| Background:Leukemia is a kind of malignant tumors deriving from hematopoietic system. According to the degree of leukemic cells mature and natural course, it can be divided into acute leukemia and chronic leukaemia.Acute myeloid leukemia (AML) is a disease with marked heterogeneity in both response to therapy and survival. The advent of molecular diagnostics and computer technology have heralded an explosion in new prognostic factors. These prognostic factors not only have an important role in guiding risk stratification of AML, disease classification and prognosis, but also some can also be used to guide treatment. In recent years, the age, cytogenetic and some genetic mutations have been used in clinic.Achieving complete remission is the first and critical step for leukemia patients with long-term disease-free survival (DFS), then, if we stop treating, relapse is almost inevitable. Recently, the main treatments include maintenance chemotherapy and autologous hematopoietic stem cell transplantation (Atuo-HSCT) and allogenetic hematopoietic stem cell transplantation (Allo-HSCT). Clinical practices prove that hematopoietic stem cell transplantation (HSCT) can significantly reduce disease relapse rate comparing with conventional chemotherapy, and the disease stage before transplant has a significant effect on the long-term survival and relapse rate. After the diagnosis of the disease, we should find a matched donor and carry out early transplantation.HSCT is, at present, the main clinical method to heal leukemia, however, about25%-30%of patients will relapse after transplantation, especially, the relapse rate of high-risk AL patients will be up to40%or more. Relapse after transplantation is the leading cause of death.The main strategy to prevent relapse is to promote the immune reconstruction, including the application of cytokines and adoptive immunotherapy. Allogeneic lymphocyte infusion is one of the most important means of adoptive immunotherapy, and it can prevent and treat relapse after transplantation. Its main complications include GVHD and bone marrow suppression. Clinical studies have shown that relapse prevention is more important than the treatment of relapse.In this study, in order to guide clinical practice, we retrospectively studied leukemia patients treated in our hospital in recent years to analyse prognostic factors in patients with primary AML, summarize the efficacy of HSCT, and explore the efficacy and safety of allogeneic lymphocyte infusion in preventing and treating relapse after transplantation.Objective:1. To explore the prognosis factors of patients with primary AML2. To analyse the clinical efficacy of HSCT for leukemia.3. To analyse the efficacy and safety of Allogeneic lymphocyte infusion to prevent and treat relapse leukemia after HSCT. Methods:Part one:The analysis of prognostic factors on primary AML1. Subject:140patients with primary acute myeloid leukemia (except AML-M3) hospitalized in our hospital between July,2006and December,2010.24cases were lost before treatment and7cases were early death (Early death is that patients died with no or less than2-week therapy). The rest of the109patients were included in this study.2. Criteria of diagnosis:All cases were diagnosed according to clinical characteristics, marrow morphocytology and chemistry, cytogenetics, immunology, molecular biology and carried out FAB classification.3. The items to investigate:Age, gender, WBC, Hb and PLT at first diagnosis, bone marrow primitive cells percentage, cytogenetics, response for the first induction chemotherapy.4. Statistical analysis:The statistical analyses were performed using the SPSS13.0. All data for continuous variables are expressed as the median (minimum, maxmum). Kaplan-Meier survival analysis was performed for analyzing overall survival (OS) and disease-free survival (DFS), the log-rank test was performed to compare survival rate. The proportion of COX regression model was performed for more factors analysis. P value<0.05was considered to be statistically significant.Part two:The clinical efficacy of hematopoietic stem cell transplantation for leukemia.1. Subjects:67patients with leukemia accepted HSCT in our hospital between June,2002and June,2011.28cases accepted Auto-HSCT.39cases accepted Allo-HSCT. On the basis of disease state undergoing HSCT, patients would be divided into high-risk groups and standard-risk groups.47cases belong to the high-risk group, and20cases belonged to the standard-risk group.2. Conditioning ReginemConditioning Reginem adopted FBC scheme. When existing at least one unmatched site between donor and receptor, antithymocyte globulin would be used. Patients unobtained CR accepted chemotherapy of moderate doses of cytarabine before pretreatment.3. The prevention of complicationsTo prevent Graft Versus Host Disease (GVHD) by cyclosporine A (CsA) and A short course methotrexate (MTX) combination.To prevent veno-occlusive disease of the liver (VOD) by combined application of Compound danshen injection, Coninuous using pd and prostaglandins E.4. Implanted indexAfter transplantation, the cytogenetics methods (such as karyotype analysis, gender differences between donor and acceptor) and molecular biology method (PCR) detection microsatellite markers and blood type conversion were performed to assess hematopoietic stem cell implant situation.5. Statistical analysis:The statistical analyses were performed using the SPSS13.0. All data for continuous variables are expressed as the median (minimum, maxmum). The chi-square test was performed to compare rate. The Kaplan-Meier survival analysis was performed for analyzing OS and DFS, the log-rank test was performed to compare survival rate. P value<0.05was considered to be statistically significant. Part three:The efficacy and safety of allogeneic lymphocyte infusion on preventing and treating relapse leukemia after HSCT.1. Subjects:35patients with hematological malignant diseases accepted allogeneic lymphocyte infusion after hematopoietic stem cell transplantation in our hospital between2000and2011.20cases accepted autologous hematopoietic stem cell transplantation, and15cases accepted allogeneic stem cell transplantation.20cases accepted preventive infusion before relapse, and15cases accepted the final treatment infusion after relapse.2. Conditioning ReginemConditioning Reginem adopted FBC scheme. When existing at least one unmatched site between donor and receptor, antithymocyte globulin would be used. Patients unobtained CR accepted chemotherapy of moderate doses of cytarabine before pretreatment.3. Allogeneic lymphocyte infusion and the prevention of GVHDRelapse or chronic myeloid leukemia (CML) progressing to acute phase period after the transplant, we should shut down the immune inhibitors and/or chemotherapy treatment, then carried out allogeneic lymphocyte infusion. Patients liable to relapse received preventive infusion. Patients accepted intravenous injection of dexamethasone5mg,10%calcium gluconate injection10ml before infusion to prevent allergic reaction, furosemidum20mg to promote bilirubin excretion. Immune inhibitors were routinely used after infusion.4. Statistical analysis:The statistical analyses were performed using the SPSS13.0. The Kaplan-Meier survival analysis was performed for analyzing OS and DPS. the log-rank test was performed to compare survival rate. The chi-square test was performed to compare rate. P value<0.05was considered to be statistically significant. Results:Part one:The analysis of prognostic factors on primary AML1. General clinical dataThe median OS of109patients was12.01months. Complete response rate was67.89%. The median DFS was12.09months.2. The relationship between age and OS, DFSPatients were divided into two groups at the boundary of60years, the Kaplan-Meier survival analysis was performed to analyze the relationship between age and OS, DFS. The log-rank test was performed to compare survival rate, P values were, respectively,0.001and0.044. The results indicate that patients older than60years have shorter OS and DFS.3. The relationship between cytogenetics and OSOnly48cases got cytogenetics materials in109patients. Patients were divided into low, standard and high-risk group referencing the southwest tumor group (SWOG) standard. We would not make analysis for low-risk group because of only2cases. The OS of the high and standard-risk groups were analyzed. P value was0.005. The result shows that patients in high-risk group have shorter OS than ones in standard-risk group.4. The relationship between the response of first induction and OS, DFSPatients were divided into two groups according to the response of first induction chemotherapy, complete remission group and uncomplete remission group. The OS and DFS of both groups were analyzed. P values were<0.001and0.002respectively. The results indicate that patients unattained complete remission after first induction chemotherapy have shorter OS and DFS.5. Multivariate analysisThrough the analysis of OS, we found that older age, high-risk genetics, and unattained complete remission after first induction chemotherapy were poor prognostic factors. The proportion of COX regression model was performed to the above three factors for multivariate analysis. The results listed in the below table. The results show that the above three factors are independent prognostic factors.Part two:The clinical efficacy of HSCT for leukemia.l.HSCTOf the67patients,1patient could not be evaluated due to VOD-related death earlier. Neutrophil counts (ANC) of the remaining66patients were all recovered, and the median time of ANC≥0.5×109/L was12d (8-23d).4patients continuingly rely on platelet transfusions (one patient was still relapse-free survival, one died of severe hepatitis when in remission, and the remaining two died due to recurrence), and the median time of platelet recovery to≥20×109/L for the remaining62patients was15d (9-43d). After being identified by cytogenetics (karyotype analysis), molecular biological methods (PCR, etc.) and blood type differences,36of39cases Allo-HSCT were fully implanted.2. Overall efficacy of HSCTThe median follow-up time of67patients was17.4months (0.4-115.0months), and follow-up deadline was December31,2011.30cases relapsed, with the relapse rate44.6%. The expected5-year OS rate was53.4%, with the expected5-year DFS rate44.6%.14patients were followed-up for more than3years, and4patients for more than5years.3. Relationship between disease stage and efficacy of HSCTThe three-year OS of standard-risk group and high-risk group were expected to be76.0%and43.5%respectively, with a statistically significant difference (P=0.024). In addition, of the20patients in standard-risk group,6cases recurred, with a30.0%relapse rate; of the47patients in high-risk group,24cases recurred, with a51.1%recurrence rate; Both of the relapse rates of two groups were statistically insignificant (P=0.115). Of4deaths in standard-risk group,.3cases relapsed and died, and1case died of severe hepatitis when in remission. Of23deaths in high-risk group,21cases relapsed and died,1patient died of lung infection after transplantation, and1patient died of VOD.4. Comparison of All-HSCT and Auto-HSCTIn39patients who received Allo-HSCT, high-risk patients accounted for32cases (82.1%), while in28patients who received Auto-HSCT, high-risk patients accounted for15cases (53.6%), with the difference between two groups statistically significant (P=0.013).17cases in the allogeneic transplantation group relapsed (43.6%); of28cases of Auto-HSCT,13cases relapsed (46.4%); the relapse rate difference between two groups was statistically insignificant (P=0.819). The expected3-year OS of patients who received Allo-HSCT and Auto-HSCT were43.8%and62.3%respectively, with the difference statistically insignificant (P=0.548). Among the patients who received Allo-HSCT,17cases died,15cases of which died of relapse,1case died of VOD and1case died of pulmonary infection.10cases of Auto-HSCT died, nine cases of which died of relapse, and1patient died of severe hepatitis.Part three:The efficacy and safety of adoptive immunotherapy on preventing and treating relapse leukemia after HSCT.1. OS and DFS after Auto-HSCT using allogeneic lymphoid infusionAmong20cases of autologous transplantation,19cases received preventive allogeneic lymphocyte infusion; one case underwent therapeutic allogeneic lymphocyte infusion for relapse, and ultimately the patient died. As of December31,2011,7patients died of relapse;13cases were still alive,11cases of which were disease-free survival (DFS), one case was extramedullary relapse and one case achieved remission after allogeneic hematopoietic stem cell transplantation for bone marrow relapse.3-year OS in this group of patients was63.2%, and3-year DFS was55.0%.2. OS after Allo-HSCT using allogeneic lymphoid infusionAmong15cases of allogeneic transplantations,1case received preventive allogeneic lymphocyte infusion, and the remaining14cases received therapeutic allogeneic lymphocyte infusion±chemotherapy for recurrence. Of14patients who underwent therapeutic allogeneic lymphocyte infusion±chemotherapy,5cases achieved complete remission, and the effective rate was35.7%. Up to date of follow-up, only three cases survived, two cases of which were relapse-free survival, and1patient experienced extramedullary relapse after remission;12cases died,10cases of which died of relapse, and the remaining two died of bone marrow suppression and GVHD after infusion.3-year OS rate of this group of patients was10.0%. 3. Comparison of the efficacy between preventive and unpreventive allogeneic lymphocyte infusion in Auto-HSCT patientsThere are18cases of AML and1case of CML chronic-phase out of19cases Auto-HSCT anastomosed with lymphocytes in preventive infusion.13patient presented poor prognosis factors before transplatation (68.4%). Till the deadline of follow-up, there are13surviors, in which11are defined as DFS,1patient relapsed after preventive infusion,but is in CR now after the Allo-HSCT,1patient survived through extramedullary relapse (bone marrow CR). All patients died from relapse. The three-year OS rate is66.5%, while three-year DFS rate is57.5%. At the same time, the8Auto-HSCT patients without preventive infusion all presented with AML,3of them has poor prognosis factors before transplantation (37.5%), there is significant differences betwen the two high risk group(P=0.038). Till the deadline of follow-up,5developed DFS,3relapsed and ended in death. The3-year OS and DFS rate are both62.5%, there are no statistical differences between the prevented and unprevented group.4. Adverse reactions of adoptive immunotherapyMajor adverse reactions of allogeneic lymphocyte infusion were GVHD and bone marrow suppression. A total of six patients in this group had aGVHD after infusion, including3cases of aGVHD grade1,2cases of grade2and1case of grade3.6patients had transient bone marrow suppression, and1patient died during the bone marrow suppression period.There were a total of2allogeneic lymphocyte infusion treatment-related deaths, both of which received therapeutic allogeneic lymphocyte infusion. One died of severe aGVHD, and the other died of apparent bone marrow suppression accompanied by severe lung infection.Conclusion: 1. Age, cytogenetics, the response of first induction chemotherapy are independent prognostic factors.2. HSCT is effective treatment for leukemia. Disease state before transplantation has significant effect on long-term survival. Relapse is the death of the main factor after transplantation.3. Allogeneic lymphocytes infusion is an effective method of preventing and treating relapse after transplantation. The patients liable to replase feasible can improve the OS and DFS by preventative infusion, and related side effects have no obvious increase. |
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