Hematologic Toxicity And Kinetics Of Immune Function And Relevant Factors Analysis After Chimeric Antigen Receptor T Cells Therapy In Relapsed/Refractory Acute B Lymphoblastic Leukemia

Background Acute lymphoblastic leukemia is a rapidly developing proliferative tumor.Due to the improvement of traditional chemotherapy therapy,the development of allogeneic hematopoietic stem cell transplantation,and the discovery of new targeted drugs,the efficacy and prognosis of acute lymphoblastic leukemia have been greatly improved.For relapsed or refractory B cell acute lymphoblastic leukemia,the re-induction rate is low,and studies suggest that the 5-year disease-free survival is less than 20%.It is difficult to make an allogeneic hematopoietic stem cell transplantation. So novel therapies are urgently needed to improve the efficacy of R/R B-ALL.Chimeric antigen receptor T-cell（CAR-T）therapy is an immunotherapy method that has recently attracted much attention.At present,CD19-targeted CAR-T cell therapy has achieved unprecedented success in patients with relapsed/refractory acute B lymphoblastic leukemia（R/R B-ALL）and B-cell lymphoma,but it still faces a series of problems in the clinical treatment,such as severe cytokine release syndrome（CRS）and neurotoxicity.More and more current research focus on it.But only sporadic reports have described hematopoietic toxicity,B cell depletion,and decreased immunoglobulins caused by CD19-targeted CAR-T cells.The research on the related mechanism,relevant factors,prevention still need to be further explored.Objective To explore the hematologic toxicity and kinetics of immunefuction and relevant factors of CD19-targeted CAR-T therapy in R/R B-ALL.Methods The kinetics of blood count,lymphocyte subsets,immunoglobulins and infection in patients who received CD19-targeted CAR-T cell therapy from October2016 to October 2020 were analyzed.Results A total of 52 patients with relapsed/refractory B-ALL were enrolled.Among the 39 patients who obtained complete remission,neutropenia（≥ grade 3）occurred in38（97.4%）patients,and thrombocytopenia（≥ grade 3）occurred in 35 patients（89.7%）.Three patients did not reach normal levels of blood count after 1 year,but all were at grade 1 to 2 cytopenia.The relevant analysis suggested that the occurrence of grade 3 or above thrombocytopenia within 28 days was significantly associated with the use of tocilizumab and hormones（P<0.05,P<0.05）,but multivariate analysis showed that neither was independent risk factors of thrombocytopenia of grade 3 or higher.No relevant factors were associated with the late cytopenia（P>0.05）.Lymphocyte subsets were detected in 23 patients.CD4/CD8 ratio decreased in 21 patients（91.3%）within 14 days after CAR-T cell infusion.All 23 patients developed B cell aplasia,and the median time to onset of B cell aplasia was on day 7（0-14）.After CAR-T cell infusion in 22 patients,Ig A,Ig M,and Ig G decrease was seen in 19 cases（86.4%）,21 cases（95.5%）and18 cases（81.8%）,respectively.And patients received allogeneic hematopoietic stem cell transplantation had significantly lower Ig M than that in patients without allogeneic hematopoietic stem cell transplantation（P<0.05）.The incidence of infection within 1 month after CAR-T cell infusion was 38.4%（15/39）,and 9 severe infections in 7 patients（17.9%）was identified after 1 month of CAR-T cell infusion,and only 1 patient was 14 years old.The child died of infection with graft-versus-host disease in pulmonary on day 30 after CAR-T cell infusion,and no fatal infection occurred in other patients,and no related factors were found.Conclusion1.Severe neutropenia and/or thrombocytopenia are common toxicity with R/R B-ALL after CD19-targeted CAR-T cell therapy,and grade 3 or above thrombocytopenia is associated with the use of tocilizumab and/or hormone.Some patients did not reach normal levels of blood count after 1 year.2.The decrease of immunoglobulin is also the common adverse event with R/R B-ALL after CD19-targeted CAR-T cell therapy and the decrease of Ig M is related to a history of transplantation.3.The incidence of early infection is high,then the incidence of subsequent infection decrease with R/R B-ALL after CD19-targeted CAR-T cell therapy.The incidence of related fatal infection is low.