New therapeutics for myelodysplastic syndromes | Aplastic Anemia and MDS International Foundation

New therapeutics for myelodysplastic syndromes

PubMed Abstract: 
Original Publication Date: 
Wednesday, October 31, 2012

In recent years, several therapeutic agents have been approved for treatment of patients with myelodysplastic syndromes (MDS), including lenalidomide (Revlimidâ) and the azanucleosides, azacitidine (Vidazaâ) and decitabine (Dacogenâ).  Although these agents represent a significant step forward in the management of MDS, there remains a definitive need for further progress.  In his review, “New therapeutics for myelodysplastic syndromes,” Dr. List outlines the rationale for MDS-directed drug development efforts and describes several emerging agents currently or soon to be studied in clinical trials.  Notably, it is not an overview of all agents under active study nor is it a comprehensive description of available clinical trials in MDS.

MDS is characterized by impaired bone marrow stem cell function, resulting in low blood counts, increased rates of infection and bleeding, and a high risk of developing acute myeloid leukemia.  These clinical manifestations arise from abnormalities intrinsic to the defective stem cell itself (the “MDS clone”), as well as to imbalances among the surrounding, non-cancerous cells (the “MDS microenvironment”).  In this model, progression of an autonomous MDS clone is marked by an increasing independence from its surrounding microenvironment.  As such, it may be useful to develop a suite of distinct therapies aimed at treating different aspects of MDS biology at different stages of disease.  Whereas treatment of advanced MDS would rely upon agents directed at the MDS clone, earlier stage disease may be particularly susceptible to drugs aimed at controlling abnormal microenviromental signals.

Targeting the MDS clone:  

The azanucleosides (azacitidine and decitabine) remain the best treatment option for many higher-risk MDS patients.  For others, however, azanucleoside treatment is limited by prohibitive side effects, the requirement for parenteral (intravenous or subcutaneous) administration, or the lack of sustained benefit.  An oral formulation of azacitidine (CC-486) was designed to allow a more sustained dosing schedule.  It has been shown that oral azacitidine can be administered safely on a 21-day schedule, as opposed to a 7-day schedule for subcutaneous dosing.  However, it is not yet known whether sustained dosing translates to increased effectiveness.  SGI-110 is another novel azanucleoside that was designed to circumvent the ability of MDS cells to become resistant to treatment, as seen with its parent drug, decitabine.

Efforts are also underway to improve the effectiveness of lenalidomide, a drug with preferential activity in the group of MDS patients possessing the deletion 5q abnormality.  Like many drugs, lenalidomide is composed of two enantiomers (chemical mirror-images), only one of which is thought to account for its clinical activity.  By isolating and stabilizing this more active enantiomer, it is hoped that a more potent form of the drug may be developed.

Many so-called “targeted agents” are under development for the treatment of cancer, including MDS and acute myeloid leukemia.  These drugs are conceptually distinct from conventional chemotherapy in that they are designed to inhibit specific cellular pathways that are particularly important for cancer cell growth.  Rigosertib (ON-01910) and ARRY614 are inhibitors of key kinase enzymes and may have activity in patients who have failed prior therapy with azanucleosides.  Tosedostat is an aminopeptidase inhibitor that interferes with the cellular machinery required for tumor growth and has shown promising early results in some patients with MDS and AML.  These and other targeted agents are at various stages of evaluation in clinical trials.

A more speculative effort is directed towards interfering with the function of “MDS stem cells”.  It has been proposed that the MDS bone marrow harbors a small reservoir of cells that are intrinsically resistant to current therapies.  These “MDS stem cells” are thought to be reliant upon distinct growth and survival pathways that are similar to those of normal bone marrow stem cells, including as Wnt/b-catenin, Notch, and Sonic hedgehog.  Drugs targeting these pathways may be more effective in eradicating abnormal stem cells and increasing the likelihood or duration of treatment response.

Targeting the MDS microenvironment:

In addition to targeting the MDS clone itself, there is evidence to suggest that agents directed towards the MDS microenvironment may also be effective in improving clinical symptoms.  Historically, this approach has consisted primarily of immunosuppressive therapy and been restricted in effectiveness to early stage disease.  However, as we learn more about how the immune system functions (and malfunctions) in the context of cancer, more therapeutic targets are emerging.  Some new agents (such as the IDO inhibitor, INCB24360) are aimed at fine tuning the immune system by altering the balance of the body’s own anti-tumor defenses.  Others are designed to decrease the effects of inflammatory signals on blood cell development.  It is hoped that these agents, such as LY2157299, sotatercept, and siltuximab (targeted against TGFb, activin, and interleukin-6, respectively) will prove effective in improving anemia-related symptoms in patients with lower-risk MDS.