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Romiplostim and eltrombopag: in a class of their own
These new thrombopoietin agents have changed the treatment of chronic adult ITP.
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In 2008, the FDA approved two new orphan drugs, romiplostim and eltrombopag, for the treatment of chronic adult idiopathic thrombocytopenic purpura, marking a significant change in treatment of the disease.
Traditional treatments for ITP focused on reducing platelet destruction. However, in more recent years ITP experts have begun to accept that stimulating thrombopoiesis in patients with ITP could also be an important approach to treatment.
Both romiplostim (Nplate, Amgen), a subcutaneous thrombopoiesis-stimulating Fc-peptide fusion protein approved in August 2008, and eltrombopag (Promacta, GlaxoSmithKline), an oral, small-molecule, nonpeptide thrombopoietin-receptor agonist approved in November 2008, treat ITP by stimulating platelet production.
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“I have more than 30 years of ITP practice, and this is simply the most dramatic advance in therapy that I have been aware of,” said John G. Kelton, MD, hematologist at the Michael G. DeGroote School of Medicine at McMaster University, Ontario. “These two agents have an effect, especially in refractory patients, that is essentially unheard of.”
“Both of these drugs are the most effective therapy for patients who have failed splenectomy,” said David Kuter, MD, DPhil, professor in the department of medicine, Harvard Medical School, and chief of clinical hematology at Massachusetts General Hospital. “There is no other medication that has this enormous high response rate — anywhere from 75% to 80% response — in these patients.”
As with any new drug, there has been some hesitancy in the hematology community about widespread use. HemOnc Today spoke with several ITP experts about how romiplostim and eltrombopag have changed the disease prognosis and the questions that remain.
A new approach
“These drugs really do represent a major advancement in ITP treatment,” said Donald Arnold, MD, an assistant professor in the department of medicine at McMaster University, Ontario.
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“The history and the rationale of treating ITP have always been targeted towards immune suppression or diminishing the accelerated destruction of blood platelets,” said James N. George, MD, professor of medicine and chief, hematology-oncology section, University of Oklahoma Health Sciences Center.
“Every medication has been an immune suppressive, or IVIg or WinRho (anti-D), and splenectomy, of course, ‘removes’ the site of destruction of platelets. So this is really a paradigm shift for these new agents to work on the other end of the problem, which is to increase platelet production,” George said.
Romiplostim’s approval was based on the results of a phase-3 trial published in 2008 in The Lancet. The trial included two parallel studies; one enrolled splenectomized patients, and the other, nonsplenectomized patients. All patients had a baseline platelet count <30,000/mcL. Patients were randomly assigned 2-to-1 to receive weekly subcutaneous injections of romiplostim or placebo for 24 weeks. The starting dose of 1 mcg/kg was increased as needed to achieve the target platelet count of 50,000/mcL to 200,000/mcL.
The overall platelet response rate was 88% in nonsplenectomized patients assigned romiplostim compared with a 14% response rate in nonsplenectomized patients assigned placebo (P<.0001). The rate was 79% in splenectomized patients assigned romiplostim vs. a zero response rate in splenectomized patients assigned placebo (P<.0001).
“In both groups the results were impressive in that platelet counts were achieved at target goals of 50,000 platelets or higher in 70% to 80% of patients treated vs. a much smaller number in the placebo group,” Arnold said. “These data really are most important in the splenectomized group because that is clearly a gap in our current treatments.”
The two studies leading to eltrombopag’s approval demonstrated a similar efficacy. The first study was published in November 2007 in The New England Journal of Medicine. It too examined both splenectomized and nonsplenectomized patients with platelet counts <30,000/mcL who were relapsed or were refractory to at least one other ITP treatment. They were randomly assigned to 30 mg, 50 mg or 75 mg eltrombopag or placebo. Results indicated that 70% of patients assigned to 50 mg eltrombopag and 81% of patients assigned to 75 mg achieved platelet counts in the target range compared with 11% of patients assigned placebo (P<.001).
A phase-3 study recently published in The Lancet further examined the efficacy of the 50 mg and 75 mg dosage of eltrombopag. Data from this trial of 114 patients indicated that 59% of patients assigned to the drug achieved a platelet count ≥50,000/mcL compared with 16% of patients assigned placebo (P<.0001).
How and when to use
Both eltrombopag and romiplostim are currently only indicated for treatment of adults with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.
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Photo by Sam Riley |
“The current standard of care for adults with ITP is to try to use something to keep platelet counts in a therapeutic range for at least six months to see if the disease will go away, which happens in one-quarter of all patients,” Kuter said.
If disease persists at six months, many patients will undergo splenectomy. “Splenectomy still remains the gold standard for treating patients with ITP. It has a high rate of success: 80% at one year and 60% at 10 years,” Kuter said. Although the procedure does have a high response rate in this patient population, it will not cure everyone with ITP.
“Patients with ITP postsplenectomy have been difficult to treat. Conventional treatments have not been sufficient and these drugs really filled a need,” Arnold said.
The decision to use these two agents when splenectomy has failed seems an obvious choice; however, their use in almost every other type of patient with ITP is where the situation becomes more confusing, particularly in patients who have not had a splenectomy.
“That is more of a gray area as to how it will play out in practice,” Arnold told HemOnc Today. “There certainly are groups of patients who have not had a splenectomy who may be appropriate candidates; for example, people who refuse to have splenectomy or have contraindications to the procedure but still have severe enough thrombocytopenia that they need some additional treatment.”
“It depends on how you feel about it,” said James Bussel, MD, professor of pediatrics and medicine at Weill Cornell Medical College. “It is clear where [the drugs] fit into the picture in somebody who has undergone splenectomy and failed it, but I think the majority of use will come much earlier than that.”
Many of the physicians interviewed agreed that treatment of any patient with ITP largely depends on their physician. Five physicians could treat the same patient in five different ways.
“Patients might end up on these agents as soon as one to three months from diagnosis,” Bussel told HemOnc Today. “The drugs could easily be something that physicians could prescribe with whatever your front-line treatment is at diagnosis and then transition over to these drugs. That wouldn’t be impossible.”
However, eltrombopag and romiplostim should never be considered as front-line treatment of the disease, George said.
“These drugs are very expensive and they are maintenance therapies,” he said. “I describe this to patients like insulin for diabetes. You don’t cure diabetes with insulin; you only keep blood sugar at a safe level. You don’t cure ITP with these agents, only keep platelet counts at a safe level. … You won’t commit patients to that unless you have gone through the standard disease-modifying treatment to try to induce remission.
“The first-line treatment is always going to be a prescription for prednisone. You just can’t beat it for cost, convenience and initial effectiveness — but side effects may soon become intolerable,” he said. That is when romiplostim and eltrombopag may be used.
Guidelines
Confusion about the use of the two new agents could be avoided if there were a clinical practice guideline for treating patients with ITP. ASH released its last ITP guideline in 1996; the British Society of Haematology published its most recent ITP guidelines in 2003. New international guidelines for ITP are currently being written.
“There is a crucial need for guidelines for ITP for many reasons,” Kuter said. “If you go to a nonacademic oncologist or hematologist who deals with ITP patients only occasionally, there are a number of mistakes that are encountered because they don’t see a lot of these patients.”
Kuter said that some physicians may be overly enthusiastic about treating patients with ITP. Many patients who are diagnosed with the disease still have a platelet count >30,000. Even at this below-normal level, therapy may not be required, he said.
“The problem that we face as experts in this area is that our colleagues end up treating patients with 60,000 to 70,000 platelet counts with drugs that may not be necessary,” Kuter said. “Guidelines are necessary to establish when to treat, who to treat, how long to treat and with what to treat.
“The new guidelines that will be out later this year will describe that the upfront therapy for most patients will be some kind of corticosteroids, IVIg or WinRho, and in patients who fail those medications or can’t tolerate them, they will recommend a wide variety of second-line therapies including these new agents and splenectomy,” he said.
Guidelines could also address the use of rituximab (Rituxan, Genentech), commonly used off-label to treat the disease. “Standard of care began to shift within the past 10 years with the introduction of rituximab,” Kuter said.
“I would say that now, within community practice, rituximab may be moving ahead of splenectomy as the option for patients who need further therapy after an initial trial of steroids. Many nonspecialists in ITP will use rituximab just because there are a number of reports that it works, but when critically analyzed, rituximab has a low long-term response rate,” he said.
Long-term safety
Because both of these drugs were approved within the last year, long-term safety data are lacking. “There have only really been two or three years of follow-up in these patients, and that is not long in the spectrum of a drug that could be maintained for the long term,” Arnold said.
Both of the phase-3 studies followed patients for only 24 weeks; however, ongoing studies of long-term safety outcomes are underway.
Eltrombopag’s increase in liver enzymes has been one of the more attention-grabbing adverse effects. “For eltrombopag the most commonly reported adverse event in 13% of patients was abnormal liver function tests, most of which did not cause the drugs to be stopped,” Kuter said.
Despite the attention, increased liver enzymes are not among the major complications that clinicians should be monitoring, according to Kuter. An increased rate of blood clots, formation of reticulin in the bone marrow and the rebound in platelet counts caused by discontinuing the medication deserve more attention.
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“There is a continuous concern about thrombosis with these drugs because you are churning out an increasing number of young platelets that are more effective than average-age platelets,” George said. “There would intuitively be some greater risk for thrombosis.”
According to George, this intuitive assumption about an increased risk of thrombosis is the reason why the FDA approved the two drugs with such restrictive distribution programs. “The requirement of patient registries is the FDA’s effort to prevent the issues that it dealt with involving erythropoietin drugs,” he said. “The FDA stated explicitly that it didn’t want to risk getting into the same difficulty once these new thrombopoietin drugs were approved that it experienced with erythropoietin agents.”
“People are worried about thrombosis but thus far there has been no evidence to drive that worry,” Bussel agreed.
Increased levels of bone marrow reticulin are also a concern in patients treated with these drugs. A reversible increase in reticulin was observed in eight patients with acute myeloid leukemia who were treated with a thrombopoietin preparation that is no longer in development to support induction therapy, as well as in a few patients with ITP in the clinical trials of romiplostim and eltrombopag.
“There again, it is hard to find a causal relationship to the drug,” Arnold said. “It does appear that a proportion of patients had an increase in bone marrow reticulin — like scar tissue — after being on this drug for a prolonged period, but once the drug was stopped the scar tissue went away. There was nothing to suggest a malignant transformation in any of those patients.”
Arnold said that the reticulin itself may not be the cause for concern. Instead the worry is that, in theory, increased reticulin often accompanies a “more sinister diagnosis.”
“The worry is that if you stimulate stem cells with a growth factor, which is essentially what romiplostim and eltrombopag are, then you could potentially induce some sort of cancerous transformation. However, when the drug is stopped, the reticulin goes away. There have not been any long-term malignancies observed,” he said.
According to George, it is likely that the increase in reticulin may be a dose-related phenomenon because it has not been reported in more recent trials where researchers are using lower doses than were initially used.
“The major complication of both medications is that if you stop, either the platelet count plummets back to prior baseline levels or below,” Kuter said. Data from the clinical trials indicate that when either drug is stopped, thrombocytopenia recurs with platelet counts returning to baseline levels or below within two weeks.
“The adverse effects of these growth factors have become increasingly apparent from the clinical trials,” said Craig Kessler, MD, professor of medicine and director, division of coagulation at Georgetown University. Kessler described his approach to the use of these drugs as much more cautious.
“Again, the drugs were used in a highly monitored population of patients and consequently the side effects were caught early and had no long-term sequelae, but once these drugs are used more freely that may not be the case,” he said.
Drug registries
In order to closely monitor the long-term safety of these drugs as well as any adverse effects, the manufacturers of both romiplostim and eltrombopag have created drug registries designed to capture postmarketing data. Amgen created the NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program, designed “to promote informed risk-benefit decisions before initiating treatment and while patients are on treatment” to ensure appropriate use of the drug.
Physicians must complete baseline and periodic safety information for every patient in order to prescribe the drug. They must also enroll in the program and complete educational program requirements such as reading the full prescribing information, understanding the approved indication and risks, and more.
GlaxoSmithKline also launched a registry after receiving priority review for eltrombopag. Physicians who wish to prescribe eltrombopag must first enroll in Promacta Cares, along with the patients. This program was created “in accordance with the FDA’s requirements to help assure the appropriate and safe use of eltrombopag, while minimizing risks, including the risk of hepatoxicity.”
“What they are trying to do is get physicians to become experts on the use of the drug and to limit the ability of just anybody being able to prescribe it,” Kessler said.
“Until there is broader experience, not many practicing hematologists will be using these drugs right away for ITP,” Kelton said. “However, once there is greater experience, there will be broad utilization. This new class of drugs is a completely novel way of treating ITP that, to date, has been proven to be highly successful.” – by Leah Lawrence
Could eltrombopag and
romiplostim play a role in treatment of pediatric ITP?
For more information:
- Amer J Clin Path. 2002;117:844-850.
- N Engl J Med. 2007;357:2237-2247.
- Lancet. 2008;371:395-403.