Irish and international perspectives in the treatment of immune thrombocytopenic purpura were recently discussed at a Dublin meeting
Immune thrombocytopenic purpura (ITP), an autoimmune disease, is characterised by a decreased number of circulating platelets. First noted in the 17th century, ITP was not properly defined until 1951, having received many misnomers along the way, including ‘morbus maculosus haemorrhagicus’ and ‘purpura hemorrhagica’.
A recent meeting in Dublin, entitled Nplate — a Novel Therapeutic in the Chronic ITP Paradigm, chaired by Dr Patrick Thornton, Consultant Haematologist at the Mater Misericordiae University and Connolly Hospitals, offered both a local and international perspective of treatment for ITP.
The guest speaker was Prof David Kuter, Chief of Haematology, Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, Boston, who outlined the most recent management guidelines pertaining to ITP, as well as discussing the basis for the latest therapies.
Prof Kuter began by reminding the audience that some 80 per cent of patients are symptomatic at diagnosis, with the condition manifesting itself in cutaneous bleeding, mucosal bleeding or menorrhagia, as well as intra cranial haemorrhage.
Recent studies have further elucidated the pathophysiology of ITP, with in vitro experiments showing the growth of megakaryocytes and production of platelets to be suppressed to a ‘variable extent’ in ITP patients.
Furthermore, Houwerzijl et al (2004)1 showed morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura and produced electron micrograph pictures that clearly showed megakaryocytes undergoing apoptosis, or programmed cell death, in the blood of ITP patients, added the professor.
Megakaryocyte population
“All this tells us is that despite the expanded megakaryocyte population in ITP patients, those megakaryocytes are probably not making platelets and are instead undergoing apoptosis,” he explained.
Prof Kuter explained that, instead of attempting to halt destruction of platelets like most current treatments, new chronic therapies work on improving platelet production by introducing thrombopoietin.
Similar to erythropoietin for red blood cells, thrombopoietin was first postulated to exist in 1951 but was not purified until 1994 (by Prof Kuter’s research team and four other teams simultaneously).
Prof Kuter explained that the thrombopoietin molecule has two binding sites, one with high affinity and one with markedly lower affinity. When it binds to and activates the thrombopoietin receptor, a number of signaling pathways are also activated including various anti-apoptotic pathways, leading to an increased platelet count.
Following the identification and isolation of TPO in 1994, the first generation thrombopoietins were developed. These were highly successful in making platelets count rise but development was stopped due to antigenic properties of the molecules, stated the professor. Second-generation molecules are mostly TPO mimetics, which include peptides such as romiplostim (Nplate), or non peptide small molecules such as eltrombopag.
Peptide agents generally have short half-lives, which is not suitable for outpatient therapy, explained Prof Kuter. The construction of romiplostim as a peptibody, i.e. a fusion protein of Fc and TPO mimetic peptides, avoided this issue.
Nplate is a highly effective molecule at increasing platelet counts and has a half-life of 120 hours. Also, this molecule cannot cross-react with native thrombopoietin and thus cannot cause the same problems as the first-generation molecules did, he said.
Platelet transfusions
A 2004 study showed romiplostim takes five days to exert its effect on platelet counts, said Prof Kuter, explaining that this means it will not replace platelet transfusions as an emergency treatment measure. The study also showed that it is a highly potent molecule, with response being dose-related.
The Phase I and Phase II trials were carried out in small groups of ITP patients, and both trials showed extremely good responses for patients who either did not respond to other therapies or were contraindicated. “All patients who had 1ug/kg or greater responded positively to treatment,” said Prof Kuter.
The pivotal trial in romiplostim which was published in The Lancet in 2008 (Kuter et al, 2008)2 assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. This study covered a 24-week treatment period, with patients randomised to either romiplostim or placebo in a ratio of 2:1.
The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response and treatment safety. Durable platelet responses were achieved in 38 per cent of splenectomised patients and 61 per cent of non-splenectomised patients.
Some 83 per cent of patients (both splenectomised and non splenectomised) achieved an overall platelet response, reaching platelet counts greater than 50,000 per microlitre, versus 7 per cent of patients in the placebo groups.
“The vast majority of pat-ients responded but it was seen that once treatment ceased, platelet counts reverted to baseline levels. This showed us that Nplate is an effective treatment for ITP but not a cure,” explained Prof Kuter.
Eighty-seven per cent of patients on romiplostim were able to reduce or discontinue concurrent therapy compared with 38 per cent of those given placebo.
Use of rescue medications, such as intravenous immune globulin (IVIG) or high-dose prednisolone, were necessary in 21.7 per cent of patients receiving romiplostim, compared with almost 60 per cent of those receiving placebo. “However, these rescue medications were used in the period before platelet counts had risen,” added Prof Kuter.
Bleeding events
In terms of bleeding events, no clinically significant (severe, life-threatening or fatal) bleeding events occurred in this trial. “Those patients that had bleeding events, did so in the weeks before their platelet count rose,” Prof Kuter explained.
Two areas of potential concern are rebound thrombocytopenia once romiplostim is stopped and also the issue of reticulin formation, which is under further investigation.
A long-term, five-year analysis involving 219 patients was presented at the American Society for Haematology meeting 2009 (Bussel et al, 2009)3. According to Prof Kuter, this study involved the ‘most difficult’ ITP patients, but the results showed that, for at least five years, ITP can be controlled ‘quite effectively with this modality’.
Providing a local perspective on ITP management, Dr Thornton spoke about his experience to date on Nplate. Patient initiated on Nplate treatment have achieved haematological and clinical responses and platelet counts greater than 50 x 109/L have been reached within three weeks of commencing Nplate. He concluded that Nplate ‘is an effective and well tolerated treatment’.
ITP guidelines
Prof Kuter also discussed the recently published ITP guidelines (Provan et al, 2010)4. He explained that he and members of the international consensus committee reviewed over 8,000 manuscripts regarding ITP over two years, 5,000 of which contributed to the development of these recommendations.
First-line therapy includes corticosteroids and IVIG as the ITP standard of care.
Second-line therapy goals are to attain a haemostatic platelet count and possibly to ‘cure’. The TPO-receptor agonists including romiplostim have been given a grade A recommendation as a second-line treatment and for patients who have failed second line therapies (grade A – requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendation).
Excellent response
TPOs have provided excellent responses in splenectomised and non-splenectomised patients. “These have robust randomised clinical trial data and most patients are able to decrease or discontinue concurrent corticosteroid therapy. Although cessation of therapy can lead to rebound thrombocytopenia, the low toxicity and good tolerability mean many patients might choose to be on them indefinitely,” added Prof Kuter.
According to the guidelines, for those patients who fail both first- and second-line therapies, the risk with further therapies must be discussed with the patient and compared with the benefits analysed. These new guidelines also address the need for protocols in emergency situations.
Prof Kuter concluded the meeting, saying that studies demonstrate Nplate is a potent stimulator of platelet production, increases platelet counts in the majority of patients and reduces the need for rescue and concurrent therapies with minimal adverse events.
Effective treatment
“Nplate is an effective long-term treatment for ITP. We’re entering a brand new era of ITP therapy and these are quite exciting days for those in haematology,” he concluded.
Date of preparation: April 2010 NPO-IRL-AMG-57-2010.
References:
Reference 1: Houwerzijl EJ et al. Blood 2004;103(2):500-506.
Reference 2: Kuter D et al. Lancet 2008;371:395-403.
Reference 3: Bussel B et al. ASH 2009: #681.
Reference 4: Provan D et al. Blood 2010 ;115(2):168-86.
About Greg Baxter
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