May 19, 2009 — Oral iron-chelation products have been heavily promoted for use in patients with myelodysplastic syndrome (MDS) and, recently, in patients with primary myelofibrosis (PMF), but this use is based on nonevidence-based and often industry-sponsored consensus statements and opinions, says a group of hematologists from the Mayo Clinic in Rochester, Minnesota.
Iron-chelation therapy is directed at iron overload resulting from frequent blood transfusions, which form part of the standard treatment for most MDS and PMF patients.
However, the value of iron-chelation therapy in terms of meaningful health outcomes remains dubious for both MDS and PMF, say the researchers, headed by Ayalew Tefferi, MD, professor of medicine and hematology at the Mayo Clinic. Their study was published in the May issue of the American Journal of Hematology.
In an accompanying editorial, Thomas DeLoughery, MD, from the Oregon Health & Science University in Portland, remarks on the recent heavy promotion of these products. "Hematologists are under increasing pressure to prescribe iron chelation for seemingly any patients being transfused," he writes.
There has also been a "remarkable increase in anxiety" about "the dangers of iron overload," he writes. But there is no evidence to justify this "current hysteria over transfusion-related iron toxicity in patients receiving chronic transfusion therapy."
In an interview with Medscape Oncology, Dr. DeLoughery said that the increased publicity surrounding iron overload can be traced back to the launch of the first oral iron-chelation product in the United States, deferasirox (Exjade, Novartis), in late 2005. Prior to this, the only product available in the United States was the parentally administered deferoxamine (Desferral), which is cumbersome to give and has huge compliance problems, he said. There is another oral product, deferiprone (Ferriprox), available in some countries, but not the United States. However, that product has been dogged by its own controversy, sparked by disputes over research carried out with the drug in Canada in the late 1980s. "Iron-chelation therapy is an area where there has been a lot of controversy," he said.
"Unfortunately, the recent focus on iron overload as a priority and not the stem-cell defect is leading to a misallocation of resources," Dr. DeLoughery writes in the editorial. The challenge in MDS and myelofibrosis is to avoid transfusions by developing better therapies to reverse the stem-cell defect that causes these diseases. The focus should be on the disease itself and the underlying defect in this disease, he said; iron overload is just a side effect of one of the treatments for the disease.
Accepted in Congenital Anemias, But Not Other Syndromes
The use of iron-chelation therapy is well accepted for congenital anemia disorders, such as thalassemia, and it has been shown to prolong survival in these patients, Dr. DeLoughery explained. However, the benefit is only seen long term, after a decade or even 2, when these patients with congenital anemia reach their teenage years after lifelong blood transfusions that began when they were infants.
The situation with MDS and PMF is rather different, he continued. These patients are older and have a shortened life-expectancy because of their disease, and they might not be receiving blood transfusions for many years. The time frame might not be long enough to see any benefit from iron-chelation therapy, he said.
In addition, although the blood transfusions clearly increase iron stores, it is not clear whether the iron overload leads to toxicity and end-organ damage in these patients, he said. In fact, the study by Dr. Tefferi and colleagues — which prompted the editorial — shows that for PMF patients with a good prognosis who have been receiving blood transfusions, there is no evidence that the iron overload is harmful, he said.
There is also unease over the use of serum ferritin levels as a marker of iron overload, Dr. DeLoughery said. Serum ferritin is an acute-phase reactant, and is increased when there is inflammation, so it does not always reflect what is happening with iron stores in the tissues. In addition, iron-chelation therapy is not without adverse effects — there is a risk for liver and kidney toxicity, he added.
Hence, the use of iron-chelation therapy in patients with MDS and PMF is controversial, Dr. DeLoughery said. It has not been properly studied, and it should be, he added. At the moment, its use in these syndromes is based on "blanket recommendations based on evidence from other diseases."
Among Most Controversial Questions in Contemporary Practice
Both the paper and the editorial refer to a review of "myelodysplasia paranoia," by David Steensma, MD, also from the department of hematology at the Mayo Clinic, which was published online November 24, 2008 in Leukemia Research.
"Deferasirox has clearly been a boon for young patients with severe thalassemia or other congenital anemias," Dr. Steensma writes, but says the situation in MDS is more complicated.
The question of whether patients with MDS should receive iron-chelation therapy is "one of the most controversial in contemporary hematological practice," he says.
There is disagreement about whether or not iron overload is important in MDS patients, and disagreement about the risk–benefit ratios and cost-effectiveness of iron-chelation therapy in such patients. Several clinical guidelines have been issued, but they all differ markedly from one another, he points out.
"Some physicians paint a grim picture of the dangers associated with iron overload for their patients, and urge all to undergo iron-chelation therapy as soon as they begin requiring blood transfusions," Dr. Steensma writes. But others are more skeptical and use iron-chelation therapy rarely, if at all.
It's not surprising, then, that MDS patients are getting mixed messages, he says. In fact, some patients are now more worried about this aspect of their disease than about other more important aspects of their disease, about which there is no controversy, he notes.
"If iron-chelation therapy were perfectly safe and cheap, there would be little reason not to use it in patients with MDS, even for patients who have higher-risk disease, Dr. Steensma writes, adding that this is "thinking optimistically."
"Unfortunately, available iron-chelation therapy is neither cheap nor risk-free," he continues.
Iron Overload is the Wrong Focus
Some investigators have raised ethical concerns with respect to the use of deferasirox as iron-chelation therapy, says Dr. Steensma. He likens the situation to other prescription-drug-related controversies, such as the use of pregabalin for fibromyalgia, pramipexole for restless legs syndrome, and paroxetine for social anxiety. Although all 3 are FDA-approved indications, they are also "syndromes for which there are some physicians who are advocates and 'believers', while others are skeptical not only about drug efficacy, but also about the clinical distinctiveness and importance of the disease being treated."
Dr. Steensma concludes that more study is needed, because only additional high-quality laboratory and prospective clinical data will resolve the questions about iron-chelation therapy in MDS.
In the meantime, limiting iron-chelation therapy to transfusion-requiring patients with lower-risk forms of MDS who have evidence of iron overload beyond simply a (potentially misleading) ferritin level seems the most prudent approach, he adds.
The researchers have disclosed no relevant financial relationships.
Am J Hematol. 2009;84:263-264, 265-267. Abstract, Abstract
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου