Trial Information

A Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms - A National Randomized Prospective Study With Focus on Efficacy, Toxicity and Quality of Life

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.