The US Food and Drug Administration approved deferasirox, the first oral iron chelator, in 2005 for the treatment of iron overload in children and adults. The drug has greatly improved quality of life and overall survival for individuals with thalassemia, a congenital disorder that necessitates regular transfusions throughout life. However, the drug's benefit for patients with myelodysplastic syndromes (MDS) remains controversial, with some experts contending that this is all about drug company marketing and profits and others arguing there is real benefit for patients.
There are currently no randomized placebo-controlled trial data to answer the question. However, the FDA has mandated that Novartis, which makes deferasirox, test the drug in a randomized controlled trial in MDS patients.
In response to an inquiry from OT, the agency and Novartis acknowledge that enrollment is proceeding slowly, but both say they remain committed to continuing enrollment.
In the meantime, Novartis's financial documents show that deferasirox was the company's 11th biggest seller in 2009 and brought in $652 million (USD), which was a 23% increase over the previous year, and the MDS research community remains polarized on the issue.
Below are three differing views from MDS experts who represent the spectrum of opinions—a definite yes, a definite no, and a considered maybe—as well as a comment from OT Clinical Advisory Editor for Hematology/Oncology Mikkael Sekeres, MD, MS.
Interestingly, though, none of the eaxperts interviewed are planning to enroll patients in the randomized placebo-controlled trial designed to answer the question.
‘Iron Chelation Is Associated with Improved Survival’
Even without a randomized trial, there is enough evidence to support the use of deferasirox in MDS patients, or at least consider its use, says Heather Leitch, MD, PhD. “We have increasing amounts of data that transfusion-dependence and iron overload impact adversely on survival.”
For example, researchers reported at the most recent American Society of Hematology Annual Meeting that increased ferritin levels were associated with poorer survival in low- and intermediate-1 risk MDS patients included in the European LeukemiaNet MDS Registry, even when other factors were accounted for in a multivariate analysis (Abstract 2917).
“The researchers showed that not just high ferritin levels, but also even mildly increased levels, in MDS had quite a big hazard ratio in overall survival, with very significant confidence intervals,” Dr. Leitch said. “Now the opponents [to chelation therapy] would say that is just a marker of worse disease and worse bone marrow failure, but, you know, I think the European group has shown quite nicely that survival decreases with increasing ferritin level.”
Additionally, another abstract at the same meeting suggested that iron chelation may improve bone marrow function (Abstract 2912). Specifically, in an unplanned retrospective analysis of 341 MDS patients with iron overload who enrolled in the EPIC trial, which tested deferasirox's effect on ferritin levels for one year, reduced transfusion dependence was evident in 11% of patients, as well as improvements in platelet (14%) and neutrophil (20%) counts. (Authors on both studies reported potential conflicts of interest with financial support from Novartis or employment at Novartis.)
“This, again, is not direct data from a Phase III clinical trial, but it does tell us that a substantial minority of patients will, at least, have improvement in myelopoeisis,” Dr. Leitch said. “If they can reduce their transfusion requirements, that can certainly improve their quality of life, which is a clinical endpoint. It is not overall survival, but it is an important endpoint, particularly when our treatments in MDS up to this point have been aimed at improving quality of life.”
Dr. Leitch, who has received research funding and honoraria from Novartis Canada, says she has seen improvements in her own patients. One of her patients, for example, has become transfusion-independent following deferasirox treatment. “I was amazed,” she said.
Dr. Leitch also points to the thalassemia literature as evidence that iron overload has a negative impact on survival. In that setting, chelation dramatically prolongs survival and reduces organ damage, particularly to the heart and liver.
“In MDS, there is more back-and-forth debate, because the population is older and has a shorter lifespan,” she said. However, because the older population has more comorbidities, she thinks protecting organs from iron overload may be even more important. Some studies have shown a decrease in previously elevated liver enzymes in MDS patients with deferasirox therapy.
“Critics are right that [thalassemia and MDS] populations are quite different, but that doesn't mean that there isn't a benefit in MDS,” Dr. Leitch said. “We should take the lessons learned from thalassemia and at least consider applying them to MDS.”
As for participating in the ongoing randomized trial, she is not planning to participate because she lacks the equipoise to do so ethically, she said. And, she thinks, that is likely to be the case for other researchers involved in the debate. “It is not going to enroll well because people either believe that it is beneficial and so they are not going to want to randomize their patients to placebo. Or they are passionately opposed to it, so they are not going to put their patients on the trial at all, which is unfortunate,” Dr. Leitch said.
“I really think the people who are opposed to iron chelation are the ones who should be opening this trial and answering the question, because they can maintain some equipoise about the question.”
As for the critics who say it is too expensive and too toxic, Dr. Leitch said she doesn't see either factor as prohibitive. Though she does acknowledge there is more of a problem with cost than in Canada, given the different health care systems.
As for toxicity, she simply doesn't think the side effects are that serious: “It does have some side effects, but it is a relatively safe intervention if it is used appropriately,” she said.
In her view, learning how to use the agent and manage side effects is a good reason for physicians to enroll their MDS patients in the ongoing trial. As for how she selects her own patients for deferasirox therapy, she said, “I don't think there is a good algorithm for selecting them. It needs to be done on an individual basis. But I do think we should ask ourselves for any patient with MDS and iron overload, transfusion-dependent or not, we should, at least, be considering this therapy.”
‘It's All About Profits’
Prior to the approval of deferasirox, iron overload was not a high-profile problem in MDS, Ayalew Tefferi, MD, pointed out. The previously available chelation therapy was inconvenient, and there was no driving need for ferritin reduction in MDS patients.
“Iron overload was never a problem. For MDS, the problem was deaths from leukemia, from infections, etc. MDS is a disease of the elderly, with a median age of about 70 at diagnosis. These patients don't live long enough—even if there is an iron problem—to develop the problems from iron overload. But now, all of a sudden there is a pill that they can take and the company can make money out of it, and iron overload became perceived as a problem.”
He emphasizes that deferasirox clearly benefits individuals with thalassemia: “These are children who live 20, 30, 40 years. For these children, using an iron chelating agent has been shown to improve their survival and decrease their morbidity, and for these patients, there is no question that iron chelation is good.
“But how can you extrapolate from literature on a children's disease and apply it to a cancer that affects elderly people? I have no idea. The median survival in MDS is about three years.”
He said that when he weighs the scientific evidence, there are simply no randomized controlled data to show that giving deferasirox is better than not giving it.
“There are two components of the issue,” he said. “One, has iron been shown to affect survival or quality of life in patients with MDS? Nobody has shown that. In fact, I have published several papers showing that it did not affect survival or morbidity. Two, okay, let's say that it did, then has anyone shown that intervening with chelation changes survival or improves quality of life? Absolutely not.”
Dr. Tefferi adds that treating patients with deferasirox comes at a high price in terms of both financial burden and increased toxicity: “It costs about $50,000 per year, and the patients and their families go bankrupt. That is what bothers me. They go bankrupt for nothing.”
Safety is also a concern that needs to be weighed into the equation. The FDA added a black box warning to the label in February 2010 stating that “Exjade [deferasirox] may cause renal impairment, including kidney failure, hepatic impairment, including liver failure, and gastrointestinal hemorrhage. In some reported cases, these reactions were fatal.
As for existing treatment guidelines, which suggest that patients should be treated when their ferritin levels rise above a certain number, Dr. Tefferi is equally emphatic. “People use ferritin as a measure, but that has nothing to do with quality of life. When you don't have evidence or rigorous trials, the company gets like-minded people together to put together guidelines. None are evidence-based guidelines; these are gut feelings. And most are extrapolations from thalassemia literature.”
Dr. Tefferi also says, like Dr. Leitch, that he will not participate in the ongoing randomized controlled trial. “I applaud the FDA for making them do it,” he said. “But [the company] knows where we stand at Mayo.”
‘We Need the Data to Know’
The clinical value of deferasirox in MDS remains unclear, said David P. Steensma, MD. “There are a couple of papers that are suggestive that it could be harmful in some circumstances, and there are some retrospective data that suggest that patients who get chelation might have benefit.
“But the thing that limits enthusiasm for it, is that there are no prospective clinical trials showing that anything other than ferritin, the number, goes down. There are no trials that show that iron chelation improves heart function or extends life or prevents disease progression.”
Moreover, he continued, the price and the black box warning cannot be ignored. “If it was five dollars per month and totally benign, many of us would say, ‘Why don't you take it,’ but it is many thousands of dollars a month, and it is something that can cause kidney failure.”
And, from his vantage point, the company's enthusiasm for the drug is not helping. “Any time a company aggressively pushes or markets a product, there is going to be a little bit of pushback unless the data are really, really good,” Dr. Steensma said. “And they are not in this case.”
Like the other experts interviewed, Dr. Steensma, who sat on one advisory board for Novartis about 15 months ago, emphasizes that the drug is, without question, valuable in the thalassemia setting. But, like Dr. Tefferi, he is not sure that data gained in that setting can be translated to a cancer with a median survival of just a few years. Moreover, MDS is the setting in which many of the adverse events appear to occur, likely because of the patients' age and comorbidities.
Dr. Steensma said that between now and when the randomized trial data become available, he thinks it is appropriate to use deferasirox, but that it is hard to know in exactly which patients: “I think we should be judicious about the patients we should use it in. I have a handful of patients I use it in. They are people with evidence for iron overload other than just high ferritin, such as having increased hepatic iron concentration measurable by MRI.
“I don't treat on the basis of ferritin alone, but some of my colleagues do. If a patient has two measurements of ferritin of 1,500 or 2,000 mcg/L and the patient has low-risk disease, then they will start treatment.”
The relative paucity of data contributes to a high degree of variability in both practice and in guidelines. “I think that highlights that we don't know the best way to use this drug,” Dr. Steensma said. And, like Dr. Tefferi, he notes that many of the organizations or groups that have written guidelines have received considerable support from the company and “were fairly generous in their recommendations.”
As for the FDA-mandated randomized trial, Dr. Steensma said he considers that to be a good trial. Still, his group at Dana-Farber decided not to participate because, as a tertiary center, they do not have many low-risk patients.
“The company is really advocating for the drug in clinical settings where it is not clear that it actually benefits,” he concluded. “And a lot of patients with MDS have bigger fish to fry. If they have a life expectancy of six months to a year, that is not a patient you want to be bankrupting with iron chelation.”
Mikkael Sekeres: Arguments Similar to Those of Folate Supplementation in Cardiac Disease
Mikkael Sekeres, MD, MS, OT's Clinical Advisory Editor for Hematology/Oncology, noted that the arguments surrounding use of chelation agents remind him of those that used to occur regarding folate supplementation in patients with cardiac disease.
“Folate was shown to reduce homocysteine levels, just as deferasirox reduces ferritin levels in MDS patients, and it was clear that patients with homocysteinuria had worse heart disease, just as it is clear that MDS patients with high ferritin levels have worse survival,” said Dr. Sekeres, Director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee. “So, the assumption was that giving folate to patients would reduce their risk of heart disease.
“Yet, multiple, well-done, prospective studies then showed that folate supplementation had absolutely no impact on cardiovascular morbidity or mortality. Until a prospective study demonstrates an impact of chelation therapy on some ‘hard’ endpoints in MDS patients, it is difficult to recommend it enthusiastically.”