Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin:Analysis of 1,085 WHO classified cases in a single institution in China

Objective: To explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma(DLBCL)patients in China according to the primary site.Methods: A total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site.Results: In the 1,085 patients, 679(62.6%) cases were nodal DLBCL(N-DLBCL) and 406 cases(37.4%) were extranodal DLBCL(EN-DLBCL). The most common sites of N-DLBCL were lymphonodus(64.8%), Waldeyer's ring(19.7%), mediastinum(12.8%) and spleen(2.7%), while in EN-DLBCL, stomach(22.4%), intestine(16.0%),nose and sinuses(8.9%), testis(8.4%), skin(7.9%), thyroid(6.9%), central nervous system(CNS)(6.4%), breast(5.7%), bone(3.4%), and salivary gland(2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival(OS) rate and progression-free survival(PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9%(P=0.008), and the 5-year PFS were57.0% and 49.0%(P=0.020). Waldeyer's ring originated DLBCL possessed the highest 5-year OS rate(83.6%) and PFS rate(76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach,breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%,respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%.Conclusions: In our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis

Objective： The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation （AHSCT） in the treatment of lymphoblastic lymphoma （LL）. Methods： We relxospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation （HSCT） from December 1989 to December 2009 in a single institution. Results： HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months （range, 24.6-173.1 months）. The 5-year overall survival （OS） and event-free survival （EFS） rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow （BM） involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. Conclusions These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission （CR1）.

Clinical features, survival and prognostic factors of primary testicular diffuse large B-cell lymphoma

Objective： To assess the clinical features, survival and prognostic factors of primary testicular diffuse large B-cell lymphoma （DLBCL）. Methods： A retrospective study of 37 patients with primary testicular DLBCL was carried out from November 2003 to May 2012. Their clinical features, survival and prognostic factors were analyzed. Results： During a median follow-up period of 39.8 months （5.4-93.0 months）, the median progression-free survival （PFS） was 26.2 months （95% CI：0-65 months） and the 3-year overall survival （OS） rate was 78.4%. Within the whole cohort, the factors significantly associated with a superior PFS were limited stage （stage Ⅰ/Ⅱ）, lactate dehydrogenase （LDH） ≤245 U/L, international prognostic index （IPI） ≤1, primary tumor diameter 〈7.5 cm, and patients who had complete response （CR） and received doxoruhicin-contained chemotherapy （P〈0.05）. There was a trend toward superior outcome for patients who received combined therapy （surgery/ chemotherapy/radiotherapy） （P=0.055）. Patients who had CR, primary tumor diameter 〈7.5 cm and IPI score ≤1 were significantly associated with longer PFS at multivariate analysis. Conclusions： Primary testicular DLBCL had poorer survival. CR, primary tumor diameter and IPI were independent prognostic factors. The combined therapy of orchectomy, doxorubicin-contained chemotherapy and contralateral testicular radiotherapy （RT） seemed to improve survival.

Autologous peripheral blood stem cell mobilization following dose-adjusted cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy alone or in combination with rituximab in treating high-risk non-Hodgkin's lymphoma

Background: The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone(CHOP) is an eicient treatment of non-Hodgkin's lymphoma(NHL). This study aimed to assess the eicacy and toxicity of dose-adjusted CHOP alone or in combination with rituximab(R-CHOP) by examining the stem cell mobilization in NHL patients. Factors afecting the collection of CD34+ cells were also explored.Methods: Our retrospective study included 39 patients eligible for autologous stem cell transplantation: 14 patients who expressed CD20 and were inancially eligible received R-CHOP for autologous peripheral blood stem cell(APBSC) mobilization; the remaining 25 patients received CHOP.Results: The median CD34+ cell yield was 7.01 × 106 cells/kg body weight(range 1.49–28.39 × 106 cells/kg body weight), with only two patients failing to meet the target CD34+ cell harvest of ber of apheresis procedures per patient was 1(range 1–3). The≥2.0 APBS× 106 cells/kg body weight. The median numC mobilization yield of the CHOP group appeared to be higher than that of the R-CHOP group(P response(CR) rate in = 0.005), whereas the success rate was similar between groups. R-CHOP elevated the completeB cell lymphoma patients as compared with CHOP(P = 0.01). No signiicant diferences in toxicity or engraftment were observed between the two groups.Conclusion: The present study demonstrated that dose-adjusted CHOP chemotherapy efectively mobilized APBSCs in NHL patients and that the addition of rituximab to dose-adjusted CHOP chemotherapy elevated the CR rate for patients with B-cell lymphoma.

PhaseⅠdose-finding study of sorafenib with FOLFOX4 as firstline treatment in patients with unresectable locally advanced or metastatic gastric cancer

Objective： To determine the maximum tolerated dose（MTD）, dose-limiting toxicity（DLT） and efficacy of sorafenib in combination with FOLFOX4（oxaliplatin/leucovorin（LV）/5-fluorouracil） as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Methods： According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level（from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily）. If the patient achieved complete response（CR）, partial response（PR） or stable disease（SD） after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. Results： In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9（77.8%） evaluable patients achieved PR, with a median overall survival（OS） of 11.8 [95% confidence interval（CI）： 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea.Conclusions： Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Phase I study of chimeric anti-CD20 monoclonal antibody in Chinese patients with CD20-positive non-Hodgkin＇s lymphoma

Objective： This study was designed to determine the safety, pharmacokinetics and biologic effects of a humanmouse chimeric anti-CD20 monoclonal antibody （SCT400） in Chinese padents with CD20-positive B-cell non- Hodgkin＇s lymphoma （CD20 B-cell NHL）. SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. Methods： Fifteen patients with CD20＋ B-cell NHL received dose-escalating SCT400 infusions （250 mg/m2： n=3; 375 mg/m2： n=9; 500 mg/m2： n=3） once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacoklnetics and pharmacodynamics analyses. Results： No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 ncutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer （NK） cell count or immunoglobulin levels. No patient developed anti- SCT400 antibodies during the course of the study. SCT400 serum half-life （Tin）, maximum concentration （Cmax and area under the curve （AUC） generally increased between the first and fourth infusions （P〈0.05）. At the 375 mg/m2 dose, the T1/2 was 122.5±46.7 h vs. 197.0,75.0 11, respectively, and the Cmax was 200.6±20.2 pg/mL vs. 339.1±71.0 ng/mL, respectively. From 250 mg/m2 to 500 mg/m2, the Cmax and AUC increased significantly in a dose-dependent manner （P〈0.05）. Patients with a high tumor burden had markedly lower serum SCT400 concenmations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. Conclusions; SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20＋ B-cell NHL.

Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma patients treated with R-CHOP

Objective:Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse large B-cell lymphoma(DLBCL)are available.This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients,and examine correlation of BCL2,TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL.MYC,BCL2,and BCL6 protein expressions were detected by immunohistochemistry.Results:The presence of BCL2 alterations significantly correlated with poor progression-free survival(PFS)(5-year PFS:13.7%vs.40.8%;P=0.003)and overall survival(OS)(5-year OS:34.0%vs.70.9%;P=0.036).Importantly,patients who harbored BCL2 gain/amplifications(BCL2GA/AMP)also had a remarkably inferior 5-year PFS(11.1%vs.38.3%;P<0.001)and OS(22.1%vs.69.6%;P=0.009).In contrast,neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival.Multivariable analyses showed that the presence of BCL2 alterations,especially BCL2GA/AMP,TP53 mutations,and International Prognostic Index(IPI)were significantly associated with inferior PFS and OS.Novel prognostic models for OS were constructed based on 3 risk factors,including BCL2 alterations(Model 1)or BCL2GA/AMP(Model 2),TP53 mutations,and IPI,to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLBCL patients treated with R-CHOP,BCL2 alterations,especially BCL2GA/AMP and TP53 mutations were significantly associated with inferior outcomes,which were independent of the IPI.The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP,but further validation of the prognostic models is still warranted.

Addition of rituximab is not associated with survival benefit compared with CHOP alone for patients with stage I diffuse large B-cell lymphoma

Background： The role of rituximab in combination with CHOP regimen in patients with stage I diffuse large B-cell lymphoma （DLBCL） remains to be defined. We aimed to compare CHOP plus rituximab （R-CHOP） with CHOP alone and determine the value of radiotherapy in these patients. Methods： Between 2003 and 2009, 140 untreated patients with stage I DLBCL were retrospectively analyzed in this study. Results： Seventy-eight patients were treated in R-CHOP group and 62 in CHOP group. Ninety-one patients received additional radiotherapy at the end of chemotherapy. The different treatment groups were well-balanced with respect to baseline characteristics. Complete response （CR） rate was 77% both in R-CHOP and CHOP groups （P=0.945）. After a median follow-up period of 56 months, patients received R-CHOP regimen had similar 5-year progression-free survival （PFS） （76% vs. 85%; log-rank P=0.215） and 5-year overall survival （OS） （90% vs. 96%; log-rank P=0.175） compared with those with CHOP alone. Patients with radiotherapy had significantly increased 5-year PFS compared with those who had chemotherapy alone （86% vs. 71%; log-rank P=0.005）. At multivariate analysis, patients who had CR （P=0.008） and received radiotherapy （P=0.003） were significantly associated with superior PFS. Conclusions： CHOP alone could be as effective as R-CHOP regimen and additional radiotherapy would be necessary for stage I or stage I non-bulky DLBCL patients.

Pathobiology of ovarian carcinomas

Ovarian tumors comprise a heterogeneous group of lesions, displaying distinct tumor pathology and oncogenic potentiel. These tumors are subdivided into three main categories: epithelial, germ cell, and sex-cord stromal tumors. We report herein the newly described molecular abnormalities in epithelial ovarian cancers(carcinomas). Immunohistochemistry and molecular testing help pathologists to decipher the significant heterogeneity of this disease. Our better understanding of the molecular basis of ovarian carcinomas represents the first step in the development of targeted therapies in the near future.

Clinical characteristics and treatment outcomes of Chinese diffuse large B-cell lymphoma patients in the era of rituximab(2005–2018)

Background Rituximab combined with cyclophosphamide,doxorubicin hydrochloride,vincristine,and prednisone(R-CHOP)regimen has improved the survival of diffuse large B-cell lymphoma(DLBCL)patients worldwide,compared with CHOP alone.Several limitations were seen in previous studies of Chinese DLBCL patients treated with R-CHOP or R-CHOP-like regimens.This study aimed to investigate the clinical characteristics and treatment outcomes of Chinese DLBCL patients treated with the standard first-line treatment.Methods Clinical data were collected from DLBCL patients who received frontline R-CHOP or R-CHOP-like regimens at the Cancer Hospital Chinese Academy of Medical Sciences&Peking Union Medical College(CHCAMS)between January 1,2005,and December 31,2018.The treatment outcomes were compared with those of patients diagnosed with DLBCL between 2004 and 2017 and who received immunochemotherapy from the United States Surveillance,Epidemiology,and End Results(SEER)database.Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test.Multivariate analysis of progression-free survival(PFS)and overall survival(OS)was performed using Cox proportional hazard regression.Results Overall,1084 patients from the CHCAMS and 4013 patients from the SEER database were included in the study.As of April 30,2022,the median follow-up period for the CHCAMS group was 87.3(range:0.5-195.4)months.For the CHCAMS group,the 5-year PFS and OS rates were 61.7%(95%confidence interval[CI]:58.8-64.7%)and 70.6%(95%CI:67.8-73.4%),respectively.For the SEER group,the 5-year OS rate was 66.5%(95%CI:65.0-68.0%),which was inferior to that of the CHCAMS group(P<0.001).After adjusting for clinical factors and treatment,no significant difference was observed in the OS between the CHCAMS and SEER groups(P=0.867).In the CHCAMS group,multivariate analysis showed that an Eastern Cooperative Oncology Group performance status score≥2,presence of B symptoms,Ann Arbor stage III-IV,elevated serumβ2-microglobulin levels,and bulky mass were independent adverse prognostic factors affecting PFS and OS(P<0.05).Additionally,patients aged over 60 years,elevated lactate dehydrogenase levels,and more than two extranodal sites were independent adverse prognostic factors for OS(P<0.05).Local radiotherapy was significantly associated with better PFS(P<0.001)and OS(P=0.001).Conclusion After adjusting for clinical and treatment-related factors,no significant difference was observed in the 5-year OS rate between Chinese DLBCL patients treated with standard first-line treatment and those from the SEER database.

Recombinant human thrombopoietin prior to mobilization chemotherapy facilitates platelet recovery in autologous transplantation in patients with lymphoma:Results of a prospective randomized study

Background:Chemotherapy plus granulocyte colony-stimulating factor (GCSF) regimen is one of the available approaches to mobilize peripheral blood progenitor cells (PBPCs).It causes thrombocytopenia and delays leukapheresis.This study aimed to evaluate the role of recombinant human thrombopoietin (rhTPO) before mobilization chemotherapy in facilitating leukapheresis in patients with lymphoma.Methods:In this randomized open-label phase 2 trial, patients were randomly assigned in a 1:2 ratio to receive mobilization with rhTPO plus GCSF in combination with chemotherapy (the rhTPO plus GCSF arm) or GCSF alone in combination with chemotherapy (the GCSF alone arm).The recovery of neutrophils and platelets and the amount of platelet transfusion were monitored.Results:Thirty patients were enrolled in this study between March 2016 and August 2018. Patients in the rhTPO plus GCSF arm (n = 10) had similar platelet nadir after mobilization chemotherapy (P=0.878) and similar amount of platelet transfusion (median 0 vs.1 unit,P=0.735) when compared with the GCSF alone arm (n = 20). On the day of leukapheresis, the median platelet count was 86 ×10^(9)/L (range 18-219) among patients who received rhTPO and 73 ×10^(9)/L (range 42-197) among those who received GCSF alone (P=0.982). After the use of rhTPO, the incidence of platelet count <75 ×10^(9)/L on the day of leukapheresis did not decrease significantly (30.0% vs. 50.0%,P=0.297).Platelet recovery after PBPC transfusion was more rapid in the rhTPO plus GCSF arm (median 8.0 days [95% confidence interval 2.9-13.1] to platelets ≥50 ×10^(9)/L vs. 11.0 days [95% confidence interval 8.6-13.4],P=0.011).The estimated total cost of the mobilization and reconstitution phases per patient was similar between the two treatmtent groups (P=0.362 andP=0.067,respectively).Conclusions:Our findings indicate that there was no significant clinical benefit of rhTPO use in facilitating mobilization of progenitor cells,but it may promote platelet recovery in the reconstitution phase after high-dose therapy.Trial registration:This trial has been registered in Clinicaltrials.gov as NCT03014102.