The immunomodulatory drug lenalidomide can induce striking hematologic and cytogenetic responses in patients with myelodysplastic syndromes (MDS), especially among patients whose clonal cells bear a somatic deletion of the long arm of chromosome 5q (del(5q)). Unfortunately, most patients whose cytopenias and burden of clonal cells improve during lenalidomide therapy will relapse within three years — including the approximately 45 percent of patients with lower-risk del(5q) MDS who achieve a complete cytogenetic remission.
In order to better understand the cellular basis for such relapses, a multinational team led by Sten Eirik Jacobsen serially examined flow cytometrically sorted CD34+, CD38+ hematopoietic progenitors and CD34+, CD38 undetectable or low (CD38-/low), and CD90+ multipotent stem cells (a subpopulation previously shown to be Thy1+) from seven patients with del(5q) MDS who developed red blood cell transfusion independence and also experienced a partial or complete cytogenetic response during lenalidomide therapy. Study subjects included two patients in whom del(5q) became undetectable by both conventional G-banded metaphase cytogenetics and fluorescent in situ hybridization (FISH) of whole bone marrow.
The investigators found that despite clearance of most or all of the del(5q)-bearing CD38+ progenitor cells during lenalidomide treatment, a small fraction of del(5q) CD38-/low stem cells remained, lurking undetected by conventional assays just as saprophytic insects can hide in the diseased core of outwardly healthy-appearing timber. These persistent drug-resistant cells served as a nidus for subsequent clonal expansion and karyotypic evolution at the time of clinically apparent disease progression.
It is well recognized that small numbers of therapy-resistant neoplastic cells, regardless of whether they exhibit a stem cell-like phenotype, can presage relapse. Clinicians are accustomed to searching for evidence of these cells — e.g., monitoring for minimal residual disease by flow cytometry in acute lymphoblastic leukemia, or repeatedly testing for persistent BCR-ABL positivity by polymerase chain reaction in chronic myeloid leukemia. The findings of Tehranchi et al. using serial samples from MDS patients extend these observations to a different disease state and complement a large body of clever work on human cancer stem cells using murine models or in vitro assays.
Precisely how that small population of stubborn stem cells managed to evade destruction during lenalidomide treatment remains unclear, in part because the critical mechanisms of action of lenalidomide, in MDS generally and in del(5q) MDS in particular, are still undefined. Several attractive hypotheses for the origin of lenalidomide’s beneficial effects have been put forward, including inhibition of haplodeficient phosphatases encoded on chromosome 5q, T cell or NK cell activation, alteration of immune cell subsets (e.g., Th1 cells), anti-angiogenesis activity, and changes in the cytokine profile. Del(5q) stem cells might escape the lenalidomide poisoning to which other clonal cells are susceptible, either directly (by effluxing the drug or by activating compensatory signaling pathways) or indirectly (by evading an immune response or by “taking cover” in a protective microenvironmental niche). Greater understanding of these details will aid clinicians in designing trials specifically targeting lenalidomide-resistant cells.
In Brief
This study confirms the existence of rare and phenotypically distinct lenalidomide-resistant stem cells in del(5q) MDS and suggests that a small, quiescent fraction of cells may be driving relapse in patients who appear to be responding well to therapy. Monitoring for the presence of these dangerous cells during lenalidomide treatment is straightforward, but determining how to eliminate them will be more challenging.
Competing Interests
Dr. Steensma indicated no relevant conflicts of interest.
