Comparison of Hypomethylator Monotherapy with Hypomethylator plus Chemotherapy for Intermediate/High-Risk MDS or AML: A Meta-Analysis

Aim: This meta-analysis aimed to compare the efficacy, survival benefit and safety of hypomethylating agents (HMA) monotherapy and combination 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. Studies on HMA combination therapy were further divided into two subgroups according to the intensity of combined chemotherapy. Meanwhile, subgroups with similar patients' baseline characteristics were selected for further analysis. Complete response (CR) rate, overall response (ORR) rate, two-year overall survival (OS) rate, one-month and 24-month death rate and the proportion of adverse events (AE) were pooled and compared. Results: 21 RCT or cohort studies with 1764 patients (1266 patients for monotherapy group and 498 patients for HMA combination group) were selected for meta-analysis. For the pooled data, the age of patients was significantly younger and the percentage of patients with favorable/intermediate cytogenetic risk was significantly higher in the HMA combination group than that in the HMA monotherapy group. Combination therapy group had a significantly higher CR and ORR rate (55% vs 22%, P=0.000 for CR and 67% vs 42%, P=0.000 for ORR), and a higher two-year OS rate (37% vs 21%, P=0.000). However, the incidence of infection and gastrointestinal disorder was significantly higher (51% vs 23% for infection, P=0.000; 21% vs 0% for gastrointestinal disorder, P=0.000) in combination group. In subgroups with different intensity of combined chemotherapy, all baseline characteristics were compatible except that the percentage of patients with favorable/intermediate cytogenetic risk was significantly lower (63% vs 88%, P=0.000) in the HMA + high-intensity chemotherapy subgroup, and this group presented with a lower CR and ORR rate (46% vs 65% for CR, P=0.000; 57% vs 79% for ORR, P=0.000), but a compatible two-month to 24-month death rate compared with HMA + low-intensity chemotherapy subgroup (9% vs 14% for 2-month death rate, P=0.060; 58% vs 65% for 24-month death rate, P=0.242). In subgroup with similar patients' baseline characteristics, 208 and 205 patients were included in combination group and HMA monotherapy group, respectively. Although combination group had a significantly higher CR rate (62% vs 24%, P=0.000) and ORR rate (68% vs 48%, P=0.000), it finally had a lower two-year OS (30% vs 45%, P=0.001) compared with monotherapy group, and the death rate was significantly higher since the ninth month in combination therapy group than that in the monotherapy group (42% vs 31%, P=0.032). In this subgroup, patients with HMA+ high-intensity chemotherapy had a compatible CR, ORR and 1.5-year OS rate as compared with baseline-compatible patients with HMA + low-intensity chemotherapy. Conclusions: HMA combined with chemotherapy could increase CR rate and ORR rate in all patients. HMA combined with high-intensity chemotherapy can rescue the 2-year OS with less favorable cytogenetic stratification to some extent. For patients with similar older age and risk stratification, combination therapy even had a lower long-term OS regardless of the intensity of combined chemotherapy.