By Becky McCall
Medscape Medical News
June 12, 2009 (Berlin, Germany) — The platelet-stimulating drug romiplostim (Nplate) prevents a significant number of splenectomies in patients with immune thrombocytopenia (ITP), according to phase?3 study data presented here at the 14th Congress of the European Hematology Association.
Results show that 8% of patients taking the trial drug underwent surgery, compared with 35% of patients treated with standard-of-care (SOC) therapies (odds ratio, 0.17; 95% confidence interval [CI], 0.06 - 0.36). Treatment failure, another primary end point, occurred in 12% of patients in the romiplostim group, compared with 27% of the SOC group (odds ratio, 0.37; 95% CI, 0.12 - 0.74).
Mathias Rummel, MD, from Justus-Liebig University in Giessen, Germany, who led the study, said previous long-term data comparing romiplostim and placebo showed successful treatment of ITP for more than 4 years, but this new study was clinically more meaningful. "It compares the drug against the main standard-of-care treatments rather than placebo, and shows that romiplostim can prevent splenectomies in many patients."
Romiplostim was recently approved for treatment for chronic ITP in the United States, the European Union, Canada, and Australia on the basis of results from a placebo-controlled study and long-term extension studies. Dr. Rummel concluded that longer-term results, over 52 weeks in this analysis, were eagerly awaited.
In the trial, 234 patients were treated either with romiplostim or SOC therapies, such as cyclosporine, rituximab, azathioprine, and corticosteroids. Dr. Rummel noted that 42% of patients in the SOC group and 36% in the romiplostim group had received more than 3 previous ITP therapies. At baseline, patients randomized to romiplostim had a median platelet count of 27?× 109/L, whereas those randomized to SOC had a median platelet count of 33?× 109/L.
Over a 52-week period, romiplostim 3?μg/kg was administered subcutaneously once weekly, with dose adjustments based on platelet counts. Treatment failure was defined as a platelet count of 20?× 109/L or less at the highest recommended dose of romiplostim or SOC, a major bleeding event, or a change in therapy owing to adverse effects or intolerable symptoms.
Romiplostim, an engineered protein that combines the benefits of peptides and antibodies, stimulates platelet production at the thrombopoietin receptor. Similar to the natural growth factor thrombopoietin, romiplostim helps the proliferation and differentiation of cells in the bone marrow, boosting platelet counts.
Current SOC therapies address the destruction of platelets by the immune system but do little to increase platelet production. "The success of romiplostim in treating ITP has led us to rethink the pathophysiology of the disease. Historically, it was considered a disease of platelet destruction by autoantibodies, but now it is thought that reduced platelet production is equally important," Dr. Rummel told Medscape Oncology.
Safety in the romiplostim group was found to be similar to that in the SOC group. Serious treatment-related adverse events occurred in 7% of SOC patients and in 5% of romiplostim patients. In particular, bleeding events were experienced by 52% of the SOC group and 49% of the romiplostim group; bleeding events of grade?3 or above were seen in 8% and 3%, respectively; and thrombotic events were seen in 3% and 4%, respectively.
James Bussel, MD, from Weill Cornell Medical College in New York City, pointed out that these results suggest benefits for patients and providers. "These results describing avoidance of splenectomy in patients receiving romiplostim illustrate specific utility of treatment with this thrombopoietic agent. In addition to improvement in health-related quality of life, the avoidance of splenectomy provides a huge offset in cost for the care of these patients."
Cynthia Dunbar, MD, from the Hematology Branch of the National Heart, Lung and Blood Institute in Bethesda, Maryland, believes the choice of whether to take the drug or have a splenectomy ultimately belongs to the patient. "Splenectomy has a good response rate but, over time, some patients can relapse. I think it will come down to health insurance and national health programs, because these drugs are costly. You would need to be on the drug indefinitely, and we need to ask if stimulating marrow constantly for years is any good."
"What is clear in the [United States], at least, is that we see a lot of patients that are referred for treatment who don't need treatment. Judicious use of the drug is essential; we need to decide whether to do this in place of splenectomy when, in fact, splenectomy could resolve the problem," concluded Dr. Dunbar.
The study was supported by Amgen. Dr. Rummel and Dr. Bussel have disclosed no relevant financial relationships.
14th Congress of the European Hematology Association: Abstract 1059. Presented June 7, 2009.
根據發表於歐洲血液協會第14屆研討會的第3期研究，血小板刺激藥物Romiplostim(Nplate)可預防多數免疫性血小板缺乏(immune thrombocytopenia，ITP)病患進行脾臟切除。
結果顯示，服用該試驗用藥的病患只有8%接受手術，而以標準照護(SOC)治療的病患有35%進行手術(勝算比為0.17；95%信心區間[CI]為0.06 - 0.36)。另一個初級終點是治療失敗，Romiplostim組有12%病患、SOC組有27%病患(勝算比為0.37；95% CI為0.12 - 0.74)。
領導本研究的德國Justus-Liebig大學Mathias Rummel醫師表示，之前比較Romiplostim和安慰劑的長期資料顯示，可以成功治療ITP超過4年，但這個新研究更具有臨床意義。本研究是和標準照護進行比較而非安慰劑，結果顯示Romiplostim可以防止許多病患進行脾臟切除。
美國、歐盟、加拿大和澳洲最近根據安慰劑控制研究以及長期擴大研究的結果，核准Romiplostim用於治療慢性ITP。Rummel 醫師結論表示，本研究分析長達52週的結果，是大家迫切等待的。
在該試驗中，234名病患接受Romiplostim或SOC，如cyclosporine、rituximab、azathioprine以及類固醇治療。Rummel醫師指出，SOC組有42%的病患、Romiplostim組有36%的病患接受過3次以上的ITP治療。開始時，隨機分到Romiplostim組的病患，其平均血小板數量為27 ×109/L，隨機分到SOC組者的平均血小板數量為33 × 109/L。
經過52週，每週皮下給予Romiplostim 3μg/kg ，且根據血小板數量調整劑量。治療失敗定義為，給予最高建議劑量之Romiplostim或SOC時，血小板數量20 × 109/L 以下、嚴重出血、或者因為副作用或無法耐受而改變治療。
Romiplostim是一種生物工程蛋白質，同時具有胜肽與抗體的好處，刺激血小板生成素受體產生血小板。就像血小板生成素的天然成長因素一樣，Romiplostim可以幫助骨髓內細胞的增生與分化，增加血小板數量。
目前的SOC治療為，處理免疫系統對血小板的損壞，少有增加血小板產生。Rummel醫師向Medscape Oncology表示，Romiplostim成功治療ITP，可讓我們再度思考此病的病理生理學。在過去，它被視為自體抗體損壞血小板的疾病，但是現在，它被認為是血小板產生降低，這也很重要。
Romiplostim組的安全性和SOC組相當。SOC組有7%病患、Romiplostim組有5%病患發生嚴重的治療相關副作用。特別的是，SOC組有52%病患、Romiplostim組有49%病患發生出血事件；兩組發生等級3以上的出血事件比率分別是8%和3%；兩組發生栓塞事件的比率分別是3%和4%。
紐約市威爾康乃爾醫學院的James Bussel醫師指出，這些結果提出對病患與照護提供者的幫助。這些結果指出接受Romiplostim的病患可避免脾臟切除，點出這個血小板缺乏製劑的特殊效果。除了改善健康相關的生活品質之外，避免進行脾臟切除也大幅減少了這些病患的照護支出。
國家心、肺與血液研究中心血液學小組的Cynthia Dunbar醫師相信，選擇服用藥物或進行脾臟切除的決定在於病患。脾臟切除有好的反應率，但是，有些病患後來可能復發。我認為這終究會變成健康保險與國家健康的問題，因為這些藥物所費不貲。你需要的是別在藥物設限，我們需要的是瞭解經年刺激骨髓是否是可行的。
Dunbar醫師結論表示，至少，在美國清楚的是，我們看見許多無須治療的病患被轉介治療。審慎用藥是重要的；我們需要決定這是否取代脾臟切除，而事實上，脾臟切除也可以解決問題。
Amgen公司支持本研究。Rummel醫師與 Bussel醫師宣告沒有相關財務關係。
歐洲血液協會第14屆研討會：摘要1059。發表於2009年6月7日。
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