| Object:Acute lymphoblastic leukemia(ALL)is the most common malignant hematological disease,accounting for approximately 20-30% of adult acute leukemia and 80% of childhood acute leukemia.The complete remission rate(CR)of ALL induced chemotherapy was 70-90%,the disease-free survival rate(DFS)of 3-5 years was 30-60%,and the long-term DFS of children ALL was more than 85%.However,30-60% of patients still show refractory or relapse,which is one of the major causes of death in ALL patients.There is no standard effective treatment for refractory/relapsed ALL.Even if allogeneic hematopoietic stem cell transplantation(allo-HSCT)is performed,the long-term survival rate is still not optimistic,which brings a huge challenge to clinical treatment.Urgently looking for new effective treatment options.With the rapid development of biotechnology,biotherapy has performed well in the treatment of cancer,and has become the fourth largest treatment of cancer treatment.Cancer immunotherapy mainly includes adoptive cell therapy,immunomodulatory agents,tumor vaccines,and blocking of immune binding sites.A new generation of chimeric antigen receptor T cells(CAR-T)with tumor antigen specificity overcomes the shortcomings of the lack of specificity of traditional cell therapy,which greatly promotes precise targeting based on immune cells.The development of immunotherapy,the global CAR-T technology in the treatment of hematological cancer is affirmed.As a novel and effective immunotherapy,CAR-T technology has made breakthrough progress in the clinical trials of hematological tumors and has received extensive attention.CAR-T cell therapy for refractory and recurrent hematological B-cell neoplasms is effective 60-90%,but the survival time of CAR-T cells in the body is short,and short-term relapse rate after remission is high.How to find an effective way to use the advantages of CAR-T cells and overcome their shortcomings to improve the long-term survival of patients is a clinical problem that needs to be solved urgently.Studies have found that patients who undergo allogeneic hematopoietic stem cell transplantation after CAR-T cell therapy have a significant increase in long-term survival.Therefore,CAR-T cell bridging allogeneic hematopoietic stem cell transplantation for the treatment of refractory/recurrent hematological malignancies is expected to become a new treatment.We conducted CAR-T bridging allogeneic hematopoietic stem cell transplantation for refractory/relapsed acute B-lymphocytic leukemia patients in order to improve the remission rate and long-term survival rate of refractory/relapsed acute B-lymphocytic leukemia patients.Method:1.To collect data on 194 newly diagnosed acute B-lymphocytic leukemia patients from January 2010 to December 2015 in our center.We retrospectively analyzed the patient's newly diagnosed immune phenotype and prognosis to evaluate the presence of abnormal antigen expression on B-ALL.Patients with complete response to induction chemotherapy,2-year progression-free survival,and 2-year overall survival,evaluation of abnormal antigen expression on post-transplantation hematopoietic reconstitution in B-ALL patients,2-year progression-free survival after transplantation,and 2-year overall survival The impact of the rate;2.Car-T cell therapy was applied to patients with refractory/recurrent acute B-lymphocytic leukemia in our center,the effectiveness of CAR-T cell therapy was clarified,CAR-T cell therapy protocol was summarized,and treatment-related complications(CRS,nervous system)were observed.Toxicity)and prognosis;3.Car-T bridging allogeneic hematopoietic stem cell transplantation for refractory/relapsed acute B-lymphocytic leukemia patients in our center,clarifying the effectiveness of its treatment,summarizing the CAR-T bridging allogeneic hematopoietic stem cell transplantation treatment plan,and observing treatment-related concurrency Symptoms(CRS,neurotoxicity,GVHD)and prognosis.Main results:1.The median disease-free survival time of the 194 patients included in the analysis was 12 months(95% CI = 7.549 to 16.451),and the 1-year and 2-year disease-free survival rates were 48.3% and 39.8%,respectively.The median overall survival time was 18 months(95% CI = 13.09 to 22.90).The 1-year and 2-year overall survival rates were 56.6% and 47.4%,respectively.There was no significant difference in the remission rate of first induction chemotherapy with or without abnormal antigen expression in B-ALL patients.The disease-free survival(=19.502,P<0.001)and overall survival(=22.619,P<0.001)in patients without abnormal antigen expression were better than patients with abnormal antigen expression.Analysis of 106 patients with abnormal antigen expression,disease-free survival of patients with abnormal myeloid antigen expression,abnormal T-lymphocyte antigen expression,and myeloid and T-line abnormal antigen expression(=0.105,P=0.949)Differences in overall survival(=0.09,P=0.956)were not statistically significant.The single factor analysis of the COX proportional hazards model showed that the disease-free survival and overall survival of patients without abnormal antigen expression were better than patients with abnormal antigen expression.The risk of disease progression in patients with abnormal antigen expression was not abnormal.2.323-fold(95% CI=1.559-3.461,P<0.001)of antigen expression;disease-free survival and overall survival were better in patients who had remission with first induction chemotherapy than those who did not remit;patients who had been treated with first-time induction chemotherapy were remitted The risk of progression was 0.24 times(95% CI=0.151 to 0.383,P<0.001).The disease-free survival and overall survival of patients undergoing hematopoietic stem cell transplantation were better than those without hematopoietic stem cell transplantation.The risk was 0.35 times untransplanted(95% CI = 0.211 to 0.581,P < 0.001).The univariate analysis of meaningful variables was included in the Cox proportional hazards model for multivariate analysis.The age>14 years,the regression coefficient of abnormal antigen expression was positive,and the regression coefficient of transplantation and first induction chemotherapy was negative,suggesting that the age> The 14-year-old,abnormal antigen expression,no transplantation,and no response to first induction chemotherapy were the conditional combinations of disease progression and death.Analysis of 49 patients undergoing hematopoietic stem cell transplantation showed that there was no significant difference in the presence or absence of abnormal antigen expression in WBC,PLT reconstruction time and post-transplantation MRD,P>0.05.There was no significant difference in disease-free survival(=1.526,P=0.217)and overall survival(=0.883,P=0.347)between patients with and without abnormal antigen expression in transplantation patients(=1.526,P=0.217)..Among the 106 patients with abnormal antigen expression,the most common abnormal antigens were CD56,CD13,and CD123.Correlation analysis showed that there was a negative correlation between CD123 aberrant expression and disease-free survival time and overall survival time,which was further analyzed at different age stages.There was no correlation between CD56,CD123,and CD13 in age group and disease-free survival time and total survival time.2.Our center used the CAR-T cell therapy for 14 patients with CD19 positive expression in refractory/recurrent B-ALL patients.Before the treatment,the FC protocol was used to treat lymphocytes.No serious adverse reactions occurred during the infusion process,which led to the termination of treatment.Infusion volume 10^6-10^8,the final remission rate was 57.14%,CAR-T cell therapy can also achieve relief effect on central nervous system leukemia,but 37.5% of remission patients relapse within 3 months.One patient had severe CAR-T cell-associated CRS 1 day after the CAR-T infusion and eventually died.Other common adverse reactions include agranulocytosis,anemia,thrombocytopenia,fever,hematuria,bleeding of the skin mucous membranes and digestive tract,bleeding tendency of the lower extremities and lower back,neurological toxicity including headache,aphasia,photophobia and other symptoms.However,there was no severe cerebral edema that caused the death of the patient.Other adverse reactions included gastrointestinal symptoms(nausea,vomiting,anorexia),abnormal liver function,abnormal renal function,electrolyte imbalance,and abnormal coagulation function.3.Our center targeted CAR-T bridging allogeneic hematopoietic stem cell transplantation for 2 cases of CD19-expressing refractory/relapsed B-ALL patients,and integrated CAR-T cell therapy into pre-transplantation pretreatment to combine with fludarabine + Pretreatment with Busulfan + Cyclophosphamide,Simoxetine + Busulfan + Cyclophosphamide + Cytarabine,Pretreatment with Tacrolimus,Mycophenolate Mofetil,Methotrexate,and ATG GVHD.Both patients achieved complete remission,no serious CRS,no neurotoxicity,and the severity of aGVHD was within control.However,the hematopoietic reconstitution Time of bottles was is relatively late.4.Main conclusion:1.Abnormal antigen expression in patients with B-ALL had no effect on the remission rate of first induction chemotherapy,but abnormal expression of antigens reduced the 2-year disease-free survival rate and 2-year overall survival rate of patients with different types of abnormal antigen expression.There was no significant difference in the 2-year disease-free survival rate and 2-year overall survival rate.Age>14 years old,abnormal antigen expression,no hematopoietic stem cell transplantation,and no induction of first-time induction chemotherapy are important factors for disease progression and death.The most common abnormal antigens were CD56,CD13,and CD123.Correlation analysis revealed a negative correlation between CD123 aberrant expression and disease-free survival and overall survival.2.CAR-T cells are an effective method for the treatment of refractory/relapsed B-ALL.The currently accepted method is to take “de-lymphocyte therapy” before treatment,and to perform incremental infusion of CAR-T cells,CAR-T.The cell infusion volume was between 10^6-10^9.The patient's body temperature,blood pressure,oxygen saturation,and related indicators such as inflammatory markers were closely monitored.The use of glucocorticoids and immunosuppressive agents was avoided before and after infusion.If severe cytokine release syndrome(CRS)occurs,glucocorticoids,IL-6 monoclonal antibodies,etc.may be given.However,the short-term recurrence rate of patients after CAR-T cell therapy is high and needs to be further solved.3.CAR-T cell bridging allogeneic hematopoietic stem cell transplantation is an intractable/relapsed B-ALL and is an effective means to improve long-term survival of patients.However,more issues such as pretreatment programs,prevention of GVHD treatment,CAR-T cell and stem cell infusion require further research. |
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