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Objective:To explore the strategies of reducing relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with high-risk myelodysplastic syndrome (MDS) from the perspectives of optimizing the conditioning regimen and pre-transplant cytoreductive therapy.Methods:A total of 84 patients with high-risk MDS undergoing allo-HSCT between January 2013 and September 2019 were retrospectively analyzed. Based upon preparative regimens, they were divided into two groups of decitabine intensified BUCY2 ( n=49) and BUCY2 regimen ( n=35), based upon whether or not pre-treatment prior to allo-HSCT: cytoredutive treatment ( n=34) and none ( n=50). Two groups were compared with regards to hematopoietic reconstitution, graft-versus-host disease (GVHD), relapse rate, transplant-related mortality (TRM) and survival. Results:No significant inter-group differences existed in hematopoietic reconstitution or acute/chronic GVHD. The relapse rate was significantly lower in decitabine intensified group than that in BUCY2 group (18.7% vs 40.0%, P=0.025). Survival was significantly better in decitabine intensified group than that in BUCY2 group (3-year OS: 71.3% vs 51.2%, P=0.038; 3-year DFS: 65.3% vs 45.2%, P=0.033). Moreover, the incidence of recurrence was markedly lower in pre-transplant treatment group than that in non-treatment group (20.7% vs 38.9%, P=0.035). The inter-group incidence of TRM was not different. Three-year OS/DFS of treatment group were remarkably superior to those of non-treatment group (71.2% vs 50.8%, P=0.024; 64.7% vs 45.9%, P=0.044). Conclusions:As an optimal conditioning regimen for high-risk MDS, decitabine intensified BUCY2 regimen could better eliminate tumor burden, remarkably lower relapse rate and improve OS after allo-HSCT. In addition, pre-transplant treatment significantly reduces relapse and offers benefit for OS after allo-HSCT. Therefore intensified conditioning regimen and pre-transplant treatment may be promising strategies of reducing relapse and improving survival for high-risk MDS. However, it still needs further confirmation from prospective randomized controlled trials.
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Objective To explore the role of cerebrospinal fluid chimerism in central nervous relapse surveillance for patients of acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods The follow-up data were retrospectively collected and analyzed in 104 patients with acute leukemia after allo-HSCT.Comparisons were made between patients with complete chimerism and mixed chimerism in cerebrospinal fluid.The role of recipient DNA percentage and its changing trend in predicting central nervous relapse were also explored.Analysis was conducted for determining the risk factors of central nervous relapse.And the effectiveness of prophylaxis with intrathecal injection was also examined.Results The incidence of relapse was higher in patients with mixed chimerism (P＜0.001),high percentage of recipient DNA (P＜0.05) and higher mixed chimerism (P＜0.001).Hyperleukocytosis at an initial diagnosis was a risk factor of central nervous relapse.Whether or not intrathecal injection prophylaxis was applied showed no significant difference in relapsing rate.Conclusions Monitoring cerebrospinal fluid chimerism can effectively help predict central nervous relapse among patients of acute leukemia after allo-HSCT.Yet intrathecal injection prophylaxis failed to benefit recipients.
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Objective To observe the anti-relapse and anti-graft versus host disease (GVHD) effects and side effects of ruxolitinib on patients who have relapsed leukemia after allo-hematopoietic stem cell transplantation (HSCT).Methods The clinical data of four patients sufferring from relapsed leukemia were collected and analyzed retrospectively.Three cases had a positive gene and 1 case had a extramedullary recurrence.All of them had serious GVHD involving multiparts,as the result of attenuating immunosuppressant aggressively.One case had central nervous system leukemia before allo-HSCT.Those patients were treated with ruxolitinib,according to the degree of GVHD,the treatment strategy and curative effect of GVHD,and the residual condition of original leukemia.Then,the degree of GVHD,the residual condition of original leukemia and the side effects of ruxolitinib were revaluated once a month after taking ruxolitinib.Results One case achieved completer remission (CR) and there partial remission (PR) in consideration of GVHD.Up to date,2 cases had no relapse in any level and 2 cases replased according to any of the results related to bone marrow aspiration.Conclusion Ruxolitinib is effective in patients with GVHD after allo-HSCT and doesn't influence GVL effect or increase the risk of relapse at the same time.Ruxolitinib doesn't have obvious side effects when treating GVHD.
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Objective To analyze the motivation of Chinese patients with chronic myelogenous leukemia (CML) who have stopped the tyrosine kinase inhibitor (TKI). Methods Forty-seven CML patients who have stopped TKI provided informed consent prior to their participation in the study. These patients were divided into relapse and non-relapse group at the endpoint of the observation. None of the patients received any CML-associated therapies after TKI cessation. The reasons of withdrawal were analyzed statistically. Results The reasons for cessation included patient's request due to cost(59.57 %, 28/47), patient's plan to getting pregnant(8.52 %,4/47),side-effect of TKI(23.40 %,11/47)and other reasons(8.52 %,4/47).At the endpoint of observation, 23 patients suffered molecular relapse. Among them, 15 cases (65.22 %) were due to cost; 1 case (4.35 %) was due to getting pregnant, 5 cases (21.74 %) were due to side-effect and 2 cases (8.69 %) were due to other reasons. There was more frequency relapse in the group of insufficient cost. Conclusion The motivation of Chinese CML patients who have stopped TKI might show impact on the outcome,and the motivation is mainly related with history of drug reduction and withdrawal.
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Objective To analyze the motivation of Chinese patients with chronic myelogenous leukemia (CML) who have stopped the tyrosine kinase inhibitor (TKI). Methods Forty-seven CML patients who have stopped TKI provided informed consent prior to their participation in the study. These patients were divided into relapse and non-relapse group at the endpoint of the observation. None of the patients received any CML-associated therapies after TKI cessation. The reasons of withdrawal were analyzed statistically. Results The reasons for cessation included patient's request due to cost(59.57 %, 28/47), patient's plan to getting pregnant(8.52 %,4/47),side-effect of TKI(23.40 %,11/47)and other reasons(8.52 %,4/47).At the endpoint of observation, 23 patients suffered molecular relapse. Among them, 15 cases (65.22 %) were due to cost; 1 case (4.35 %) was due to getting pregnant, 5 cases (21.74 %) were due to side-effect and 2 cases (8.69 %) were due to other reasons. There was more frequency relapse in the group of insufficient cost. Conclusion The motivation of Chinese CML patients who have stopped TKI might show impact on the outcome,and the motivation is mainly related with history of drug reduction and withdrawal.
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Objective To study early diagnosis and treatment of Wernicke's encephalopathy(WE) in allogeneic peripheral blood stem cell transplantation recipients.Method A 17 years old patient with acute B-lymphocytic leukemia received HLA-matched nonrelative allogeneic peripheral blood stem cell transplantation after conditioning with total-body irradiation/idamycin/cyclophosphamide (TBI/IDA/Cy) regimen.CD25 monoclonal antibody and cyclosporine A+mycophenolate mofetil + methotrexate were administrated for graft versus host disease prophylaxis.Result On the day 8,the platelet was over 20 × 109/L; On the day 10,the neutrophile granulocyte was over 0.5 × 109/L; On the day 28,full engraftment was confirmed by a bone marrow medicolegal identification.The continued nausea and vomiting after HSCT resulted in deficiency of intake and malabsorption.On the day 54,illusion and tremor occurred,and the follow-up brain MRI suggested WE,but the patient died before thiamine replacing therapy.Conclusion WE is also a rare neurologic complication of HSCT,however,it can easily be overlooked.So early radiologic surveillance and treatment for patients with WE is very important to minimize central nervous system complications and unwanted mortality.
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<p><b>OBJECTIVE</b>To exam the role of leukemia cells-derived microparticles in the post-complete molecular response stratification.</p><p><b>METHODS</b>Blood samples from 29 patients diagnosed with chronic myeloid leukemia (CML) were collected. Microparticles (MP) were extracted from the peripheral blood. Real-time PCR was performed to measure the level of BCR-ABL mRNA.</p><p><b>RESULTS</b>BCR-ABL mRNA could be stably detected both in MP and peripheral blood cells; BCR-ABL in MP showed significant difference within complete molecular response, major molecular response and complete cytogenetic response (9.1±2.8, 25.2±6.9 and 62.8±6.3 respectively, P<0.05). BCR-ABL was detected in MP even when it was negative in peripheral blood cells (3.7-15.3). For patients with complete molecular response, BCR-ABL in MP but not cells were significantly different between imatinib and stem cell transplant recipients (3.3±2.1 vs 9.1±2.8, P<0.05).</p><p><b>CONCLUSION</b>This study indicated that MP may serves as a new target for monitoring of CML. Quantification of BCR-ABL in MP may offer a novel strategy for stratification of molecular response.</p>
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Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Cell-Derived Microparticles , Fusion Proteins, bcr-abl , Genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Genetics , Therapeutics , RNA, Messenger , Genetics , Real-Time Polymerase Chain ReactionABSTRACT
Objective To evaluate the effect of cytokine-induced killer cells (CIKs) as an adoptive immunotherapy option for treatment of leukemia relapse after allo-hematopoietic stem cell transplantation (allo-HSCT).Methods Two cases of infusion of donor CIKs in patients with leukemia relapse after allo-HSCT were retrospectively analyzed.Patient one relapsed 986 days (+986d) after HLA-matched unrelated donor allo-HSCT.Applications of chemotherapy only resulted in short term remission,but allo-CIKs were successfully expanded from the patient's peripheral blood mononuclear cells of donor origin.Totally five cycles of CIKs infusion were infused as an alternative of adoptive immunotherapy.Patient two had recurrent in the + 158d after HLA-matched sibling alloHSCT.At + 204d and + 294d,two cycles of CIKs which were expanded from donor peripheral blood mononuclear cells were infused.Results One cycle of CIKs was given to patient one after the application of chemotherapy to reduce the tumor burden,and the patient successively achieved complete remission.Again after additional four cycles of CIKs infusion,consistent remission was maintained during the following seven months.Patient two who had relapsed disease posttransplantation,achieved cytological complete remission after withdrawal of immunosuppressants and undergoing chemotherapy combined with G-CSF mobilized stem cell infusion.However,at + 187d,the patient suffered from side-effect of acute graft versus host disease and extramedullary infiltration.The symptoms were alleviated markedly after one cycle of CIKs infusion at + 204d.Moreover,the pain disappeared after an additional infusion at + 294d.And up to the present,the bone marrow aspiration showed complete remission while the extramedullary disease vanished.Conclusion The use of CIKs in the treatment of leukemia relapse after allogeneic bone marrow transplantation can be feasible and well tolerated.
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ObjectiveTo evaluate the primary effect of granulocyte-monocyte colony stimulating factor (GM-CSF) as an immunotherapy option for treatment of residual disease after alloHSCT.Methods Immunotherapy was performed on two patients with blood malignancy to treat residual disease after allo-HSCT. The patient one,who was diagnosed as having MDS-RAEB Ⅱ,showed bone marrow displasis and incomplete chimerism 6 months after unrelated donor HSCT.Immunosuppressive drug was withdrawn without induction of graft-versus-host disease (GVHD).The patient two B-ALL demonstrated a residual disease at molecular level 30 days post-transplantation.Both of them were given GMCSF (300 μg) subcutaneously once every two days for totally three weeks.During the whole period,skin itch and rash,liver function,subgroups of lymphocytes,and MDSCs and DCs in peripheral blood were investigated.Results In case one,grade Ⅰskin acute GVHD (aGVHD) appeared as early as one week after GM-CSF administration,as well as grade Ⅱ (skin and liver) by the end of the third weeks,and GM-CSF injection was withdrawn.One month later since the start of GM-CSF,the patient showed normal bone marrow morphology and full donor type chimerism. Cyclosporine A (CsA), mycophenolate mofetil and methylprednisolone were administered for two weeks to control GVHD.In the other case,grade Ⅰ aGVHD occurred 9 days after GMCSF administration,and whole blood CsA maintained at 0.134-0.472 μmol/L.Prednisone (30mg per day for 5 days) was used to control grade Ⅱ GVHD from the 11th day after GM-CSF,and grade Ⅰ GVHD continued without any intervention.On the 30th day after GM-CSF treatment,bone marrow aspiration showed complete molecular remission.In both of the two cases,no differences in lymphocytic subtypes were revealed before and after GM-CSF administration,while there were trends of increased DC number and decreased MDSCs in peripheral blood.ConclusionThe administration of GM-CSF as an immunotherapy option for blood malignancy may contribute to the clearance of residual disease after Allo-HSCT.
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Objective To retrospectively analyze and compare the curative outcome of hematopoietic stem cell transplantation (HSCT) from HLA identical siblings vs intensive immunosuppression therapy (IST) for severe aplastic anemia (SAA).Methods From January 2008 to December 2010,41 patients with severe aplastic anemia were treated with related HSCT (n =14) or IST (n =27) which combined antithymocyte globulin (ATG) with cyclosporine-A (CsA) therapy.Results All the patients receiving HSCT reached complete response.Among the patients receiving IST,21 patients could be responsive to the therapy,and 2 patients died.There was significant difference in the response rate between HSCT group and IST group (100 ％ vs 77.8 ％,P＜0.01 ).Conclusion With the improvement of HSCT technology,the curative outcome of HSCT from HLA identical siblings for SAA is much better than IST.
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Objective To evaluate the outcome of combination of intensive preconditioning regimen allo-HSCT with imatinib for treatment of Ph chromosome positive acute lymphocyte leukemia (ALL). Methods Between 2009 and 2010, 8 patients diagnosed as Ph+ ALL received allo-HSCT from HLA identical sibling during complete remission. Imatinib was added into the therapies of 5 patients.Seven patients received the intensive preconditioning regimen based on BuCy2, one patient received the regimen of TBI-Cy. A median of 6. 02 × 108/kg mononuclear cells and 3. 14 × 106/kg CD34+ cells were transfused. GVHD prophylaxis included cyclosporine A and methotrexate. Results All patients were well tolerant to the regimen without serious regimen-related toxicity. The median time of ANC≥0. 5 × 109/L was 15. 5 days, and that of PLT≥20 × 109/L was 19 days. Thirty days after allo-HSCT, all patients got donor engraftment successfully. Among 8 cases, 4 cases presented acute GVHD, 2 developed degree Ⅰ , one developed degree Ⅱ , and one developed degree Ⅳ. Seven patients were alive 100 days after allo-HSCT, 3 of whom presented chronic GVHD. At the end of following-up period, 6 patients were alive, among them, 3 patients were alive without relapse; 3 patients relapsed; Two patients died, one from acute GVHD, and one from leukemia relapse. Conclusion Combined intensive preconditioning regimen allo-HSCT with Imatinib was an effective treatment for Ph+ ALL, but the effect of anti-chronic GVHD of imatinib should arouse certain attention.
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BACKGROUND: Allogeneic hematopoietic stem cell transplantation is recognized as the only method of curing chronic myelocytic leukemia (CML). Lmatinib mesylate (STI571) is a competitive inhibitor of the bcr-abl tyrosine kinase, as a represent of synthetic gene-targeting drug in recently, which has been used more and more on the Philadelphia chromosome positive CML patients.OBJECTIVE: To compare the efficacy and safety of STI571 to related allogenic hematopoietic stem cell transplantation in the treatment of CML patients.DESIGN, TIME AND SETTING: A controlled observation between ST1571 treated group and transplantation group was performed in the Department of Hematology, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology between April 2002 and October 2006. PARTICIPANTS: All 90 patients with CML in the chronic phase were selected from Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, and they were diagnosis based on the examinations of bone marrow morphologic, cytogenetics and/or molecular genetics. METHODS: All 90 patients with CML in the chronic phase were divided into two groups. 67 patients received oral STI571 (400 mg/day) in succession at the beginning time from April 2002 to June 2006, and the observation ended until October 2006, Blood routine will be done weekly, and bone marrow morphologic and cytogenetic examination would be done every three months. Other 23 patients selected from Union Hospital from March 1999 to April 2006 accepted allo-HSCT, with BuCy2 or modified BuCy2 as conditioning regimens. Cyclosporin A combining with short-term MTX were used in all patients for prophylaxis of graft-versus-host disease (GVHD). MAIN OUTCOME MEASURES: Hematology responses, eytogenetic response and two years survival in two groups were observed. RESULTS: Complete cytogenetic response was achieved in 60% and 100% of the patient treated with STI571 and transplantation respectively (P < 0.01). But two years survival of ST1571 and transplantation were 83.33% and 77.03% respectively, and no difference was found between the two groups (P > 0.05). No one died or discontinued therapy for adverse effects, and 4 out of 67 (5.97%) had grade 3 or 4 thrombocytopenia and/or leucopenia in the ST1571 group. Moreover, in transplantation group, 7 patients (30.4%) developed grade 2 to 4 acute GVHD, but 4 died of failed treatment. CONCLUTION: Compared with transplantation, patients treated with ST1571 achieved low complete cytogenetic responses and the treatment-related complications were mild and manageable or no need for treatment.
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Objective To investigate the role of toll-like receptor 4 (TLR4) of endothelium or bone marrow derived cells in the acute lung injury (ALI) induced by lipopolyscccharide (LPS) in mice with reciprocal bone marrow transplantation. Method Chimeric mice were produced by reciprocal bone marrow transplantation between TLR4mut/mut and TLR4+/+ mice and divided into 4 groups: WT/WT (recipient/donor),WT/Mutant, Mutant/WT and Mutant/Mutant group. Six to eight weeks following transplantation, LPS was injected inot mice's tail vein in order to produce ALI model,and mice were sacrificed five hours later on.Samples of lung tissues were taken for the following analysis of wet/dry weight (W/D), lung permeabifity index (LPI), myeloperoxidase (MPO),levels of cytokines (TNF-α, IL-1β) and adhesion molecules (ICAM-1). Results Lung injury in the Mutant/Mutant mice was the mildest in the 4 groups. And lung injury in WT/Mutant mice was more serious than that in Mutant/WT mice. levels of MPO and ICAM-1 in WT/Mutant mice were much higher than those of Mutant/WT. In addition,the expression of ICAM-1 in WT/Mutant mice is comarable to that in WT/WT mice. Mutant/WT mice expressed higher levels of TNF-α and IL-1β than WT/Mutant mice. Conclusions Endothelial cell derived TLR4 plays ker-nel role in ALI induced by LPS via lung PMN recruitment,although bone marrow cells derived TLR4 are more im-portant for the release of cytokines.
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In order to explore a new special and effective way to prevent graft versus host disease (GVHD) after allogenic bone marrow transplantation (allo-BMT), the stem cell antigen-1 (Sca-1) + early hematopoietic cells (EHC) from BALB/c mouse (H-2d) were introduced with exogenous mouse Fas ligand (mFasL) cDNA gene by the retrovirus-mediated gene transfer and expanded for one week, and then they were co-cultured with the spleen mononuclear cells (SMNC) from BAC mouse (H-2dxb) as one way mixed lymphocyte reaction (OWMLR). The cytotoxicity of treated BAC mouse SMNC against Na2 51CrO4 labeling SMNC from BALB/c mouse was observed. The bone marrow mononuclear cells (BMMNC) from BAC mouse treated by the above methods were transplanted into lethally-irradiated congenic BALB/c mice to observe the occurrence of GVHD. The results showed that the SMNC from BAC mouse after OWMLR with exogenous mFasL cDNA gene-transduced hematopoietic cells (HC) from BALB/c mouse in a ratio of 1 to 5 exhibited an obvious inhibition of the cytotoxicity against the BALB/c mouse spleen cells at different effector/target ratios as compared to the control group (P<0.01). The grade I GVHD or no GVHD and the 80% survival rate at day 60 post-BMT were observed in the BALB/c mouse receiving BAC mouse BMMNC treated with similar way, while the grade II - III GVHD and the 20% survival rate were noted in the control group (P<0.01). It is suggested that the attenuation of GVHD in allo-BMT recipient could be successfully achieved through FasL-Fas pathway in an H-2 haplotype disparate mouse combination.
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Animals , Female , Mice , Rats , Bone Marrow Transplantation , Fas Ligand Protein , Graft vs Host Disease , Allergy and Immunology , Therapeutics , H-2 Antigens , Genetics , Haplotypes , Hematopoietic Stem Cells , Cell Biology , Allergy and Immunology , Membrane Glycoproteins , Allergy and Immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Rats, Wistar , Signal Transduction , Spleen , Cell Biology , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology , Transfection , fas Receptor , Allergy and ImmunologyABSTRACT
The feasibility of using cord blood mesenchymal stem/progenitor cells (CB-MSPCs) to regenerate cardiomyocytes and the optimal inducing conditions were investigated. The CB mononuclear cells were cultured in low serum DMEM medium to produce an adherent layer. After expansion, the adherent cells were added into cardiomyocyte inducing medium supplemented with 5-azacytidine. Cardiogenic specific contractile protein troponin T staining was performed to identify the cardiomyocyte-like cells. The results showed that the frequency of CB-MSPCs clones in CB mononuclear cells was 0.5 x 10(-6) and about 1.3 x 10(7)-fold expansion was achieved within 20 sub-cultivation. After cardiogenic induction, 70% CB-MSPCs was differentiated into cardiomyocyte-like cells. It was indicated that low serum culture could expand CB-MSPCs extensively and the expanded CB-MSPCs could be induced to differentiate into cardiomyocyte-like cells in high efficiency.
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Azacitidine/pharmacology , Cell Differentiation , Cells, Cultured , Culture Media, Conditioned , Fetal Blood/cytology , Fluorescent Antibody Technique , Mesenchymal Stem Cells/cytology , Myocytes, Cardiac/cytology , Troponin TABSTRACT
The feasibility of using cord blood mesenchymal stem/progenitor cells (CB-MSPCs) to regenerate cardiomyocytes and the optimal inducing conditions were investigated. The CB mononuclear cells were cultured in low serum DMEM medium to produce an adherent layer. After expansion, the adherent cells were added into cardiomyocyte inducing medium supplemented with 5-azacytidine. Cardiogenic specific contractile protein troponin T staining was performed to identify the cardiomyocyte-like cells. The results showed that the frequency of CB-MSPCs clones in CB mononuclear cells was 0.5 x 10(-6) and about 1.3 x 10(7)-fold expansion was achieved within 20 sub-cultivation. After cardiogenic induction, 70% CB-MSPCs was differentiated into cardiomyocyte-like cells. It was indicated that low serum culture could expand CB-MSPCs extensively and the expanded CB-MSPCs could be induced to differentiate into cardiomyocyte-like cells in high efficiency.
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Female , Humans , Male , Pregnancy , Azacitidine , Pharmacology , Cell Differentiation , Cells, Cultured , Culture Media, Conditioned , Fetal Blood , Cell Biology , Fluorescent Antibody Technique , Mesenchymal Stem Cells , Cell Biology , Myocytes, Cardiac , Cell Biology , Troponin TABSTRACT
In order to regulate the apoptosis induced by Fas-FasL system, a soluble isoform of mouse Fas was cloned from thymocytes of immature mice with the primers designed according to the full-length Fas cDNA sequence in the GeneBank. It was directionally inserted into the intermedium vector pUC19. DNA sequencing proved that it was consistent with the expected sequence. Then it was subcloned into the eukaryotic expression vector pCA13, which was used to construct the recombinant vector pCA13-FasC. By lipofectamine (LF2000)-mediated transfection, pCA13-FasC was transfected into the 293 cells. RT-PCR and Western blot indicated that the murine soluble Fas C protein was expressed in the 293 cells. Apoptosis inducing test showed that the expression of this murine Fas C could block the Fas-induced apoptosis, which confirmed the biological activity of the recombinant Fas C.