Treatment And Prognosis Of Relapsed Or Refractory Diffuse Large B-cell Lymphoma

Objective Diffuse large B-cell lymphoma(DLBCL)is a aggressive entity with biological and clinical heterogeneity.This study aim to analyze characteristics,treatment and prognosis of patients with relapsed or refractory(R/R)DLBCL,revealing the genomic alteration associated with disease progression and exploring treatment approaches to improve patient outcome.Method Patients with DLBCL were enrolled to analyze characteristics,treatment and prognosis of patients and evaluate the role of rituximab in the second-line setting;construct and validate prognostic model based on R-CHOP pre-treated patients;identify parameters independently correlated with response to second-line treatment;explore correlation between genomic alteration and resistance through capture-based targeted sequencing on baseline samples of 105 DLBCL;analyze treatment and outcome of 47 TP53-mutated patients.Result In patients pre-treated with rituximab,use of rituximab in salvage treatment independently add benefit to patient survival.However,in rituximab pre-treated patients,this survival benefit was not observed.The 3-year and 5-year OS rates for the patients failing R-CHOP treatment were 26.2%and 17.5%,respective.Four independent prognostic factors including rituximab in the second-line setting,initial performance status,response to front-line treatment,and invasion on progression/recurrence were used to construct the nomogram.The nomogram had a C index of 0.70.A multivariate ordinal regression analysis identified prior response to front-line treatment and bulky disease at diagnosis were two independent factors for second-line treatment efficacy.Patients with TP53 mutations especially those with TP53 disruptive mutations,were more likely to have primary refractory disease.BCL-2 amplification,B2M mutation and TP53 mutation were correlated with shorter time to progression.For the47 patients with TP53 mutation,surgical resection plus R-CHOP was correlated longer progression-free survival.Conclusion We provide real-world data on treatment and survival data of R/R DLBCL,revealing the clinical and biological risk factor,which provide guidance for clinical trial design and treatment decision.Part 1.Clinical characteristics and prognosis analysis of relapsed or refractory diffuse large B-cell lymphomaObjective We performed this study on relapsed or refractory(R/R)diffuse large B-cell lymphoma(DLBCL),analyzing prognosis and the role of rituximab in salvage treatment.Methods Patients with R/R DLBCL pretreated with first-line anthracycline-based chemotherapy,aged 18-79 were retrospectively enrolled(n=526).Results Overall,526 R/R DLBCL patients were included in this study,with 194(36.9%)patients aged ?60 years.The ratio of male to female was 1.3:1.There were 43.9%(231/526)patients classified as limited-stage and 56.1%(295/526)patients as advanced-stage.At baseline,20.5%(108/526)patients had bulky disease.Among the 526 patients,292(55.5%)patients received rituximab-containing treatment in the front-line setting.A total of 390 patients had second-line treatment at out center,with 95.9%(374/390)receiving systematic treatment,4.1%(16/390)receiving only local treatment,30.0%(158/390)receiving rituximab-containing treatment.The median overall survival(OS)was 11.0 and 7.0 months in the relapsed and refractory group,respectively.Patients with secondary central nervous system involvement had dismal outcome,with a median OS of 8 months.In rituximab pre-treated patients,adding rituximab in the second-line setting could bring survival benefit(25 vs.13 months,p=0.007).This benefit is enhanced in rituximab-naive patients(47 vs.10 months,p<0.001).Multivariate analysis established that Eastern Cooperative Oncology Group(ECOG)performance status(PS)score at diagnosis(p=0.007),lactate dehydrogenase(LDH)at diagnosis(p=0.011),initial treatment efficacy(p<0.001),invasion on R/R and rituximab(p=0.025)in the second-line setting(p<0.001)were independent indicators of OS.Subsequently,subgroup analysis performed in patients pre-treated with rituximab showed after adjusting for initial ECOG,initial elevated LDH,initial treatment efficacy and invasion on R/R,use of rituximab in salvage treatment independently add benefit to patient survival(Hazard Ratio=0.679,95%confidence interval=0.476-0.970,p=0.033).However,in rituximab pre-treated patients,this survival benefit was not observed(p=0.351).Conclusions Our report described the features of R/R DLBCL patients and confirmed benefit of rituximab use in salvage treatment,providing evidence for clinical trial design and treatment decision.Part 2.Treatment and prognosis analysis of relapsed or refractory diffuse large B-cell lymphoma failing first-line R-CHOP treatmentObjective:This study focused on the clinical characteristics of relapsed or refractory(R/R)diffuse large B-cell lymphoma(DLBCL)after first-line R-CHOP(rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone)treatment,int he purpose of exploring the predictors of the efficacy of second-line treatment as well as patient outcome,constructing a nomogram for risk stratification in this population.in a post-rituximab real-world contextMethods Among 296 R/R DLBCL patients pretreated with R-CHOP at the Cancer Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College between 2006 and 2017,231 were included for nomogram construction.After randomization,we constructed the prognostic nomogram in the primary cohort(n=161)based on a multivariate analysis and confirmed it in the validation cohort(n=70).Additionally,we explored predictive factors for second-line therapy using a ordinal regression analysis.Results For patients alive at the last follow-up,the overall median follow-up time was 13.0 months(interquartile range,6.0-38.0 months).The 3-year and 5-year OS rates for the entire group were 26.2%and 17.5%,respectively.Four independent prognostic factors including rituximab in the second-line setting,initial performance status,response to front-line treatment,and invasion on progression/recurrence were used to construct the nomogram.The nomogram had a C index of 0.70 with area under receiver operating characteristic curve(AUC)values of 0.73 and 0.71 for the primary and validation cohorts,respectively.Subsequently,three risk groups(low,intermediate,and high)were determined with median overall survival(OS)of 38.0(95%confidence interval[CI]:33.0-43.0),25.0(95%CI:16.7-33.3),and 7.0(95%CI:4.7-9.3)months,respectively.Among 183 patients with medical records at our center for response to second-line treatment,96(52.5%)responded to second-line treatment with 39(21.3%)complete remission and 57(31.1%)partial response;23(12.6%)received stable disease and 64(35.0%)experienced disease progression.Additionally,the univariate ordinal regression to filter factors correlated with the response to second-line treatment based on p value were R/R patterns,prior response to front-line treatment,bulky disease at diagnosis and second-line treatment regimens.Decreased ORR of second-line treatment was found for those with initial bulky disease than those without(30.4 vs.89.3%,p<0.001)as well as nonresponders(28.2 vs.65.9%,p<0.001)compared with those with a previous response to R-CHOP regimen.Subsequently,we conducted a multivariate ordinal regression analysis and identified prior response to front-line treatment(odds ratio=4.50,95%CI:1.84-11.27,p=0.001)and bulky disease at diagnosis(odds ratio=0.36,95%CI:0.182-0.702,p=0.003)were two independent factors for second-line treatment efficacy.Conclusions This study established predictors for treatment efficacy in the second-line setting and the novel nomogram for survival in R/R DLBCL patients failing R-CHOP treatment could potentially be applied for risk stratification and treatment guidance in the post-rituximab era.Part 3.Molecular profiling of R-CHOP treated DLBCL patients:identifying adverse biomarkersObjective Diffuse large B-cell lymphoma(DLBCL)is a clinically aggressive non-Hodgkin's lymphoma,with biological and clinical heterogeneity.Although most patients can be cured by immunochemotherapy,30-40%patient will ultimately develop relapsed or refractory disease.Here,we investigated the molecular landscapes of patients with diverse responses to R-CHOP.Methods We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes.After excluding primary central system lymphoma,81 treatment-naive patients with measurable disease and followed for over 1 year were included for survival analysis.Results Collectively,the most commonly seen mutations included IGH fusion(69%),PIMI(33%),MYD88(29%),BCL2(29%),TP53(29%),CD79B(25%)and KMT2D(24%).Patients with TP53 mutations were more likely to have primary refractory disease(87.0%vs 50.0%,p=0.009).For those with TP53 disruptive mutations,91.7%patients were in the primary refractory group.Interestingly,BCL-2 somatic hypermutation was only seen in patients without primary refractory disease(p=0.014).Furthermore,BCL-2 amplification,B2M mutation and TP53 mutation were correlated with shorter time to progression.TP53 mutations remain as the only significant predictor for OS(p=0.049).Next,we investigated mutation landscape in patients with wild-type TP53 and found that patients harboring MYD88 L265P had significantly inferior time to progression than those with wild-type or non-265P(p=0.040).Conclusion This study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients.It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 wild-type patients.Part 4.Characteristics and management of TP53-mutated Diffuse Large B-cell Lymphoma PatientsObjective TP53 mutation was recognized as a negative prognostic factor for patients with malignancies including diffuse large B-cell lymphoma(DLBCL).Exploratory therapy for this group of patients is in great need for potential clinical benefit.Here,we investigated the effect of adding loco-regional treatment to standard immunochemotherapy on survival of TP53MUT DLBCL patients.Methods Capture-based targeted sequencing was performed on 214 DLBCL patients,of which 47 was detected TP53MUT and included for further analysis.Refractory patients were defined as individuals did not achieve complete remission(CR)or develop relapse after 6 months in response to initial treatment.Results For 47 patients confirmed with TP53 mutation,44(93.6%)received R-CHOP based regime were included for survival analysis.Among them,26 patients developed refractory and received second-line chemotherapy.Seven limited-stage patients after early complete resection and one patient with residue resection remained event free with a median follow-up of 37 months.Multivariate analysis revealed baseline lactate dehydrogenase(LDH),extranodal involvement,Ann Arbor stage and loco-regional treatment are independent indicators for progress-free survival in survival analysis group.After adjusting for baseline LDH and extranodal involvement,adding loco-regional treatment including surgery and radiation to R-CHOP regime significantly improved progression-free survival(hazard ratio[HR]=0.092,95%confidence interval[CI]:0.016-0.543,p=0.008)and overall survival(HR=0.032,95%CI:0.002-0.535,p=0.017)of limited-stage TP53MUT DLBCL patients compared to R-CHOP only treatment.Conclusions Our study showed loco-regional treatment may provide additional clinical benefit for patients with limited-stage DLBCL,which offered new treatment consideration for patients with TP53-mutated DLBCL.