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

• molecular response (changes from baseline) [ Time Frame: 18, 36 and 60 months ] [ Designated as safety issue: No ]
  Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.
  
  

• toxicity (discontinuation of therapy due to intolerability) [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability
  
  
• Quality of life (changes from baseline) [ Time Frame: 4, 12, 24, 36, 48 and 60 months ] [ Designated as safety issue: No ]
  Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF
  
  
• Histopathological response (changes from baseline) [ Time Frame: 36 and 60 months ] [ Designated as safety issue: No ]
  A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.
  
  
• Sustained molecular response (changes from level at time of discontinuation of therapy) [ Time Frame: 12, 24 and 36 months ] [ Designated as safety issue: No ]

  investigation of the sustainability of an obtained molecular remission (<

  1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.

  
  
• Neutralizing antibodies against PegIntron and Pegasys [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Proprotion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.
  
  
• hematological response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Hematological response will be evaluated according to the ELN guidelines.
  
  

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.