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An all-oral combination of decitabine-cedazuridine (Inqovi) plus venetoclax (Venclexta) was active and safe in older or unfit acute myeloid leukemia (AML) patients deemed ineligible for intensive chemotherapy, results of a phase II trial suggested.

In the ongoing, single-center study, 64% of the 47 evaluable newly diagnosed patients responded to the combination, with complete remissions or complete remissions with incomplete recovery (CR/CRi) in 57%, reported Farhad Ravandi, MD, of MD Anderson Cancer Center in Houston, and colleagues.

In 13 patients with relapsed or refractory disease, 46% responded, including CR/CRi's in all of these patients, according to findings published in .

The safety profile consisted mostly of gastrointestinal side effects, myelosuppression, and infections, which the researchers said were "in line with expectations" for the combination of decitabine-cedazuridine (a chemotherapy plus a cytidine deaminase inhibitor) plus venetoclax (a BCL-inhibitor).

The most common grade ≥3 treatment-emergent adverse events (AEs) were febrile neutropenia (18%), pneumonia (13%), respiratory failure (8%), bacteremia (6%), and sepsis (6%). Three deaths from sepsis, gastrointestinal hemorrhage, and respiratory failure occurred in patients in remission and were considered to be potentially treatment related.

If the current findings are confirmed in a multicenter phase III trial, the regimen "could become the new standard of care" for these older AML patients who are ineligible for intensive chemotherapy, wrote Anna Candoni, MD, of the University of Modena and Reggio Emilia in Italy, in an . "This new total oral regimen would be an additional and very important step forward in the treatment of acute myeloid leukemia in older or unfit patients."

However, Candoni cautioned that the infectious complications observed in the trial were "not negligible."

"It would be very important for future total oral treatment trials to pay special attention to the issues of infectious complications and hematological toxicity, by providing detailed information on the anti-infectious prophylaxis and its preventive effect and on the best use of granulocyte growth factors," she added.

For the AE of myelosuppression, Ravandi and colleagues said that they "strongly encourage the use of triple anti-infective prophylaxis (i.e., antiviral, antibacterial, and mold-active triazole antifungal) to minimize these risks" and noted that "although the optimal duration of venetoclax per cycle has not been determined, these data suggest remissions can be maintained with shorter durations of venetoclax in patients who experience difficulties with myelosuppression."

Oral venetoclax (400 mg) was given for 21 to 28 days of 28-day cycles, but a reduction in the duration of venetoclax administration was needed for most patients beyond the first cycle following remission. Beyond cycle five, most patients were receiving either 5 or 7 days of venetoclax per cycle. (Decitabine (35 mg)/cedazuridine (100 mg) was given for the first 5 days of each cycle.)

The enrolled 62 patients with newly diagnosed AML who were not eligible for intensive chemotherapy or with relapsed or refractory AML. Reasons patients could not receive chemotherapy included age (≥75 years), performance status (ECOG 2-3), or major comorbidities.

The cohort "was representative of an older acute myeloid leukemia population at high risk of poor outcomes," Ravandi and colleagues observed.

Participants had a median age of 78 years, and 58% were men, while 85% were white, 6% were Black, and 3% were Asian. Patients had a number of unfavorable prognostic factors: 77% had an adverse European LeukemiaNet 2022 risk classification, 39% previously had myelodysplastic syndromes, 19% previously failed treatment with a hypomethylating agent, 16% had therapy-related AML, and 18% had TP53 mutations.

With a median follow-up of 18.3 months, median overall survival (OS) reached 11.5 months in the newly diagnosed cohort. Among those with CR/CRi, the relapse-free survival reached 12 months and median duration of response was 13.2 months.

In the relapsed or refractory group, median OS was 7.2 months, relapse-free survival was 4.6 months, and duration of response was 5.4 months.

The main trial limitation was that it was done at a single, large academic center with a relatively small number of patients, particularly in the relapsed or refractory cohort, Ravandi and co-authors acknowledged.

But they noted that the frontline results in this study were similar to those seen with other venetoclax-based regimens, such as azacitidine plus venetoclax in the VIALE-A trial. That study established parenteral azacitidine plus venetoclax as the new standard of care in older or unfit patients, with a reported composite complete remission rate of 66.4% and a median OS of 14.7 months.

"Compared with parenteral regimens, this fully oral regimen has the potential advantages of less hospital visits and shorter inpatient stays. In turn, this could lead to improved quality of life and preservation of functional status in older patients with acute myeloid leukemia or those with substantial comorbidities," Ravandi's group stated.

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