A Clinical Study Of Allogeneic Natural Killer Cell Infusion To Elderly Patients With Acute Myeloid Leukemia Based On Genetic

Background Acute myeloid leukemia(AML)is one of the common hematological malignancies in the elderly.Current treatment consists of intensive chemotherapy,non-myeloablative hematopoietic stem cell transplantation,hypomethylating agents,low-dose cytarabine,or supportive care,etc.Compared to younger patients,elderly patients with AML are generally less responsive and tolerant to treatment due to old age,more co-morbid conditions,organ damage,unfavorable cytogenetic,and expression of multidrug resistance genes,etc.The median survival time of elderly patients is about 5-16 months,and 3-year survival rate is<10%.With the continuous optimization of chemotherapy and hematopoietic stem cell transplantation programs and the emergence of highly efficient and low-toxic targeted drug therapy,complete remission(CR)rates in elderly patients can reach 40%-70%,but many patients after treatment to achieve CR still have minimal residual disease(MRD).MRD cannot usually be cleared by further chemotherapy or SCT,which eventually leads to disease recurrence,disease progression,and with poor prognosis.Therefore,new therapies other than chemotherapy and HSCT are urgently needed to further reduce or eradicate MRD to reduce disease recurrence and thus prolong the survival of elderly AML patients.In view of the particularity of the multiple complications of poor organ function in elderly patients,the selection of effective treatment and the reduction of the toxic and side effects of treatment at the same time have become the focus of the selection of schemes for elderly AML patients.In recent years,natural killer(NK)cell adoptive cell therapy(ACT)has received increasing attention.NK cells are cytotoxic lymphocytes of the innate immune system.NK cell recognition and killing of target cells do not require prior sensitization,independent of antibodies,and not restricted by MHC,but depend on a tune balance between NK inhibitory and activating receptors expressed on their surface that interact with their ligands on stressed cells.With the advanced studies on the anti-tumor mechanism of NK cells,NK cell immunotherapy has been gradually applied in the treatment of acute myeloid leukemia,and many studies have shown that allogeneic NK cell infusion can exert anti-AML activity without inducing graft-versus-host disease(GVHD)and is clinically well tolerated.In order to improve the survival of elderly AML patients,our study intends to use genetic guidance to select allogeneic NK cells that theoretically have a killing effect on leukemia cells and infusion it after AML remission,so as to reduce the recurrence of AML and prolong the Overall Survival of elderly patients.Objective To evaluate the safety and efficacy of allogeneic NK cell infusion in the treatment of intermediate or high-risk elderly acute myeloid leukemia.Methods A retrospective analysis was performed on the clinical data and the donor and recipient KIR genotyping results of elderly AML patients who received allogeneic NK cell infusion after complete remission from decitabine combined with CAG chemotherapy from October 2017 to March 2019.To evaluate the safety and efficacy of NK cell infusion.To examine the effect of donor-recipient KIR gene matching/mismatching?KIR genotypes?KIR2DS1 on disease-free survival(DFS)in elderly patients with acute myeloid leukemia(AML),so as to provide a basis for clinical selection of suitable NK cell donors.Results Seven intermediate or high-risk elderly AML patients received allogeneic NK cell infusion after low-dose decitabine combined with CAG chemotherapy.The median CD56+CD3-NK cell infusion amount was 1.45(1.12 to 1.76)×108/Kg,and the median survival rate of NK cells was 90%(88%to 92%).Among them,the median purity of NK cells was 87%(85%to 89%),and the median killing activity of NK cells was 87%(85%to 88%).Patients with allogeneic NK cell infusion were well-tolerated,no adverse events or manifestations of graft versus host disease(GVHD)were observed in all 7 patients.By the end of follow-up,the median follow-up was 596(356?901)days.5 of 7(71.4%)are disease-free,1 patient MRD+turned negative after NK cell infusion,and the remaining 4 patients MRD continued negative after infusion.Two patients(28.5%)relapsed after NK infusion(1 patient with morphological relapse and 1 patient with molecular relapse)Among the 7 patients,donor-recipient KIR gene mismatching?donor Cen-B KIR motif?haplotype B/X?positive of KIR2DS1 was no statistically significant difference in the influence of DFS.Conclusion Infusion of allogeneic NK cells is safe and feasible for elderly AML patients in complete remission after chemotherapy,which may help intermediate or high-risk AML patients to achieve further remission,reduce disease recurrence rate,and prolong overall survival time.This study has been approved by the ethics committee of Shunde Hospital of Southern Medical University and registered in the China Clinical Trial Registration Center(ChiCTR1900022598).