Comparison Of The Efficacy And Safety Of Decitabine Alone Or Combined With Low-dose Chemotherapy In The Treatment Of Myelodysplastic Syndrome With Excess Blasts

BackgroundMyelodysplastic syndrome(MDS)is a group of heterogeneous myeloid clonal diseases,characterized by a decrease in peripheral blood cells counts and a high risk of transforming into acute myeloid leukemia.Most patients are dependent on blood transfusion,specifically the cases of the elder men and those who have received chemotherapy previously.The cases with increased blasts(MDS-EB)has a poorer prognosis and shorter survival time in comparing to those without.Allogeneic hematopoietic stem cell transplantation(ASCT)is currently the only possible cure for the cases with MDS-EB.However,ASCT has some shortcomings:adequate donors and the patient fit,expensive,and accompanied by many complications after transplantation.Therefore not all of the patients are eligible for ASCT,especially for the elderly patients with many comorbidities.In the past,therapy for middle-high risk MDS patients mainly used AML-like chemotherapy based on cytarabine.But in the last decade,with the advance of research on the pathogenesis of MDS,it has been found that aberrant methylation of genes plays an important role.Hypomethylating agents(including decitabine and azacitidine)can arrest the cell cycles of tumor cells,promote tumor cell apoptosis,and prolong survival of the patients.In previous reports,decitabine alone in the treatment of MDS shown the lower overall response rate and complete remission(CR)rate,a longer course to achieve the best effect,and the shorter effect maintenance time,which restricted the application of the agent.So many scholars explored the application of decitabine in combination with chemotherapy in the treatment of the patients with MDS.But they were mostly limited to one certain chemotherapy regimen.Because of the high heterogeneity of the disease and the high clinical recurrence rate,it is almost impossible to treat with a single regimen alone for all the subtypes of MDS.With the availability of of DEC with different dosage forms in this country,it provided an opportunity to explore the treatment of MDS-EB with different doses of DEC or combined with a variety of conventional chemotherapy.ObjectiveHypomethylating agents such as decitabine and azacitidine are the standard therapy for the patients with higher-risk MDS.Single-drug application demonstrated low CR rate,low effective rate,and short duration of efficacy.This study aims to explore the clinical efficacy and safety of decitabine combined with low-dose chemotherapy regimen in the treatment of newly diagnosed MDS-EB.The factors affecting the efficacy and survival of decitabine in the treatment of the patients with MDS-EB were further assessed.We hope that the data will provide more information for the clinical precise application of decitabine.MethodsCases:A retrospective analysis of 135 patients with MDS-EB according to WHO(2016)classification criteria was performed All of the cases were admitted to the Department of Hematology of the First Affiliated Hospital of Zhengzhou University from April 2016 to December 2019 and received decitabine-based treatment.55 patients who received decitabine alone were included in the single-drug group,and 80 patients who received decitabine combined with other agents were included in the combined group.Clinical data:clinical characteristics including sex,age,blood counts at diagnosis,liver and kidney function at diagnosis,ratio of bone marrow blasts and pathological hematopoiesis at diagnosis and before each course of treatment,mutant genes and their mutation frequency at diagnosis,karyotype,etc.were collected from cases files.During chemotherapy,monitor the patient’s temperature every day,regularly monitor blood counts and biochemical results.Each course of therapy,bone marrow was assessed before initiation of treatment.Minimal residual disease,gene mutation,liver and kidney function and other information were analyzed.Statistical analysis:Chi-square test was used to analyze and compare the clinical characteristics,efficacy and adverse reactions between the two groups.Logistic regression analysis was used to assess the influencing factors of CR rate and ORR.Kaplan-Meier survival curve and Cox multivariate regression were used to analyze the factors affecting the prognosis of the patients.Results1.The clinical characteristics:the proportion of patients aged ≥65 years in the single-drug group was higher than that of the combined group(32.73%vs.15.00%,P=0.015),and the proportion of MDS-EB-2 classification in the combined group was higher than that of the single-drug group(56.25%vs.29.09%,P=0.002),and the proportion of IPS S prognosis stratification(medium risk-2+high risk)in the combined group was higher than that of the single-drug group(62.50%vs.38.18%,P=0.005).There were no significant differences in gender,and blood counts before treatment between the two groups(P>0.05).2.The clinical efficacy:the ORR of the combined group was significantly higher than that of the single-drug group(91.25%vs.74.55%,P=0.009),and the overall efficacy of the combined group was better than that of the single-drug group(Z=-2.374,P=0.018).The patients who received the combination therapy at the time of diagnosis had a higher ORR than DEC therapy alone(97.44%vs.74.55%,P=0.004),a higher CR rate(66.67%vs.36.36%,P=0.003).Comparison between the patients who received the combination therapy at the time of diagnosis and the patients who started combination therapy in the middle somewhere of treatment,the CR rate of the former was higher(66.67%vs.36.59%,P=0.007),no significant difference in ORR between the two groups(97.44%vs.85.37%,P=0.109).3.Survival analysis:there was no difference in PFS between the two groups(median PFS:14.7 months in the combined group vs.14.1 months in the single-drug group,P=0.930),and no difference of OS between the two groups(median OS:38.0 months vs.25.6 month,P=0.263).4.The impact of clinical features on efficacy:Univariate analysis found that patients’ age ≤65 years old may have a higher CR rate(χ2=5.341,P=0.021).Compared with low dose of decitabine based regimen,patients accepted the standard dose of decitabine based regimen achieving a higher CR rate(χ2=6.409,P=0.041).The ORR of the combined group was higher than that of the single-drug group(χ2=6.924,P=0.009),and the ORR of patients without FLT3 mutation was higher(χ2=6.553,P=0.010).The other characteristics had no effect on the efficacy.5.The impact of clinical characteristics on PFS time:The following clinical characteristics as assessed with univariate analysis were favor of PFS:patients achieving CR(χ2=25.600,P=0.000),and patients responding to therapy(χ2=15.439,P=0.000),and patients with lower WPSS risk stratification(χ2=8.430,P=0.015),and patients without chromosome 7 abnormalities(χ2=6.167,P=0.013),and patients without TP53 mutation(χ2=7.389,P=0.007),and patients without SETBP1 mutation(χ2=5.398,P=0.020),and patients without PHF6 mutation(χ2=4.133,P=0.042).Out of all above,patients reaching CR(P=0.000,EXP(B)=0.282,95%CI=0.152-0.522)was an independent favorable factor to the PFS in multivariate analysis.But chromosome 7 abnormalities(P=0.009,EXP(B)=3.093,95%CI=1.322-7.236)and PHF6 mutation(P=0.004,EXP(B)=6.220,95%CI=1.812-21.345)were the independent unfavorable factors of PFS.6.The impact of clinical characteristics on OS time:The following clinical characteristics as assessed with univariate analysis were favor of OS:patients achieving CR(χ2=15.413,P=0.000),and patients responding to therapy(χ2=23.742,P=0.000),and patients without PHF6 mutation(χ2=4.687,P=0.030),and patients without NPMl mutation(χ2=6.195,P=0.013),and patients without TP53 mutations(χ2=4.797,P=0.029).Out of all above,patients reaching CR(P=0.001,EXP(B)=0.237,95%CI=0.101-0.559)was an independent favorable factor to the OS in multivariate analysis.But NPM1 mutation(P=0.009,EXP(B)=7.796,95%CI=1.688-35.995)was the independent unfavorable factor of OS.7.Side effects:The combined group had more severe bone marrow suppression after chemotherapy:the ratio of grade 3 and above neutropenia was higher than that of the single-drug group(93.75%vs.80.00%,χ2=5.858,P=0.015),but the ratio of grade 3 and above anemia was not statistically different from that of the single-drug group(90.00%vs.80.00%χ2=2.695,P=0.101);and the ratio of grade 3 and above thrombocytopenia was not significantly different from that of the single-drug group(92.50%vs.83.64%,χ2=2.593,P=0.107).There were no differences in non-blood system adverse reactions between the two groups.Conclusions1.The combined therapy had higher effective rate than single-drug therapy,and the earlier the combined treatment was performed,the better the curative effect.However,the combination therapy cannot significantly prolong the survival of patients.2.The combined group had more severe neutropenia after chemotherapy.3.The patients with mutations of NPM1 and PHF6 genes or chromosome 7 abnormalities had worse survivals.Cases reached CR after treatment experienced longer survival time.