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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.
