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ATLANTA -- A dual oral regimen for older patients with untreated acute myeloid leukemia (AML) failed to improve survival as compared with a single drug in a randomized trial reported here.

The combination of sapacitabine and decitabine led to a median overall survival of 5.9 months in patients ≥70 versus 5.7 months with decitabine alone. Results were similar for all secondary endpoints, as well.

A subgroup analysis suggested the combination might have greater activity in patients with a baseline white blood-cell count (WBC) <10,000, Hagop Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported here at the meeting.

"The stratified subgroup analyses suggested that in older patients without aggressive disease the addition of sapacitabine might potentially improve the outcome, with a chance for better median survival and a higher complete response rate," Kantarjian said. "We think this hypothesis is plausible and reflects the heterogeneity of AML, where patients with more aggressive disease need more intensive therapy but for patients with lower-risk, less aggressive disease, the addition of sapacitabine could improve the outcome."

"Sapacitabine is an oral agent, making it more convenient, and it could be administered as outpatient therapy. The statistical robustness of the subgroup results is currently being investigated."

With almost 500 patients, the negative randomized trial was by far the largest of several studies evaluating regimens for older patients with AML. Collectively, the results were mixed:

• Long-term follow-up for a phase I/II dose-escalation study of venetoclax (Venclexta) and low-dose cytarabine showed a median overall survival of 11.4 months in 61 patients.
• A phase II study of fixed-dose liposomal cytarabine/daunorubicin (CPX-351, Vyxeos) produced complete responses in 20% to 53% of patients in different dose groups.
• Maintenance therapy with the anti-KIR antibody lirilumab failed to improve survival in older AML patients in complete remission.

Sapacitabine/Decitabine

In preliminary trials, sapacitabine demonstrated single-agent activity in AML and myelodysplastic syndromes. The agent exhibited a safety profile suitable for long-term administration, said Kantarjian. An evaluation of the sapacitabine-decitabine combination in older patients with AML led to complete responses in 24% and a median survival of 7.7 months.

The multicenter randomized, open-label trial of the combination included 482 patients who were either not candidates for or had refused intensive therapy. They were randomized to decitabine alone or to the combination, administered in alternating 8-week cycles. The primary endpoint was overall survival, analyzed after 444 deaths.

The study population had a median age of 77 to 78, and more than 90% of patients qualified for the trial because their physicians recommended low-intensity treatment.

In addition to the lack of difference in overall survival, the two randomized groups had similar rates of complete response (17% for the combination, 11% for decitabine alone), 1-year survival (34%, 35%), number of transfusions of red blood cells and platelets per week (1.2, 1.1), median number of hospital days (15, 14), percentage of days alive out off hospital during the first year after randomization (88%, 84%).

The subgroup analysis showed that patients with WBC <10,000 (66% of the study population) had a median survival of 8.0 months with the combination versus 5.8 months with decitabine alone, which represented a trend toward improvement (HR 0.84, 95% CI 0.66 to 1.06, P=0.1446). Rates of complete response in the subgroup were 21% with the combination and 8.6% with decitabine alone (P=0.0017), and the combination achieved durable responses, Kantarjian said.

Additional Studies

The rationale for came from the recognition that older patients with AML often receive only palliative treatment, said Andrew Wei, MD, of Monash University in Melbourne, Australia. Low-dose cytarabine is often used in patients who cannot tolerate intensive treatment, but the drug produces objective responses in fewer than 20% of patients.

Wei and colleagues previously reported a complete response rate >60% for the combination of venetoclax and low-dose cytarabine in older AML patients (median age 74) ineligible for intensive therapy. He updated the findings with a survival analysis, performed after all patients had been followed for more than a year.

The patients had a 1-year overall survival of 45.9%. The combination led to complete responses in 38 of 61 patients, and the median duration of complete response was 13.2 months. Among patients who achieved complete response, the median survival had yet to be reached, but was at least 16.9 months. Complete response was associated with a 12-month overall survival of 100%.

The results provided the basis for an ongoing phase III pivotal trial, said Wei.

The involved 55 patients treated with one of three doses of the combination (1.0 mg cytarabine/0.44 mg daunorubicin per unit). All patients had a high risk of induction mortality, defined as age ≥60 plus one additional risk factor or age <60 and two clinical risk factors. CPX-351 led to complete responses in three of 15 (20%) patients treated at the lowest dose, 10 of 24 (42%) treated with the intermediate dose, and eight of 15 (53%) patients treated with the highest dose, reported Gautam Borthakur, MD, of MD Anderson Cancer Center.

Median overall survival was 3.6 months with the lowest dose of CPX-351 (50 U/m²), 8.2 months at the intermediate dose (75 U/m²), and 6.1 months at the highest dose (100 U/m²). Relapse-free survival ranged between 3.0 and 5.8 months, with the best results occurring in patients who received the intermediate dose.

The results added to previously favorable findings from studies of CPX-351, including a large of older patients with untreated AML. In the randomized trial, CPX-351 demonstrated superiority versus a standard 3 + 7 regimen with respect to complete response, overall survival, and event-free survival.

The monoclonal antibody lirilumab is a checkpoint inhibitor targets killer immunoglobulin-like receptors (KIRs). The drug blocks the NK cell inhibitor receptor and prevents interaction with HLA-C class I molecules and potentiate NK cell killing, said Norbert Vey, MD, of Paoli-Calmettes Institute, in Marseilles, France.

Two different doses of lirilumab were evaluated as maintenance therapy in a randomized, placebo-controlled, phase II trial involving 153 patients (median age 70) with AML in complete response. The primary endpoint was leukemia-free survival. Neither dose of the antibody improved survival compared with placebo (13.9 months versus 17.6 months with low-dose lirilumab and 6.7 months with the higher dose).