Programmed cell death protein-1 inhibitor combined with chimeric antigen receptor T cells in the treatment of relapsed refractory non- Hodgkin lymphoma: A case report

BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema.A large mass was detected in the pelvis,and pathology indicated non-Hodgkin diffuse large B-cell lymphoma.After three cycles of the R-CHOP chemotherapeutic regimen,the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine.Pathological examination of the nodules indicated DLBCL again.The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma.We recommended CAR-T cell treatment.Before treatment,the patient’s T cell function and expression of immune detection points were tested.Expression of PD-1 was obviously increased(52.7%)on cluster of differentiation(CD)3+T cells.The PD-1 inhibitor(3 mg/kg)was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide.CAR-CD19 T cells of 3×10^(6)/kg and CAR-CD22 T cells 1×10^(6)/kg were infused,respectively.The therapeutic effect was significant,and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable.Presently,the patient has been disease-free for more than 12 mo.CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cellsimproved therapeutic efficacy in B-cell lymphoma.

Treatment of refractory/relapsed extranodal NK/T cell lymphoma with decitabine plus anti-PD-1:A case report

BACKGROUND Extranodal natural killer/T cell lymphoma,nasal type(ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus(EBV) and extranodal involvement,which shows a poor clinical outcome.Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory(R/R) ENKL,relapse occurs in up to 50% of patients with disseminated disease.CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1(PD-L1) or other molecular pathways.Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression.Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.CONCLUSION The treatment experience,in this case,demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL,thus providing a new treatment strategy for this tumor.

The role of radiotherapy in patients with refractory Hodgkin’s lymphoma after treatment with brentuximab vedotin and/or immune checkpoint inhibitors

Background:Approximately 10%–30%of patients with Hodgkin’s lymphoma(HL)experience relapse or refractory(R/R)disease after first-line standard therapy.Brentuximab vedotin(BV)and immune checkpoint inhibitors(ICIs)have important roles in the salvage treatment of R/R HL.However,subsequent treatment for HL refractory to BV and/or ICI treatment is challenging.Methods:We retrospectively analyzed patients in two institutions who had R/R HL,experienced BV or ICI treatment failure,and received radiotherapy(RT)thereafter.The overall response rate(ORR),duration of response(DOR),progression-free survival(PFS),and overall survival(OS)were analyzed.Results:Overall,19 patients were enrolled.First-line systemic therapy comprised doxorubicin,bleomycin,vinblastine,and dacarbazine(ABVD,84.2%);AVD plus ICIs(10.5%);and bleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine,and prednisone(BEACOPP,5.3%).After first-line therapy,15(78.9%)and four patients(21.1%)had refractory disease and relapsed,respectively.After R/R HL diagnosis,six(31.6%),two(10.5%),and 11(57.9%)patients received BV and ICIs concurrently,BV monotherapy,and ICI monotherapy,respectively.All patients received intensity-modulated RT(n=12,63.2%)or volumetric modulated arc therapy(VMAT;n=7,36.8%).The ORR as well as the complete response(CR)rate was 100%;the median DOR to RT was 17.2 months(range,7.9–46.7 months).Two patients showed progression outside the radiation field;one patient had extensive in-field,out-of-field,nodal,and extranodal relapse.With a median follow-up time of 16.2 months(range,9.2–23.2 months),the 1-year PFS and OS were 84.4%and 100%,respectively.PFS was associated with extranodal involvement(P=0.019)and gross tumor volume(P=0.044).All patients tolerated RT well without adverse events of grade≥3.Conclusion:RT is effective and safe for treating HL refractory to BV or ICIs and has the potential to be part of a comprehensive strategy for HL.

Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma

AIM： To evaluate computed tomography （CT） findings, useful to suggest the presence of refractory celiac disease （RCD） and enteropathy associated T cell lymphoma （EATL）. METHODS： Coeliac disease （CD） patients were divided into two groups. Group Ⅰ ： uncomplicated CD （n = 14） and RCD type Ⅰ （n = 10）. Group Ⅱ ： RCD type Ⅱ （n = 15） and EATL （n = 7）. RESULTS： Both groups showed classic signs of CD on CT. Intussusception was seen in 1 patient in group Ⅰ vs 5 in group Ⅱ （P = 0.06）. Lymphadenopathy was seen in 5 patients in group Ⅱ vs no patients in group Ⅰ （P = 0.01）. Increased number of small mesenteric vessels was noted in 20 patients in group Ⅰ vs Ⅱ in group 11 （P = 0.02）. Eleven patients （50%） in group 11 had a splenic volume 〈 122 cm^3 vs 4 in group Ⅰ （14%）, 10 patients in group Ⅰ had a splenic volume 〉 196 cm^3 （66.7%） vs 5 in group Ⅱ （33.3%） P = 0.028. CONCLUSION： CT scan is a useful tool in discriminating between CD and （Pre） EATL. RCD Ⅱ and EATL showed more bowel wall thickening, lymphadenopathy and intussusception, less increase in number of small mesenteric vessels and a smaller splenic volume compared with CD and RCD Ⅰ.

Low-Dose Involved-Field Radiotherapy in Relapsed Low-Grade Non-Hodgkin's Lymphoma in Elderly Patients (Mansoura University Experience)

Purpose: To assess the response rate, duration of response and prognostic factors affecting response after low-dose involved-field radiotherapy in patients with relapsed low-grade B-cell non-Hodgkin lymphoma. Patients and Methods: Forty-four patients were included. Patients were treated with a total dose of 4 Gy (2 × 2 Gy) using 6 - 15 Mv photon or electron beam. Results: most patients were above age of 60 years (59%) with male predominance. Follicular lymphoma was the most common pathological type;bulky disease (>5 cm) was presented in 61.4%. Patients who received only 2 regimens were 63.7% and 31.8% had >2 involved sites. No treatment related toxicity was observed. The overall response rate was 88.7%;complete response was reached in 59.1% and stable disease in 6.8%, progressive disease in 4.5%. Median time to local progression was 33 months (95% CI 23.70 - 42.29);2-year local progression free survival was 78%. Response rate was found to be dependent on age, number of involved sites and lymph node size but independent on sex, pathological type, number of prior regimens, LDH level and time since diagnosis. Conclusion: Short-course-low dose palliative radiotherapy (2 × 2 Gy) affords an attractive option for treatment of relapsed low-grade non-Hodgkin’s lymphoma due to high response rates. However, these results had to be confirmed in a larger number of patients.

Temozolomide plus rituximab for elderly with relapsed primary central nervous system lymphoma

Objective: The aim of our study was to analyze the long-term results of rituximab combined with temozolomide in treatment of elderly patients (> 60 years) with relapsed primary central nervous system lymphoma (PCNSL). Methods: Twelve postoperative elderly patients (> 60 years) were treated between August 2004 and October 2009. Temozolomide 100 mg/m2 to 200 mg/m2 days 1 to 7 and 15 to 21 and rituximab 375 mg/m2 days 1, 5, 8, 22. The maximum number of rituximab cycles was two. After one or two cycles of this combination, patients with an objective response and an acceptable level of toxicity continued treatment with single agent temozolomide (days 1 to 5, every 28 days). The overall survival was analyzed by using Kaplan-Meier. Results: The overall survival was 9 months. Toxicity was very mild with no grade 3-4 neurotoxicity toxic events. Conclusion: Rituximab combined with temozolomide seems to yields substantial long-term survival with moderate toxicity for the treatment of elderly relapsed PCNSL.

Combination of atezolizumab and chidamide to maintain long-term remission in refractory metastatic extranodal natural killer/T-cell lymphoma:A case report

BACKGROUND The prognosis of refractory extranodal natural killer/T-cell lymphoma(ENKTL)is poor.Recent data have indicated that immune checkpoint blockade with a programmed cell death protein-1(PD-1)antibody in combination with administration of histone deacetylase inhibitors represents a potentially effective treatment strategy.Compared with PD-1 antibodies,programmed death-ligand 1 antibodies have fewer side effects.Here,we present a rare case of a patient with refractory metastatic ENKTL who achieved sustained remission of approximately 10 mo with minor adverse effects after combination therapy with atezolizumab,chidamide,and radiotherapy.CASE SUMMARY A 56-year-old woman underwent resection of a tumour in her left nasal cavity and was diagnosed with ENKTL(nasal type).Medical examination revealed tumours observed in the bilateral nasal mucosa,the subcutaneous soft tissue of the inner side of the left eye,the soft tissue of the nasopharynx,the bilateral tonsils,and the left preauricular,right hilar,bilateral neck lymph nodes and bone marrow.However,tomography/computed tomography showed increased metabolism of the bilateral nasal mucosa and subcutaneous soft tissue of the inner side of the left eye and newly increased metabolism of the left cervical lymph node after chemotherapy.Therefore,combination therapy with chidamide,atezolizumab,and radiotherapy was performed.Fortunately,the patient achieved a complete response following 10 mo of combination therapy.CONCLUSION The outcome in this case suggests that the combination of atezolizumab,chidamide,and radiotherapy is a promising regimen for treating refractory metastatic ENKTL following chemotherapy treatment failure.

Refractory lymphoma treated with chimeric antigen receptor T cells combined with programmed cell death-1 inhibitor:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing approximately 1%-2%of lymphoma.Approximately 30%–40%of patients are refractory to frontline therapy or relapse after complete remission.Refractory DLBCL responds poorly to other lines of chemotherapy,and experiences short-term survival.CASE SUMMARY We present a 41-year-old male patient who was diagnosed with PT-DLBCL.Further disease progression was observed after multiline chemotherapy.Chimeric antigen receptor T cells(CAR-T)therapy salvaged the patient.Unfortunately,a new mass was observed in the right adrenal area after six months.The patient was administered programmed cell death protein-1(PD-1)inhibitor therapy and maintained progression-free survival at more than 17 mo of follow-up.CONCLUSION Our findings support the potential benefit of CAR-T combined with PD-1 inhibitor therapies in this type of relapsed and refractory PT-DLBCL.

Brentuximab Vedotin Monotherapy and Combined with Low Dose Donor Lymphocyte Infusion to Control Minimal Residual Disease and Sustain Clinical Remission in a Child with Relapsed Anaplastic Large Cell Lymphoma

Minimal residual disease (MRD) appears to have a strong negative predictive value for disease recurrence in children with anaplastic large cell lymphoma (ALCL). Brentuximab vedotin (BV) can be a therapeutic option for MRD-positive patients to achieve molecular remission and to decrease risk of subsequent relapse. We here report a 4-year-old child with ALCL progression during relapse treatment who received BV as a bridging therapy before haploidentical hematopoietic stem-cell transplantation, and as a maintenance therapy post-transplant alone or combined with simultaneous low dose donor-lymphocyte infusions. MRD monitoring showed a complete molecular response and reflected both BV efficiency and graft-versus-lymphoma effect.

Disseminated soft tissue diffuse large B-cell lymphoma involving multiple abdominal wall muscles:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is the most common subtype of non�Hodgkin lymphoma,and patients with DLBCL typically present rapidly growing masses.Lymphoma involving muscle is rare and accounts for only 5%;furthermore,multiple muscles and soft tissue involvement of DLBCL is unusual.Due to unusual clinical manifestation,accurate diagnosis could be delayed.CASE SUMMARY A 61-year-old man complained of swelling,pain and erythematous changes in the lower abdomen.Initially,soft tissue infection was suspected,however,skin lesion did not respond to antibiotics.18Fluoro-2-deoxy-D-glucose(18F-FDG)positron emission tomography-computed tomography demonstrated FDG uptake not only in the skin and subcutaneous tissue of the abdomen but also in the abdominal wall muscles,peritoneum,perineum,penis and testis.DLBCL was confirmed by biopsy of the abdominal wall muscle and subcutaneous tissue.After intensive treatment including chemotherapy with rituximab,cyclophosphamide,doxorubicin,vincristine and prednisolone,central nervous system prophylaxis(intrathecal injection of methotrexate,cytarabine and hydrocortisone)and orchiectomy,he underwent peripheral blood stem cell mobilization for an autologous hematopoietic stem cell transplantation.Despite intensive treatment,the disease progressed rapidly and the patient showed poor outcome(overall survival,9 mo;disease free survival,3 mo).CONCLUSION The first clinical manifestation of soft tissue DLBCL involving multiple muscles was similar to the infection of the soft tissue.

Efficacy and safety of fourth-generation CD19 CAR-T expressing IL7 and CCL19 along with PD-1 monoclonal antibody for relapsed or refractory large B-cell lymphoma

Objective To explore the efficacy and safety of fourthgeneration chimeric antigen receptor T-cells (CAR-T),which express interleukin 7 (IL7) and chemokine C-C motif ligand 19 (CCL19) and target CD19,in relapsed or refractory large B-cell lymphoma.Methods Our center applied autologous 7×19 CAR-T combined with tirelizumab to treat 11 patients with relapsed or refractory large B-cell lymphoma.The efficacy and adverse effects were explored.

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma:a retrospective study

Background: In patients with difuse large B?cell lymphoma(DLBCL), central nervous system(CNS) relapse is uncom?mon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the eicacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction.Methods: A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat?sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R?CHOP regimen(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen(cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathe?cal chemotherapy prophylaxis(methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R?CHOP set in particular, the Kaplan–Meier method coupled with the log?rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Diferences were evaluated using a two?tailed test, and P < 0.05 was considered signiicant.Results: At a median follow?up of 46 months, 25(4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3?year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R?CHOP group(P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much beneit in terms of preventing CNS relapse. Bone involvement [hazard ratio(HR) = 4.21, 95% conidence interval(CI) 1.38–12.77], renal involvement(HR = 3.85, 95% CI 1.05–14.19), alkaline phosphatase(ALP) >110 U/L(HR = 3.59, 95% CI 1.25–10.34), serum albumin(ALB) <35 g/L(HR = 3.63, 95% CI 1.25–10.51), treatment with rituxi?mab(HR = 0.34, 95% CI 0.12–0.96), and a time to complete remission ≤ 108 days(HR = 0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement(HR = 4.44, 95% CI 1.08–18.35), bone marrow involvement(HR = 11.70, 95% CI 2.24–60.99), and renal involvement(HR = 10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R?CHOP set.Conclusions: In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemo?therapy prophylaxis alone was not suicient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R?CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

The Lower Peripheral Blood Lymphocyte to Monocyte Ratio Following Completion of First Line Chemotherapy Is a Risk Factor for Predicting Relapse in Patients with Diffuse Large B-Cell Lymphoma

Background and objective: During routine follow up, there is no specific predictor to ascertain relapse after standard first line chemotherapy in diffuse large cell lymphoma. Therefore, this study was designed to assess the prognostic significance of the ratio between absolute lymphocyte and monocyte counts (LMR) in the peripheral blood to verify relapse in diffuse large B cell lymphoma. Patients and methods: A total of 139 patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) were evaluated and treated with CHOP or R-CHOP between the years 2009 and 2016. Three months following completion of first line therapy, Lymphocyte/monocyte ratio (LMR) was calculated from the routine automated complete blood cell count (CBC) attained a plateau after the bone marrow recovery after first line chemotherapy. The absolute lymphocyte count/absolute monocyte count ratio (LMR) was calculated by dividing the ALC by the AMC. Results: ROC curve analysis of 139 patients established 2.8 as cutoff point of LMR for relapse with AUC of 0.97 (95% CI 0.93 - 0.99, P ≤ 0.001). Cox regression analysis was performed to identify factors predicting relapse. In univariate regression analysis, ALC (95% CI 0.003 - 0.03, p ≤ 0.001), AMC (95% CI 15.4 - 128.8, p ≤ 0.001), LMR (95% CI 0.001 - 0.01, p ≤ 0.001), and LDH (95% CI 0.1 - 0.5, p ≤ 0.001) following completion of therapy are significant factors for relapse. Other significant factors for relapse are Ann Arbor stage (95% CI 1.1 - 6.9, P = 0.03), extranodal sites (95% CI 1.2 - 6.1, P = 0.01), age (95% CI 1.3 - 6.5, P = 0.01) and treatment of CHOP protocol (95% CI 0.05 - 0.6, P = 0.007). In a multivariate analysis LMR following completion of therapy was predictive for relapse (95% CI 0.001 - 0.2, P = 0.005). ALC was also significant in multivariate analysis (95% CI 0.01 - 0.8, P = 0.03). LDH following completion of therapy (95% CI 0.2 - 14.9, P = 0.5), AMC following completion of therapy (95% CI 0.3 - 43.1, P = 0.3), age (95% CI 0.9 - 205.4, P = 0.06), extra-nodal sites (95% CI 0.04 - 9.8, P = 0.8), Ann Arbor stage (95% CI 0.3 - 28.7, P = 0.3), and Treatment of CHOP protocol (95% CI 0.01 - 2.4, P = 0.2) were not statistically significant. Conclusion: This study observed that LMR assessed after first line chemotherapy during routine follow up is an independent predictor of relapse and clinical outcome in DLBCL patients. LMR at follow up can be used a simple inexpensive biomarker to alert clinicians for relapse during follow up after standard first line chemotherapy in DLBCL patients.

Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4)

This study(ORIENT-4)aimed to assess the efficacy and safety of sintilimab,a humanized anti-PD-1 antibody,in patients with relapsed/refractory extranodal NK/T cell lymphoma(r/r ENKTL).ORIENT-4 is a multicenter,single-arm,phase 2 clinical trial(NCT03228836).Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 months.The primary endpoint was the objective response rate(ORR)based on Lugano 2014 criteria.Twenty-eight patients with r/r ENKTL were enrolled from August 31,2017 to February 7,2018.Twenty-one patients(75.0%,95%CI:55.1–89.3%)achieved an objective response.With a median follow-up of 30.4 months,the median overall survival(OS)was not reached.The 24-month OS rate was 78.6%(95%CI,58.4–89.8%).Most treatment-related adverse events(TRAEs)were grade 1–2(71.4%),and the most common TRAE was decreased lymphocyte count(42.9%).Serious adverse events(SAEs)occurred in 7(25.0%)patients,and no patient died of adverse events.Sintilimab is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

Long-term survival benefit of anti-PD-1 therapy in patients with relapsed or refractory classical Hodgkin lymphoma

Anti-programmed cell death-1(anti-PD-1)therapies have shown a favorable efficacy and good tolerance for relapsed or refractory(r/r)classical Hodgkin lymphoma(cHL).However,there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies.A total of 260 responders from four,phase 2 clinical trials were included in this study.The median age was 32 years with a male/female ratio of 1.3:1.After a median follow-up period of 31.1 months,116(44.6%)responders experienced disease progression and 18(6.9%)died.

Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle cell lymphoma

Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.

Different sites of extranodal involvement may affect the survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T cell therapy

Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T(CAR-T)cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma(r/r NHL)have not been well characterized.In this study,we found that the different sites of extranodal involvement may affect response,overall survival(OS),and progression-free survival(PFS)in patients with r/r NHL treated with anti-CD19 CAR-T cells.In a cohort of 32 treated patients,12(37.5%)and 8(25%)patients exhibited soft tissue lymphoma and bone marrow(BM)infiltrations,respectively,and 13(41%)patients exhibited infiltration at other sites.The factors that may affect prognosis were identified through multivariable analysis.As an independent risk factor,soft tissue infiltration was the only factor significantly correlated with adverse prognosis(P<0.05),whereas other factors did not reach statistical significance.Furthermore,the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy.PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone.Thus,anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.

Prognostic factors and efficacy of GDP-R therapy in refractory/relapsed diffuse large B-cell lymphomas not eligible for high-dose therapy

Aim:The main aim of the present study was to evaluate the overall survival(OS)and time to treatment failure(TTF)in a cohort of relapsed/refractory diffuse large B-cell lymphomas(DLBCLs)not eligible for high-dose therapy(HDT)treated with gemcitabine in association with dexamethasone,cisplatin and rituximab(GDP-R)protocol.The secondary aim was to identify the prognostic factors impacting OS and TTF.Methods:The authors retrospectively analyzed 45 patients with refractory/relapsed DLBCLs treated with GDP-R.Results:Overall response rate(ORR)was 48.8%;complete response 15/45(33.3%),partial response 7/45(15.5%).Response was influenced by the number of previous therapies administered and International Prognostic Index(IPI)value.Although no significant impact occurred with regard to OS,patients pre-treated with 2 or<2 chemotherapeutic regimens had better ORR(P=0.014)and a longer TTF(P=0.029 in multivariate Cox model).IPI value also influenced TTF.Patients with<2 IPI value had significantly more prolonged TTF than the other ones(P=0.048 in multivariate Cox model).Treatment was well-tolerated,with the majority of patients treated on out-patient modality.GDP-R regimen represents a valid treatment for aggressive relapsed/refractory B-cell lymphoma not eligible for HDT thanks to its efficacy and good toxic profile.Conclusion:The number of previous chemotherapeutic regimens and IPI value select those who benefit more from this treatment.

Real-world outcomes of ibrutinib therapy in Korean patients with relapsed or refractory mantle cell lymphoma:amulticenter,retrospective analysis

Dear Editor,Despite the introduction of novel front-line therapies including rituximab plus high-dose cytarabine followed by consolidative autologous stem cell transplantation(ASCT)and salvage therapy with bendamustine,lenalidomide or bortezomib,mantle cell lymphoma(MCL)is still considered incurable and most patients experience relapse or refractory(RR)disease.

Outcomes in refractory diffuse large B-cell lymphoma:results fromamulticenter real-world study in China

Background:Diffuse large B-cell lymphoma(DLBCL)patients refractory to rituximab-based immunochemotherapy have a dismal prognosis.However,the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries.To validate the definition and outcomes of refractory DLBCL in China,we conducted a multicenter,retrospective cohort study.Methods:The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL(REAL-TREND)study was performed using real-world data from 8 centers in China.DLBCL patients with curative intent were included in the REAL-TREND dataset.Overall survival(OS)was estimated using the Kaplan-Meier method and compared by the log-rank test.Due to heterogeneity in response rates among different centers,the response rates of refractory patients were pooled using random-effect models.Multivariate survival analysis was performed using the Cox regression model.Results:A total of 2778 DLBCL patients diagnosed between January,2010 and December,2015 were enrolled to this study.After validating previous definitions,the SCHOLAR-1 study was most suitable to define refractory DLBCL.The estimated 5-year cumulative incidence of refractory patients was 20%(95% confidence Interval[CI]=18%-22%).After the determination of refractory disease,overall response rate and complete remission rate were 30%(95%CI=22%-38%)and 9%(95%CI=4%-15%),respectively.Patients with either no response to immunochemotherapy or relapse within 12 months after stem-cell transplantation had inferior survival with a median OS of 5.9 months(95%CI=5.5-7.1 months)and 2-year OS rate of 16%(95%CI=12%-20%).International prognostic index score 4-5(hazard ratio[HR]=2.22;95%CI=1.47-3.35),central nervous systemrelapse(HR=1.43;95%CI=1.04-1.97),and best response status(HR=2.68;95%CI=1.42-5.03 for partial remission.HR=5.97,95%CI=3.21-11.11 for stable disease/progressive disease)were independent unfavorable prognostic factors.Conclusions:This is the first large-scale Asian cohort study focusing on outcomes of refractory DLBCL.The definition of the SCHOLAR-1 study identifies patients with homogenously inferior survival,thus is appropriate to select refractory DLBCL.Due to poor clinical outcomes in the rituximab era,patients with refractory DLBCL may be potential candidates for novel treatment modalities.