Oral Decitabine-Cedazuridine: Adverse Effects and Tolerability in a Real-World, Multicenter Retrospective Study

Background

Emerging evidence has shown that oral hypomethylating agents (HMAs) are effective and safe alternatives to intravenous (IV) HMAs for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our objective is to evaluate incidence of adverse effects, including hospitalizations and mortality, in a real-world cohort of patients treated with the oral HMA decitabine-cedazuridine.

Methods

We conducted a multicenter, retrospective study at three U.S. academic medical centers. Eligible patients were 18 years or older, had a history of MDS or AML, and received decitabine-cedazuridine as active or maintenance therapy between January 1, 2016 and June 1, 2023. Patient data was collected by each site and analysis was performed by the lead site. Descriptive statistics were used to evaluate the depth and duration of decitabine-cedazuridine-induced cytopenias and incidence of adverse effects, including hospitalizations and mortality, associated with treatment.

Results:

A total of 64 patients were treated with decitabine-cedazuridine for an average of 4.5 cycles (range 1-22 cycles), with 22 patients (34.4%) requiring a dose reduction. Median age at diagnosis was 74 years. The cohort was predominantly male (60.9%) and white (76.6%), with an average of 1.9 NCI-comorbidities (range 1-9). Of these patients, 58 (90.6%) had myelodysplastic syndromes (MDS), categorized as follows: 15 (25.9%) with low or very low risk, 15 (25.9%) with intermediate risk, 12 (20.7%) with high risk, and 14 (24.1%) with very high risk disease. Additionally, 13 patients (22.4%) had TP53 mutations. Among the 6 patients (9.4%) with AML, 4 (66.7%) had adverse risk disease, with 1 (16.7%) harboring a TP53 mutation.

During treatment with decitabine-cedazuridine, patients experienced an average hemoglobin (Hb) nadir of 6.9 g/dL from a baseline of 9.1 g/dL. The average white blood cell (WBC) count nadir was 2.4 × 10^9/L, down from a baseline of 6.1 × 10^9/L. The average absolute neutrophil count (ANC) nadir was 400 cells/µL, decreased from a baseline of 1600 cells/µL. On average, the ANC nadir occurred 40 days after treatment initiation. The average platelet (Plt) nadir was 32 from a baseline of 109 × 10^9/L.

Significant adverse events while on treatment with decitabine-cedazuridine included severe anemia requiring transfusions (51, 79.7%), neutropenic fever (27, 42.2%), and significant bleeding events (12, 18.8%). Other common adverse events were fatigue (55, 85.9%), nausea (21, 32.8%), vomiting (8, 12.5%), diarrhea (12, 18.8%), myalgia (15, 23.4%), arthralgias (12, 18.8%), and rash (13, 10.3%). While on treatment with decitabine-cedazuridine, 25 patients (39.0%) were hospitalized for neutropenic fever, 5 (7.8%) for bleeding complications, 4 (6.3%) for severe anemia requiring transfusion and 2 (3.1%) for tumor lysis syndrome, respectively. Discontinuation of therapy occurred in 23 patients (35.9%) due to cytopenias and in 21 patients (32.8%) due to treatment failure. 11 patients (17.2%) completed therapy and 3 patients (4.7%) died while on treatment.

Conclusions:

This real-world, multicenter retrospective cohort study demonstrates that oral HMAs induce cytopenias to a similar extent as IV HMAs with comparable rates of hospitalization for adverse effects and similar incidence of neutropenic fever. These findings support those outlined in a recent phase 3 trial of 133 individuals (Garcia-Manero et al. 2023) which concluded that oral HMAs are safe and acceptable alternatives to IV HMA for patients with MDS and AML.

Wilde:Karyopharm: Research Funding; Protagonist: Research Funding; Gilead: Research Funding; Servier: Research Funding. Keiffer:Astellas: Honoraria; Prelude: Research Funding; Sumitomo Pharma America: Research Funding; Schrodinger: Research Funding; Cyteir: Research Funding; AbbVie: Research Funding. Lai:Servier: Other: Advisory board; Daiichi: Other: Advisory board; BMS: Other: Advisory board, Research Funding; AbbVie: Consultancy, Other: Advisory board; Astellas: Consultancy; Rigel: Other: Advisory Board; Genentech: Other: Advisory Board; Jazz: Research Funding. Kasner:Astellas: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CTI: Honoraria; Gilead: Research Funding; ONO: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding.