Phase II randomized study of high-dose LEN and AZA in newly-diagnosed AML

This month, in Haematologica, Bruno C. Medeiros from Stanford University School of Medicine, Stanford, CA, USA, and colleagues published results of their randomized open-label phase II study (NCT01358734) which compared the safety and efficacy of continuous high-dose lenalidomide (LEN), sequential azacitidine (AZA) and LEN or AZA alone in patients aged ≥ 65 years with newly diagnosed Acute Myeloid Leukemia (AML).

Overall, 88 newly diagnosed AML patients were randomized to receive either high-dose continuous LEN (n = 15, median age = 80 years), sequential AZA and LEN (n = 39, median age = 76 years) or AZA alone (n = 34, median age 75 years).

Key Findings:

• All patients discontinued treatment in the high-dose LEN cohort due to adverse events (AEs [n = 4]), death (n = 3), progressive disease (n = 5), consent withdrawal (n = 6) and other reasons (n = 2)
• Thirty-seven patients in the sequential AZA plus LEN cohort discontinued treatment due to AEs (n = 7), lack of efficacy (n = 1), consent withdrawal (n = 6), death (n = 7), progressive disease (n = 11) and other reasons (n = 5)
• Twenty-nine patients in the AZA alone cohort discontinued treatment due to AEs (n = 3), lack of efficacy (n = 3), consent withdrawal (n = 3), death (n = 2), progressive disease (n = 13), non-compliance with study drug (n = 1) and other reasons (n = 4)
• One-year survival
  • High-dose LEN = 21% (95% CI, 0, 43%)
  • Sequential AZA and LEN = 44% (95% CI, 28, 60%)
  • AZA alone = 52% (95% CI, 35, 70%)
• Hazard of death in the first four-months post randomization
  • Patients in the high-dose LEN cohort had a higher hazard of death than patients in the AZA cohort; Hazard Ratio (HR) = 5.73, P = 0.002
  • Patients in the high-dose LEN cohort had a higher hazard of death than patients in the sequential AZA plus LEN cohort; HR = 2.19, P = 0.071
  • Patients in the sequential AZA plus LEN cohort had a higher hazard of death than patients in the AZA cohort; HR = 2.51, P = 0.081

In summary, high-dose continuous LEN was not well tolerated and led to a high rate of discontinuation and an increased hazard of death compared to sequential AZA and LEN or AZA alone in patients aged ≥ 65 years with newly diagnosed AML.

Medeiros et al., suggested that based on the early HR for death observed in their study, their data does not support the use of continuous high-dose LEN or sequential AZA plus LEN over AZA alone in patients aged ≥ 65 years with newly diagnosed AML.   

Abstract

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase-2 trial compared safety and efficacy of three therapeutic strategies in persons ≥65 years with newly-diagnosed acute myeloid leukemia: (1) continuous high-dose lenalidomide (N=15); (2) sequential azacitidine and lenalidomide (N=39); and (3) azacitidine (N=34) only. The efficacy endpoint was 1-year survival. Median age was 76 years (range, 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%), adverse cytogenetics. One-year survival was 21% (95% confidence interval, 0, 43%) with high-dose lenalidomide, 44% (28, 60%) with sequential azacitidine and lenalidomide, and 52% (35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early-therapy discontinuations. Hazard of death in the 1st 4 months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential lenalidomide and azacitidine over the conventional dose and schedule of azacitidine only in persons aged ≥65 years with newly-diagnosed acute myeloid leukemia. The study is registered at ClinicalTrials.gov (NCT01358734).