The Comparison of Hypomethylating Agents (HMA) Monotherapy with HMA Combined with Intensive Chemotherapy for Intermediate / High-Risk MDS or AML
Authors: Ji Jiang , Wang Zhao , Han Bing 
Published: November 2019

Introduction: Hypomethylating agents (HMA) azacitidine and decitabine were the first-line therapy for intermediate/ higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients unsuitable for hematopoietic cell transplantation (HSCT). HMA combined with chemotherapy was recently used to achieve for a better outcome. However, few studies were carried out to compare the HMA monotherapy to the HMA and chemotherapy combination therapy. This meta-analysis aimed to compare the efficacy, survival benefit and safety of HMA monotherapy and combination therapy (with chemotherapy) in patients with intermediate/high-risk MDS or AML.
Methods: Related articles published between January 2009 and April 2019 were selected and patients were separated as monotherapy group and combination group for meta-analysis. To further eliminate the potential influence of differences in patients' baseline characteristic between the two groups, subgroups with similar patients' baseline characteristics were selected for further analysis. Complete response (CR) rate, overall response (ORR) rate, 1-year overall survival (OS) rate, 1-month death rate and the proportion of adverse event (AE) were pooled and compared.
Results: 13 RCT or cohort studies with 997 patients (790 in monotherapy group, 207 in HMA combination group) were selected for meta-analysis. For the pooled data, there was no significant difference in sex and cytogenetic risk between the 2 groups, but the age of combination therapy group was significantly younger than that of the monotherapy group (61.3±13.2 year-old vs 67.7±10.2 year-old, p=0.000). The CR and ORR rate were significantly higher in combination therapy group (53% vs 17%, p=0.000 for CR and 67% vs 44%, p=0.000 for ORR). However, the 1-year OS (56% for combination therapy vs 51% for HMA monotherapy group, p=0.282) and 1-month death rate (5% for combination therapy vs 4% for HMA monotherapy group, p=0.965) were similar between the two groups. The incidence of CTCAE grade 3-4 infection and bleeding were significantly higher (infection: 50% for combination therapy vs 25.7% for monotherapy group, p=0.003; bleeding: 27.5%% for combination therapy vs 7.8% for monotherapy group, p=0.004) in combination group. In subgroup analysis, 117 and 179 patients were included in combination group and HMA monotherapy group, respectively. There was no significant difference in age (69.5±4.6 vs 69.0±6.8 years old, p=0.451) and proportion of favorable/intermediate cytogenetic risk (62% vs 71%, p=0.114) between the two groups, but a significantly lower proportion of male was found in combination therapy group (57% vs 74%, p=0.003). Although combination group had a higher CR rate (49% vs 17%, p=0.000), it had similar ORR rate (58% vs 49%, p=0.140) to monotherapy group. Meanwhile, combination therapy came with higher 1-month death rate (12% vs 3%, p=0.008) and lower 1-year OS (54% vs 68%, p=0.013) compared with monotherapy group.
Conclusions: HMA combined with chemotherapy could increase CR rate in all patients and ORR rate in younger patients, but could not improve OS. For patients with similar older age, combination therapy could result in higher 1-month death rate and less 1-year OS.

Disclosures
No relevant conflicts of interest to declare.