Fotemustine, etoposide, cytarabine, and cyclophosphamide (FEAC) conditioning regimen for autologous stem cell transplantation in lymphoma.

To investigate the efficacy and safety of the FEAC (fotemustine, etoposide, cytarabine, and cyclophosphamide) conditioning regimen for the treatment of lymphoma, we retrospectively analyzed the records of 76 Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients who underwent autologous stem cell transplantation (ASCT) after the FEAC conditioning regimen. Their survival, as well as the clinical efficacy, hematopoietic engraftment time, and toxicity, were analyzed. One patient died of severe pulmonary infection, and the transplant-related mortality (TRM) was 1.3% (1/76). Hematopoietic engraftment was achieved successfully in the remaining 75 patients. The median times of neutrophil and platelet engraftment were 11 d (6-21 d) and 13 d (8-24 d), respectively. The 2-year progression-free survival (PFS) rate was 69.1%, and the 2-year overall survival (OS) rate was 84.2%. FEAC conditioning regimen has acceptable toxicity, and the prognosis of patients is good, making it a feasible alternative to the BEAM regimen for ASCT.

Clinical analysis of patients with primary and secondary extranodal natural killer/T-cell lymphoma of central nervous system.

Extranodal natural killer (NK)/T-cell lymphoma (NKTL) is a rare non-Hodgkin lymphoma that rarely arise exclusively in or metastasizes to the central nervous system (CNS). Globally, CNS involvement of NKTL heralds a serious prognosis and there is no standard treatment. 19 of 414 patients (4.59%) with ENKL followed were diagnosed with CNS involvement between 2006 and 2020. Two patients had primary CNS (PCNS) NKTL, and 17 patients had secondary CNS (SCNS) invasion. A total of 9 patients survived and 10 patients died. The median overall survival time was 55 months, and the median survival time after CNS invasion was 17 months. The 5-year cumulative survival probability was 45.7%. In conclusion, CNS risk evaluation and prophylaxis treatment can be carried out for patients with NK/T-cell lymphoma prognostic index risk group III/IV. In terms of treatment, systemic therapy based on methotrexate combined with radiotherapy and intrathecal chemotherapy can be selected.

Strategies to overcome CAR-T cell resistance in clinical work: A single-institute experience.

The emergence of chimeric antigen receptor (CAR) T cell therapy has shifted the paradigm of malignant tumor treatment, especially the advent of CD19-directed CAR-T cell therapy for the treatment of relapsed/refractory (R/R) B-cell malignancies. Although CAR-T cell therapy has promising effects, some patients are resistant to this treatment, leaving them with limited options. Therefore, strategies to overcome resistance to CAR-T cell therapy are needed. We retrospectively studied three R/R diffuse large B-cell lymphoma patients who were resistant to CAR-T cell therapy and whose disease was controlled after receiving pembrolizumab, 21D4 CAR-T cells, or ibrutinib and venetoclax. Some promising prevention and treatment strategies to overcome treatment resistance are also discussed.

The clinical characteristics and prognostic factors of 410 patients with natural killer/T-cell lymphoma.

PURPOSE: To investigate the clinical characteristics and prognostic factors of natural killer/T-cell lymphoma (NKTCL). METHODS: We retrospectively reviewed 410 NKTCL patients admitted to our lymphoma center from 2000 to 2019. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method, and the differences between the study groups were compared by the log-rank test. RESULTS: The median age of the 410 patients was 44 (range 8-84), and the 5-year OS and PFS were 61.2% and 38.4%, respectively. For patients with stage I/II, the 5-year PFS rate was 57.5%, and the 5-year OS rate was 77.2%. For patients with stage III/IV, the 5-year PFS rate was 17.4%, and the 5-year OS rate was 43.7%. Compared to the patients who received radiotherapy alone or chemotherapy alone as their initial treatment, the patients who received combined chemoradiotherapy had longer PFS (P = 0.013). Independent prognostic factors for OS were stage III/IV (P = 0.001), elevated IPI/aaIPI score (P = 0.019), elevated PINK score (P < 0.001) and elevated plasma EBV-DNA (P = 0.003). An elevated PINK score (P < 0.001) was an independent prognostic factor for PFS. CONCLUSION: Stage III/IV, elevated IPI/aaIPI score, elevated PINK score and elevated plasma EBV-DNA were independent prognostic factors for OS. Elevated PINK score was an independent prognostic factor for PFS. In stage III/IV patients, the patients who received combined chemoradiotherapy had significantly longer PFS.

Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial.

Importance: The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking. Objective: To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL). Design, Setting, and Participants: This was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group. Interventions: Patients in each group were treated with the assigned regimen every 21 days for 6 cycles. Main Outcomes and Measures: The primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared. Results: Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%). Conclusions and Relevance: In this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01501149.

DDGP followed by radiotherapy vs VIPD followed by radiotherapy in newly diagnosed early NK/T-cell lymphoma.

PURPOSE: To explore the best treatment for early natural killer/T (NK/T)-cell lymphoma, we compared the efficacy and safety of DDGP (pegaspargase, gemcitabine, cisplatin and dexamethasone) followed by radiotherapy (RT) and VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone) followed by radiotherapy for newly diagnosed patients. MATERIALS AND METHODS: 40 newly diagnosed patients with stage I-II from January 2011 to November 2016 were treated with DDGP followed by radiotherapy or VIPD followed by radiotherapy. They were assessed in this study. RESULTS: The complete response rate (CRR) and overall response rate (ORR) of the DDGP followed by radiotherapy group were higher than those of the VIPD followed by radiotherapy group (CRR: 85 % vs 50 %, P = 0.018; ORR: 95 % vs 65 %, P = 0.048). The 5-year progression-free survival (PFS) rate was better in the DDGP followed by radiotherapy group (83.3 % vs 44.4 %, χ2 = 7.809, P = 0.005). There was no significant difference in the 5-year overall survival (OS) rate between the two groups (83.0 % vs 72.1 %, χ2 = 0.231, P = 0.631). Treatment method (P = 0.011) and IPI score (P = 0.027) were independent risk factors for PFS. The DDGP followed by radiotherapy group was more prone to grade I-II clotting dysfunction (P = 0.004). CONCLUSIONS: In patients newly diagnosed with early NK/T-cell lymphoma, those treated with DDGP followed by radiotherapy had a higher CRR and ORR and longer PFS than those treated with VIPD followed by radiotherapy, and adverse reactions were tolerable.

CD5-positive marginal zone lymphoma: Clinicopathological features and survival outcomes.

BACKGROUND: CD5 expression in different B-cell lymphomas has different clinicopathological and prognosis and the value of CD5 expression in marginal zone lymphoma is undefined. METHODS: Clinicopathological features, survival outcomes of marginal zone lymphoma were retrospectively analyzed in 204 patients. We classified patients into (i) CD5-positive marginal zone lymphoma (ii) CD5-negative marginal zone Lymphoma, Fisher's exact test was used to compare the CD5-positive and CD5-negative marginal zone lymphoma. Progression-free survival (PFS) and overall survival (OS) curves were summarized by Kaplan-Meier method and compared using the log-rank test. RESULTS: Of the 204 patients, 48 (23.53%) were CD5-positive. The 5-year PFS and OS rates for CD5-positive marginal zone lymphoma were 64.80% and 84.10%, there was no significant difference between CD5-positive and CD5-negative (P > 0.05). Diffuse large B cell lymphoma (DLBCL) transformation was pathologically indicated in 6 patients, of which 5 (83.33%) patients were CD5-positive marginal zone lymphoma. CONCLUSION: CD5 expression in marginal zone lymphoma is not relevant to the prognosis of the patients, but CD5-positive marginal zone lymphoma seems more likely to transformation to diffuse large B-cell lymphoma.

Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic Leukemia/Lymphoma.

PURPOSE: Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7-chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (R/R) T-ALL/LBL, as well as its manufacturing feasibility. PATIENTS AND METHODS: Preclinical phase was conducted in NPG mice injected with Luc+ GFP+CCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety; secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters. RESULTS: CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulum/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) 3 months after CAR T-cell infusion; 1 patient with leukemia achieved minimal residual disease-negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/µL at approximately 12 days and remained detectable up to 270 days. CONCLUSIONS: Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.

Ibrutinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Retrospective Study.

Limited treatment options are available for relapsed or refractory diffuse large B cell lymphoma (RR DLBCL). Few clinical studies have reported the use of Ibrutinib, a covalent Bruton Tyrosine kinase (BTK) inhibitor, in RR DLBCL. There are relatively few clinical studies about Ibrutinib in RR DLBCL now. We retrospectively investigated the safety and efficacy of Ibrutinib (alone or in combination with other drugs) in patients with RR DLBCL. We reviewed the medical records of 40 RR DLBCL patients who received Ibrutinib alone or in combination with other drugs in our hospital from June 2018 to August 2020. The objective response rate (ORR) of RR DLBCL patients on Ibrutinib was 22.5%. The median progression free survival time (PFS) was 13.0 months (95% CI 8.914-17.086), and the median overall survival time (OS) was 15.0 months (95% CI 11.931-18.089). Rash (25.0%) and fatigue (25.0%) were the most common adverse reactions in this study. The application of Ibrutinib to patients with RR DLBCL has good short-term efficacy, and the adverse reactions are well tolerated. Combined treatment of Ibrutinib with other drugs has been found to more effective than Ibrutinib therapy alone.

Orelabrutinib-bruton tyrosine kinase inhibitor-based regimens in the treatment of central nervous system lymphoma: a retrospective study.

BACKGROUND: Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Orelabrutinib, an oral Bruton tyrosine kinase inhibitor, is a new treatment strategy for CNSL. This study aims to evaluate the efficacy and safety of orelabrutinib-based regimens in the treatment of patients with CNSL. METHODS: Twenty-three patients with CNSL were included in this retrospective study. All patients received the orelabrutinib-based regimen. Efficacy was evaluated based on investigators' assessment of overall response rate (ORR), complete response/unconfirmed complete response (CR/CRu), partial response (PR), stable disease (SD), progressive disease (PD), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The safety of orelabrutinib-based regimens has also been evaluated. RESULTS: A total of 17.39% of patients received orelabrutinib-based regimens for consolidation therapy, and 82.61% of patients for induction therapy (4 newly diagnosed CNSL, 15 relapsed/refractory CNSL). In the newly diagnosed CNSL group, the ORR was 100% (1 CR, 1 CRu, 2 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 100%, 100%, and 100%, respectively. Of the 15 relapsed/refractory CNSL patients, five therapy regimens were applied (orelabrutinib, n = 3; orelabrutinib/immunotherapy, n = 3; orelabrutinib/chemotherapy, n = 2; orelabrutinib/immunochemotherapy, n = 6; orelabrutinib/radiotherapy, n = 1). The ORR was 60.00% (4 CR, 5 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 92.30%, 67.70%, and 70.00%, respectively. Twenty-one patients reported adverse events (AEs), and 6 patients experienced grade ≥ 3 AEs. CONCLUSION: Orelabrutinib-based regimens were efficacious and well-tolerated in patients with CNSL. These combined therapies offer a new potential therapeutic strategy for patients with CNSL.

Improving outcomes in limited-stage de novo CD5+ DLBCL: systemic approaches with consolidative radiation.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis after frontline immunochemotherapy. This retrospective study investigated the effect of consolidative radiation after systemic treatment in newly diagnosed stage I-II de novo CD5+ DLBCL. In this study, 22 patients received consolidative radiotherapy (RT) after immunochemotherapy (chemotherapy + RT group) and 28 patients received chemotherapy alone. Patients who received chemotherapy alone had a significantly shorter PFS and OS than those who received consolidative radiotherapy. The five-year PFS rates for the chemotherapy + RT and chemotherapy alone groups were 75.1% and 40.5%, respectively. The five-year OS rates for the chemotherapy + RT and chemotherapy alone groups were 84.2% and 50.1%, respectively. Even after receiving consolidation radiotherapy, 2/22 (9.1%) patients experienced CNS relapse. Age >60 years and lack of radiotherapy were independent prognostic factors for PFS and OS. Ki-67 (≥80%) was an independent prognostic factor for poor OS. Consolidative radiotherapy might be a good option for stage I-II CD5+ DLBCL, but further investigation is needed.

Fotemustine-based therapy in combination with rituximab as a first-line induction chemotherapy followed by WBRT for newly diagnosed primary central nervous system lymphoma: a prospective phase II trial.

OBJECTIVE: This study aimed to evaluate the safety, efficacy, and feasibility of the rituximab, fotemustine, pemetrexed, and dexamethasone (R-FPD) regimen followed by whole-brain radiotherapy (WBRT) for patients with primary central nervous system lymphoma (PCNSL). METHODS: A prospective, single-center phase II clinical trial was conducted. Patients with PCNSL newly diagnosed at the First Affiliated Hospital of Zhengzhou University between July 2018 and July 2020 were studied. The R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100 mg/m2 i.v. on D1), pemetrexed (600 mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1-5). Patients 60 years or younger who showed a complete response (CR) were treated with 23.4 Gy of WBRT after the end of chemotherapy; those older than 60 years with CR were treated with a wait-and-see approach; and those who did not show CR after the 4th cycle of chemotherapy were given salvage WBRT 30 Gy + local tumor field irradiation up to 45 Gy, regardless of age. RESULTS: A total of 30 patients were included. After 2 cycles, the objective response rate (ORR) was 96.5% (28/29, 1 CR, 27 PR, 0 SD, and 1 PD). After 4 cycles, the ORR was 73.1% (19/26, 11 CR, 8 PR, 4 SD, and 3 PD). After WBRT, the ORR was 90.9% (10/11, 7 CR, 3 PR, and 1 SD). The grade III and IV toxicity responses were mainly leukopenia (20.0%), thrombocytopenia (23.3%), and anemia (10.0%). CONCLUSIONS: Fotemustine-based therapy in combination with rituximab chemotherapy followed by WBRT can improve outcomes, providing ORR benefits and favorable tolerability in patients newly diagnosed with PCNSL.

Radiotherapy vs sequential pegaspargase, gemcitabine, cisplatin and dexamethasone and radiotherapy in newly diagnosed early natural killer/T-cell lymphoma: A randomized, controlled, open-label, multicenter study.

To compare the efficacy and safety of radiotherapy (RT) and chemotherapy of pegaspargase, gemcitabine, cisplatin and dexamethasone (DDGP) combined with RT in newly diagnosed stage I-II natural killer/T-cell lymphoma (NKTL), we designed a randomized, controlled, open-label, multicenter clinical trial. Data from 65 stage I-II NKTL patients whose diagnoses were confirmed using immunohistochemistry were enrolled from January 2011 to December 2013 in the First Affiliated Hospital of Zhengzhou University. Patients were randomly divided into the RT group (n = 35) and the DDGP combined with RT group (n = 30). There was a difference between the Eastern Cooperative Oncology Group (ECOG) score in the two arms (P = .013). The complete response rate (CRR) and objective response rate (ORR) of DDGP combined with RT group were superior to those in the RT group (CRR: 73.3% vs 48.6%; ORR: 83.3% vs 60.0%, respectively). The 5-year progression-free survival (PFS) rate and overall survival (OS) rate in the DDGP combined with RT group were higher than those in the RT group (82.9% vs 56.5% for PFS, P = .023; 85.7% vs 60.4% for OS, P = .040), and treatment methods and lactate dehydrogenase were independent risk factors. Myelosuppression (P < .001), gastrointestinal reactions (P < .001), abnormal liver function (P = .007), coagulation abnormalities (P < .001) and baldness (P < .001) were more likely to occur in the DDGP combined with RT group. In conclusion, DDGP combined with radiotherapy obviously obtained great efficacy and prolonged the survival time of patients, also the side effects were mild for stage I-II NKTL. This trial was registered at https://register.clinicaltrials.gov as #NCT01501136.

Research on the midterm efficacy and prognosis of patients with diffuse large B-cell lymphoma by different evaluation methods in interim PET/CT.

PURPOSE: To investigate the midterm efficacy and prognostic evaluation of patients with diffuse large B-cell lymphoma (DLBCL) by three image analysis methods: International Harmonization Project (IHP), Deauville 5-Point Scale (5-PS) and Δ SUVmax criteria in 18F-FDG PET/CT. METHODS: This was a retrospective analysis of 141 patients with DLBCL. All patients were given 3-4 cycles of chemotherapy and 18F-FDG PET/CT. According to three criteria, the patients were divided into negative and positive groups, respectively. Statistical methods were used to assess the midterm efficacy and prognosis factors. RESULTS: During the midterm follow-up, a total of 109 people achieved CR. Three methods showed statistically significant differences in OS and PFS for the interim PET/CT, and Δ SUVmax criterion was an independent risk factor for the prognosis of DLBCL patients. CONCLUSION: In our research, IHP, 5-PS and Δ SUVmax criteria all had a significant predictive value, while Δ SUVmax criterion had more advantages in evaluating the midterm efficacy and predicting prognosis for patients with DLBCL in interim PET/CT. But it should be noticed that Δ SUVmax criterion needs more strict guidelines in multicenter trials. The optimal cutoff value of Δ SUVmax% we recommended was 81.54%, which helped to judge the midterm efficacy.

Effective Treatment with PD-1 Antibody, Chidamide, Etoposide, and Thalidomide (PCET) for Relapsed/Refractory Natural Killer/T-Cell Lymphoma: A Report of Three Cases.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is a specific subtype of peripheral T cell lymphoma (PTCL) with a poor prognosis. To date, there exist no standard therapeutic regimens for relapsed/refractory (R/R) ENKTL. More potent treatment strategies are urgently needed to improve the survival of these patients with R/R ENKTL. Herein, we present three R/R ENKTL patients who failed prior therapies (L-asparaginase containing chemotherapy, radiotherapy or biological-cell therapy, etc.) benefited from the combination regimen comprised of anti-programmed-death-1 (PD-1) antibody toripalimab, chidamide, etoposide, and thalidomide. They received the treatment regimen continuously until the disease progression occurs. As of data collection, two patients achieved complete remission (CR) after 4, 6 cycles of treatment, respectively, and another patient was evaluated as partial remission (PR) after 2 cycles. Treatment-related adverse events (AEs) mainly presented grade 2~3 leukocytopenia and anemia, which were controllable. It follows that PD-1 antibody, chidamide, etoposide, and thalidomide (PCET) regimen may be a promising choice for patients with R/R ENKTL and warrants further investigation.

Outcomes of GDPT (gemcitabine, cisplatin, prednisone, thalidomide) versus CHOP in newly diagnosed peripheral T-cell lymphoma patients.

AIM: To compare the outcomes of GDPT [gemcitabine (G), cisplatin (D), prednisone (P), thalidomide (T)] versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in treating newly diagnosed PTCL (peripheral T-cell lymphoma). METHODS: An open-label prospective clinical trial with 153 newly diagnosed PTCL patients conducted between January 2010 and December 2018 was designed. Patients were randomly assigned to the GDPT (77 cases) and CHOP (76 cases) groups. Patients in each group were further divided into four subgroups: PTCL, not otherwise specified (PTCL-NOS); anaplastic large cell lymphoma (ALCL), angioimmunoblastic T cell lymphoma (AITL), and other types subgroup, in accordance with pathological patterns. Based on expression of RRM1, TOP2A, TUBB3, and ERCC1, patients were divided into groups with high and low gene expression levels. Clinical characteristics, side effects, efficacy, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: There were no significant differences in the basic clinical features or side effects between the GDPT and CHOP groups. The overall response rate (ORR) of the GDPT group was better than that of the CHOP group (66.3% versus 50.0%, p = 0.042), as was the complete remission (CR) rate (42.9% versus 27.6%, p = 0.049). Patients in the GDPT group had a longer PFS and OS than the CHOP group. The 4-year PFS and OS rates in the GDPT group were both superior to those in the CHOP group (63.6% versus 53.0% for PFS, p = 0.035; 66.8% versus 53.6% for OS, p = 0.039). In the GDPT group, the difference in CR between the four subgroups was statistically significant (p = 0.046). In the CHOP group, differences in both CR and ORR among the four subgroups were statistically significant (p < 0.001 and p = 0.005, respectively). There were also statistically significant differences in CR between patients treated with CHOP and GDPT in the PTCL-NOS subgroup, AITL subgroup, and the other types subgroup (p = 0.015; p = 0.003; p = 0.005, respectively). The data also showed a significant difference in OS among the four subgroups within the GDPT group (p = 0.001). The OS of AITL was shorter than that of the other three subgroups. Four subgroups of CHOP showed a significant difference in PFS (p = 0.019). There was no statistical association between responses and the gene expression levels of RRM1, ERCC1, TUBB3, and TOP2A. CONCLUSION: The GDPT group had better response rates and prolonged patient PFS and OS. As a promising new regimen, GDPT is expected to become the first-line therapy for PTCL. New agents should be applied to patients who do not achieve good responses with previous treatment, such as those diagnosed with angioimmunoblastic T cell lymphoma. TRIAL REGISTRATION: This open randomized prospective clinical trial was registered at ClinicalTrials.gov (NCT01664975).

Apatinib in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma: A Phase II, Open-Label, Single-Arm, Prospective Study.

PURPOSE: Treatment options for relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) represent an unmet medical need. Apatinib is a new oral tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit tumour angiogenesis. In the present study, we evaluated the efficacy and safety of apatinib for patients with RR DLBCL. PATIENTS AND METHODS: In this phase II, open-label, single-arm, prospective study, we enrolled patients aged 14-70 years with treatment failure of at least two chemotherapeutic regimens using Simon's two-stage design. All patients were administered apatinib at an initial dose of 500 mg on a 4-week cycle at home and visited the outpatient clinic every two cycles to evaluate efficacy and to record adverse events. We considered objective response rate (ORR) as the primary end point, and progression-free survival (PFS), and overall survival (OS) plus duration of response (DoR) as the secondary end point. (This trial was registered at ClinicalTrials.gov, identifier: NCT03376958.). RESULTS: From January 2017 to February 2019, we screened 35 patients and enrolled 32 eligible patients. At the cutoff point (April 2019), we noted 2 (6.3%) complete responses, 12 (37.5%) partial responses, and 9 (28.1%) stable diseases, attributing to an ORR of 43.8% and a disease control rate of 71.9%. The median PFS and OS were 6.9 (95% confidence interval [CI], 5.8-7.9) and 7.9 months (95% CI, 7.0-8.7), respectively. The median DoR was 5.0 months (95% CI, 3.5-6.5) for patients who achieved PR. The most common grade 3-4 adverse events (AE) were hypertension (12.6%), hand-foot syndrome (9.4%), and leucopenia (6.3%). No apatinib-related deaths were noted. CONCLUSION: Home administration of apatinib shows promising efficacy and manageable AEs in patients with RR DLBCL.

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma.

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

Activated hippo signal pathway inhibits cell proliferation and promotes apoptosis in NK/T cell lymphoma cells.

BACKGROUND: Natural Killer T-Cell Lymphoma (NKTCL) is a subtype of Non-Hodgkin's Lymphoma, and its morbidity is ranked the first of T-Cell Lymphoma. Hippo signaling pathway is involved in the pathogenesis of tumors. However, the role of Hippo signaling pathway in the oncogenesis of NKTCL still remains unclear. METHODS: The expressions of mammalian sterile 20-like kinase 1 (MST1) and Yes-associated protein (YAP) were investigated by RT-PCR and Western blotting. Cell viability was detected by MTT assays. Cell cycle and cell apoptosis were determined by flow cytometry. Cell proliferative capacity was detected by colony formation assay. Nude mice xenograft models were established and the tumor sections were analyzed by immunohistochemistry (IHC) staining. RESULTS: The expression of MST1 was significantly down-regulated in NKTCL tissues (n = 30) and cell lines, while the expression of YAP was significantly up-regulated, and the phosphorylation of YAP was inhibited. Overexpression of MST1, knockdown of YAP, or verteporfin (VP) treatment could inhibit cell proliferation, and promote cell cycle arrest and apoptosis in NKTCL cells, while knockdown of MST1 and overexpression of YAP promoted cell proliferation. Additionally, Bcl-2/Bax ratio and downstream effectors of Hippo signaling pathway (c-myc, survivin, cyclinD1, CTGF, and TEAD) were significantly decreased when MST1 was overexpressed and YAP was knocked down or after VP treatment. Furthermore, our mice model demonstrated that activation of Hippo signal pathway suppressed the tumorigenesis of NKTCL. CONCLUSION: The activation of Hippo signal pathway via overexpressing MST1 or down-regulating YAP can inhibit the tumorigenesis of NKTCL.