Describe a case in which iron overload might be suspected in a patient with low-risk myelodysplastic syndrome (MDS)

A 71 year old housewife with low-risk MDS presented to my practice with notes from her referring physician concerning a history of borderline anemia. Over a period of about 4 years, the patient’s hemoglobin levels dropped steadily from a level of 11.5 g to 9.0 g. When her hemoglobin reached 9.0 g, she was administered an erythropoiesis-stimulating agent (ESA) for a period of 3 months without response. Her hemoglobin levels continued to fall despite ESA therapy, dropping to 7.9 g, at which point she began receiving blood transfusions. The patient is now transfusion-dependent, receiving one to two transfusions every 6 weeks. According to her laboratory results, her cytogenetics are normal and she did not have deletion 5q disease, p53 mutation, or increases in blasts. Previously, a bone marrow test was performed, showing that ringed sideroblasts were present. At this point, the patient sought guidance on next steps in her treatment.

Considering that the patient was non‑deletion 5q erythropoietin-resistant, she was a candidate for treatment with azacytidine, a hypomethylating agent. Before initiating azacytidine, repeat bone marrow and baseline laboratory studies were performed, including an analysis of erythropoietin and ferritin levels. Results showed an erythropoietin level >1,000 ng/L and a ferritin level >900 ng/mL. There was no increase in blasts, and she had 27% ringed sideroblasts and normal cytogenetics. The genetic profile showed that the patient had a SF3B1 gene mutation.

Daily azacytidine treatment was initiated for 5 days per month and repeated for a total of six cycles, but the patient remained transfusion dependent, requiring 2 units of blood every other week. Ferritin levels were obtained every other month, showing a steady progression from 900 ng/mL to 1,100 ng/mL Recognizing that this patient already received more than 10 transfusions, I am concerned she may have iron overload.

After receiving azacytidine for 6 months, the patient’s chances of achieving a response are very low. Over time, she has been receiving blood transfusions every 2 weeks, her hemoglobin levels continue to be low, and her ferritin levels are rising. The patient feels good after receiving blood transfusions, but her anemia is not improving. Our only treatment options at this point are to either continue blood transfusions or offer enrollment into an experimental trial. Unfortunately, no clinical trials are available for lower-risk MDS patients with her characteristics at this time. This leaves us with blood transfusions and supportive care as our treatment course.

How would you confirm the diagnosis of iron overload in this patient, and what key factors and/or tests you would consider in this case?

Iron overload occurs when the iron acquired from transfused red blood cells (RBCs) exceeds the body’s storage capacity, thereby raising risk for end organ damage. Because lower-risk MDS patients are likely to live for years rather than months, the risk for end organ damage is an important consideration because it may impact overall survival (OS). Studies have reported that blood transfusion dependence and iron overload are independent risk factors for OS and progression to leukemia.1 In our case, the patient had lower-risk MDS and felt better after blood transfusions, but iron overload should be confirmed using serum ferritin and transferrin saturation. MRI T2 may also be useful, but is not essential.2

Several factors should alert clinicians to potential iron overload, but no single parameter is sufficient on its own for a diagnosis. Measuring ferritin is a universally accepted, inexpensive method of assessing iron levels in the body. Studies show that higher ferritin levels correlate with lower OS in MDS.3 Monitoring ferritin is helpful, but it can be spuriously elevated if patients have an infection or another inflammatory condition, such as an autoimmune disease. Repeat ferritin testing is therefore imperative to ensure ferritin levels are consistently high and no other complicating factor is causing a single high reading. In addition to ferritin, the patient’s history of blood transfusion is an important factor to consider when iron overload is suspected.

Among MDS patients, especially those with refractory anemia and ringed sideroblasts, iron levels can be elevated simply because of ineffective hematopoiesis in the bone marrow that results from hepcidin inhibition. Hepcidin regulates intestinal iron absorption and iron release from storage cells like macrophages and hepatocytes. Although there are currently no tests to measure hepcidin levels, researchers are working to develop these diagnostics. It is also possible that synthetic hepcidin therapies could improve our ability to modulate iron overload. Until these advances are validated, clinicians should consider iron overload in low-risk MDS patients if the patient’s ferritin levels are >1,000 ng/mL and if they have received at least 10 blood transfusions of 2 units each (20 units) for more than a year (Table 1).

Are there any prevention strategies for iron overload in MDS, and should all low-risk MDS patients be considered candidates for iron chelation therapy?

The development and introduction of chelation therapy has made it possible to remove excess iron in patients with anemia and iron overload.4 Ideally, iron chelation therapy should be initiated prophylactically before significant iron accumulation occurs. Prophylactic treatment should begin when patients have received between 10 and 20 units of RBCs.5 As more data emerge, it is possible that all low-risk MDS patients could be considered candidates for iron chelation therapy, regardless of their blood transfusion dependence. Several animal studies have been conducted in which high circulating iron has been induced. In these studies, hepcidin injections appeared to help remove iron from blood.6 This is important because excess iron in the blood could injure tissues, organs, and cells, and may worsen anemia and cytopenia in patients with MDS. The removal of excess iron may improve blood counts.4

What are the current treatment options for patients with MDS who are suspected of having iron overload?

Some clinical trials have shown that chelation therapy in MDS is capable of lowering serum ferritin levels and liver iron concentration. Current guidelines recommend using iron chelation therapy to manage low-risk MDS if patients have ferritin levels that are consistently >1,000 ng/mL and if they have received at least 20 units of blood or 10 blood transfusions over their course of disease.2,8

Iron-chelating agents can be associated with complications and side effects, causing some experts to limit use of these therapies to low-risk MDS patients who are likely to survive for several years with blood transfusions.4 While this is a valid approach, iron chelation therapy is typically well-tolerated with minimal toxicity. Creatinine levels need to be closely monitored because iron chelating agents affect renal function. Other side effects commonly seen among MDS patients receiving iron chelation therapy include diarrhea (early in their treatment), abdominal discomfort and pain, nausea, and occasional vomiting.4

Currently available iron chelators include deferoxamine, which is administered by injection, and deferasirox and deferiprone, which are administered orally (Table 2).9 Clinical trials have demonstrated erythropoietic improvement during iron chelation therapy in patients with lower-risk MDS.10 The iron chelation therapies have not been compared head-to-head in patients with MDS in randomized controlled clinical trials, meaning drug selection based on efficacy is not possible.11

After beginning iron chelation therapy, patients should be monitored regularly for the effects of continued blood transfusions on iron levels. To put this in perspective, the body requires 1 mg/day of iron, or 365 mg per year. With just one blood transfusion of 2 units, patients receive 400-500 mg of iron, exceeding the amount of iron the body requires for an entire year. When iron chelation therapy is started, some iron will be removed, but we must remember that iron levels are likely to fluctuate over time, especially when blood transfusions are used. It is helpful to monitor ferritin at least once every 2 months, but correlations between ferritin and iron chelation therapy should not be made if patients are receiving blood transfusions.12

Is there a debate over the use of iron chelation therapy in the MDS community, and if so, what are the issues surrounding this debate?

There are two schools of thought regarding iron chelation therapy in the MDS community. Some clinicians do not value iron chelation therapy because there is a deficit of OS data specifically relating to MDS. It is generally accepted, however, that MDS patients who are regularly transfused with RBCs will accumulate iron over time, and iron overload can potentially harm different organs, including the heart, pancreas, and liver, among others. Low-risk MDS patients may potentially gain protection from end organ damage by using iron chelation therapy.11

Researchers continue to investigate the effects of iron chelation therapy in MDS and establish which patients will benefit most from this treatment. There is also emerging data on the impact of iron chelation therapy and OS in low-risk MDS patients from recent clinical trials. One study was a 5-year, US-based prospective registry that consisted of 600 lower-risk MDS patients with transfusional iron overload. At 24 months, patients receiving iron chelation therapy had a longer median OS than those not receiving the treatment (104 vs 52 months) and exhibited a trend toward longer leukemia-free survival and fewer cardiac events.13 A second trial of low- and intermediate-risk MDS patients from the Dusseldorf registry showed that median OS was 74 months for iron chelation therapy recipients, compared with 49 months for no chelation.14 In a third trial, a meta-analysis showed that 7 of 8 observational studies favored iron chelation therapy over no chelation in MDS, particularly for low-risk patients, as measured by OS improvements.15

Finally, data from the TELESTO study (NCT00940602) is eagerly anticipated. The goal of TELESTO is to elucidate data concerning factors impacting event-free survival in patients with low- and intermediate-risk MDS. This pivotal trial is anticipated to provide stronger evidence for iron chelation therapy in MDS patients with transfusional iron overload. Based on what is known and expected results from TELESTO, the debate may be shifting toward favoring use of iron chelation therapy in low-risk MDS.

What are your concluding insights about iron chelation therapy in MDS patients?

Iron overload is an important issue that needs to be addressed when managing low-risk MDS patients. It requires vigilant monitoring of blood transfusions and ferritin levels. When iron overload is suspected, we should be prepared to add iron chelation therapy for low-risk MDS patients.