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Objective:To investigate the effect and prognostic factors of rituximab-containing chemotherapy regimen in treatment of patients with mantle cell lymphoma (MCL).Methods:The clinical data of 56 patients aged ≤65 years in the First Affiliated Hospital of Soochow University from June 2007 to November 2018 were retrospectively analyzed. Rituximab-containing chemotherapy regimen was used, and the effects of clinical features, treatment regimen and biological indexes on overall survival (OS) and progression-free survival (PFS) were observed.Results:The median age of 56 patients was 57 years old, including 43 males and 13 females. Among these cases, 24 patients received R-CHOP chemotherapy regimen; 29 patients received cytarabine-containing chemotherapy regimen, including R-hyper CVAD/R-MA regimen used in 15 patients and R-CHOP alternating with R-DAHP regimen used in 14 patients; and 3 patients received other treatment regimens. Among 56 patients, 19 patients received autologous hematopoietic stem cell transplantation (ASCT) consolidation therapy. The median OS time was 74 months, 2-year OS rate was 83.8%, 3-year OS rate was 70.9%, 2-year PFS rate was 72.0% and 3-year PFS rate was 49.7%. International prognostic index (IPI) high-risk and receiving ASCT or not during the treatment were independent influencing factors of OS and PFS in MCL patients. The overall response rate (ORR) in cytarabine-containing regimen group was higher compared with that in R-CHOP regimen group (93.1% vs. 83.3%), and there was no statistically significant difference ( χ2=0.465, P=0.495). In addition, there were no significant differences between two groups in both OS ( χ2=0.291, P=0.590) and PFS ( χ2=0.912, P=0.339). ASCT consolidation prolonged the median OS time (72 months vs.124 months, χ2=3.973, P=0.040) and the median PFS time (34 months vs. 90 months, χ2=3.984, P=0.046) in MCL patients achieving remission after induction therapy. Among patients in simplified MCL IPI (sMIPI) score middle-high risk group, compared with those not receiving ASCT, patients receiving ASCT therapy could obtain better OS and PFS (OS: χ2=5.037, P=0.025; PFS: χ2=6.787, P=0.009); among patients of sMIPI score low risk, there were no statistically significant differences in OS and PFS between the group receiving ASCT and not (all P > 0.05). Conclusions:Cytarabine-containing chemotherapy regimen has no predicatively satisfactory value in improving the prognosis and survival for MCL patients. For MCL patients who have achieved remission after reduction therapy and those in sMIPI score middle-high risk group, ASCT consolidation therapy can improve the prognosis and can be taken as the first-line consolidation treatment in young patients.
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Objective:To examine the efficacy of haploidentical stem-cell transplantation (haplo-SCT) for patients with refractory relapsed (R/R) non-Hodgkin lymphoma (NHL) by comparing with those contemporaneously undergoing HLA-matched SCT in myeloablative conditioning settings.Methods:Between January 2006 and December 2018, a total of 151 patients undergoing haplo-SCT ( n=81) or HLA-matched SCT ( n=70, sibling or unrelated) were enrolled. Median age of alloSCT was 30(5-59) years. And 150 patients received myeloablative conditioning (MAC) consisting of total body irradiation (12 Gy) plus cyclophosphamide or busulfan plus cyclophosphamide. Only one case had reduced intensity conditioning (RIC) with R-FBA (fludarabine, busulfan & cytarabina). It was followed by an infusion of granulocyte-colony stimulating factor-primed bone marrow (G-BM) and/or peripheral blood stem cells without in vitro T cell depletion. In haplo-SCT and HLA-matched unrelated donor for SCT, GVHD prophylaxis consisted of antithymocyte globulin, cyclosporine A, mycophenolate mofetil and a short course of methotrexate. Clinical efficacy, hematopoietic reconstitution and transplant-related complications were retrospectively analyzed. Results:Among them, 146(96%) patients engrafted with a median time to neutrophil and platelet recovery of 12 and 15 days respectively. During a median follow-up period of 19 months, 66 of them survived (43.7%) and 67 (44.4%) died (39 disease recurrence, 27 transplantation-related mortality). Between haplo-SCT and HLA-matched SCT groups, progression-free survival (PFS) rate was 49.4% and 50.5% ( P=0.577); overall survival (OS) rate 56.7% and 57.4% respectively ( P=0.963). The cumulative incidences of relapse (CIR) were 36.6% and 37.7% ( P=0.836) and those of cumulative incidences of non-relapse mortality (NRM) 22.0% and 24.7% ( P=0.530). And the cumulative incidences of chronic GVHD were 42.3% and 39.6% ( P=0.46) respectively. Conclusions:No inter-group difference exists in each major HSCT endpoint. Multivariate analysis reveals that occurrence of grade Ⅲ-Ⅳ aGVHD has a significantly worse prognosis. And primary chemorefractoriness is a strongest relapsing factor.
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The first-generation Bruton tyrosine kinase inhibitor (BTKi) ibrutinib significantly improved the survival and prognosis of patients with chronic lymphocytic leukemia (CLL), but its adverse reactions such as bleeding, infection, cardiovascular events, etc., limited the long-term compliance of patients. It has been considered that the new generation of BTKi could significantly reduce the adverse reactions caused by ibrutinib because of their higher selectivity and specificity. Among them, the efficacy and safety of acalabrutinib in untreated and relapsed/refractory patients with CLL have been confirmed in phase Ⅲ clinical trials. In addition, zanubrutinib and orelabrutinib, which were independently developed in China, have also been proven their preliminary safety and therapeutic effects in pre-clinical and phase Ⅰ and Ⅱ clinical trials, while the data from large phase Ⅲ clinical trials are still lacking. Currently, more BTKi are also under active exploration. The future therapeutic strategies of CLL may be converted to combining with a wide range of drugs to achieve the goal of drug discontinuation when minimal residual disease (MRD) is negative, or use MRD to guide the treatment. In this trend, the new generation of BTKi will provide more optimized options for the combination therapy regimens.
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Objective@#To study the value of unmethylated cytosine guanine dinucleotide oligodeoxynucleotide (DSP30) and IL-2 in the conventional cytogenetic (CA) detection of the chromosomal aberrations in chronic lymphocytic leukemia (CLL) .@*Methods@#Bone marrow or peripheral blood cells of CLL patients were cultured with DSP30 plus IL-2 for 72 h, following which R-banding analysis was conducted. Fluorescence in situ hybridization (FISH) was performed in 85 patients. CA results were compared with data obtained by FISH.@*Results@#Among 89 CLL patients, the success rate of chromosome analysis was 94.38% (84/89) . Clonal aberrations were detected in 51 patients (51/84, 60.71%) . Of them, 27 (27/51, 52.94%) were complex karyotype. Among 85 CLL patients tested by FISH, chromosomal abnormalities were detected in 74 (74/85, 87.06%) patients, of which 2 (2/74) patients were complex karyotypes, accounting for 2.70%. Of the 85 CLL patients examined by FISH, 50 had abnormal karyotype analysis, 30 had normal karyotype, 5 failed to have chromosome analysis. Among them, 25 cases showed clonal aberrations by FISH assay but normal by CA, and 4 cases were normal by FISH but displayed aberrations in chromosome analysis, and totally 78 (91.76%) cases with abnormality detected by the combination of the two methods. The frequency of 13q- abnormality detected by FISH was significantly higher than that by CA analysis (69.41%vs 16.67%, P<0.001) , while the frequency of 11q-,+12 and 17p- detected by two methods showed no significant difference (P>0.05) . The detection rate of complex abnormalities in conventional karyotype analysis was higher than that in FISH (50.98%vs 2.70%) . In addition, 11 low-risk and 9 intermediate-risk patients according to FISH results showed complex karyotype by cytogenetics, and were classified into high-risk cytogenetic subgroup.@*Conclusion@#DSP30 and IL-2 are effective in improving the detection rate of CA in CLL patients (60.71%) and CA is more effective to detect complex karyotype. However, FISH had a higher overall abnormality detection rate (87.06%) than CA, especially for 13q-. The combination of CA and FISH not only enhanced the detection rate of clonal aberrations to 91.76%, but also provided more precise prognosis stratification for CLL patients, thus to provide more information for clinical implication.
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Objective@#To study the specific killing effect of CD4 membrane protein targeted chimeric antigen receptor modified T (CAR-T) cell.@*Methods@#The second generation CD4 targeted chimeric antigen receptor containing 4-1BB costimulation domain was insert into lentiviral vector through recombinant DNA technology. Lentivirus was prepared and packaged by 293T cells with four plasmids. Beads activated T cells were transduced with lentivirus and the transduction efficiency was checked with Protein L and flow cytometry. T cell subsets and IFN-γ concentrations were detected with probe-tagged antibody and cytometric bead assay.@*Results@#①The transduction efficiency of activated T cells with prepared lentivirus were 50.0%-70.0%. A subset of CD8+ T cell acquired dim expression of CD4 membrane protein after activation. CD4+T cell and CD8+CD4dim T cell were gradually killed by CD4 targeted CAR-T post lentivirus transduction. ②The kill efficacy of CD4 targeted CAR-T cell and control T cell toward KARPAS 299 T cell at an E∶T ratio of 8∶1 for 24 h was (96.9±2.1)% and (11.2±3.1)%, CAR-T cell has a higher killing efficacy than control T cell (t=7.137, P=0.028). The IFN-γ concentrations in culture supernatant of CAR-T cell with K562-CD4 cell, CAR-T cell with K562 cell and CAR-T cell alone were (15 648±2 168), (1 978±354) and (1 785±268) pg/ml, CAR-T cell cocultured with K562-CD4 cell produced more IFN-γ than the other two controls (P<0.01).@*Conclusions@#CD4 targeted CAR-T has an immunophenotype of CD8+CD4-T cell. CD4 targeted CAR-T cell has killing efficacy toward normal CD4+T cell and CD4+T lymphoma cell. CD4 targeted CAR-T cell also has a killing efficacy toward CD4dim target cell.
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<p><b>OBJECTIVE</b>To observe the effect of rosiglitazone (RGZ) on the mRNA expression of HIF1α and IGF1 genes in the myeloma cells and explore possible mechanism of angiogenesis inhibition.</p><p><b>METHODS</b>Human myeloma cell line RPMI8226 and primary myeloma cells from five patients enriched by using CD138 immunomagnetic beads were treated with different concentrations (10, 20, 40 μmol/L) of RGZ. The mRNA expression of HIF1α and IGF1 was analyzed in cells treated with RGZ after 48h by RT-PCR, The levels of phosphorylated AKT and ERK proteins were detected by Western blotting. Bone marrow mononuclear cells from five patients with iron deficiency anemia were regarded as control.</p><p><b>RESULTS</b>Higher mRNA expression of HIF1α and IGF1 genes in RPMI8226 and in primary myeloma cells was showed as compared to those in control. Treated with RGZ of 20 μmol/L after 48 h, the mRNA expression of HIF1α (1.21 ± 0.08 vs 0.75 ± 0.06) and IGF1 (0.62 ± 0.06 vs 0.32 ± 0.04) in RPMI8226 cells was declined as compared to those without RGC treatment. The same declination was also seen in primary myeloma cells (HIF1α: 2.02 ± 0.16 vs 0.53 ± 0.04; IGF1: 1.92 ± 0.13 vs 0.58±0.03). RGZ could inhibit the expression of pAKT and pERK, nor the total AKT and ERK proteins, in RPMI8226 cells in a dose-dependent manner at the concentration of 10 μmol/L, 20 μmol/L, and 40 μmol/L.</p><p><b>CONCLUSION</b>RGZ could inhibit the mRNA expression of HIF1α and IGF1. Inhibition of angiogenesis by RGZ may be associated with down-regulation of pAKT and pERK expression.</p>
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Humanos , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular , Metabolismo , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia , Genética , Metabolismo , Fator de Crescimento Insulin-Like I , Genética , Metabolismo , Mieloma Múltiplo , Metabolismo , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-akt , Metabolismo , RNA Mensageiro , Genética , Tiazolidinedionas , FarmacologiaRESUMO
Objective To deplore the immunoregulatory function changes of mesenchymal stem cells(MSCs)from multiple myeloma(MM)patients and its effects on the pathogenesis of myeloma bone disease.Methods MSCs from MM patients and normal controls were isolated and the immunophenotype was detected.Real-time PCR was performed to detect the expressions of TGF-β1,TGF-β2,TGF-β3,IL-6,IL3,TNF-α,FasL and RANKL of MSCs.Transwell coculture systems were performed between MSCs and T cells.Lymphocyte proliferative assay was employed to detect the effect of MSCs on T cell proliferation.The effect of MSCs on T cell cycle and T cell activation markers CD25 and CD69 expression were analyzed by flow cytometry.Cleaved caspase 3 protein by western blot and hoechst 33258 staining were employed to detect the apotosis of T cells.Influence of T cells on the osteogenesis potential of MSCs were detected by Von kossa stain,real-time PCR and Western blot.Results MSCs from both MM patients and normal controls possessed similar morphology and immunophenotypes.MM derived MSCs exhibited increased expressions of TGF-β1,IL-6,IL-3,TNF-α and RANKL and decreased expression of TGF-β2,TGF-β3 and FasL.The inhibitory effect of MM derived MSCs on T cell proliferative ability was attenuated compared to control MSCs.MSCs from normal controls silence more T cells in Go/G1 phase than those from MM patients.The daupening effect of MM derived MSCs on activation-induced T apoptosis seemed to be enhanced.Expression of T cell activation markers were significantly inhibited by MSCs from normal controls.Both T cells cocultured with MM deprived MSCs and T cells directly from MM patients inhibited osteogenesis potential of MSCs from normal controls.Conclusion MSCs from MM patients showed impaired immunoregulatory capability on T cells.The activated T cells,in turn,inhibited the osteogenesis potential of MSCs.This may participate in the pathogenesis of myeloma bone disease.