Azacitidine Switch to Lenalidomide Eradicated the TP53/ CDKN2A Co-Mutated Clone and Induced Long-Term Erythroid Response in Del(5q) MDS

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Managementof progressing Myelodysplastic Syndrome (MDS) represents a very difficult task for clinicians. While targeted therapy with Lenalidomide (LEN) 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 (HR) MDS phase characterized by accumulation of adverse somatic mutations involving the tumor suppressor protein TP53. LEN therapy is not administered to MDS-progressing patients. However, it may be of clinical benefit if LEN could prolong the Azacitidine (AZA)-mediated response that is often complicated by AZA-resistance. We herein present longitudinal data from MDS del(5q) patient that progressed to HR-MDS EB1 with red blood cell transfusion dependency. While administration AZA induced the Complete marrow Response (mCR) the switch to LEN therapy repelled the progression-prone sub clones characterized by adverse somatic mutations and restored hematology parameters.

MDS progression is often associated with the accumulation of genetic aberrations that allow high survival properties for myeloblast outgrowth. In MDS subtype characterized by chromosome 5q deletion, the sensitivity to LEN treatment may lead to red blood cell recovery of transfusion-dependent anemia. LEN therapy induces tumor-specific cell lethality via Cereblon-dependent degradation of haplodeficient proteins encoded within the commonly deleted region at chromosome 5q. In non-del(5q) MDS, LEN sensitivity was documented to enhance the Erythropoietin (EPO) receptor-initiated transcriptional response. Monitoring of cytogenetic aberrations by FISH and nucleotide variants by NGS provides useful data for assessment of clinical outcomes example includes a study showing that non-del(5q) ancestral clones containing a distinct pattern of mutations may expanded over time on LEN. Inversely, loss of LEN sensitivity may lead to re-expansion of del(5q) clone with transient sensitivity to DNA-methylation inhibitor AZA. Despite the promising potential of AZA and LEN therapy to block progression in HR-MDS and to induce complete remission, the AZA-based combinations had similar response rate (ORR) to AZA alone (Sekeres, Othus et al. 2017). The del(5q) MDS patients may progress to HR-MDS, which is indicated for AZA therapy. Since this process has been in some patients associated with mutations of tumor suppressor TP53, the response to AZA may be limited.