Myelodysplastic Syndrome - Management

Management

The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia (AML).

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.

Three agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS:

1. 5-azacytidine: 21 month median survival
2. Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid.
3. Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS

Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about US$9,200 per month.

Stem cell transplantation, particularly in younger patients (i.e. less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.

Iron overload in MDS, red blood cell (RBC) transfusions are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need, many MDS patients may not respond to these treatments and may develop iron overload as well as its consequences.

Patients requiring relatively large numbers of RBC transfusions have experienced adverse effect of chronic iron overload on liver, heart, endocrine functions. It is possible that this organ dysfunction may result from iron overload in patients with MDS and that transfusional iron overload might be a contributor to increased sickness and death in early stage MDS.

For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to <1000 mcg/L.

There are currently two iron chelators available in the US, deferoxamine (Desferal) for IV use and deferasirox (Exjade) for oral use. These options now provide potentially useful drugs for treating this iron overload problem. A third chelating agent is available in Europe, deferiprone for oral use, but not available in the US.

Clinical trials in the MDS are ongoing with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy have been shown.

Both the MDS Foundation and the NCCN MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggest there is a potential value to iron chelation in patients who then undergo a stem cell transplant.

Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following post-marketing use of deferasirox, there were rare cases of acute kidney failure or liver failure, some resulting in death. Due to this, it is recommended that patients be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter.

Currently, a large international Phase III clinical trial is ongoing comparing treatment of deferasirox to placebo, which should help to establish the clinical value of deferasirox in iron- overloaded MDS patients.