Lenalidomide is an effective new agent for the treatment of patients with myelodysplastic syndrome (MDS), an acquired hematopoietic disorder characterized by ineffective blood cell production and a predisposition to the development of leukemia. Patients with an interstitial deletion of Chromosome 5q have a high rate of response to lenalidomide, but most MDS patients lack this deletion. Approximately 25% of patients without 5q deletions also benefit from lenalidomide therapy, but response in these patients cannot be predicted by any currently available diagnostic assays. The aim of this study was to develop a method to predict lenalidomide response in order to avoid unnecessary toxicity in patients unlikely to benefit from treatment.
Methods and Findings
Using gene expression profiling, we identified a molecular signature that predicts lenalidomide response. The signature was defined in a set of 16 pretreatment bone marrow aspirates from MDS patients without 5q deletions, and validated in an independent set of 26 samples. The response signature consisted of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response. Consistent with this observation, treatment with lenalidomide promoted erythroid differentiation of primary hematopoietic progenitor cells grown in vitro.
These studies indicate that lenalidomide-responsive patients have a defect in erythroid differentiation, and suggest a strategy for a clinical test to predict patients most likely to respond to the drug. The experiments further suggest that the efficacy of lenalidomide, whose mechanism of action in MDS is unknown, may be due to its ability to induce erythroid differentiation.
Using gene expression profiling, Azra Raza and colleagues identified a molecular signature that predicts response to lenalidomide in patients without Chromosome 5q deletions, which suggests that these patients have a defect in erythroid differentiation.
Myelodysplastic syndrome (MDS) is a group of disorders in which the bone marrow (the spongy material found inside bones) does not make enough healthy blood cells. Normally, immature cells in the bone marrow called hematopoietic stem cells mature (differentiate) into three types of blood cells: red blood cells (which carry oxygen around the body; people with too few red blood cells are “anemic”), white blood cells (which fight off infections), and platelets (which prevent bleeding by forming blood clots). In patients with MDS, the production of these mature cell types is defective. In addition, immature cells called leukemic blasts sometimes accumulate in the bone marrow and blood. Thus, although MDS itself is not a type of cancer, it often develops into leukemia (blood cancer). The cause of most cases of MDS, which affects mainly elderly people, is not known. Its symptoms include tiredness and breathlessness (signs of anemia), frequent infections, and easy bruising or bleeding. Patients are usually given supportive care to relieve their symptoms (for example, blood transfusions to top up their red blood cells). Chemotherapy can sometimes delay the progression of MDS to leukemia and a few patients can be helped with bone marrow transplantation.
Why Was This Study Done?
Recently, researchers have discovered that some people with MDS respond very well to a drug called lenalidomide. Three-quarters of patients whose MDS is characterized by the loss of a small part of Chromosome 5 need fewer blood transfusions after being given lenalidomide but only a quarter of people without this chromosomal defect respond to the drug. Unfortunately, most patients with MDS do not have this chromosome abnormality and there is no way to predict which of these patients are likely to respond to lenalidomide. Lenalidomide is a toxic drug that damages white blood cells and platelets, so it is important not to give it to people who might not benefit. In this study, the researchers have used gene expression profiling (a technique that catalogs all the genes expressed by a cell) to try to develop a way of predicting who will respond to lenalidomide
What Did the Researchers Do and Find?
The researchers obtained pre-treatment bone marrow samples from patients enrolled in two clinical trials of lenalidomide and compared the gene expression profiles of the bone marrow cells from the patients who subsequently responded to the drug with the profiles of cells from nonresponding patients. In all, 47 genes were more highly expressed in nonresponders than in responders. The researchers then asked whether the expression of any gene sets (collections of genes that code for proteins that work in a single pathway) was greater in the nonresponders than in the responders. This analysis revealed a “signature” of lenalidomide response consisting of a set of genes normally expressed during the differentiation of red blood cells (an “erythroid differentiation signature”). Decreased expression of this signature was associated with a response to lenalidomide in an independent set of patients (validation set). The researchers then used the response signature and the original set of samples to develop a single score that could distinguish individual responders from nonresponders. This score accurately predicted the response of three-quarters of the patients in the validation set to lenalidomide. Finally, the researchers showed that lenalidomide promotes the erythroid maturation of normal human hematopoietic stem cells grown in dishes and stimulates the expression of the lenalidomide response signature in these cells.
What Do These Findings Mean?
These findings indicate that patients with MDS who respond to lenalidomide have defective red blood cell differentiation. In addition, they suggest that it might be possible to use the response signature to develop a test that can predict which patients with MDS will benefit from treatment with lenalidomide. However, the preliminary predictive test described here will need to be tested in many more patients before it can be used as a routine clinical test. Finally, the researchers' last experiment suggests that lenalidomide may help people with MDS because it induces red blood cell differentiation. Lenalidomide therapy might, therefore be useful in other disorders in which red blood cell maturation is defective, including some forms of anemia.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050035.
See a related PLoS Medicine Perspective article
The US National Cancer Institute provides information for patients about myelodysplastic syndrome (in English and Spanish)
The UK charity Cancerbackup provides information about myelodysplastic syndrome
The American Cancer Society and the Leukemia and Lymphoma Society provide additional information about myelodysplastic syndrome
The US Food and Drug Administration provides information for patients on lenalidomide