Sequential Azacitidine and Lenalidomide for Patients with Relapsed and Refractory Acute Myeloid Leukemia: Clinical Results and Predictive Modeling Using Computational Analysis
82 Pages Posted: 4 Jan 2019More...
Background: Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in R/R AML, with the intention of applying sophisticated methods to predict responders.
Methods: Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on understood mechanisms of azacitidine and lenalidomide in the setting of each patients' disease.
Findings: Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively.
Interpretation: Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.
Funding Statement: Celgene
Declaration of Interests: DAP is a consultant for Celgene and has received research funding from Celgene. TA, SV, NKS, LD and CRC are or have been employed by or received research funding from Cellworks.
Ethics Approval Statement: The study was approved by the institutional review board; all patients provided written informed consent prior to any procedures, and the study was performed in accordance with the Declaration of Helsinki.
Keywords: acute myeloid leukemia, myelodysplastic syndrome, relapsed, azacitidine, lenalidomide, phase 2
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