The thrombopoietin mimetic romiplostim produced a higher rate of platelet response, a lower incidence of treatment failure, less need for splenectomy, and less bleeding than did a variety of standard-of-care therapies in patients with immune thrombocytopenia, according to a report in the Nov. 11 issue of the New England Journal of Medicine.

At the same time, romiplostim produced fewer adverse effects than did the traditional treatments, leading to an improved quality of life, wrote Dr. David J. Kuter of Massachusetts General Hospital, Boston, and his associates.

To assess the efficacy and safety of romiplostim for immune thrombocytopenia, the investigators compared it with standard medical therapies in 234 patients treated at 85 medical centers throughout North America, Europe, and Australia. The study subjects were adults who had not undergone splenectomy and who had failed to respond to at least one traditional treatment. They were randomly assigned to receive open-label romiplostim (157 patients) or standard-of-care therapy (77 patients) for 1 year, and then followed for an additional 6-month safety monitoring period.

The study was designed and sponsored by Amgen, maker of romiplostim, and Amgen also gathered the data, conducted the statistical analyses, and interpreted the results.

Patients in both study groups were allowed to receive additional therapies, such as intravenous immune globulin or glucocorticoids, if they were deemed necessary.

The two main end points were the rate of treatment failure and the need for splenectomy, both of which were significantly better with romiplostim.

Treatment failure rates were 11% (18 of 157 subjects) with romiplostim and 30% with traditional therapies (23 of 77 subjects). Patients receiving romiplostim fared better with every component of treatment failure, including major bleeding episodes, lack of efficacy, and severe adverse effects. The time to treatment failure also was significantly longer with romiplostim.

The incidence of splenectomy was 9% (14 of 157 patients) with romiplostim and 36% (28 of 77 patients) with traditional therapies. The time to splenectomy also was "markedly prolonged" longer with romiplostim. "Avoidance of splenectomy may allow for a spontaneous remission in a substantial number of patients and may benefit those who are not surgical candidates," Dr. Kuter and his colleagues said (N. Engl. J. Med. 2010;363:1889-99).

Additional treatments were needed in significantly more subjects in the standard-of-care group (79%) than in the romiplostim group (44%).

Moreover, patients receiving romiplostim were 2.3 times more likely to show a platelet response than those in the standard-of-care group. The proportion of patients showing a platelet response ranged from 71% to 92% with romiplostim, compared with 26% to 51% with standard-of-care treatments. Also, the mean platelet count was higher with romiplostim for the entire duration of the study.

Treatment-related serious adverse events occurred in 5% of patients taking romiplostim and 8% of those taking standard-of-care therapies. Headache and fatigue were the most frequent mild adverse effects.

Adverse events considered to be “of interest” with thrombopoietin mimetics include bleeding, thrombosis, increased bone marrow reticulin, hematologic cancer, or myelodysplastic syndromes.

The rates of overall bleeding and serious bleeding both were significantly lower in the romiplostim group, and twice the proportion of patients receiving traditional therapies required transfusions (17% vs. 8%). The only hematologic cancers that developed were in the standard-of-care group. And there were no abnormal nonhematologic lab results and no neutralizing antibodies to romiplostin or thrombopoietin.

One patient in the romiplostim group showed bone marrow reticulin during the 6-month safety follow-up, but the level was within normal limits.

Both study groups showed improved quality of life after treatment, with the romiplostin group showing significantly greater benefits. However, the magnitude of this effect “is of uncertain clinical benefit,” the investigators said.

“Our results show that romiplostim not only maintains platelet counts more effectively than standard medical therapies but also reduces the overall rate of treatment failure and the need for splenectomy,” they noted.

In an accompanying editorial, Dr. James N. George wrote that it is not yet time to declare that romiplostim is the new standard of care for immune thrombocytopenia, although that may have been a goal of the study sponsor, and it may yet be how the results of this study are interpreted (N. Engl. J. Med. 2010;363:1959-60).

More patients must be observed for a longer time before we can be confident of the drug’s safety. And the expensive maintenance therapy, which may be required indefinitely, is difficult to weigh against splenectomy, which often is curative. “Randomized clinical trials of splenectomy have not yet been done,” and they are vital to allow proper comparison between the surgery and various thrombopoietin-mimetic agents, said Dr. George of the department of biostatistics and epidemiology and the department of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City.

Advocacy for these drugs is apparent, by the manufacturers and even by the mere publication of industry-funded clinical studies in high-profile journals. But splenectomy has no organized advocacy.

For this reason, it will be particularly important to consider carefully the American Society of Hematology revised guideline for the treatment of immune thrombocytopenia, which is currently in preparation. This effort received no commercial support, nor did any of the contributors have a commercial conflict of interest, Dr. George noted.

This study was sponsored and designed by Amgen, which also gathered the data, conducted the statistical analyses, and interpreted the results. Dr. Kuter and his associates reported ties to numerous industry sources. Dr. George has consulted with Amgen on romiplostim and served as an investigator in clinical trials sponsored by Amgen.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

波士顿麻省总医院David J. Kuter博士及其同事在11月出版的《新英格兰医学杂志》上发表报告称，免疫性血小板减少症患者服用罗米司亭(romiplostim)，与服用各种标准治疗药物相比，具有较高的血小板反应率、较低的治疗失败发生率和脾切除需要率，较少发生出血，且副作用较少，生活质量得以改善(N. Engl. J. Med. 2010;363:1889-99)。

为评价罗米司亭的有效性和安全性，研究者对234例免疫性血小板减少症患者进行罗米司亭与标准治疗药物的多中心开放式比较研究。受试者为非脾切除且至少对一种标准治疗药物无效的成人患者，随机分组接受罗米司亭(157例)或标准治疗药物(77例)治疗，治疗时间1年，然后进行另外6个月的安全性监测随访。如有必要，两组患者均允许接受另外的药物治疗，如静注免疫球蛋白或糖皮质激素。主要终点为治疗失败率和脾切除需要率。

结果显示，罗米司亭组和标准治疗组治疗失败率分别为11%和30%，包括出血、缺乏疗效以及严重不良反应在内的各项治疗失败指标，罗米司亭组患者均优于标准治疗组，治疗失败的发生时间也显著推迟；脾切除发生率分别为9%和36%，罗米司亭组患者需要脾切除的时间也明显延长。罗米司亭组需要另外药物治疗的患者比例(44%)显著小于标准治疗组(79%)。此外，罗米司亭组显示有血小板反应的患者是标准治疗组的2.3倍，患者比例范围分别为71%~92%和26%~51%，整个研究期间罗米司亭组平均血小板计数也较高。罗米司亭组和标准治疗组与药物有关的不良事件发生率分别为5%和8%，头痛和疲劳是最常见的轻度不良反应。罗米司亭组总体出血率和严重出血率均显著较低，标准治疗组需要输血的患者比例高出1倍(17% 对8%)。标准治疗组发生1例血液癌症患者，罗米司亭组未见非血液学实验室结果异常，也未见罗米司亭或促血小板生成素中和抗体产生。罗米司亭组有1例患者在随访期出现骨髓网硬蛋白，但其水平在正常范围之内。两组患者均呈现生活质量改善，而罗米司亭组受益明显。