Iron chelation therapy in myelodysplastic syndromes

Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders that result in progressive cytopenias and potentially acute myelogenous leukemia. MDS can cause cytopenias involving all three hematopoietic cell lines: platelets, red blood cells and white blood cells.

The International Prognostic Scoring System (IPSS) uses the percent marrow blasts, karyotype, and number of cytopenias to calculate a score that puts patients into one of four risk categories. Each of the four risk categories — low, intermediate-1, intermediate-2, and high — predicts the percentage of patients alive at five years and the percentage who will progress to AML within five years. One of the first manifestations of the disease is anemia secondary to ineffective hematopoiesis. Patients with MDS may require multiple blood transfusions per month and therefore are at risk of iron overload.

Iron overload and chelation

Most of the 3 g to 3.5 g of total body iron is contained within RBC and bound to hemoglobin. The supply of iron for RBC and other body tissues comes mainly from recycling of endogenous iron derived from aging RBC. Only 1 mg to 2 mg of iron is absorbed daily from the diet to replace lost iron and the body has no physiological mechanism to eliminate iron. One unit of RBC contains approximately 200 mg of iron. Therefore, patients who receive multiple blood transfusions are at risk for iron accumulation and overload.

John Perpich

Deborah Blamble

As total body iron increases, the saturation of transferrin, an iron carrier protein, also increases, resulting in increasing levels of nontransferrin bound iron and off-loading of iron in tissues that express high levels of transferrin receptor (eg, heart, thyroid, liver, gonads and pancreatic islet cells). This excess free iron may act as a catalyst in the Haber-Weiss reactions within these target tissues. The products of these reactions include reactive oxygen species that have the ability to oxidize lipids, proteins, DNA and RNA resulting in tissue damage and fibrosis.

Clinical manifestations of iron overload include hepatic and cardiac dysfunction, glucose intolerance, arthropathy and fatigue. There is some evidence that the nontransferrin bound iron (NTBI) is the fraction most directly responsible for tissue damage. The fraction of NTBI that crosses membranes and accumulates in target tissues is known as labile plasma iron. Iron chelation therapy targets NTBI in an effort to reduce labile plasma iron levels and subsequently iron accumulation and toxicity.

Currently, there are two chelating agents approved for treatment of iron overload in the United States. Deferoxamine is an iron chelating agent given subcutaneously, intravenously or intramuscularly at a dose of 500 mg to 1,000 mg per day.

Adverse reactions include tinnitus, decreased visual acuity, sensorineural hearing loss, dichromatopsia, night blindness, maculopathy, vision loss, optic neuritis, and cataracts. In addition, discoloration of the urine (vin-rose color), renal impairment, infection (mucormycosis and Yersinia spp.), injection site reactions, and adult respiratory distress syndrome can occur.

Deferasirox (Exjade, Novartis) is an oral iron chelator given at an initial dose of 20 mg/kg daily and increased at three month intervals by 5mg/kg to 10 mg/kg based on ferritin levels to a maximum of 30 mg/kg per day. Adverse effects include fever, headache, rash, nausea, vomiting, diarrhea, increased serum creatinine, proteinuria, cough, decreased high frequency hearing, cytopenias, hepatotoxicity and ocular disturbances.

Iron chelation therapy in MDS

The National Comprehensive Cancer Network guidelines for iron chelation therapy in MDS patients recommend considering deferoxamine subcutaneously or deferasirox orally to decrease iron overload in patients who have received more than 20 to 30 RBC transfusions. This recommendation is emphasized in IPSS low and intermediate-1 stage MDS patients, as well as patients potentially eligible for stem cell transplantation. The guidelines recommend a goal ferritin level of < 1,000 ng/mL in patients with serum ferritin levels > 2,500 ng/mL. These recommendations are based upon studies that have shown that deferoxamine chelation therapy reduced transfusion dependence and improved cardiac iron content. In addition, transfusion-dependence is associated with decreased survival in low-risk MDS patients compared to those who do not require transfusions.

The efficacy and safety of deferasirox have been evaluated in retrospective studies and some small prospective studies. Selected studies will be discussed.

Metzgeroth and colleagues conducted a phase-2 prospective single-arm study of deferasirox treatment in 12 patients with MDS and iron overload. Patients received deferasirox 20 mg/kg to 30 mg/kg orally once daily for 12 months. The median ferritin concentration was reduced from 1,515 mcg/L (range 665-6900) to 413 mcg/L (range 105-3052), and the median liver iron concentration (LIC) decreased from 315 mcmol/g to 230 mcmol/g. The most common adverse effects were mild and transient gastrointestinal events, skin rash, and increases in serum creatinine and urine beta2-microglobulin.

In an abstract, Gattermann and colleagues reported data from the EPIC trial for 341 MDS patients treated with deferasirox during a one-year period. The median serum ferritin at baseline was 2,730 ng/mL. The authors reported a significant reduction in median serum ferritin from baseline (by last observation carried forward: –253 ng/mL; P=.0019). Of the 174 patients that had a serum ferritin measurement at 12 months, the median serum ferritin was 1,904 ng/mL. Notably, approximately 49% of patients discontinued therapy, 23% due to adverse events (13% investigator-assessed drug-related). The most common adverse effects were diarrhea, nausea, vomiting, abdominal pain, constipation and increased serum creatinine. Approximately 15% of patients had two consecutive elevations of serum creatinine from baseline of > 33%. The clinical significance of the study’s main efficacy endpoint is questionable. The reduction in serum ferritin by a median of 253 ng/mL from a baseline of 2,730 ng/mL indicates that most patients in this study failed to achieve the serum ferritin goal of < 1,000 ng/mL after one year of treatment.

In another abstract, List and colleagues reported results from the US03 study of 176 patients with intermediate-1 or intermediate-2 MDS treated with deferasirox for 12 months. This phase-2, open-label, three-year trial was designed to assess the long-term efficacy and safety of lower-risk MDS patients treated with deferasirox. The mean serum ferritin (± SEM) levels decreased from 3,397 mcg/L ±233 (n=176) at baseline to 2,501 mcg/L ±139 (n=93) at 12 months. In patients with elevated labile plasma iron at baseline, mean labile plasma iron was decreased to within the normal range after three months of therapy. The discontinuation rate due to adverse events was 10%. The most common adverse events were diarrhea, rash, and nausea. Of 147 patients with normal baseline serum creatinine, 26 (18%) increased to more than the upper limit of normal on at least two occasions. Two- and three-year follow-up results are eagerly anticipated.

Conclusions

Transfusion-induced iron overload in patients with MDS is a significant clinical problem that can affect mortality and quality of life in these patients. The availability of oral deferasirox has certainly made iron chelation therapy much more practical. However, the data to support the efficacy of this therapy look only at surrogate markers of iron overload and do not demonstrate a reduction in mortality to date. Many of the study sample sizes were small and the follow-up periods were short and thus often failed to show clinically significant outcomes. A large prospective trial is needed to properly assess the efficacy of iron chelation therapy and the effects on mortality and quality of life in MDS patients. The advent of new therapies for MDS such as the epigenetic agents that may prolong survival underscores the importance of iron chelation therapy as many patients may begin to live longer with MDS.

John Perpich, MS, PharmD, is an Oncology Pharmacy Resident at The University of Texas M.D. Anderson Cancer Center.

Deborah Blamble, PharmD, BCOP, is Manager, Clinical Pharmacy Services, The University of Texas M.D. Anderson Cancer Center.

For more information:

• Desferal (deferoxamine) prescribing information. East Hanover, NJ: Novartis. November 2007.
• Exjade (deferasirox) prescribing information. East Hanover, NJ: Novartis. April 2009.
• Gattermann N. Blood. 2008;112: 633.
• Greenberg P. Blood. 1997; 89:2079-2088.
• List A. Blood. 2008;112: 634.
• Metzgeroth G. Ann Hematol. 2009;88:301-310.
• Mahesh S. Leukemia and Lymphoma. 2008;49: 427-438.
• The National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in myelodysplastic syndromes. Published online [cited 2009 May 16]. Accessed at: http://www.nccn.org.