Oral Hypomethylating Agents Show Comparable Hematologic Toxicity to Intravenous Therapy in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia

Clinical Summary:

• Design/Population: This multicenter retrospective study evaluated hematologic toxicity and adverse events in patients with myelodysplastic syndromes or acute myeloid leukemia treated with oral hypomethylating agents, including patients who received decitabine/cedazuridine and azacitidine. An intrapatient analysis compared oral and intravenous treatment who received both formulations. 
• Key Outcomes: Oral and intravenous hypomethylating agents produced comparable reductions in hemoglobin, absolute neutrophil count, and platelet count, with no statistically significant differences between treatment routes. Hospitalization and neutropenic fever were numerically less frequent during oral treatment.
• Clinical Relevance: These findings suggest that oral hypomethylating agents may provide a practical alternative to intravenous administration without substantial differences in hematologic toxicity. However, the small study population and retrospective design limit definitive conclusions regarding comparative safety. 

Results from a multicenter retrospective study demonstrated no statistically significant differences in hematologic toxicity between oral and intravenous hypomethylating agents in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), supporting oral formulations as a potential alternative to IV treatment.

“Hypomethylating agents are a cornerstone of therapy for MDS and AML,” stated Reed Alexander Firestone, MD, Thomas Jefferson University, Philadelphia, Pennsylvania, and coauthors. “Oral formulations offer an alternative to intravenous administration, but comparative real-world toxicity data remain limited.”

This retrospective analysis included 33 patients with MDS or AML who received oral decitabine/cedazuridine or oral azacitidine between January 2016 and June 2023, across 3 academic cancer centers. Among these patients, 20 had also received intravenous hypomethylating agents and were included in an intrapatient paired analysis, allowing investigators to compare hematologic toxicity between treatment routes within the same individuals. 

Cytopenias were assessed using absolute blood count values and percentage changes from baseline to the lowest recorded value during treatment. Intrapatient comparisons were performed using Wilcoxon signed-rank tests, while clinically significant adverse events were evaluated descriptively.

Among the 20 patients in the paired analysis, the median reduction in hemoglobin was 20.8% in patients who received oral therapy and 20.5% in patients who received intravenous therapy (P = 0.60). The median decrease in absolute neutrophil count was 95.9% and 97.3%, respectively (P = 0.63). Similarly, median platelet count reduction was 81.9% in patients who received oral therapy and 88.6% in patients who received intravenous therapy (P = 0.06). Although platelet counts declined numerically less during oral treatment, the difference did not reach statistical significance. 

Hospitalizations occurred in 60.6% of patients during oral therapy and 70% of patients during intravenous therapy. Neutropenic fever was reported in 51.5% of patients and 60% of patients, respectively. Although hospitalization and neutropenic fever were numerically less frequent during oral treatment, the study did not establish whether these differences were statistically significant.

“Oral hypomethylating agents demonstrated cytopenia severity and adverse event rates comparable to intravenous hypomethylating agents, supporting oral formulations as a practical alternative in patients with MDS and AML,” concluded Dr Firestone et al. “Although encouraging, these findings should be interpreted in the context of the retrospective design and modest sample size.” 

Source:

Firestone RA, Palecki J, Rosenberg M, et al. Oral versus intravenous hypomethylating agents in myelodysplastic syndromes and acute myeloid leukemia: A multicenter real-world toxicity comparison. Acta Haematol. Published online: October 7, 2026. doi: 10.1159/aha/abkag015