Date Published: February 12, 2008
Publisher: Public Library of Science
Author(s): Jerald Radich
Abstract: The author reviews key research on the biology underlying treatment response in myelodysplasia, including a new study inPLoS Medicine.
Partial Text: Myelodysplasia (MDS) is a clonal hematopoietic malignancy as stubborn in revealing its pathogenesis as it is in responding to treatment. The disease presents with cytopenia of any or all of the three hematopoietic lineages (red blood cells, platelets, and white blood cells), manifesting clinically as fatigue, bleeding, and infectious disorders. While the disease occurs in only five per 100,000 people, its incidence rises steeply with age, reaching about 20–40 per 100,000 at age 70 years and beyond. Thus, as the population ages, the impact of MDS on the health care system will grow.
The diagnosis of MDS requires the bone marrow evidence of dysplasia (abnormal appearing cells) in at least one of the hematopoietic cell lineages. Approximately 50% of cases will have chromosomal abnormalities. The appearance of bone marrow “blasts” (immature progenitor cells) can be normal in many cases, if the blasts represent less than 5% of total bone marrow cells; increasing blasts herald a progression towards AML. Sensitive flow cytometric analysis of cell surface antigens often shows a population of cells displaying an abnormal constellation of antigens, further evidence of disturbed hematopoiesis.
The biology driving MDS has been elusive, and has greatly undermined attempts to devise rational treatment options. Any biological model of MDS must explain several features of the disease: The paradox that early in disease patients appear to have increased proliferation and apoptosis; the variable natural history of disease, from progressive cytopenia to progression to AML; and the potential contribution of the stromal environment to disease maintenance and progression.
The quest for effective therapy for MDS has been disappointing. Secondary AML is especially problematic, since at this stage of MDS, the reserve of normal hematopoietic cells is marginal, and thus after chemotherapy, patients suffer from prolonged cytopenias since they lack the ability to muster normal hematopoiesis. Attempts to adjust and apply conventional AML therapy to MDS (e.g, low-dose Ara-C) have given uninspiring results.
The recent excitement over modest response rates reflects long-standing frustration (if not desperation) in treating MDS. How do we find better therapies? A fundamental building block would be the understanding of why certain therapies work in a subset of patients. In this light, the work by Azra Raza and colleagues in this issue of PLoS Medicine is a strong step towards understanding the biology underlying treatment response in MDS . The authors studied the gene expression signature associated with lenalidomide response in low-risk MDS. They first established the response signature in low-risk non-5q- MDS patients, and used a validation set of 5q- and non-5q-patients. They found that the gene expression response signature was enriched in genes involved in erythroid differentiation; as a biological confirmation, the authors demonstrate that the application of lenalidomide to primary non-MDS CD34+ cells promoted erythroid differentiation.
The treatment of MDS is still distinctly suboptimal. New agents have brightened the picture, and studies such as that of Raza et al. promise to focus therapy on those patients who will most likely benefit. Nonetheless, substantial obstacles still confront us. We have little understanding of why MDS is age related; why patients progress to AML, and how to predict or prevent it; the relative roles of the MDS clonal cell and the stromal environment in determining response and progression; and how to add combinations of agents to better treat MDS. There is much to do, and the clock is running: we are all getting older, and MDS is waiting.