Age,gender,Ann Arbor stage,ECOG score,LDH and number of extranodal lesions were risk factors affecting OS-2 in DLBCL patients.Multivariate analysis showed that age,LDH,the number of extranodal lesions and DTI were independent risk factors for PFS-1,while age and number of extranodal lesions were independent risk factors affecting OS-1.Primary extranodal,DTI and TDTAVG were independent risk factors affecting PFS-2,while age,Ann Arbor stage and the number of extranodal lesions were independent risk factors affecting OS-2 in DLBCL patients.6.Subgroup analysis found that DTI had a more significant effect on PFS and OS in patients who were younger than 60 years,male,with higher Ann Arbor stage Ⅲ-Ⅳ,ECOG score≥2,number of extranodal lesions≥2 and elevated LDH.Part ⅡThe impact of TDTc2 and TDTAVG on PFS and OS was investigated,and the survival time from the initial chemotherapy was used for survival analysis.1.Until December 2021,a total of 234 patients in this cohort had completed at least two cycles of R-CHOP or R-CHOP-like chemotherapy,with a 3-year PFS was 66.1%and a 5-year OS was 73.6%.The average delay(TDTAVG)of patients who had completed more than two cycles of chemotherapy was further analyzed.According to TDTAVg and PFS drawn ROC curves patients were grouped as TDTAVG ≤ 5 days and TDTAVG>5 days.Survival analysis found that patients with TDTAVG<5 days had significantly better PFS than those with TDTAVG>5 days(P=0.0005),but their OS rate was not statistically significant(P=0.2796).2.Subgroup analysis showed that TDTAVG had a greater impact on the prognosis of patients with younger age(≤ 60 years),ECOG score≥ 2,non-GCB,male,number of extranet lesions≥ 2 and normal LDH.3.According to the optimal cut-off value determined by ROC analysis of TDTc2 and PFS,patients were divided into TDTc2 ≤ 5 days and TDTc2>5 days.Survival analysis showed that patients with TDTc2 ≤ 5 days had better PFS than those with TDTc2>5 days(P=0.0180).However,there was no significant difference in term of OS rate(P=0.9900).Conclusion:1.Time interval from diagnosis to the initial chemotherapy is an independent risk factor for disease progression in DLBCL patients,and it is also likely to be true in term of OS,especially for young patients(≤ 60 years old)and patients with elevated LDH.2.Prolonged interval between cycles of the former half of chemotherapy has a significantly impact on disease progression in DLBCL patients,but there seems no obvious impact on OS.