Azacitidine Switch to Lenalidomide Eradicated the TP53/ CDKN2A Co-Mutated Clone and Induced Long-Term Erythroid Response in Del(5q) MDS
Abstract
Management of progressing Myelodysplastic Syndrome (MDS) represents a very difficult task for clinicians. While targeted therapy with lenalidomide is administered at low-risk phase and is primarily effective in patients with deletion of chromosome 5q, it is largely ineffective upon progression at high-risk MDS phase characterized by accumulation of adverse somatic mutations involving the tumor suppressor protein TP53.
We herein report a 68-year old male MDS del(5q) patient that progressed to higher risk MDS EB1 with red blood cell transfusion dependency. Administration of 17 cycles of azacitidine inhibited further progression by stabilizing disease with Complete Marrow Response (mCR) without hematology improvement.
The patient despite of reaching mCR on AZA further increased the allelic burden of gene mutations in the Cyclin- Dependent Kinase Inhibitor 2A, CDKN2A at residue D74A, Tumor Suppressor TP53 (K373R+T377P), and the splicing factor ZRSR2 (P13T). Based on the fact that the patient reached lower blast count on AZA but was accumulating adverse mutations we decided to switch the therapy into lenalidomide.
The lenalidomide therapy repelled the progression-prone subclones characterized by the somatic mutations, fully normalized blood counts, and produced a longlasting remission. Our data suggest that the del(5q) patient progressing to high risk MDS could be treated by azacitidine to block MDS progression, however, only additional therapeutic line of lenalidomide was capable to suppress the progression-prone clones characterized by unfavorable mutations involving also TP53.