EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma.

BACKGROUND: Overexpressed EZH2 is oncogenically involved in the pathogenesis of different cancerous contexts including extranodal natural killer/T cell lymphoma (ENKTL). However, the underlying mechanisms of EZH2 upregulation have not been fully clarified and it is still difficult to target EZH2 in ENKTL. RESULTS: Current study identifies an E3 ligase TRIP12 that triggers K63-linked polyubiquitination of EZH2 in ENKTL and unexpectedly, stabilizes EZH2. As determined by gene expression profiling (GEP), TRIP12 and EZH2 levels correlate with each other in ENKTL patient samples. Aided by quantitative mass spectrometry (MS) and follow-up analysis, we identify K634 as the ubiquitination site of EZH2. Further study confirms that TRIP12-mediated EZH2 K634 ubiquitination enhances the interaction between EZH2 and SUZ12 or CDK1 and increases the level of EZH2 T487 phosphorylation. This study further demonstrates the TRIP12-EZH2 signaling might be regulated by cytoplasmic HSP60. Importantly, the TRIP12-EZH2 axis mediates ENKTL cell migration via accelerating epithelial-mesenchymal transition (EMT). Moreover, our study finds out dexamethasone treatment manipulates TRIP12-EZH2 signaling and may represent a novel therapeutic strategy against ENKTL metastasis. CONCLUSIONS: Altogether, TRIP12 induces K63-linked site-specific polyubiquitination of EZH2 for stabilization, which promotes ENKTL cell migration and could be targeted by dexamethasone treatment.

A retrospective cohort study of polatuzumab vedotin combined with immunochemotherapy in Chinese patients with relapse/refractory diffuse large B cell lymphoma.

Background: There are no standard therapies for patients with relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for transplantation. Recently, polatuzumab vedotin (pola) combined with rituximab and bendamustine (pola-BR) has been validated in clinical trials. However, pola is not approved in China and clinical data in Chinese population is still lacking. This study is intended to preliminarily evaluate the clinical effectiveness of this regimen in China. Methods: This study retrospectively evaluated the efficacy and tolerability of pola-BR regimen in Chinese R/R DLBCL patients treated in a compassionate use program (CUP; pola CUP) after failing ≥2 prior regimens. Patients participated in CUP at 4 Chinese centers from December 2019 to July 2020 were enrolled. The outcomes were the overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS). Adverse events (AEs) were collected. Results: A total of 28 patients enrolled in the pola CUP were included. At data analysis cut-off (30 September 2020), the best overall response (BOR) rate was 71.4%, and a CR rate of 25.0% was obtained. The estimated median PFS of all patients was 200 [95% confidence interval (CI): 97 to not evaluable (NE)] days. The most common AEs were thrombocytopenia (32.1%), neutropenia (28.6%), and fever (14.3%). High-grade (grade ≥2) peripheral neuropathy (PN) was not observed. Conclusions: These preliminary data suggested that the pola-BR regimen has promising efficacy and tolerable safety in Chinese transplantation ineligible R/R DLBCL patients. Hence, pola-BR may be an optional regimen. Considering the limited sample size and short follow-up, larger sample and long-term survival outcome studies are warranted.

An Immune Risk Score Predicts Survival of Patients with Acute Myeloid Leukemia Receiving Chemotherapy.

PURPOSE: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. EXPERIMENTAL DESIGN: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. RESULTS: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. CONCLUSIONS: Our immune risk score complements current AML prediction models.

MicroRNA­145 promotes the apoptosis of leukemic stem cells and enhances drug­resistant K562/ADM cell sensitivity to adriamycin via the regulation of ABCE1.

Leukemia is a type of cancer which originates in blood­forming tissues. MicroRNAs (miRNAs or miRs) have been shown to be involved leukemogenesis. In the present study, following the gain­ and loss­function of miR­145 and ATP­binding cassette sub­family E member 1 (ABCE1) in K562 cells and K562 adriamycin­resistant cells (K562/ADM cells), the levels of multidrug resistance protein 1 (MRP1) and P­glycoprotein (P­gp) were measured. The viability of the K562 cells and K562/ADM cells treated with various concentrations of ADM, and cell sensitivity to ADM were measured. The apoptosis of stem cells was detected. K562/ADM cells were transfected with miR­145 mimic or with miR­145 mimic together with ABCE1 overexpression plasmid to examine the effects of ABCE1 on the sensitivity of K562/ADM cells to ADM. The association between miR­145 and ABCE1/MRP1 was then verified. The dose­ and time­dependent effects of ADM on the K562 cells and K562/ADM cells were examined. The K562/ADM cells exhibited a greater resistance to ADM, higher levels of MRP1 and P­gp, and a lower miR­145 expression. The K562/ADM cells and stem cells in which miR­145 was overexpressed exhibited a suppressed cell proliferation, decreased MRP1 and P­gp levels, and an increased apoptotic rate. However, K562 cells with a low expression of miR­145 exhibited an increased cell proliferation, increased levels of MRP1 and P­gp, and a suppressed apoptotic rate. Compared with the overexpression of miR­145, the combination of miR­145 and ABCE1 decreased the sensitivity of drug­resistant K562/ADM cells to ADM. The above­mentioned effects of miR­145 were achieved by targeting ABCE1. Taken together, the findings of the present study demonstrate that the overexpression of miR­145 promotes leukemic stem cell apoptosis and enhances the sensitivity of K562/ADM cells to ADM by inhibiting ABCE1.

Cladribine with Granulocyte Colony-Stimulating Factor, Cytarabine, and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia: A Phase II Multicenter Study.

LESSONS LEARNED: Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C-CAG regimen was 67.6%, and 1-year overall survival and disease-free survival rates were 59.7% and 72.9%, respectively. The C-CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML. BACKGROUND: The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony-stimulating factor (G-CSF), low-dose cytarabine, and aclarubicin (C-CAG) regimen for patients with R/R AML. METHODS: A total of 34 patients received C-CAG regimen for salvage treatment as follows: cladribine 5 mg/m2 , days 1-5; G-CSF 300 µg, days 0-9; aclarubicin 10 mg, days 3-6; cytarabine 10 mg/m2 every 12 hours, subcutaneously, days 3-9; 4 weeks per cycle. Patients were allowed to withdraw from the study if complete remission (CR) was not achieved after two courses of chemotherapy. If conditions were right, the patients achieving CR were recommended to receive allogeneic hematopoietic stem cell transplantation. Otherwise, they were treated for a total of six cycles unless disease progression or unacceptable side effects were observed or they withdrew their consent. RESULTS: All patients received at least two cycles of C-CAG regimen chemotherapy. After two cycles of C-CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow-up of 15 months (range, 3-38 months), the 1-year overall survival (OS) and disease-free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%-76.8%) and 72.9% (95% CI, 54.3%-91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment-related deaths occurred. CONCLUSION: Preliminary data indicate that the C-CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.

Pegaspargase Combined with Concurrent Radiotherapy for Early-Stage Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Two-Center Phase II Study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid tumors. Considering the benefits of frontline radiation and pegaspargase in localized extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL), we conducted a phase II study on pegaspargase-based CCRT to explore an effective treatment. MATERIALS AND METHODS: In this study, 30 patients with newly diagnosed nasal ENKTL in stages IE to IIE received CCRT (radiation 50 Gy and two cycles of pegaspargase 2,500 unit/m2 every 3 weeks). Four courses of pegaspargase were performed after CCRT. RESULTS: The patients completed CCRT and four cycles of pegaspargase. The complete remission (CR) rate was 90%, with a 95% confidential interval (CI) of 73.5%-97.9% after CCRT. The CR rate was 100% (95% CI, 88.4%-100%) at the end of the treatment. The 2-year overall survival and progression-free survival rates were 90.9% (95% CI, 78.4%-100%) and 92.8% (95% CI, 83.2%-100%), respectively. The major adverse events were in grades 1-2. CONCLUSION: Preliminary data indicate that pegaspargase combined with concurrent radiotherapy for newly diagnosed patients with nasal ENKTL was efficacious and well tolerated. Registered at www.chictr.org. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OIC-15007662. IMPLICATIONS FOR PRACTICE: This clinical trial, evaluating the efficacy and toxicity of concurrent chemoradiotherapy by using single-drug pegaspargase for patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) in stage IE to IIE, showed pegaspargase combined with concurrent radiotherapy was efficacious and well tolerated. Pegaspargase has a long half-life and is easy to administer via intramuscular injection. Consequently, pegaspargase combined with concurrent radiotherapy for patients with ENKTL can be completed in the outpatient clinic.

A Modified NHL-BFM-95 Regimen Produces Better Outcome Than HyperCVAD in Adult Patients with T-Lymphoblastic Lymphoma, a Two-Institution Experience.

PURPOSE: Lymphoblastic lymphoma (LBL) is an invasive neoplasm of precursor T-cell or B-cell lineage. A broadly accepted standard treatment for adult LBL has not yet been defined. MATERIALS AND METHODS: To address this issue, we compared two chemotherapy regimens: a modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-95 (NHL-BFM-95) regimen and HyperCVAD/MA. This retrospective study consecutively enrolled 207 adult LBL patients at two hospitals from 2000 to 2018. Univariate and multivariate analysis were used to assess prognostic factors. RESULTS: In the present study, most clinical characteristics were similar between the two treatment groups except for age and lactate dehydrogenase (LDH) level. Patients treated with modified NHL-BFM-95 regimen tended to be younger and with elevated LDH level. The modified NHL-BFM- 95 regimen produced better treatment outcomes than those with HyperCVAD/MA in patients with T-LBL or patients < 40 years. Treatment with HyperCVAD/MA, high Eastern Cooperative Oncology Group scores, and bone marrow involvement were independent risk factors in T-LBL. No patients interrupted treatment for severe adverse events. CONCLUSION: The results suggested that the modified regimen is well-tolerated and can produce the promising outcomes in patients with T-LBL or patients < 40 years.

Increased serum levels of interleukin-10 predict poor prognosis in extranodal natural killer/T-cell lymphoma patients receiving asparaginase-based chemotherapy.

There are currently no prognostic biomarkers for extranodal natural killer/T-cell lymphoma (ENKTL) patients receiving asparaginase-based chemotherapy. Interleukin-10 (IL-10) is a pleiotropic cytokine that is involved in the stimulation and suppression of immune responses and influences the prognosis of different subtypes of lymphoma. We retrospectively analyzed 98 newly diagnosed patients with ENKTL receiving asparaginase-based chemotherapy. Baseline serum IL-10 levels were tested with sandwich enzyme-linked immunosorbent assays. Patients with high IL-10 (≥12.28 pg/mL) at diagnosis tended to have more adverse clinical features. Patients with low IL-10 (<12.28 pg/mL) at diagnosis had better progression-free survival (PFS) (P>0.001) and overall survival (OS) (P<0.001). Multivariate analysis revealed that baseline serum IL-10 level ≥12.28 pg/mL, stage III/IV, elevated serum ferritin, and elevated serum Epstein-Barr virus DNA level at diagnosis were four adverse factors for PFS and OS. Based on these four independent prediction factors, we divided the patients into different subgroups as follows: group 1, no adverse factors; group 2, one factor; group 3, two factors; and group 4, three or four factors. Furthermore, significant differences in PFS and OS were found between the groups. Our results suggest that pretreatment serum IL-10 is a novel, powerful predictor of prognosis for ENKTL patients receiving asparaginase-based chemotherapy, which suggests a role for IL-10 in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.

A prognostic model to predict survival in stage III colon cancer patients based on histological grade, preoperative carcinoembryonic antigen level and the neutrophil lymphocyte ratio.

BACKGROUND: Stage III colon cancer patients demonstrate diverse clinical outcomes. The aim of this study was to develop a prognostic model in order to better predict their survival. MATERIALS AND METHODS: From 2004 to 2010, 548 patients were retrospectively analyzed, among whom 328 were defined as the study group and the remaining 220 served as a validation group. Clinico-pathologic features, including age, gender, histological grade, T stage, number of positive lymph nodes, number of harvest lymph nodes, pretreatment carcinoembryonic antigen (CEA) levels and pretreatment neutrophil lymphocyte ratio (NLR), were collected. Kaplan-Meier survival curves were used to detect prognostic factors and multivariate analysis was applied to identify independent examples on which to develop a prognostic model. Finally, the model was further validated with the validation group. RESULTS: Histological grade (p=0.002), T stage (p=0.011), number of positive lymph nodes (p=0.003), number of harvested lymph nodes (p=0.020), CEA (p=0.005), and NLR (p<0.001) were found as prognostic factors while histological grade [RR(relative risk):0.632, 95%CI (Confidence interval) 0.405~0.985, p=0.043], CEA (RR:0.644, 95%CI:0.431~0.964, p=0.033) and NLR (RR:0.384, 95%CI:0.255~0.580, p<0.001) levels were independent. The prognostic model based on these three factors was able to classify patients into high risk, intermediate and low risk groups (p<0.001), both in study and validation groups. CONCLUSIONS: Histological grade, pretreatment CEA and NLR levels are independent prognostic factors in stage III colon cancer patients. A prognostic model based on these factors merits attention in future clinical practice.

Comparison of gemcitabine, oxaliplatin and L-asparaginase and etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: a multicenter retrospective study.

Optimal chemotherapy regimen for Extranodal natural killer/T-cell lymphoma (ENKTL) has not yet been defined. We retrospectively compared the outcome of 93 patients newly diagnosed with stage IE to IIE ENKTL who received gemcitabine, oxaliplatin and L-asparaginase (GELOX) (n = 40) or etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (EPOCH) (n = 53) as induction chemotherapy. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were higher than those for the EPOCH group (70.0% vs. 41.5%, p = 0.007 for CR; 87.5% vs. 67.9%, p = 0.047 for ORR). The GELOX regimen resulted in significantly superior 5-year progression-free survival (PFS) (79.0% vs. 46.5%, p = 0.005) and overall survival (OS) rates (78.9% vs. 50.4%, p = 0.003). Toxicity of both regimens was acceptable. The GELOX regimen produces a better long outcome with less toxicity than the EPOCH regimen for patients with early stage ENKTL.

A prognostic model based on pretreatment platelet lymphocyte ratio for stage IE/IIE upper aerodigestive tract extranodal NK/T cell lymphoma, nasal type.

Patients with stage IE/IIE natural killer T (NK/T) cell lymphomas have discrepant survival outcome. This study aims to establish a prognostic model based on the pretreatment platelet lymphocyte ratio (PLR) specifically for localized extranodal NK/T cell lymphoma to guide the therapy. We retrospectively analyzed the data of 252 patients with early-stage upper aerodigestive tract NK/T cell lymphoma. The 5-year overall survival rate in 252 patients was 67.1%. Prognostic factors for survival were female (P = 0.025; relative risk, 0.51; 95% CI 0.28-0.92), older age (P = 0.000; relative risk, 3.34; 95% CI 1.94-5.75), stage II(P = 0.020; relative risk, 1.79; 95% CI 1.10-2.91), lactate dehydrogenase (LDH) level (P = 0.009; relative risk, 2.00; 95% CI 1.19-3.35), and PLR (P = 0.020; relative risk, 1.77; 95% CI 1.10-2.87). Based on these five parameters, we identified three different risk groups: group 1(106 cases, 43.4%), no or one adverse factor; group 2(85 cases, 34.8%), two factors; group 3(53 cases, 21.7%), three to five factors. Five-year overall survival was 83.3% for group 1, 62.2% for group 2, and 43.1% for group 3 (P = 0.000). Compared with International Prognostic Index and Korean Prognostic Index, the new model has a better prognostic discrimination for the patients of stage IE/IIE upper aerodigestive tract NK/T cell lymphoma. The PLR-based prognosis model is useful to stratify patients with localized extranodal NK/T cell lymphoma into different risk groups and guide the treatment modalities selection.

Long-term outcomes of modified Berlin-Frankfurt-Münster-90 regimen in adults with T-lymphoblastic lymphoma: a single-center experience.

The standard treatment for adult T-Lymphoblastic lymphoma (T-LBL) has not been defined. This study was to analyze the efficiency of modified BFM-NHL-90 regimen in 36 adult patients with newly diagnosed T-LBL at the Sun Yat-Sen cancer center between August 2000 and December 2010. After the induction protocols, 34/36 (94%) of the patients achieved complete remission or unconfirmed complete remission. At the median follow-up of 36 months, 13 patients relapsed, but no relapses were observed in the CNS. The 3-year overall survival and 3-year event-free survival rates were 66.9% and 65.4%, respectively. Patients of female gender with hepatomegaly and hemoglobin less than 120 g/L, and the time interval exceeding 38 days between induction 1a and 1b, had inferior EFS and OS. The results was comparable to the previous regimens and the regimen could prevent CNS relapse with 4 high-dose MTX every 3 months during the maintenance phase.