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.

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

Simple Summary Anticancer nucleoside analogs are promising treatments that often result in damaging toxicities and therefore ineffective treatment. Mechanisms of this are not well-researched, but cellular nucleoside transport research in mice might provide additional insight given transport’s role in mammalian hematopoiesis. Cellular nucleoside transport is a notable component of mammalian hematopoiesis due to how mutations within it relate to hematological abnormities. This review encompasses nucleoside transporters, focusing on their inherent properties, hematopoietic role, and their interplay in nucleoside drug treatment side effects. We then propose potential mechanisms to explain nucleoside transport involvement in blood disorders. Finally, we point out and advocate for future research areas that would improve therapeutic outcomes for patients taking nucleoside analog therapies. Abstract Anticancer nucleoside analogs produce adverse, and at times, dose-limiting hematological toxicities that can compromise treatment efficacy, yet the mechanisms of such toxicities are poorly understood. Recently, cellular nucleoside transport has been implicated in normal blood cell formation with studies from nucleoside transporter-deficient mice providing additional insights into the regulation of mammalian hematopoiesis. Furthermore, several idiopathic human genetic disorders have revealed nucleoside transport as an important component of mammalian hematopoiesis because mutations in individual nucleoside transporter genes are linked to various hematological abnormalities, including anemia. Here, we review recent developments in nucleoside transporters, including their transport characteristics, their role in the regulation of hematopoiesis, and their potential involvement in the occurrence of adverse hematological side effects due to nucleoside drug treatment. Furthermore, we discuss the putative mechanisms by which aberrant nucleoside transport may contribute to hematological abnormalities and identify the knowledge gaps where future research may positively impact treatment outcomes for patients undergoing various nucleoside analog therapies.

https://www.mdpi.com/2072-6694/14/13/3113/pdf?version=1656390325

Solute Carrier Nucleoside Transporters in Hematopoiesis and Hematological Drug Toxicities: A Perspective

Decitabine is a hypomethylating drug that is used to treat myelodysplastic syndrome (MDS) at a recommended dose and schedule (20 mg/m2 per day, for 5 consecutive days). However, due to its relatively high incidence of side effects and its effects on neoplastic cells, many studies have begun to explore the clinical application of a low dose of decitabine for treating MDS. In this retrospective study, we examined the effects of a very-low-dose decitabine schedule for treating MDS. A total of 13 patients diagnosed with de novo MDS received a schedule of intravenous decitabine administration at 6 mg/m2 per day for 7 days, repeated every 4 weeks. The complete response rate was 30.8%, and the overall response rate was 69.2%. In patients with complete remission, the median time to granulocyte recovery greater than 0.5 × 109/L during complete remission (CR) was 15 days. In patients with remission, the median time to granulocyte recovery greater than 0.5 × 109/L was 10.5 days. The 1-year survival rate was 72.7% and the median survival was 28.0 months. In summary, we demonstrated that a very-low-dose decitabine schedule has an appreciable response and survival rate, as well as appreciable tolerance and medical compliance for treating MDS.

Very-low-dose decitabine treatment for patients with intermediate- or high-risk myelodysplastic syndrome: a retrospective analysis of thirteen cases

We retrospectively studied 133 myelodysplastic syndrome patients receiving decitabine during January 2009 and September 2017. The dose of 15 mg/m2/d (n = 83) and 20 mg/m2/d (n = 50) had comparable overall response rates (ORR) (51.8% vs. 52.00%) and complete remission rate (CRR) (15.66% vs. 22.00%). The 15 mg/m2/d group had a lower incidence of grade 3/4 neutropenia (60.24% vs. 88.00%, p < .05) and thrombocytopenia (65.06% vs. 88.00%, p < .05). The 15 mg/m2/d group had a longer median overall survival (OS) (21.60 months vs. 15.23 months, p = .02). The same results were seen in refractory anemia with excess blasts (RAEB) patients: The 15 mg/m2/d group also had comparable ORR, CRR, decreased hematological toxicities and longer OS. Further analysis suggested that survival benefit of 15 mg/m2/d group was mainly in those patients with lower risk stratification. In conclusion, 15 mg/m2/d decitabine is associated with a lower incidence of hematological toxicities and longer OS and may be more suitable for patients with relatively lower risk.

Fangjing Shi

Papers

Decitabine for myelodysplastic syndromes: dose comparison in a real world clinical setting.