Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemia

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 II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 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 first four 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 azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).

Trial registration: ClinicalTrials.gov NCT01358734.

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.

Study design and therapy regimens. Stratification factors were Eastern Co-operative Oncology Group (ECOG) performance score (0–1 vs. 2) and blood blast level (<1 vs. ≥1×109/L). Randomization in the lenalidomide regime was suspended 11th September 2013 and permanently closed on 15th April 2014 as per Amendment 2 because of the high rate of discontinuation of the study treatment in subjects receiving high-dose continuous lenalidomide. AML: acute myeloid leukemia; PO: per oral administration; SC: subcutaneous injection; SPM: secondary primary malignancies.

Figure 2.

CONSORT study-flow diagram. *Four randomized subjects were not treated because of withdrawal of consent, adverse events, or other reasons, e.g. hospitalization. Percents are based on the intention-to-treat population.

Figure 3.

Kaplan-Meier estimates of 1-year survival. Subjects in the high-dose continuous lenalidomide cohort had a higher hazard of death in 0–4 months than subjects in the azacitidine alone cohort (P=0.002) and subjects in the sequential azacitidine and lenalidomide cohort (P=0.071).