Analysis Of The Efficacy And Safety Of Venetoclax Based Regimens In Patients With FLT3 Mutated Acute Myeloid Leukemia

ObjectiveAcute myeloid leukemia(AML)is an aggressive hematologic malignancy,fms-like tyrosine kinase 3(FLT3)mutations present in approximately 25%-30%of patients,FLT3 mutated AML presents with a significantly poor outcome,higher rates of relapse and inferior overall survival.FLT3 inhibitor(FLT3i)can lead to improvements in clinical remissions in patients with FLT3 mutated AML,but the short duration of remission with single-agent FLT3i limited outcomes,which compel the development of multi-agent combinatorial or sequential therapies for FLT3 mutated AML.Venetoclax(VEN),a selective B-cell lymphoma 2(BCL-2)inhibitor,has been shown in preclinical and clinical studies that combination with hypomethylating agents(HMA)led to significant improvements in the incidence of remission and overall survival of acute myeloid leukemia(AML)patients,especially those who were unfit for intensive chemotherapy.In the analysis of FLT3 mutated subgroups,the regimen of VEN was associated with a significantly better remission.However,there were few real-world statistics,this retrospective study aimed to evaluate the efficacy and safety of the regimen based on VEN,compared VEN plus HMA with a triple regimen of VEN plus HMA plus FLT3 inhibitor(FLT3i)in patients with FLT3 mutated AML.MethodsWe conducted a retrospective analysis focus on the clinical data of 28 patients with FLT3 mutated AML who received a regimen based on VEN in Qilu hospital of Shandong University from January 1,2020 to March 1,2022.The patients were divided into two groups,according to whether the regimen including FLT3i,17 patients were treated with VEN plus HMA regimen and 11 patients were treated with VEN plus HMA plus FLT3i regimen.Efficacy and safety were assessed according to composite complete remission rate(CRc)including complete remission(CR)and CR with incomplete hematological recovery(CRi),objective response rate(ORR),overall survival(OS),minimal residual disease(MRD)negative rate and adverse events.Results1.Basic characteristics of FLT3 mutated AML patients.A total of 28 FLT3 mutated AML patients,the median age is 56(19-88).Overall,the most common FAB subtype is M5(16 patients);the median proportion of bone marrow primordial cells is high,about 77%;the median number of peripheral white blood cells is 24.28×109/L,7 patients were hyperleukocytosis.About 2/3 patients were low allelic ratio of FLT3-ITD,the correlated genes including DNMT3A、IDH1/2 and NPM1.2.Efficiency of VEN based regimens in FLT3 mutated AML.2.1 The total efficacy of 28 patients.The total ORR of 28 patients was 53.57%,CRc was 50.00%,median time to respond was 1.3 months,MRD negative rate is 35.71%,median time to MRD negative was 1.5 months.The duration of response for all CRc patients was 6.0 months.At a median follow-up of 9.8 months,the median OS for all patients was not reached;the median PFS for all patients was 2.8 months.2.2 Subgroup efficacy analysisIn the VEN+HMA group and VEN+HMA+FLT3i group,the ORR was 29.41%vs 90.91%respectively(P=0.002);CRc was 29.41%vs 81.82%respectively(P=0.018);the median OS was 3.7 months vs not reached(P=0.554);the median PFS was 2.7 months vs 6.1 months(P=0.111).In all new diagnosed patients and relapsed or refractory patients,CRc was 75.00%vs 40.00%respectively(P=0.209);The median OS was not reached vs 6.1 months(P=0.262).The median PFS was not reached vs 2.5 months(P=0.035).In the VEN+HMA group,CRc of new diagnosed patients and relapsed or refractory patients was 60.00%and 16.67%(P=0.093);The median OS was not reached vs 2.7 months(P=0.341).The median PFS was not reached vs 2.1 months(P=0.024).In the VEN+HMA+FLT3i group,CRc of new diagnosed patients and relapsed or refractory patients was 100.00%and 75.00%respectively(P=1.000);The median OS was not reached either(P=0.354).The median PFS was 3.5 months vs 2.1 months(P=0.477).2.3 Prognostic factors studyThe 30-day and 60-day mortality rates were 0.00%and 3.57%,respectively.The COX proportional hazards regression model was used to analyze the factors that may affect survival,and it was found that the high baseline proportion of bone marrow primordial cells before treatment and not underwent allogeneic stem cell transplantation(allo-SCT)is the unfavorable factors affecting the patients’ OS.OS was not reached of the patients who achieved CRc and 2.7(1.5-14.6)months of the patients who not.OS was not reached of the patients who achieved MRD negative and 6.1 months of the patients who not.6 patients received allo-SCT after CR.OS was not reached in these 6 patients and 3.9 months of the patients who not received alloSCT.3.Safety of VEN based regimens in FLT3 mutated AML.Hematological and infection adverse events(AEs)were the most common toxicities observed.Common grade 3/4 AEs in the first cycle included decreased WBC count(75.00%),neutropenia(78.57%),febrile neutropenia(53.57%),anemia(75.00%),thrombocytopenia(67.86%),and lung infection of mixed bacteria and fungi(42.86%).There was no statistical difference in the incidence of hematological and infection events.The incidence of AEs decreased in the second cycle.Conclusion1.FLT3 mutated AML has the clinical characteristics of a high degree of M5 subtype,high proportion of leukocytes and bone marrow primordial cells,more likely to correlate with DNMT3A、IDH1/2 and NPM1.2.VEN based regimens were effective in the FLT3 mutated AML patients,with higher ORR,CRc,early remissions and longer OS and PFS.The novel combination of VEN+HMA+FLT3i presents better clinical outcomes.Especially,in the new diagnosed patients.VEN based regimens are a good bridge to transplant and whether underwent allo-SCT were independent factor of survival.3.VEN based regimens were well tolerated with the hematological and infection adverse events.The incidence of AEs decreased in the second cycle.The novel combination of VEN+HMA+FLT3i had a favorable safety profile.