Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…The clinical efficacy of lenalidomide has been explored as either low-dose or high-dose lenalidomide as monotherapy 50-54 and in combination with azacitidine 55,56 for both newly diagnosed and relapsed/refractory AML. Overall, these clinical trials were somewhat disappointing with CRR as low as 11%–20% and remission duration below 5–7 months.…”

Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients

“…1 High-dose lenalidomide is effective in AML, alone 2,3 or in combination with azacitidine. [4][5][6] Biomarkers that are able to predict response to lenalidomide would be extremely useful.…”

“…Bone marrow evaluation was performed after 1, 2, 4 and 6 cycles. Responding patients experiencing a non-hematological toxicity 42 WHO received reduced courses (lenalidomide (10 mg) once daily (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and cytarabine (10 mg, subcutaneously) twice daily (days 1-10)). All patients were hospitalized for the first cycle.…”

“…CR rate was 28%, with 4 patients alive and disease-free after 88 weeks of median follow-up. 4,5 Ramsingh et al 6 reported on a prospective trial combining concomitant HDL and azacitidine (days 1-5 three-dose cohorts: 25, 50, 75 mg/m 2 ), followed by maintenance therapy with lenalidomide (10 mg) and azacitidine (75 mg/m 2 , up to 1 2 cycles). CR/CRi rate was 30.8%.…”

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR

“…In a phase I/II study that evaluated sequential therapy with 5-azacytidine followed by lenalidomide in older patients with previously untreated AML (n=18), the regimen resulted in a CR in 44% of patients (including CR with incomplete recovery of blood counts). 165 The median duration of response was approximately 6 months. The maximum tolerated dose of the regimen was not reached in this study.…”