The Efficacy And Safety Analysis Of Venetoclax Combined With Azacitidine In Newly Diagnosed Patients With Acute Myeloid Leukemia Who Are Elderly And Unfit For Intensive Chemotherapy In The Real World

Objective:To observe the clinical efficacy and safety of venetoclax(VEN)combined with azacitidine(AZA)in the treatment of newly diagnosed patients with acute myeloid leukemia(AML)who are elderly and unfit for intensive chemotherapy in the real world.Method:The clinical data of 46 newly diagnosed elderly and unfit AML patients treated with VEN combined with AZA in our department from January 2021 to February 2023 in the department of Hematology of the Second Hospital of Shanxi Medical University were collected.The clinical efficacy and safety after the first course of treatment with VEN combined with AZA were retrospectively analyzed,and analyzing the related factors of influencing efficacy and prognosis.Results:1.After receiving a course of VEN combined with AZA treatment for 46 newly diagnosed elderly and unfit AML patients,the overall response rate(ORR)was 82.6%,the complete remission/complete remission with incomplete blood count recovery(CR/CRi)rate was 69.6%,and the negative conversion rate of minimal residual disease(MRD)was 81.3%.Among the 46 patients,5 patients underwent intensive chemotherapy or allogeneic hematopoietic stem cell transplantation after removing the unfit factor.After intensive chemotherapy or allogeneic hematopoietic stem cell transplantation,three patients with CR maintained a MRD negative remission state,and one patient with partial remission(PR)and one patient with non remission(NR)patient obtained MRD negative CR;2.Analyzing the correlation of different clinical characteristics and curative efficacy,The CR/CRi rate of patients with a score of 3-4 from the Eastern Cooperative Oncology Group(ECOG)was not significantly lower than that of patients with a score of0-2(55.6% vs 73%,P>0.05);The CR/CRi rate in elderly patients was not lower than that in young patients(72.2% vs 60%,P>0.05);The CR/CRi rate in patients with secondary/treatment related AML was not lower than that in patients with primary AML(70% vs 69.4%,P>0.05);The European Leukemia Network(ELN)did not significantly lower the CR/CRi rate in adverse risk patients with prognosis than in favorable and intermediate risk patients with ELN(60% vs 75%,P>0.05);The CR/CRi rate in patients with cytogenetic favorable and intermediate risk was significantly higher than that in patients with cytogenetic adverse risk AML(82.1% vs 37.5%,P=0.024).3.Analyzing the correlation of different molecular mutation types and curative efficacy,the ORR of the subgroup with IDH1/2 mutations was significantly higher than that of the subgroup without IDH1/2 mutations(100% vs 68%,P=0.036);The ORR and CR/CRi rates in the FLT3-ITD/TKD mutation subgroup and the TP53 mutation subgroup were not significantly lower than those in the non-corresponding mutation subgroup(ORR:63.6% vs 84.6%,75% vs 78.8%;CR/CRi rates:54.5% vs 65.4%,50% vs 63.6%;P>0.05);4.Analyzing the correlation of different treatment days and doses of VEN and curative efficacy,there were no significant difference in ORR,CR/CRi rate,and MRD negative conversion rate between the VEN 400 mg group and <400mg group(ORR:73.3% vs 87.1%;CR/CRi rate: 60% vs 74.2%;MRD negative conversion rate: 88.9% vs78.3%;P>0.05);There were no significant difference in ORR,CR/CRi rate,and MRD negative conversion rate between the VEN 28 day group and <28 day group(ORR:77.8% vs 85.7%;CR/CRi rate: 55.6% vs 78.6%;MRD negative conversion rate: 90% vs77.3%;P>0.05);5.In terms of survival,the median follow-up time was 7.8(1.5-25.1)months,and the median survival(m OS)time was 15.3 months.The OS rates at 6 and 12 months were83.5% and 62.6%,respectively.The median event free survival(EFS)time was 8.3months,and the EFS rates at 6 and 12 months were 65.8% and 38.9%,respectively;Prognostic analysis of different clinical characteristics and molecular mutation subgroups showed that the m OS and median EFS in the ELN favorable and intermediate risk groups were significantly longer than those in the ELN adverse risk group(m OS: not reached vs8 months;median EFS: 14.2 months vs 6 months;P<0.05);The m OS and median EFS in the non RAS mutant subgroup were significantly longer than those in the RAS mutant subgroup(m OS: 12.3 months vs 4 months;median EFS: 9.4 months vs 6.7 months;both P<0.05);6.In terms of safety,The incidence of hematological adverse event(AE)in patients with ≥ 3 grade was 95.7%,of which the incidence of leukopenia in patients with ≥ 3grade was 63%,the incidence of neutropenia with fever was 45.7%,the incidence of anemia was 45.7%,and the incidence of thrombocytopenia was 19.6%.The duration of median neutrophil deficiency was 20.5(0-58)days,and the median platelet recovery time was 18(0-78)days.The average red blood cell infusion volume was 10.28 ± 5.85 U(0-24 U),and the average platelet infusion volume was 5.43 ± 4.94 U(0-21 U).The most common non hematological AE is infection,followed by gastrointestinal reactions.The main infections were pulmonary infection(50%)and intestinal infection(26.1%),both ≥ grade 3,The main pathogen is gram-negative bacteria.The main gastrointestinal reactions were nausea(23.9%),vomiting(17.4%),constipation(13%),and diarrhea(10.9%).9 patients(19.6%)developed hypokalemia,and 4 patients(8.7%)had ≥ grade3 hypokalemia.Drug induced liver injury occurred in 9 patients(19.6%),and only 1patient(2.2%)had ≥ grade 3 liver injury.After active liver protection treatment,liver function recovered.No tumor lysis syndrome was observed.Conclusions:1.VEN combined with AZA can enable newly diagnosed elderly and unfit AML patients to quickly obtain deep remission,with good safety,and can achieve similar efficacy in the real world as clinical trials;2.The combination of VEN and AZA is more widely applicable in the real world,with good efficacy for elderly patients and patients with poorer physical fitness(ECOG score 3-4),and can serve as a bridge between intensive chemotherapy and allogeneic hematopoietic stem cell transplantation for patients with unfit AML;3.VEN combined with AZA can provide AML patients with adverse prognostic factors such as secondary/treatment related AML,ELN adverse risk AML,TP53 mutations,and FLT3-ITD/TKD mutations with a therapeutic effect that is not inferior to those with favorable prognostic factors.AML patients with adverse prognostic characteristics can benefit from the VEN combined with AZA regimen;4.VEN combined with AZA has significant efficacy in AML patients with cytogenetic favorable and intermediate risk and IDH1/2 gene mutations;5.Patients with ELN adverse risk AML and RAS mutant AML have shorter EFS and OS.