Analysis Of Efficacy And Adverse Reactions Of Cytarabine For Consolidation In 85 Patients With Acute Myeloid Leukemia (Not M3) In Qilu Hospital Of Shandong University

BackgroundAcute myeloid leukemia(AML)is a malignant disease originating from myeloid hematopoietic stem/progenitor cells.It’s also the most common leukemia affecting adults.Approximately 300,000 patients worldwide are diagnosed annually with AML.AML has some characteristics such as developing rapidly,relapsing easily,poor prognosis and so on.Therefore,how to control the disease in time and prevent it recurrence are serious challenges for during the AML clinical treatment.According to NCCN guideline,the treatment strategies of AML consists of induction chemotherapy,post-remission chemotherapy,salvage chemotherapy,prevention and monitoring of the central nervous system(CNS)leukemia,supportive treatment,and hematopoietic stem cell transplantation(HSCT).In recent decades the "3+7" regimen acts the first-line induction chemotherapy for adult AML.The "3+7" regimen is anthracyclines such as daunorubicin(DNR)or idarubicin(IDA)dl-3 combined with standard dose Ara-c d1一7.Modern therapy makes it possible for 60-80%patients with AML to achieve complete remission(CR)after induction therapy.However,most of them will relapse within six months to a year without additional cytostatic therapy.Once AML relapsing patients’ resistance will increase significantly and the prognosis will bevery poor.Thereby post-remission therapy is always one of the most important parts for AML therapy.A number of studies around the world have suggested that the post-remission therapy consisting high-dose Ara-c has been the leading chemotherapy.However,Cytarabine(Ara-c)has a variety of adverse reactions,including hematology toxicity,gastrointestinal adverse reactions,skin rashes,conjunctivitis,fever,renal toxicity,oral ulcer and so on.High-dose cytarabine will cause severe bone marrow suppressioncharacterized by anemia,agranulocytosis and thrombocytopenia.resulting in a series of adverse clinical reactions.There are manystudiesshowing the comparison of post-remission therapy with different dose Ara-c.However the question about the dose and cycle of Ara-c in post-remission still remain unanswered leaving many unknown questions for us to explore.Objective:This study aims to analyzethe effect and adverse reactions of85 newly diagnosed cases with AML(not M3)inQilu Hospital of Shandong University using different dosage,course of cytarabine during consolidation chemotherapy.Thereby we could explore an optimal consolidation chemotherapy regimens and provide the reference for the clinical treatment of AML.Method:Our study enrolled 85 newly diagnosed AML patients in Qilu Hospital from January 2010 to December 2016.All patients were in complete remission and had at least one cycle Ara-c with different dose during post-remission therapy.We collected the patients’ age,sex,blood routine(white blood cells,hemoglobin and platelets),primitive bone marrow cells,chromosome,gene mutation and so on,and follow-up patients through the telephone or outpatientservice.The patients were divided into different groups:(1)according to single dose of Ara-c,85 cases were divided into 2 groups,HDAra-c group(2-3 g/m2 ql2h,d1-3)and non-HDAra-c group(intermediate dose or standard dose);(2)according to total cumulative dose of Ara-c.HDAra-c group were divided into three groups.HDAra-c-1 group(<18 g/m’),HDAra-c-2 groups(18-36 g/m2)and HDAra-c-3 groups(≥36 g/m2);(3)HDAra-c group were divided into two groups depending on the course,HDAra-1 cycle group(1-2 course)and HDAra-2 cycle group(3-4cycles);(4)the non-HDAra-c group were divided into three groups according to total cumulative dose,non-HD Ara-c-1(<9 g/m2),non HDAra-c-2(9-18 g/m2)and non HDAra-c-3(≥18 g/m2).We compare the relapse-free survival(RFS),overall survival(OS)and adverse effects among different groups.Results:1.Our study enrolled 85 newly diagnosed AML patients,between 14-60.The median age is 38.Overall,patients with 1 year RFS rate and OS rate were 83.2%and 84.7%respectively;2 years of RFS rate and OS rate were 59.7%and 78.6%respectively.Follow-up time was 83 months,and median follow-up time was 42 months.Patients in general have not reached the median overall survival(OS).2.Comparison effect between each group:(1)According to single dose of Ara-c.the overall patients were divided into two groups.53 patients in HDAra-c group(2-3g/m2).32 patients in non-HDAra-c group.RFS of HDAra-c group in 1,2 years were 87.6%and 66.6%respectively.RFS of non-HDAra-c group in 1,2 years were 67.3%and 50.5%respectively.Compared with non-HDAra-c group,HDAra-c group have significant advantages on RFS(P= 0.006).COX multiple factors analysis shows that single dose is the main influencing factor of RFS(P= 0.004,HR = 0.004.95%CI 0.170-0.708).OS of HDAra-c group in 1,2 years were 89.5%and 77.2%respectively.OS of non-HDAra-c group in 1,2 years were 78.7%and 62.7%respectively.HDAra-c group also have advantage on OS(P= 0.043).COX multiple factors analysis shows that single dose group is potential influencing factors for OS(P= 0.093,HR = 0.467,95%CI 0.192-1.137).(2)According to cumulative dose of Ara-c,the HDAra-c group were divided into 3 groups,16 patients in HDAra-c-1 group(<18 g/m2),18 patients in HDAra-c-2 group(18-36g/m=).19 patients in HDAra-c-3 group(≥36g/m2).HDAra-c-3 group have significant advantages in RFS than HDAra-c-1 group(P = 0.041).There was no significant differences betxween HDAra-c-2 group and HDAra-c-1 in RFS(P=0.069).There was also no significant differences between HDAra-c-2 group and HDAra-c-3 in RFS(P = 0.103).COX multi-factor analysis suggests that the cumulative dose of Ara-cis the potential factors influencing the RFS(P= 0.066.HDAra-c-1 groupvs HDAra-c-3 group:P = 0.062,HR = 4.297,95%CI 0.932-19.808;HDAra-c-2 group vs HDAra-c-3group:P=0.020,HR = 7.904,95%CI 1.378-45.345).HDAra-c-3 group have no significant difference in OS compared with the other two groups(P= 0.772,HDAra-c-1 groupvs HDAra-c-3 group:P = 0.420,HR = 1.854,95%CI 0.414-8.306;HDAra-c-2 group vs HDAra-c-3group:P = 0.654,HR = 1.443,95%CI 0.290-7.172).(3)According to cycles of Ara-c,HDAra-c group were divided into 2 groups.31 patients in HDAra-c cycle 1 group(I-2cycles),22 patients in HDAra-c cycle 2 group(3-4cycles).HDAra-ccycle 2 grouphave significant advantages in RFS than cycle 1 group(P = 0.03).HDAra-ccycle 2 group have no significant advantage in OS than cycle 1 group(P= 0.228).COX multi-factor analysis shows that cycle group is the potential factors influencing the RFS(P= 0.098,HR = 0.615,95%CI 0.346-1.093).(4)According to cumulative dose of Ara-c,the non-HDAra-c group were divided into 3 groups,17 patients in non-HDAra-c-1 group(<9 g/m2),5 patients in non-HDAra-c-2 group(9-18g/m2),10 patients in non-HDAra-c-3 group(≥18g/m2).Non HDAra-c-3 group have significant advantages in RFS than theother two groups(non-HDAra-c-1 group vs non-HDAra-c-3:P= 0.002.non-HDAra-c-2 group vs non-HDAra-c-3:P = 0.040).There are no significant differences in RFS between HDAra-c-3 groups and non HDAra-c-2 group(P = 0.850).COX multi-factor analysis shows that cumulative dose group is the main risk factor affecting the RFS(P=0.047,HR = 2.013,95%CI 1.009-4.017).Non-HDAra-c-3 group have significant advantage in OS compared with non-HDAra-c-1(P= 0.027).There was no significant differencesbetween other two groups.3.Theadverse reactions in patients with HDAra-c groups:(1)Regarding hematologic toxicity:84.9%of patients expressed grade 4 myelosuppression.The median duration of NEU<0.5*109/L、NEU<0.2*109/L and PLT<20*109/Lare 7(2-14)d、6(1-12)d and 6(2-13)d respectively.(2)Regarding non-hematologic toxicity:The rate of post-chemotherapy infection(upper respiratory tract infection,lung infection,perianal infection,etc.)is 88.7%,fever rate 81.1%,liver toxicity 32%,grade 1 to 3 gastrointestinal function damage 26.4%,skin rash 11.3%,conjunctivitis 9.4%.No severe cardiac dysfunction and neurotoxicity occurred.Conclusion:1.HDAra-c group have advantages on the OS and RFS for AML(not M3)patients relative to the non-HDAra-c group.2.HDAra-c group with cumulative dose ≥36 g/m2have significant advantages for AML(not M3)patients to those with cumulative dose<18 g/m2 on the RFS.HDAra-c group with 3-4 courses have significant advantages on RFS than those with 1-2 cycles.3.The AML(not M3)patients can tolerate consolidation treatment of HDAra-c.