Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B-cell lymphoma.

PURPOSE: Large B-cell lymphoma with IRF4 rearrangement (LBCL, IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due to IRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates of IRF4+. METHODS: The histopathology, immunophenotype, IRF4 status of the tumors, and clinical data were reviewed. RESULTS: Twenty-one tumors were diagnosed as LBCL, IRF4+, which were more frequently associated with a follicular growth pattern, medium-sized blastoid cytology, germinal center B-cell-like, and CD5+ phenotype, compared with IRF4- ones. While most of the patients received chemotherapy with or without radiation, eight IRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome. IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared with IRF4- ones. Multivariate analysis confirmed IRF4+ correlates with a better survival. CONCLUSION: Our work confirmed the unique clinicopathologic features of LBCL, IRF4+, and disclosed for the first time the independent favorable prognostic impact of IRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.

Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study.

Relapsed or refractory (r/r) mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis. Bruton tyrosine kinase (BTK) is a mediator of B-cell receptor signaling and is associated with the development of B-cell lymphomas. Patients with r/r MCL were enrolled in this phase 1/2 study and treated with orelabrutinib, a novel, highly selective BTK inhibitor. The median number of prior regimens was 2 (range, 1-4). The median age was 62 years (range, 37-73 years). Eligible patients received oral orelabrutinib 150 mg once daily (n = 86) or 100 mg twice daily (n = 20) until disease progression or unacceptable toxicity. A dose of 150 mg once daily was chosen as the preferred recommended phase 2 dose. After a median follow-up duration of 23.8 months, the overall response rate was 81.1%, with 27.4% achieving a complete response and 53.8% achieving a partial response. The median duration of response and progression-free survival were 22.9 and 22.0 months, respectively. The median overall survival (OS) was not reached, and the rate of OS at 24 months was 74.3%. Adverse events (AEs) occurring in >20% of patients were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Grade ≥3 AEs were infrequent and most commonly included thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%). Three patients discontinued treatment because of treatment-related adverse events (TRAEs), but no fatal TRAEs were reported. Orelabrutinib showed substantial efficacy and was well tolerated in patients with r/r MCL. This trial was registered at www.clinicaltrials.gov as #NCT03494179.

Bortezomib in combination with fludarabine plus cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study.

This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).

Cell-of-Origin Subtyping of Diffuse Large B-Cell Lymphoma by Using a qPCR-based Gene Expression Assay on Formalin-Fixed Paraffin-Embedded Tissues.

The well-established cell-of-origin (COO) algorithm categorizes diffuse large B-cell lymphoma (DLBCL) into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subgroups through gene expression profiling. We aimed to develop and validate a qPCR-based gene expression assay to determine the COO subgroups of DLBCL with formalin-fixed paraffin-embedded (FFPE) tissue. We first established a DLBCL transcriptome database of 1,016 samples retrieved from three published datasets (GSE10846, GSE22470, and GSE31312). With this database, we identified a qPCR-based 32-gene expression signature (DLBCL-COO assay) that is significantly associated with the COO subgroups. The DLBCL-COO assay was further validated in a cohort of 160 Chinese DLBCL patients. Biopsy samples from DLBCL patients with paired FFPE and fresh frozen tissue were collected to assign COO subtypes based on the immunohistochemistry (IHC) algorithm (Han's algorithm), DLBCL-COO assay, and global gene expression profiling with RNA-seq. For 111 paired FFPE and fresh DLBCL samples, the concordance between the IHC, qPCR, and RNA-seq methods was 77.5% and 91.9%, respectively. The DLBCL-COO assay demonstrated a significantly superior concordance of COO determination with the "gold standard" RNA-seq compared with the IHC assignment with Han's algorithm (P = 0.005). Furthermore, the overall survival of GCB patients defined by the DLBCL-COO assay was significantly superior to that of ABC patients (P = 0.023). This effect was not seen when the tumors were classified by the IHC algorithm. The DLBCL-COO assay provides flexibility and accuracy in DLBCL subtype characterization. These findings demonstrated that the DLBCL-COO assay might serve as a useful tool for guiding prognostic and therapeutic options for DLBCL patients.

Prognostic Significance of LDH Ratio in Serum/Cerebral Spinal Fluid of Patients with Primary Testicular Diffuse Large B-Cell Lymphoma.

OBJECTIVE: Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is relatively rare, and risk factors of this disease are still not well understood. This study aims to identify clinical features and prognostic factors of PT-DLBCL patients. METHODS: Thirty-two patients were included in this retrospective study who were diagnosed as PT-DLBCL and treated in Fudan University Shanghai Cancer Center between November 2010 and May 2018. The demographic details, clinico-pathological characteristics of the patients were summarized, and the impact on progression-free survival (PFS) and overall survival (OS) was analyzed. RESULTS: The median age of the patients was 57 (range 36-76) years old. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 4-6 cycles and central nervous system (CNS) prophylaxis, with a CR rate 87.5% and an ORR 96.9%. Nineteen patients continued prophylactic contralateral testis radiation therapy (PCTRT) in our hospital. The 3-year PFS and OS rates were 79% and 92%, respectively. None of the 19 patients who received PCTRT experienced local recurrence. All three patients who suffered from CNS relapse were germinal center B-cell subtype. Kaplan-Meier analyses showed that PT-DLBCL patients with late-stage (Stage IV) (P =0.022), higher IPI score (IPI≥ 2) (P =0.017), B symptoms (P =0.004), and elevated LDH level (P =0.03) had a shorter PFS. More importantly, we found that patients with the ratio of the LDH level in serum to that in CSF ≥ 6.5 suffered from a worse PFS (P =0.028). CONCLUSION: Our work revealed that staging IV, IPI score ≥2, having B symptoms and elevated LDH level were risk factors for PT-DLBCL patients. Significantly, the PT-DLBCL patients with a high ratio of LDH level in serum to that in CSF were indicated to have a worse PFS.

The size and depth of lesions measured by endoscopic ultrasonography are novel prognostic factors of primary gastric diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma is one of the predominant histological subtypes of primary gastric lymphomas. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. We analyzed 73 primary gastric diffuse large B cell lymphoma patients retrospectively, and found that patients characterized by late stage, multiple localization, B symptoms, lower serum albumin level and elevated LDH level had a shorter overall survival through Univariate Cox regression analysis. Multivariate Cox regression analysis demonstrated that ALB ≤ 35g/L, staging ≥ IIE and multiple sites localization were independent adverse prognostic factors. Significantly, in 35 patients who received endoscopy at diagnosis, Kaplan-Meier analyses indicated that patients with large (≥3 cm) and deep lesions (≥11 mm) had an inferior OS (p = .01 and .039). These findings implicated that tumor size and depth are two indicators of prognosis under ultrasonography. Further randomized studies with large number of cases are needed.

Reassessment of the prognostic value of the International Prognostic Index and the revised International Prognostic Index in patients with diffuse large B-cell lymphoma: A multicentre study.

The International Prognostic Index (IPI) is a widely accepted model that is used to predict the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) who are treated using chemotherapy. However, the prognostic value of the IPI has been a focal point of debate in the immunochemotherapy era. The aim of this study was to reassess the value of the IPI and revised IPI (R-IPI) in a Chinese population. A multicentre retrospective analysis of DLBCL patients who were treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy alone or chemotherapy plus rituximab (R-CHOP-like) was performed. The prognostic values of IPI and R-IPI at the time of diagnosis with respect to overall survival (OS) and progression-free survival (PFS) were evaluated. Among the 438 patients in the study, 241 received a CHOP-like regimen and 197 patients received an R-CHOP-like regimen. Although the IPI remained predictive for the CHOP-like group, it failed to distinguish between the various prognostic categories in the R-CHOP-like group. Notably, redistribution of the IPI factors into R-IPI factors identified three discrete prognostic groups with significantly different outcomes in both the CHOP-like and R-CHOP-like groups. In the R-CHOP-like group, these three risk groups, very good, good and poor, had distinctly different 3-year PFS rates of 96, 84.3 and 67.5% (P=0.001), and 3-year OS rates of 96, 87.6 and 71.1% (P=0.003), respectively. Our study demonstrates the power of the R-IPI as a simplified and more clinically relevant predictor of disease outcome than the standard IPI in DLBCL populations in the rituximab era. Therefore, the R-IPI merits further study in a larger population-based prospective study.

[Evaluation of the impact of R-CHOP chemotherapy on efficacy, safety and prognosis in newly diagnosed diffuse large B-cell lymphoma patients and its prognostic impact: a multicenter retrospective study with long term follow-up].

OBJECTIVE: To evaluate the efficacy, safety and prognostic impact of rituximab plus CHOP (R-CHOP) regimen on patients with diffuse large B-cell lymphoma (DLBCL), to access the impact of R-CHOP on patients' prognosis and to compare that with CHOP regimen. METHODS: Five hundred and seven newly diagnosed DLBCL patients were enrolled from Jan. 1, 2000 to May 1, 2010. Patients were administered with 6 cycles of CHOP or at least 4 cycles of R-CHOP treatments. Rituximab was administered intravenously on day 1 at a dose of 375 mg/m(2). The typical CHOP regimen include cyclophosphamide (750 mg/m(2), IV), doxorubicin (50 mg/m(2), IV) and vincristine (1.4 mg/m(2), IV, maximum 2 mg) and prednisone (60 - 100 mg, oral, day 3 - 7). The complete response (CR) rates, overall response (OR) rates, and side events of these 2 groups were compared. RESULTS: Of the 411 analyzable patients, 224 received CHOP regimen and 187 received R-CHOP regimen. CR rate for R-CHOP group and CHOP group was 77.01% and 71.43%, respectively. OR rate in R-CHOP group was higher than that in the CHOP group (95.19% vs 87.95%, P = 0.007). The median follow-up time of R-CHOP group was 28.1 months vs that of 35.2 months in CHOP group. There was significant difference in progression free survival (PFS) and overall survival (OS) between 2 groups (P = 0.018 and 0.034, respectively). At the end of follow-up, the estimated median PFS in R-CHOP group had not been reached, while that was 84.8 months in CHOP group. The median OS in both groups had not yet been reached. The adverse events in R-CHOP group were similar with that in CHOP group. CONCLUSIONS: R-CHOP is a safe and effective regimen for management of newly diagnosed DLBCL, with a better remission rate, PFS and OS.

Oral fludarabine in combination with doxorubicin and dexamethasone as first-line therapy for nodal peripheral T-cell lymphomas: early results of a prospective multicenter study.

PURPOSE: Nodal peripheral T-cell lymphomas (PTCLs) have particularly poor prognoses. Few data enabling establishment of an accepted standard treatment modality for PTCLs are available. We hypothesized that fludarabine-based regimens are tolerable and effective in treatment for nodal PTCLs. Therefore, this study was to analyze the toxicity of, response rate for, and outcome of treatment for nodal PTCLs with oral fludarabine, doxorubicin, and dexamethasone (FAD). METHODS: Patients with PTCLs received FAD every 28 days, consisting of oral fludarabine at 40 mg/m(2) on days 1-3, doxorubicin at 50 mg/m(2) on day 1, and oral dexamethasone at 20 mg/day on days 1-5. Patients who did not exhibit disease progression received at least four courses of treatment. RESULTS: Thirty-one of 35 patients with previously untreated nodal PTCLs enrolled in the study from 2007 to 2008 were evaluable. The incidence of grade 3-4 neutropenia was 55%. Nine patients had to have dose reductions of fludarabine and doxorubicin, none of whom had grade 3 or 4 toxic effects at the lower dose. Five of 31 patients had pneumonitis. No treatment-related mortality occurred. The response rate for the entire patient population was 71%, and the complete remission rate was 48%. The PFS and OS rates at 2 years were 54.2 and 77.1%, respectively. Four patients had died of cancer progression at the time of this analysis. The serum lactate dehydrogenase level had a significant effect on PFS and OS. CONCLUSION: The FAD regimen had encouraging efficacy with an acceptable toxicity profile in patients with nodal PTCLs.

A clinical analysis of primary testicular diffuse large B-cell lymphoma in China.

The objective of this study was to analyze the clinical behavior and treatment policy of patients with primary testicular diffuse large B-cell lymphoma by retrospective analysis of 32 patients at our institute. All patients underwent orchidectomy. Anthracycline-based chemotherapy was administered to 27 patients (84·38%), six of whom also received rituximab; prophylactic intrathecal chemotherapy was given to seven patients (21·88%); and eight patients (25%) received prophylactic scrotal radiotherapy. Thirteen patients had relapse, among whom 12 cases were extranodal recurrences. Seven patients had central nervous system involvement, and four patients relapsed in the contralateral testis. The presence of B symptoms, poor Eastern Cooperative Oncology Group performance status, left testicular involvement, central nervous system involvement, and first relapse within 1 year were associated with worse progression-free survival using univariate analysis. Poor Eastern Cooperative Oncology Group performance status, left testicular involvement, and surgery alone were negative prognostic factors for overall survival.

Clinical features and treatment outcomes of 14 cases of primary ovarian non-Hodgkin's lymphoma: a single-center experience.

To analyze the clinical characteristics, results of treatment, and prognostic factors of patients diagnosed as primary ovarian non-Hodgkin's lymphoma (PONHL). Fourteen cases of PONHL treated in Fudan University Cancer Center during a 10-year period were retrospectively reviewed, and the clinical data of the patients were analyzed for correlation between KPS, clinical stage, tumor size, IPI, ovary involvement, treatment and prognosis. The median age was 45 years, and thirteen patients were diagnosed of diffuse large B-cell lymphoma and one patient lymphoblastic lymphoma. Four patients were stage IE, three stage IIE, and seven stage IVE. The median tumor size was 8 cm (range, 4.0-15.0 cm). The median overall survival (OS) of the 14 patients was 23.0 months (range 11.5-71.2 months). Thirty-six percentage of patients with bilateral ovary involvement had a shorter survival time than those with unilateral ovary involvement (median OS: 19.0 vs. 37.2 months, P=0.014). The OS of Stage IVE was worse than stage IE and stage IIE (median OS: 18.75 vs. 37.5 months, P=0.047). Patients with IPI>2 had worse prognosis than those with IPI≤2 (median OS: 19.0 vs. 42.1 months, P=0.03). PONHL patient with larger tumor mass had worse prognosis (median OS: 19.1 vs. 37.2 months, P=0.019). R-CHOP regimens had a tendency to improve the OS but was not shown to be statistically significant (median OS: 22.4 vs. 37.2 months, P=0.436). The management of PONHL should be based on multi-modality treatment including surgery and chemotherapy. The significant prognostic factors of survival are tumor size, Ann Arbor staging, and IPI.

[Clinical analysis of primary gastric diffuse large B-cell lymphoma].

OBJECTIVE: To analyze the clinical features and prognostic factors of primary gastric diffuse large B-cell lymphoma (PG-DLBCL) and to evaluate the staging system and treatment modality of PG-DLBCL. METHODS: The clinicopathological data of 69 patients with PG-DLBCL were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) were the primary endpoints. RESULTS: The EFS rates at 1, 3, and 5 years were 83.8%, 71.1%, and 69.0%, respectively, with a mean EFS of 91.3 months. The 1-, 3-, and 5-year OS rates were 91.3%, 80.3%, and 72.4%, respectively, with a mean OS of 98.8 months. Univariate analysis revealed that either EFS or OS was significantly prolonged by the following factors (P < 0.05): modified Ann Arbor stage I(E) or II(E1) disease; normal lactate dehydrogenase (LDH) level; normal hemoglobin level; normal albumin level; International Prognostic Index (IPI) of 0 or 1; tumor size < 5 cm; and less depth of invasion. While gender, age, B symptoms at presentation, performance status and treatment modality were not significantly associated with the prognosis (P > 0.05). Cox regression model revealed that only modified Ann Arbor stage and albumin level were independent prognostic factors for EFS and OS. CONCLUSION: The most accurate staging system and the exact role of different therapeutic options for PG-DLBCL are still debated. Further randomized prospective studies with a large number of patients are still needed to establish an optimal management for this disease.

[Prognosis of primary non-Hodgkin's lymphoma of the breast].

OBJECTIVE: To analyze the clinical characteristics and prognosis of primary non-Hodgkin's lymphoma of the breast (PNHLB). METHODS: The characteristics, treatment methods and outcomes of 45 patients with PNHLB were retrospectively analyzed. Chemotherapy including CHOP and CHOP-like regimens was administered in 43 patients, and monoclonal antibody therapy in 6 patients. Furthermore, 19 patients underwent radiotherapy after chemotherapy. RESULTS: Of these 45 patients, 37 patients had diffuse large B cell lymphoma (DLBCL), patients with T cell or mucosa-associated lymphoid tissue (MALT) lymphoma were 4, respectively. Overall response rate of first-line chemotherapy was 90.7%. Median overall survival (OS) and progression-free survival (PFS) of all patients was 6.82 and 4.25 years, respectively. The results of Cox regression model analysis showed that international prognostic index score (IPI) (RR = 5.682, P = 0.002) and Ann Arbor stage (RR = 1.836, P = 0.040) were negative independent prognostic factors for OS. Central nervous system involvement (RR = 1.107, P = 0.005) was a negative independent prognostic factor for PFS. CONCLUSION: The patients with PNHLB have early occurrence in lifespan. Most pathologic type was DLBCL. IPI and Ann Arbor stage are two independent prognostic factors for survival.

[Vinorelbine plus cisplatin in the treatment of advanced non-small cell lung cancer previously treated with taxane-based chemotherapy].

OBJECTIVE: To evaluate the efficacy and toxicity of vinorelbine plus cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC) previously treated with taxane-based chemotherapy. METHODS: Thirty patients (0 - 1 score ECOG performance status) with stage IIIB/IV NSCLC previously treated with taxane-based chemotherapy were eligible for the study. Fifteen patients received the regimen of vinorelbine plus cisplatin (NP), the others received mitomycin, vindesine plus cisplatin (MVP). RESULTS: The overall response rates were 13.3% in NP and 0 in MVP (P > 0.05). Time to progression was longer for NP patients than that for MVP ones (6 v 3 months, P < 0.05), so was median survival (9 v 6 months, P < 0.05). The 1-year survival rate of 40.0% in the NP group was significantly higher than that of 0 in MVP (P < 0.05). Grade III-IV toxicity was observed at a similar rate in both groups (P > 0.05), though both well tolerated. CONCLUSION: Regimen of vinorelbine plus cisplatin is appropriate for good performance status patients with advanced non-small cell lung cancer previously treated with taxane-based chemotherapy. Time to progression, median survival and 1-year survival are satisfactory in patients treated with NP, which is complicated with acceptable toxicity.