Clinical trial NCT01387763: A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
Official title: Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
First posted: 2011-07-06
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

In order to decrease drop out rates and thereby increasing response rates patients will be started of at a low-dose of IFN-alpha. If patients fail to respond or looses their response and develops neutralizing antibodies against IFN-alpha therapy will be stopped. If patients have a sustained deep molecular response (below 1 % JAK2 V617F mutated alleles for 12 months) therapy will be stopped to asses the sustainability of the remission off therapy.Patients over the age of 75 and intolerant or resistant to hydroxyurea will be offered rescue treatment with orally busulfan (Myleran). As an important part of the study quality of life will be investigated.

Eligibility criteria: Inclusion Criteria:

* 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)
* Pruritus
* splenomegaly causing symptoms
* previous thrombosis

Exclusion Criteria:

* 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

Primary outcomes:
measure: molecular response (changes from baseline)
timeFrame: 18, 36 and 60 months
Secondary outcomes:
measure: toxicity (discontinuation of therapy due to intolerability)
timeFrame: 18 months
measure: Quality of life (changes from baseline)
timeFrame: 4, 12, 24, 36, 48 and 60 months
measure: Histopathological response (changes from baseline)
timeFrame: 36 and 60 months
measure: Sustained molecular response (changes from level at time of discontinuation of therapy)
timeFrame: 12, 24 and 36 months
measure: Neutralizing antibodies against PegIntron and Pegasys
timeFrame: 24 months
measure: hematological response
timeFrame: 12 months
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Dept of Hematology, Aalborg hospital
city: Aarhus
country: Denmark
facility: Dept. of Hematology, Aarhus University Hospital
city: Esbjerg
country: Denmark
facility: Dept of Hematology, Esbjerg Hospital
city: Herlev
country: Denmark
facility: Dept of Hematology, Herlev Hospital
city: Holstebro
country: Denmark
facility: Dept of Hematology, Holstebro Hospital
city: København
country: Denmark
facility: Dept of Hematology, Rigshospitalet
city: Odense
country: Denmark
facility: Dept of hematology, Odense University Hospital
city: Roskilde
country: Denmark
facility: Dept. of Hematology, Roskilde Hospital
Study officials:
affiliation: Dept. of Hematology, Odense University Hospital
name: Thomas S Larsen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: