A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms

Primary Myelofibrosis Clinical Trial

— DALIAH  

Official title:

Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01387763
• Other study ID #: daliah2011
• Status: Completed
• Phase: Phase 3
• Start date: January 2012
• Est. completion date: June 2020

Study information

• Verified date: April 2022
• Source: Odense University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: June 2020
• Est. primary completion date: June 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Essential Thrombocythemia
• Neoplasms
• Polycythemia
• Polycythemia Vera
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• PegIntron
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
• Pegasys
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
• PegIntron
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
• Pegasys
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
• Hydrea
Capsule Hydrea 500-2000 mg orally QD or BID

Locations

Country	Name	City	State
Denmark	Dept of Hematology, Aalborg hospital	Aalborg
Denmark	Dept. of Hematology, Aarhus University Hospital	Aarhus
Denmark	Dept of Hematology, Esbjerg Hospital	Esbjerg
Denmark	Dept of Hematology, Herlev Hospital	Herlev
Denmark	Dept of Hematology, Holstebro Hospital	Holstebro
Denmark	Dept of Hematology, Rigshospitalet	København
Denmark	Dept of hematology, Odense University Hospital	Odense
Denmark	Dept. of Hematology, Roskilde Hospital	Roskilde

Sponsors (1)

Lead Sponsor	Collaborator
Thomas Stauffer Larsen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	molecular response (changes from baseline)	Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.	18, 36 and 60 months
Secondary	toxicity (discontinuation of therapy due to intolerability)	The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability	18 months
Secondary	Quality of life (changes from baseline)	Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF	4, 12, 24, 36, 48 and 60 months
Secondary	Histopathological response (changes from baseline)	A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.	36 and 60 months
Secondary	Sustained molecular response (changes from level at time of discontinuation of therapy)	investigation of the sustainability of an obtained molecular remission (<; 1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.	12, 24 and 36 months
Secondary	Neutralizing antibodies against PegIntron and Pegasys	Proportion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.	24 months
Secondary	hematological response	Hematological response will be evaluated according to the ELN guidelines.	12 months