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Myeloproliferative Neoplasms
achieve after 12 months of treatment complete haematological therapy for JAK2-positive patients with ET, PV and MF. These clinical
remission in 90%, complete cytogenetic response in 70–80% and studies are currently in phase I and II. The most advanced studies
major molecular response in 40% of patients in the chronic phase involve the ICNB018424 compound, a selective JAK2 inhibitor. The first
of this disease. promising results of phase I and I/II studies were published in 2008.
30
Although initial enthusiasm was dampened by long-term
Clinical decisions are based on
observation, nothing can deny the fact that oral, patient-friendly
and low-intensity adverse-effect-causing therapy improved the life
increasingly precise assessment of the
expectancy of CML patients, even compared with bone marrow
risk factors of thrombotic/haemorrhagic
transplantation. This conclusion was the basis for profound
changes in standard therapy to imatinib as a first-line treatment in
complications and the risk of progression
nearly all patients. However, long-term observations revealed that
to the fibrotic phase or blast
molecular remission is not obtained in 20–30% of patients even
after 60 months of treatment, and it is lost in time by some patients.
transformation as well.
The patients having no benefits of target therapy with imatinib The studies concerned patients with primary MF (independently of JAK2
became a group of special interest for clinical studies with imatinib. status) and JAK2-positive post-PV/ET myelofibrosis. Administered orally,
Long-term observations showed that the time to the consecutive ICNB018424 invokes a clinical response, including improvement of the
phase of response varies among patients. This finding resulted in general condition of the patient, reduction of splenomegaly and
optimisation of the treatment time needed to achieve the next diminishing constitutional symptoms; however, it was also responsible
phase of clinical response.
22
The studies in the group of patients for thrombocytopenia, especially when given at higher doses.
with late molecular response as well as in those who lost molecular
response created the necessity for defining laboratory methods In the pre-clinical phase of studies there are other selective inhibitors
and therapy-monitoring standards.
23
(TG101209 and TG101348). Compounds identified as other mutation
inhibitors showing activity towards JAK2 are still awaiting clinical
The next milestone in CML therapy was the discovery of mutations in assessment. Due to the good prognosis, long-term survival
the kinase BCR-ABL gene domain responsible for acquired imatinib expectancy and the so far unclear prognostic value of JAK2 mutation,
resistance
24
and the development of BCR-ABL kinase inhibitors that the use of ICNB018424 and other inhibitors in patients with PV and
were compatible with these mutations. Two of these inhibitors, ET needs detailed description of the safety profile. Due to the central
dasatinib and nilotinib, were successfully validated in clinical studies role of JAK2 signalling in several cellular processes, there is
and approved for clinical use as a second-line therapy. apprehension about toxicity associated with wide JAK2 inhibition and
‘off-target’ inhibition of JAK1, JAK3 and TYK2.
Both mastocytosis and FIP1L1-PDGFRA-positive CEL included by the
authors in the MPN group can also be included in diseases in which The therapy for the third group, i.e. no molecular target disease, is
target therapy can be applied. Mutation D816V of the KIT gene results based on the primum non nocere rule. Clinical decisions are based
in ligand-independent activation of KIT kinase and provides resistance on increasingly precise assessment of the risk factors of
to imatinib.
25
In these cases, dastinib appeared to be an effective thrombotic/haemorrhagic complications and the risk of progression
drug.
26
However, activating point mutations in other codons of the KIT to the fibrotic phase or blast transformation as well. The appraisal of
gene may be sensitive to imatinib. In our unpublished data, we have the risk of blast transformation is complicated by the fact that long-
evidence of achieving a good response in patients with SM and codon term use of cytostatics is responsible for increased risk of disease
transformation. Although there was no direct evidence, this was the
reason for abandoning myleran therapy in ET patients.
The patients having no benefits of The risk of complications in PV and ET was studied by some
authors. Thrombotic history and age >60 years in both PV and ET
target therapy with imatinib became a
seem to be incontestable factors. The importance of cardiovascular
group of special interest for clinical risk factors is still unclear. The latest reports show that leukocytosis
can be regarded as a risk factor for complications as well as blast
studies with imatinib.
transformation.
31
The recognition of these risk factors needs further
study; moreover, the platelet count seems not to be prognostic. The
high risk of bleeding in patients with extremely high platelet counts
502–503 duplication of the the KIT gene mutation, which was (>1,000G/l) is currently regarded as a phenomenon related to
previously described in patients with gastrointestinal stromal tumours acquired von Willebrand disease.
32
The presence of any known risk
(GIST).
27
Low doses of imatinib could also be used in patients with CEL factors classifies the patient into the high-risk group.
and FIP1L1-PDGFRA mutation with excellent therapeutic effects,
28
even compared with results of bone marrow transplantation.
29
In the case of PV, patients usually undego phlebotomies and are put
on low-dose aspirin. When patients are in the high-risk group,
As mentioned above, the second group of MPNs is composed of therapy with hydroxyurea (HU) is started. When intolerance or
diseases with somatic mutations that constitutively activate JAK2 signal resistance to HU occurs, it is permitted to use interferon-α,
transduction. This fact provides for the development of novel target pipobroman or myleran as a second-line therapy.
EUROPEAN HAEMATOLOGY 59
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