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An all-oral combination therapy appeared to show promising activity for patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with acceptable safety, according to results from a small phase I/II study.

At a median follow-up of 10.8 months among 39 patients, the overall response rate was 95% with the combination of decitabine plus cedazuridine (Inqovi) and venetoclax (Venclexta), with a complete response rate of 44%, reported Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

These responses were achieved in a short period of time -- a median of one cycle to reach the first and best response, they noted in .

All patients had at least one treatment-emergent adverse event (TEAE) of any grade, the most common of which included thrombocytopenia (87%), neutropenia (77%), fatigue (59%), edema (36%), and constipation (33%). Grade 3 and 4 TEAEs occurred in 77% and 87% of patients, respectively, with the most common including thrombocytopenia (85%), neutropenia (74%), and febrile neutropenia (21%).

Of the patients in the study, 19 went on to undergo hematopoietic stem-cell transplantation (HSCT), with a median time to HSCT of 3.7 months.

"To the best of our knowledge, this study was the first trial of totally oral therapy for previously untreated patients with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia," Garcia-Manero and team wrote.

"The ability of the combination treatment to achieve quick and deep responses probably enabled eligible patients to proceed to HSCT," they suggested, adding that the outcomes were encouraging -- a median overall survival after HSCT that was not reached, a cumulative incidence of death after HSCT at 12 months of 14%, and a cumulative incidence of relapse after HSCT at 12 months of 15%.

"In patients who could not proceed to HSCT, this combination could also be beneficial in achieving deeper remissions that translated to longer disease-free survival," they added. "However, this hypothesis needs to be assessed in a larger cohort with a longer follow-up time."

In a , Sarit Assouline, MD, of Jewish General Hospital at McGill University in Montreal, noted that "the delivery of this entirely oral regimen and its associated high and rapid response rate might be paradigm changing for patients with high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia who currently receive mainly a hypomethylating agent with associated low rates of response and an inconvenient parenteral administration route."

Potential benefits of this regimen also include reduced travel time, chair time, and injection site reactions, she added.

This enrolled 39 patients with treatment-naive higher-risk MDS or CMML (risk level categorized as intermediate-2 or higher by the International Prognostic Scoring System) from January 2021 to January 2023. Median age was 71 years, and 72% were men.

Of these patients, 32 had MDS with excess blasts, six had CMML, and one had atypical CMML.

In the phase I portion of the trial, treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1 to 5, and variable doses of venetoclax (100-400 mg) on days 1 to 14 in a 28-day cycle. The maximum tolerated dose was not reached, and the recommended phase II dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax 400 mg for 14 days.

While not included in the trial's protocol, Garcia-Manero and colleagues conducted a subgroup analysis applying the International Working Group 2023 response criteria, which showed an overall response rate of 82%, with complete responses in 59%.

Four deaths occurred during the study, two due to sepsis, one due to lung infection, and one of undetermined cause.

"The median follow-up of 10.8 months ... for this study is short, and median overall survival of patients was not reached," Assouline noted. "Before this pioneering regimen can be deployed outside the context of a clinical trial, further dose optimization and controlled, randomized data with survival endpoints will be needed, in addition to dose modification and supportive care approaches."

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