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Personalized medicine for MDS

PubMed Abstract: 
Original Publication Date: 
Thursday, November 19, 2015

Research Review:

Myelodysplastic syndromes (MDS) are a complex, heterogeneous disorder of the bone marrow.  The disease behaves in a wide spectrum, manifesting in an indolent manner in some patients as opposed to aggressively in others.  Therefore, treatment decisions have to be tailored to the individual patient.  Age and concurrent medical problems also play a role in determining therapy. 


-The International Prognostic Scoring System (IPSS) helps to risk stratify MDS patients into “lower-risk” disease, where improvement in blood counts is the main goal of therapy, and “higher-risk” disease, where improvement in survival and delay in progression to acute myeloid leukemia (AML) are the main goals.  The IPSS has recently been revised to include 5 risk groups to further classify patients in terms of survival and risk of progression to AML. 

-It is essential to properly diagnose MDS before initiating treatment.  One critical part of the workup is a bone marrow aspirate and biopsy, which is used to assess morphology and chromosomal abnormalities.  Fluorescence in-situ hybridization (FISH) can be sent on bone marrow samples and is useful in detecting specific chromosomal abnormalities, such as del (5q).  Flow cytometry can also help to detect abnormal clonal populations of cells. 

-The results of the bone marrow provide important information that may help to predict subsequent response to therapy, which is one way we can personalize treatment for MDS.  The classic example is the use of lenalidomide for patients with a del (5q) abnormality. 

-In recent years, research has led to the improvement in our understanding of the molecular pathogenesis of MDS, identifying mutations in 80-90% of MDS patients.  These mutations can aid in confirming the diagnosis of MDS in cases where it is unclear.  One caveat is that some of these mutations occur in healthy older individuals without MDS. 

- Many of these mutations have an impact on prognosis, such as RUNX1, ASXL1 and TP53 and therefore can help guide treatment.  For example, a younger patient with a negative prognostic mutation may be considered for a more intensive treatment, such as allogeneic stem cell transplant, earlier in the course of disease.  This personalized approach, however, has not been tested in a clinical trial

-One personalized approach for lower-risk patients with MDS is “watch and wait” which is appropriate for the lower-risk patient who does not require transfusions, has no increase in blasts, nor any poor-risk cytogenetic abnormalities. These patients, however, need to be monitored carefully for any change in their disease that warrants therapy.  Future improvements in molecular diagnostic tools may help to guide which of these “watch and wait” patients require earlier treatment.  Supportive care alone is also a reasonable option for patients who have a short life expectancy or cannot tolerate standard therapies.

-Treatment with erythropoiesis-stimulating agents (ESAs) as a single agent reduces transfusion dependence in about 50% of lower-risk MDS patients.  However, no specific ESA is licensed for the treatment of MDS.  Regardless, ESAs are generally considered first-line therapy for patients with lower-risk MDS and anemia who have a low (<500 U/L) erythropoietin level as well as low transfusion requirement.  Most responses to ESAs will occur within 12 weeks of treatment, and the average length of response is 2 years. 

-Lenalidomide works best in patients with red blood cell transfusion dependent MDS patients with lower-risk disease and del (5q).  It is also active in patients with del (5q) higher-risk MDS although response rates are lower than lower-risk disease.  About 20% of patients with del (5q) have a concurrent TP53 mutation which suggests more aggressive disease and should be treated accordingly.

-Hypomethylating agents, such as azacitidine and decitabine, are standard care for older patients with higher-risk MDS who are not candidates for stem cell transplant.  Azacitidine in particular has been shown to have a survival advantage compared to conventional care regimens. 


-There has been a significant improvement in the understanding of the pathogenesis of MDS in recent years with the development of new molecular techniques, and it is anticipated that this will continue to improve in the future.  As new research continues to develop, so will the advent of personalized medicine for the MDS patient.

Reviewer Bio: 
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