A phase 2 study of methotrexate, etoposide, dexamethasone, and pegaspargase chemotherapy for newly diagnosed, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type: a multicenter trial in Northwest China.

The nasal type of extranodal natural killer/T-cell lymphoma is a rare aggressive lymphoma with poor prognosis. To discover a successful treatment, we investigated the efficacy and safety of chemotherapy with methotrexate, etoposide, dexamethasone, and polyethylene glycol-asparaginase (MESA). Three cycles of MESA were administered to 46 patients with new or relapsed/refractory natural killer/T-cell lymphoma. Complete response after 3 treatment cycles was 43.5%, the overall response rate was 87%, and 2-year overall survival was 83.4%. Complete response was significantly better for newly diagnosed patients than for patients with relapsed/refractory disease. Patients with newly diagnosed disease had a significantly better overall response rate after 1, but not after 2 or 3 treatment cycles. Overall survival and progression-free survival did not differ over 2 years. Grade 1/2 toxicities were frequent, but MESA was associated with fewer grade 3/4 events or treatment-related deaths. These results will require confirmation in larger prospective trials.

Rituximab-based combination therapy in patients with Waldenström macroglobulinemia: a systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of rituximab-based combination therapy for Waldenström macroglobulinemia (WM), we conducted this meta-analysis by pooling the rates of overall response, major response, complete response, and grade ≥3 hematological adverse events. METHODS AND MATERIALS: We searched for relevant studies in the databases of PubMed, Web of Science, Embase, and the Cochrane Library. The qualitative assessment of all the included articles was conducted with reference to the Newcastle-Ottawa Scale. A random-effects model was selected to perform all pooled analyses. RESULTS: We identified altogether 22 studies with a total of 806 symptomatic WM patients enrolled. The pooled analysis indicated that the rituximab-based combination therapy achieved an overall response rate (ORR) of 84% (95% CI: 81%-87%), a major response rate (MRR) of 71% (95% CI: 66%-75%), and a complete response rate (CRR) of 7% (95% CI: 5%-10%). Rituximab plus conventional alkylating agents-containing chemotherapy (subgroup A) yielded an ORR of 86% (95% CI: 81%-89%), an MRR of 74% (95% CI: 69%-79%), and a CRR of 8% (95% CI: 4%-14%). Rituximab plus purine analog (subgroup B) resulted in an ORR of 85% (95% CI: 79%-89%), an MRR of 74% (95% CI: 66%-81%), and a CRR of 9% (95% CI: 4%-15%). Rituximab plus proteasome inhibitor (subgroup C) resulted in an ORR of 86% (95% CI: 81%-90%), an MRR of 68% (95% CI: 58%-77%), and a CRR of 7% (95% CI: 3%-11%). Rituximab plus immunomodulatory drug (subgroup D) attained relatively lower response rates, with an ORR of 67% (95% CI: 51%-81%), an MRR of 56% (95% CI: 27%-83%), and a CRR of 5% (95% CI: 1%-12%). Common grade ≥3 hematological adverse events consisted of neutropenia (33%, 95% CI: 17%-52%), thrombocytopenia (7%, 95% CI: 3%-11%), and anemia (5%, 95% CI: 3%-9%). CONCLUSION: Rituximab in combination with an alkylating agent, purine analog, or proteasome inhibitor is highly effective with tolerable hematological toxicities for WM.

[Clinicopathological Characteristics and Prognosis Analysis of the Patients with Plasmablastic Lymphoma].

OBJECTIVE: To evaluate the clinicopathological characteristics, treatment and prognosis of the patients with plasmablastic lymphoma(PBL). METHODS: The clinical and pathological data of 21 patients with PBL diagnosed and treated in our center between January 2009 and September 2017 were retrospectively analyzed. The clinical and pathological features, treatment and therapentic outcome were summarized and the high risk factors affecting the prognosis of patients were investigated. RESULTS: The 21 PBL patients included 12 males and 9 females, and their median age was 52 years old. The human immunodeficiency virus (HIV) was negative in all patients. The primary involved sites of 16 patients were extranodal, and the patients staged in III-IV accounted for 81%; 18 patients receved first-line chemotherapy with standard CHOP(E) (cyclophosphamide +epirubicin +vincristine +prednisone±etoposide). After treatment, only 1 patient achieved complete response (CR), and 8 patients achieved partial response (PR). The median overall survival time was 6.3 months. Multivariate analysis showed the America Eastern Cooperative Oncology Group (ECOG) physical score and bone marrow infiltration were significant prognostic factors (P<0.01). CONCLUSION: Plasmablastic lymphoma frequently occurrs in the middle-old aged persons with all HIV negative. Primary extranodal lesions are frequent. Most patients were in advanced stage with poor treatment response. ECOG score≥2 and bone marrow infiltration are independent prognostic factors related with worse prognosis.

Chinese guidelines for treatment of adult primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is a bleeding disorder commonly encountered in clinical practice. The International Working Group (IWG) on ITP has published several landmark papers on terminology, definitions, outcome criteria, bleeding assessment, diagnosis, and management of ITP. The Chinese consensus reports for diagnosis and management of adult ITP have been updated to the 4th edition. Based on current consensus positions and new emerging clinical evidence, the thrombosis and hemostasis group of the Chinese Society of Hematology issued Chinese guidelines for management of adult ITP, which aim to provide evidence-based recommendations for clinical decision making.

Natural Killer/T Cell Lymphoma, Nasal Type: A Retrospective Clinical Analysis in North-Western China.

BACKGROUND: Extranodal natural killer (NK)/T cell lymphoma (ENKTL) is an aggressive non-Hodgkin's lymphoma with high mortality and poor prognosis despite radiotherapy and chemotherapy. The current analysis aimed to assess the pathological features, clinical features, and prognostic indicators of ENKTL. MATERIAL AND METHODS: 120 ENKTL patients were analyzed for pathologic diagnosis and clinical disease manifestations from April 2007 to October 2012. Complete remission, 2-year overall survival, and progression-free survival were analyzed. RESULTS: Compared with the nasal group, a greater percentage of patients in the non-nasal group intended to receive autologous stem cell transplantation had Epstein-Barr virus (EBV) DNA, Ann Arbor stage IV, Ki-67 expression ≥ 60%, and abnormal ferroprotein and ß-microglobulin levels. The rate of complete remission in the non-nasal group was higher than that in the nasal group. The overall survival rate was 74.9% at 24 months. Patients receiving chemotherapy and radiotherapy were more likely to have disease progression compared with patients who received chemotherapy or radiotherapy alone. CONCLUSIONS: Further understanding the pathological and clinical features of ENKTL will be critical for moving forward. Ki-67, ß-microglobulin, EBV DNA, and primary site prognostic indicators may be useful to stratify patients into different risk groups, to gain insight into patient-specific treatments, and to potentially improve survival.

[Valproic Acid Represses Autophagy and Enhances the Anti-myeloma Activity of DNA-damaging Drugs].

OBJECTIVE: To explore the effect of valproic acid(VPA) on anti-myeloma activity of Doxorubicin(DOX) or Melphalan(MEL) and its related mechanism. METHODS: Human multiple myeloma(MM) cells were treated with VPA of non-toxic dose in absence and presence of DOX or MEL at different concentrations (ie. IC10, IC20, IC40). The cell proliferation was detected by MTT method. Western blot was used to detect the expression levels of autophagy-related proteins (LC3, ATG5, ATG7) and acetylated histone H4K16ac. RESULTS: Cell proliferation inhibition markedly increased in VPA plus DOX or MEL as compared with DOX or MEL alone (P<0.05). Both LC3 and H4K16ac expression levels in co-treatment were between VPA and DOX or MEL treated alone. Importantly, VPA of non-toxic dose not only augmented the anti-myeloma activity of DOX or MEL, but also down-regulated the autophagy-related protein expression and increases H4K16ac protein levels. CONCLUSION: H4K16ac can inhibit the transcription of autophagy-related genes, The VPA enhance the anti-myeloma activity of DNA-damaging drugs, at least in part, via H4K16ac-mediated suppression of cytoprotective autophagy.

[Inducing effect of chidamide on apoptosis of multiple myeloma cells and its relerance to DNA damage response].

OBJECTIVE: This study was aimed to explore the effect of a novel histone deacetylase inhibitor Chidamide on apoptosis of human multiple myeloma(MM) cells and its relevance to DNA damage response(DDR). METHODS: The cell proliferation was detected by MTT method, apoptosis and cell cycle distribution were analyzed by flow cytometry, the expression levels of targeted proteins were detected by Western blot, the DNA damage response was blocked by ATM kinase inhibitor KU-55933. RESULTS: Chidamide inhibited RPMI 8226 cell proliferation in dose- and time-dependent manner and its IC50 values of 24,48,72 h were 9.6, 6 and 2.8 µmol/L respectively. Chidamide induced cell cycle arrest of RPMI 8226 cells in G0/G1 phase by upregulating the expression of P21. Chidamide triggered caspase-3 dependent apoptosis and upregulated expression of DDR-related proteins including γH2AX, pATM in RPMI 8226 cells. Pretreatment with ATM kinase inhibitor KU-55933 down-regulated expression of DDR related proteins induced by chidamide, thereby inhibiting DNA damage response and finally resulting in suppression of apoptotic cell death. CONCLUSION: Proliferative inhibtion, cell cycle arrest and apoptosis of multiple myeloma cells induced by chidamide involve DDR.

[Influence of CD117 Expression on Response of Multiple Myeloma Patients to Chemotherapy].

OBJECTIVE: To investigate the influence of CD117 expression on response of multiple myeloma patients to chemo-therapy. METHODS: A total of 65 cases of newly diagnosed multiple myeloma in our hospital from 2011 to 2013 were enrolled in this study. Cytogenetic abnormalities and immunophenotype were detected by using fluorescence in situ hybridization and flow cytometry before chemotherapy. The therapeutic efficacy of patients was evaluated after 4 cycles of PAD or TAD regimen. RESULTS: The positive rates of 1q21 amplification, RB1: 13q14 deletion, D13S319: 13q14.3 deletion, IgH: 14q32 rearrangement and p53: 17p13 deletion were 32.2%, 40%, 40%, 20% and 3.1% respectively; the positive rates of CD38, CD138, CD56, CD117, CD20 were respectively 100%, 100%, 60%, 20%, 10.8%; the positive rates of CD19 and CD10 were 4.6% and 4.6% respectively; the positive CD22, CD7, CD5, CD103 did not found in any patients. The therapeutic efficacy of CD117⁻ patients was better than that of CD117⁺ patients (P < 0.05), there was no correlation of the remaining indicators with efficacy; the proportion of CD117⁺ patients with ß2-microglobulin ≥ 5.5 mg/L was significantly higher than that of CD117⁻ patients (P < 0.05); the rest of baseline data had no significant difference (P > 0.05). CONCLUSION: CD117 can be used as an indicator for evaluating efficacy of patients with newly diagnosed multiple myeloma.

[Efficacy comparison between standard and reduced doses of bortezomib combined with adriamycin and dexamethasone in the treatment of patients with multiple myeloma].

OBJECTIVE: To compare the efficacy and safety of standard or reduced doses of bortezomib combined with adriamycin and dexamethasone (PAD) in patients with multiple myeloma (MM). METHODS: Eighty-two newly diagnosed or refractory/relapsed patients received bortezomib [either 1.2-1.3 mg/m(2) (standard dose) or 1.0-1.1 mg/m(2) (reduced dose) on day 1, 4, 8 and 11], and adriamycin (10 mg/m(2)) plus dexamethasone (40 mg/m(2)) on day 1-4 at 3-week intervals for 1 to 6 courses. The International Myeloma Working Group Criteria were used to evaluate the response. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (Version 3.0). RESULTS: Two courses of standard dose of PAD resulted in a similar response rate of partial and very good partial complete remissions (PR) compared with reduced dose (80.0% vs 80.8%, P=0.728). Grade III- Ⅳ neutropenia and thrombocytopenia were higher with standard dose than that with reduced doses of PAD (21.1% vs11.1%, P=0.270; 10.5% vs 6.3%, P=0.619, respectively). Grade III-Ⅳ bortezomib-induced peripheral neuropathy, herpes zoster, fatigue or abdominal distention were significantly higher with standard dose than that with reduced dose of PAD (15.8% vs 1.6%, P=0.037; 26.3% vs 6.3%, P=0.028; 36.8% vs 14.3%, P=0.046; 15.8% vs 1.6%, P=0.037, respectively). CONCLUSION: Reduced dose of PAD appears to result in a similar overall response rate, but a better tolerance and safety compared with standard dose.

Reduced tumor lysis syndrome with low dose chemotherapy for hyperleukocytic acute leukemia prior to induction therapy.

Patients with hyperleukocytic acute leukemia (HAL) can succumb to leukostasis. In an attempt to reduce its incidence, 45 patients with newly diagnosed HAL and hyperleukocytosis were administered half the conventional dose of etoposide and cytosine arabinoside (EA: 50 mg/m2 daily each) until WBC counts were significantly reduced and standard induction therapy was initiated. We retrospectively reviewed their outcomes and analyzed potential factors with a logistic regression model. The incidence of early mortality (<30 days) was 4.4% (2/45). Patients who achieved complete remission with induction chemotherapy had significantly lower median WBC counts (26x10(9) L-1) after low dose EA treatment than the no response patients (median WBC: 65x10(9) L-1 (P<0.05). Low dose EA treatment of HAL patients reduced WBC for both lymphoid and myeloid leukemic cells and can be considered for preemptive administration to HAL patients prior to the differential diagnosis of the acute leukemia. This approach warrants further studies as a cytoreduction therapy for HAL.

[Clinical analysis on 28 patients with hemophagocytic lymphohistiocytosis syndrome].

In order to profoundly understand the clinical and laboratorial characteristics and inducing factors of hemophagocytic lymphohistiocytosis syndrome (HLH), 28 HLH patients received from 2004 to 2009 years in our hospital were analyzed retrospectively. The results indicated that all of the patients had a history with prolonged fever (more than 1 week), pancytopenia, hepatosplenomegaly, elevated ferritin level, hypofibrinogen, and hemophagocytosis in bone marrow. HLH was the first characteristic sign of malignant lymphoma in 9 patients; 1 patient had a clinical manifestation similar to fulminant hepatic failure; severe psycho-abnormality occurred in 1 HLH patient and pronounced hemophagocytosis were detected in his cerebrospinal fluid; 1 patient was eventually diagnosed as having HLH by the findings in a lymph node biopsy showing obvious hemophagocytosis. Additionally, the analysis of underlying factors in 28 patients with HLH indicated 11 patients with EB virus-associated HLH, 11 with lymphoma-associated HLH, 2 with Leishmania-associated HLH, and 3 with autoimmune disease-associated HLH. It is concluded that HLH disease is characterised with high heterogenicity in both clinical features and inducing factors; in addition, the patients from a pasturing area should be paid attention to parasite infection such as leishmania.

[Effects of xbp-1 gene silencing on bortezomib-induced apoptosis in human multiple myeloma cells].

This study was purposed to investigate the effect of xbp-1 gene silencing on bortezomib-induced apoptosis in multiple myeloma cell line NCI-H929 (H929). After xbp-1 gene expression was interfered by small hairpin RNA, the cell apoptosis was assayed by flow cytometry with Annexin V-FITC/PI staining, and the expression level of XBP-1 protein was detected by Western blot. The results showed that XBP-1 protein level of H929 cells was inhibited effectively by the PLL3.7 lentiviral vector mediated expression xbp-1 shRNA. The apoptosis rate was significantly higher in xbp-1 shRNA-expressing cells than in untreated control group [(10.13±0.61)% vs (2.5±0.2)%, p<0.05]. After treatment with bortezomib, the apoptosis rate of XBP-1 protein functionally deficient H929 cells was significantly higher than those in vector control group [(45.07±1)% vs (19.53±0.8)%, p<0.05]. It is concluded that xbp-1 gene silencing can significantly enhance the pro-apoptotic activity of bortezomib in multiple myeloma cells.

[PAD regimen for relapsed or refractory patients with multiple myeloma].

OBJECTIVE: To investigate the efficacy and safety of PAD [bortezomib (PS-341), doxorubicin and dexamethasone] regimen for relapsed or refractory multiple myeloma (MM). METHODS: Seventeen patients with relapsed or refractory MM received two to four 21-day cycles of PAD: an intravenous bolus of bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11; doxorubicin 10 mg per day on days 1 to 4, and dexamethasone 40 mg on days 1-4. Response was evaluated according to International Myeloma Working Group Criteria (IMWG 2006), toxicity was graded according to NCI CTCAE (common terminology criteria for adverse events) v 3.0. RESULTS: After 2-4 courses of PAD, 14 patients (82.4%) response, including complete response (CR) in 4 (23.5%), very good partial response (VGPR) in 4 (23.5%), partial response (PR) in 6 (35.3%) and stable disease (SD) in 3 (17.6%). Median time to progression was 9.5 months. The median course to response was 1.6 (1-3). All of 5 patients with extramedullary plasmacytoma achieved at least PR after the first cycle therapy; the plasmacytoma disappeared after 1-2 cycles of PAD. The efficacy was independent of other prognostic factors such as beta2-MG. Adverse events included thrombocytopenia in 9 patients (52.9%), leukopenia in 4 (23.5%), peripheral neuropathy in 4 (23.5%), varicella herpes zoster in 3 (17.6%), fatigue in 6 (35.3%) and diarrhea in 2 (11.7%). All of these adverse reactions could be controlled with routine supportive treatment, only one patient died from respiratory failure during his fifth PAD cycle. CONCLUSIONS: PAD regimen should be considered as an appropriate treatment for relapsed or refractory MM, especially for MM with extramedullary plasmacytoma. Its efficacy is independent of traditional prognostic factors. The side effects are usually manageable.

[Role of CD4(+) CD25(high) T cells in the pathogenesis of idiopathic thrombocytopenic purpura].

This study was aimed to investigate the expression level of CD4(+) CD25(high) T cells in peripheral blood of patients with idiopathic thrombocytopenic purpura (ITP) before and after treatment and to explore its significance in pathogenesis of ITP. The expressions of CD4(+) CD25(high) T cells in peripheral blood of 20 ITP patients before treatment, 20 ITP patients after treatment and 14 normal individuals (control) were detected by immunofluorescence and flow cytometry. The result showed that the expression of CD4(+) CD25(high) in ITP group before treatment was evidently lower than that in treated ITP group and control (p < 0.01), but there was no remarkable difference between the treated ITP group and the control group p > 0.05). In conclusion, the expression of CD4(+) CD25(high) T cells in the ITP group before treatment was evidently lower than that in the control group, which becomes higher than before when the patients showed effective response to the treatment. Correlation of CD4(+) CD25(high) T cell expression rate in peripheral blood with platelet level was positive. Therefore the expression level of CD4(+) CD25(high) T cells can be used as an effective index to judge the ITP prognosis. Further study of CD4(+) CD25(high) T cells regarded as an immune target is needed.