| [Objective]To evaluate the efficacy and safety of hypomethylating agents in patients with acute myeloid leukemia and myelodysplastic syndromes,and analyze the factors that may affect the efficacy and survival of patients.[Methods]A retrospective analysis of the clinical data of 118 patients with AML and 74 patients with MDS who were treated with hypomethylating agents(HMAs)in Qilu Hospital of Shandong University.Among them,107 patients with AML who received HMAs combined with chemotherapy from January 2018 to June 2020.Among them,74 patients with MDS were treated with hypomethylating agents,and 11 patients with AML who received AZA combined with Venetoclax from March 2021 to May 2021.All patients met the 2016 WHO diagnostic criteria.Among AML patients,88 patients received decitabine(DAC)combined with chemotherapy,of which 32 patients(36.4%)had a DAC dose of 20 mg/m2/d,and 56 patients(63.6%)received 15 mg/m2/d,both intravenous injection dl-5,4 weeks as a cycle.19 cases received azacitidine(AZA)combined with chemotherapy,of which 18 cases(94.7%)AZA dose was 100mg/d,1 case(5.3%)was 75mg/m2/d,all were subcutaneous injection d1-7,4 weeks as a cycle.According to the baseline situation,the patients were divided into the newly diagnosed group(group A),the after one cycle standard chemotherapy group(group B)and the refractory/relapse group(group C)to evaluate the treatment effect and safety,and the factors that may affect the patient’s treatment effect and OS.11 patients received AZA combined with Venetoclax.The dose of AZA was 75mg/m2/d,d1-7,and the dose of the first cycle of Venetoclax climbs:100mg d1,200mg d2,400mg d3,and then 400mg d4-28;the second cycle was 400mg qd.Azoles drugs were used when combined with granule deficiency,and the dosage was adjusted according to the principle of dosage adjustmentAmong MDS patients,60 received DAC treatment,among which 28 were DAC 20mg/m2/d,17 were DAC 15mg/m2/d,and 16 were DAC 10mg/m2/d intravenous injection d1-5,4 weeks as a cycle;14 patients receiving AZA treatment are all 100mg/d subcutaneously injected d1-7,4 weeks as a cycle.The patients were divided into the effective group and the progressive group,and the treatment effect,safety and factors that may affect the treatment effect and OS of the patient were evaluated respectively[Results]1.Efficacy and safety evaluation of hypomethylating agents combined with chemotherapy or Venetoclax in AML patients1.1 Evaluation of the efficacy of HMAs combined with chemotherapyA total of 107 AML patients were enrolled,of which 59(55.1%)were in group A,27(25.1%)were in group B,and 21(19.2%)were in group C.The median age of the three groups was 63(19-89).Compared with the age of three groups,group A was older than group B(P<0.001)and group C(P=0.007).There was no statistical difference between group B and group C(P=0.896).Compared with the bone marrow blasts of the three groups,group B was higher than group C(P=0.043),and there was no statistical difference between group A and group C,group B and group C.In addition to the above,the baseline characteristics of the three groups of patients,such as gender,baseline white blood cell count,ECOG score,comorbidities,prognostic stratification,karyotype,and fusion genes were similar,and there was no statistical differenceEvaluation after the first cycle of treatment,ORR:78.0%(46/59)in group A,74.1%(20/27)in group B,42.9%(9/21)in group C,and ORR in group A and B were higher than those in group C(P values are 0.003 and 0.028,respectively),there is no statistical difference between group A and group B(P=0.069).CR rate:group A 55.9%(33/59),group B 66.7%(18/27),C Group A was 28.6%(6/21).Groups A and B were both higher than group C(P values were 0.003 and 0.009,respectively).There was no difference between group A and group B(P=0.347).After the second cycle,there are 96 patients can be evaluated.The ORR of group A was 74.1%(40/54),group B was 64.0%(16/25),and group C was 58.8%(10/17).The CR rate of group A was 62.9%(34/54),group B was 60.0%(15/25),group C was 47.0%(8/17),there was no significant difference in ORR and CR rates among the three groups.The efficacy of the DAC combined chemotherapy group and the AZA combined chemotherapy group was compared.After the first cycle of treatment,there was no statistical difference in ORR and CR rates between the two groups.After the second cycle of treatment,the ORR of the DAC combined chemotherapy group was 86.1%(62/72),the AZA combined chemotherapy group was 53.8%(7/13),and the DAC combined chemotherapy group was higher(P=0.035);the CR rates of the two groups were compared There is no statistical difference.1.2 Survival analysis of HMAs combined with chemotherapyThe median follow-up time was 36.6(1.0-63.0)months.As of the last follow-up time,76 patients was died,and 7 patients underwent hematopoietic stem cell transplantation.The median OS of the entire group was 13.0(0.6-63.0)months,of which group A was 15.0(1.0-58.0)months,group B was 13.0(0.6-59.0)months,and group C was 9.6(1.0-63.0)months.There was no statistical difference in OS between the three groups(P=0.965).The Cox proportional hazards regression model was used to analyze the factors that may affect survival,and it was found that ECOG score>2(P=0.037),white blood cell count>10×109/L(P=0.028),poor prognosis group(P=0.027),NR after the second cycle of treatment(P=0.025)were unfavorable factors affecting the patient’s OS.Comparing the OS of patients in the DAC combined chemotherapy group and the AZA combined chemotherapy group,the median OS of the DAC combined chemotherapy group was 18.0(1.0-59.0)months,the AZA combined chemotherapy group was 5.0(0.6-35.0)months,and the DAC combined chemotherapy group was 5.0(0.6-35.0)months.The patient’s OS was longer(P<0.001).1.3 Factors affecting the efficacy in HMAs combined with chemotherapy groupCompare the gender,age,ECOG score,comorbidities,baseline white blood cell count,bone marrow blast cell count,karyotype,prognostic stratification,and patient type(initial diagnosis,one cycle after standard chemotherapy and refractory/relapse)in the DAC combined chemotherapy group and AZA combined chemotherapy group.There was no significant difference between the two groups.The effects of the above baseline characteristics on the efficacy of patients were analyzed in the DAC combined chemotherapy group and the AZA combined chemotherapy group.There was no statistically significant difference in the above baseline characteristics in the DAC combined chemotherapy group.In the AZA combined chemotherapy group,the efficacy of patients ≤60 years old was better(P=0.023).The curative effect of the newly diagnosed group was better than the after one cycle standard chemotherapy group(P=0.015)and the refractory/relapse group(P=0.007),but there was no difference between the after one cycle standard chemotherapy group and the refractory/relapse group.1.4 Safety of HMAs combined with chemotherapy groupAfter the first cycle of treatment,15 patients(71.4%)in group C had anemia of grade≥3,and 13 patients(61.9%)had neutropenia of grade≥ 3,which was higher than that in group A(71.4%vs.61.0%)and group B(71.4%vs.66.7%);13 cases(61.9%)had neutropenia≥ grade 3,which was higher than that in group A(61.9%vs.37.3%)and group B(61.9%vs.55.6%);17 cases(81.0%)had grade 3 thrombocytopenia,which was higher than that of group A(81.0%vs.64.4%)and group B(81.0 vs.74.1%).However,the differences were not statistically significant.The most common non-hematological adverse reaction was infection.The incidence of infection in group A was 28 cases(47.5%),15 cases in group B(55.6%),17 cases in group C(81.0%),group C is higher than group A(P=0.064)and group B(P=0.008),among which,the mixed infections of bacteria and fungi in the lungs were the main ones.After the second cycle of treatment,26 patients(48.1%)in group A had anemia of grade≥3,which was higher than that in group B(48.1%vs.35.3%)and group C(48.1%vs.32.0%)27 cases(50.0%)had ≥grade 3 neutropenia,which was higher than that of group B(50.0%vs.36.0%)and group C(50.0%vs.47.1%);8 cases of group C(47.1%)had≥ 3 Grade thrombocytopenia was higher than that of group A(47.1%vs.31.5%)and group B(47.1%vs.36.0%).Similarly,the non-hematological adverse reaction was mainly infection.There were 13 cases(24.1%)in group A,and group B(47.1%vs.36.0%).Group 9 cases(36.0%),group C 8(47.1%),group C was higher than group A and group B,but the difference was not statistically significant.At the same time,comparing the hematological and non-hematological adverse reactions of patients in the DAC combined chemotherapy group and the AZA combined chemotherapy group,after the first cycle,the incidence of neutropenia≥ grade 3 in the AZA combined chemotherapy group was higher than that of the DAC combined chemotherapy group(42.0%vs.68.4%,P=0.037).There was no statistical difference in the incidence of anemia,neutrophils,and infection.After the second cycle,there was no statistical difference in non-hematological and hematological adverse reactions between the two groups of patients.1.5 Comparison of the efficacy and adverse reactions of different doses of DAC combined with chemotherapyThe ORR and safety of lower-dose DAC(15mg/m2/d)and standard-dose DAC(20mg/m2/d)were compared in group A,group B,and group C.There was no statistical difference in baseline characteristics,ORR and adverse reactions between the two groups.Because the cases in group B and group C was little,the OS was compared only in group A.The results showed that the median OS of patients in the lower-dose group was longer than that in the standard-dose group(19.0 months vs.11.0 months,P=0.014).1.6 The impact of gene mutations on efficacy and survivalA total of 94 patients had genetic mutation test results,of which 77 patients had≥1 genetic mutations,and a total of 29 different types of mutations were involved,including NPM1(21.3%),DNMT3A(20.2%),FLT3-ITD(18.1%))were more common.Due to the small number of cases in the AZA combined chemotherapy group,only analyzed gene mutations affecting patient efficacy and OS in the DAC combined chemotherapy group,and no single mutation was found to have an impact on the patient’s efficacy and OS.1.7 Evaluation of the efficacy and safety of AZA combined with VenetoclaxA total of 11 patients with refractory/relapsed AML treated with AZA combined with Venetoclax were enrolled.The median treatment cycle of patients was 3(1-4)cycles.After the first cycle of treatment,ORR was 81.8%,and 7 cases(63.6%)achieved CR,2 cases(18.2%)PR,2 cases(18.2%)NR,and 1 case reached CR after 1 cycle and did not continue treatment.After the second cycle of treatment,ORR was 100.0%,and 8 cases(80.0%)achieved CR,2 cases(20.0%)PR.Eleven patients were well tolerated by AZA combined with Venetoclax.Nearly 50%of patients had grade 3 cytopenia after the first cycle,and fewer patients had grade 4 cytopenia,with 3 cases(27.3%)had a lung infection,and 1 case(9.1%)had abnormal liver function.After the second cycle,2 patients(20.0%)had grade 4 neutropenia,and 1 patient had a lung infection.1.8 Comparison of the efficacy of AZA combined with chemotherapy and AZA combined with VenetoclaxComparing the efficacy of the AZA combined chemotherapy group with the AZA combined Ven group,there was no statistical difference in baseline characteristics between the two groups.The efficacy of the AZA combined Ven group was better than that of the AZA combined chemotherapy group,but due to the small sample size,only the first The CR rate was statistically different after the second cycle(P=0.019).2、Evaluation of the efficacy and safety of hypomethylating agents in MDS patients2.1 Efficacy evaluationA total of 74 patients with MDS were included in the study,of which 60(81.1%)were treated with DAC,14(18.9%)were AZA.The median course of was 5(1-25).Among 74 patients,18(24.3%)achieved CR,26(35.1%)mCR,4(5.4%)HI,12(16.2%)SD,and 14(18.9%)PD.The overall remission rate was 81.1%.Subgroup analysis,there were 18(30.0%)patients achieved CR,21(35.0%)mCR,4(6.7%)HI,7(11.7%)SD,10(16.7%)PD,and the overall remission rate was 83.3%in the DAC group.And 5(35.7%)mCR,5(35.7%)SD,4(28.6%)PD,the overall remission rate was 66.7%in the AZA group.The CR rate(P<0.001)and ORR(P=0.009)of AZA group were all higher.2.2 SurvivalThe patients were divided into effective group(including CR+mCR+HI+SD)and progress group(PD)according to their curative effect.The median OS of patients in the effective group was 26.0(2.0-54.0)months,the patients in the progression group was 14.0(6.0-18.0)months,and the OS of patients in the effective group was longer(P=0.009).A multivariate Cox proportional hazard regression model was used to analyze the factors that affect the patient’s OS in the entire group of patients.It was found that age≥65 years(P=0.033),platelets<30 X 109/L(P=0.030),and poor treatment effect(P=0.005)were unfavorable factors of OS.The median OS of the DAC group was 25.0(3.2-54.0)months,and the AZA group was 9.0(4.0-28.0)months.Because the number of patients in the AZA group was little,the survival curve was different,and the OS of the two groups was not statistically significant.Difference(P=0.553).2.3 Factors affecting the efficacyComparing the baseline characteristics of patients in the effective group and the progress group,such as gender,age,ECOG score,comorbidities,triline blood cell count,blast cell count,prognostic group,and karyotype.It was found that there were more patients with 60g/L(P=0.033)and platelets≥ 30 ×109/L(P=0.012)in effective group.In addition,comparing the baseline characteristics of patients in the DAC group and the AZA group,the results showed that there were more men in the DAC group(P=0.023),and there was no statistical difference in other baseline characteristics.2.4 SafetyAfter treatment with demethylation drugs,hematological adverse reactions of grade≥3 in the effective group were mainly neutropenia(80.0%)and anemia(85.0%),while the progressive group showed anemia(92.9%)and thrombocytopenia(71.4%)has a high incidence.The main non-hematological adverse reactions of the two groups of patients were pulmonary infection,30.0%in the effective group and 28.6%in the progressive group,but there was no statistical difference in the occurrence of hematological and non-hematological adverse reactions between the two groups.2.5 Comparison of the efficacy of different dose groups of DACThe efficacy,survival and safety of the three groups-DAC standard dose(20mg/m2/d)group,medium dose(15mg/m2/d)group and low dose(10mg/m2/d)group were compared,and no difference was found.2.6 The impact of gene mutations on efficacy and survivalA total of 64 patients had genetic mutation test results,of which 48 patients had≥1 genetic mutation.Of them,ASXL1(20.3%),SF3B1(17.2%)and TET2(12.5%)were more common.There was no gene mutations associated with the patient’s treatment response and OS.[Conclusion]1.In AML patients,the efficacy of DAC combined with chemotherapy is better than that of AZA combined with chemotherapy,and the side effects are less.The efficacy of AZA combined with Venetoclax is better than AZA combined with chemotherapy.Compared with standard-dose DAC combined with chemotherapy,lower-dose DAC has no significant difference in efficacy and adverse reactions.In the newly diagnosed group,patients in the low-dose DAC group have longer OS.ECOG score>2 points,baseline white blood cell count>10×109/L,poor prognosis grouping,and NR after the second cycle are unfavorable factors that affect the patient’s OS.2.Hypomethylating agents can effectively treat patients with MDS and improve their OS.The total effective rate and CR rate of the DAC group were higher than those of the AZA group,but there was no difference in OS between the two groups.There is no difference in the efficacy,survival and safety of patients with different doses of DAC.Patients with baseline hemoglobin ≥ 60g/L and platelets ≥ 30 × 109/L have a better treatment effect.Age≥ 65 years,platelets<30 X 109/L,and poor response to treatment are unfavorable factors of OS. |
