Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 202
- 试验地点
- 8
- 主要终点
- molecular response (changes from baseline)
研究概览
简要总结
The purpose of the study is to compare the efficacy and toxicity including quality of life of two types of low-dose interferon alpha compounds (PegIntron and Pegasys) with hydroxyurea (Hydrea), and to investigate the occurence of neutralizing antibodies against recombinant interferon.
详细描述
Chronic myeloid neoplasms (CMPN) consists of three main entities, polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These three disorders have many overlapping clinical features. The diseases are clonal stem cell disorders characterized by a chronic excess production of mainly mature myeloid cells. The excess production of clonal red cells (in PV), platelets (in PV, ET and PMF) and leukocytes (mainly PV and PMF)leads to a highly increased risk of thrombosis. Patients may also suffer from constitutional symptoms, pruritus and splenomegaly. An inherent feature of these diseases are the risk of ET and PV of transformation to myelofibrosis and a risk of both ET, PV and PMF of leukemic transformation.
In 2005 major breakthrough in our understanding of the molecular pathophysiology was achieved with the identification of the JAK2 V617F mutation which is present in almost all patients with PV (98%) and about half of patients with ET and PMF. This somatic gain-of-function point mutation in the JAK2 tyrosine kinase leads to constitutive activation of the kinase. By this mechanism a clonal non-growth factor dependent myeloproliferation is established.
Traditionally the excess platelet and white cell production in ET, PV and PMF has been treated with cytoreductive agents such as hydroxyurea and busulfan in order to normalize the blood counts and thereby reducing the risk of thrombosis. However, in younger patients there is a concern of the leukemogenic potential of these agents. In younger patients an alternative treatment option is recombinant pegylated interferon alpha (IFN-alpha), which has demonstrated high clinical efficacy and has no leukemogenic potential. Within recent years IFN-alpha has demonstrated a capacity of inducing deep molecular remission (evaluated by JAK2 V617F qPCR) and normalisation of bone marrow morphology. These remissions have been sustained for up to 3 years after discontinuation of IFN-alpha therapy. Accordingly a perspective of changing the natural history of these disorders towards myelofibrosis and ultimately acute leukemia has emerged. However toxicity has been a major issue and drop-of rates have been reported consistently around 25 %.
It is well known from other diseases (e.g multiple sclerosis and hepatitis) that some patients develop neutralizing antibodies against IFN-alpha. This issue is however only scarcely investigated in CMPN and has never been tested in a prospective design.
The purpose of this study is to compare the efficacy (hematological and molecular) and toxicity profile of two different recombinant interferon alpha products, IFN-alpha2a and IFN-alpha2b in a prospective randomized design. In patients over the age of 60 there will be a third study arm with hydroxyurea.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female > 18 years of age
- •Newly diagnosed, or previously diagnosed untreated patients with ET, PV or PMF including prefibrotic myelofibrosis according to the WHO classification
- •Active disease defined by one of the following criteria:
- •need for phlebotomy
- •leukocytosis > 10 mia/l
- •thrombocytosis > 400 mia/l
- •constitutional symptoms (fatigue, weight loss, night sweats or fewer > 38 degrees celsius)
- •splenomegaly causing symptoms
- •previous thrombosis
排除标准
- •Fertile women without a negative pregnancy test
- •Other malignant disease within last 5 years
- •ECOG performance score >/= 3
- •Creatinine > 2x ULN
- •Bilirubin > 1.5x ULN
- •ALAT > 3x ULN
- •Previous psychiatric disorder (depression)
- •active autoimmune disease
- •Uncontrolled thyroid disease
研究组 & 干预措施
PegIntron <= 60 years
In patients <= 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.
干预措施: PegIntron (Drug)
Pegasys <= 60 years
In patients <= 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
干预措施: Pegasys (Drug)
PegIntron > 60 years
In patients < 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.
干预措施: PegIntron (Drug)
Pegasys > 60 years
In patients > 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
干预措施: Pegasys (Drug)
Hydroxyurea > 60 years
Capsule Hydrea 500-2000 mg orally QD or BID
干预措施: Hydrea (Drug)
结局指标
主要结局
molecular response (changes from baseline)
时间窗: 18, 36 and 60 months
Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.
次要结局
- toxicity (discontinuation of therapy due to intolerability)(18 months)
- Quality of life (changes from baseline)(4, 12, 24, 36, 48 and 60 months)
- Histopathological response (changes from baseline)(36 and 60 months)
- Neutralizing antibodies against PegIntron and Pegasys(24 months)
- hematological response(12 months)
- Sustained molecular response (changes from level at time of discontinuation of therapy)(12, 24 and 36 months)
研究者
Thomas Stauffer Larsen
MD PhD
Odense University Hospital