Myeloproliferative neoplasia (MPN)

All forms of myeloproliferative neoplasia (MPN) are treated at the Department of Internal Medicine III. The most common MPNs include chronic myeloid leukaemia (CML), essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF) (Fig. 1). Rarer MPNs include systemic mastocytosis (SM) and chronic eosinophilic leukaemia (CEL). A particular focus is on conducting and participating in clinical trials with the aim of improving current treatment standards and making newly developed drugs available to patients before they are authorised. Due to the improved understanding of the biology of the diseases, a targeted therapy strategy is increasingly being pursued for MPN. The Ulm Centre is intensively involved in the clinical studies of the German CML Study Group (CMLSG). To further improve the treatment of ET, PV and PMF, the MPN Study Group (GSG-MPN) was founded in 2008. The first GSG-MPN study was activated in 2009. Ulm is a co-founder of the study group and a national reference laboratory. Patients with MPN are mainly cared for in the specialised outpatient clinic.

An important focus of the Department of Internal Medicine III is research into the genetic basis of these diseases. To this end, bone marrow and/or blood cells from patients affected by the disease are analysed for the presence of genetic changes. In recent years, great progress has been made in the genetic characterisation of MPN. A number of genetic alterations in MPN patients are now known that allow a more precise differentiation between the diseases. This means that not only can CML be differentiated from other MPNs on the basis of the presence of the so-called Philadelphia chromosome, but it has also become possible to diagnose Philadelphia-negative MPNs more easily and classify them better on the basis of the genetic changes present. One example of this is the identification of mutations in the JAK2, TET2 and EZH2 genes (Fig. 2). This genetic classification will also have a significant impact on the treatment of MPN in the coming years. In addition, the continuous development of new technologies enables research into previously unknown genetic changes.

Both clinical studies and basic research are carried out in close co-operation with German or international study groups. The aim is for the results of this research to contribute to finding more effective therapies in future that are tailored to the specific genetic characteristics of individual patients.

Basic information

MPN are malignant bone marrow diseases (site of haematopoiesis) with a slow progression. The clinical spectrum of the diseases is diverse. CML is typically characterised by a strong proliferation of white blood cells (leukocytes) in various forms of maturation (Fig. 3). If left untreated, the insidious disease ("chronic phase") changes after a few years into a more threatening and faster progressing form ("acceleration phase") and finally progresses like an acute leukaemia ("blast crisis"). In over 90% of cases, the disease is caused by a defined genetic change, the so-called Philadelphia chromosome. This is caused by an exchange of genetic material between chromosomes 9 and 22. Substances have now been developed on the basis of this genetic alteration that have a very specific and targeted effect. These are the so-called tyrosine kinase inhibitors (TKIs). In later or more advanced stages of the disease, other genetic changes occur in addition to the Philadelphia chromosome. This proves that the disease also progresses on a biological level.

In ET, the proliferation of blood platelets (thrombocytes) is at the forefront of the disease. In PV, an increase in the number of red blood cells (erythrocytes) is typical, although platelets and leukocytes may also be increased. In the early phase of PMF, as in ET, the number of platelets in the blood is increased, but as the disease progresses, there is increasing connective tissue remodelling of the bone marrow, resulting in cell depletion. In addition to these three classic forms of Philadelphia-negative MPN, there are also fluid transitions between ET, PV and PMF. In contrast to CML, the genetic causes of ET, PV and PMF are complex. However, in recent years it has been possible to identify various gene mutations that at least partially explain the pathogenesis of ET, PV and PMF. For example, the mutation V617F in the tyrosine kinase gene JAK2 is found in almost all patients with PV and in around 50% of patients with ET and PMF. Numerous research projects are currently being activated with the aim of utilising these findings therapeutically, as in the case of CML. The aim is to develop targeted drugs that inhibit the proliferation of the diseased cells. In Germany, approximately 1-2 adults per 100,000 inhabitants are diagnosed with MPN each year. The risk increases with age. However, the diseases can occur in all age groups.

The above-mentioned use of TKIs has increasingly changed the treatment of MPN in recent years. The principle of molecularly targeted therapy has revolutionised the treatment of CML in particular. The effect of TKIs is based on the targeted treatment of the changes in the diseased cells caused by the Philadelphia chromosome. TKIs are taken in tablet form. Imatinib (trade name Gleevec®) is the most commonly used. Side effects such as nausea, muscle cramps and fluid accumulation in the tissue (oedema) occur in some patients. Regular, daily administration of the drug is necessary on a permanent basis, as this is the only way to effectively reduce CML and prevent the progression of the disease. It is also important that treatment is started immediately after diagnosis, as CML is more difficult to treat in more advanced stages than in the early phase. In most cases, the white blood cells normalise after just a few weeks of therapy. In addition, the success of the treatment is precisely determined by regular blood tests using modern laboratory methods. In some patients, the treatment responds so well that after months of therapy there is little or no detectable disease activity. Nevertheless, according to current knowledge, there is no cure for CML, as the disease recurs quickly after discontinuation of the drug and may then be more difficult to treat. The problem is that the diseased cells can become resistant to the drug during treatment with TKIs. It is possible that newer TKIs, which are currently undergoing clinical trials, have an even more lasting effect on the diseased cells and are also better tolerated. Nilotinib (Tasigna®) and dasatinib (Sprycel®) are two promising new-generation TKIs that are being investigated in trials. Ulm is a participating centre in a CMLSG-supported study that enables the use of nilotinib in newly diagnosed CML patients. The use of TKIs means that intensive forms of therapy with more side effects, such as chemotherapy and blood stem cell transplantation, have clearly taken a back seat. However, these can be used in the event of TKI intolerance or failure.

Some forms of rare MPN, such as CEL with evidence of the FIP1L1-PDGFRA gene fusion, also respond to treatment with imatinib. However, this does not apply to patients with ET, PV and PMF, as the V617F mutation in the JAK2 gene is not sensitive to imatinib. Various JAK2 inhibitors are currently undergoing clinical trials. Initial study phases for the substances have been completed. Renewed study activities are expected at the end of 2010, which will enable the treatment of MPN patients with a JAK2 inhibitor. In addition to JAK2 inhibitors, other substances such as IMiDe are currently being trialled, particularly in MF patients. If they fulfil the inclusion criteria, MF patients can currently be included in the MPNSG-01-09 study (Fig. 4). This is a single-arm study with pomalidomide that was activated in December 2009. Pomalidomide belongs to the group of immunomodulatory drugs. The background to the use of IMiDen is data showing an improvement in haematopoiesis in MF patients. The substance, which is available as a tablet, appears to be particularly effective in the treatment of anaemia and low platelet counts.

Outside of studies, the treatment of ET, PV and PMF patients is based on established risk characteristics derived from the patient's medical history, age and blood count values. By recording these parameters, the course of the disease can be better assessed on an individual basis. In low-risk ET patients, monitoring the blood count alone may be sufficient. In PV patients, phlebotomies are usually performed to reduce the number of erythrocytes and acetylsalicylic acid is administered in low doses (100 mg daily). If there is an increased risk of thromboembolic complications, additional medication can be used to reduce the platelets and/or erythrocytes in the blood. Examples include hydroxyurea and interferon-alpha. In PMF patients, risk stratification can be used in particular to assess the prognosis of the disease. In patients with an unfavourable constellation, in whom a rapid progression of the disease is likely, a recommendation can then be made, for example, to administer more intensive chemotherapy followed by a blood stem cell transplant. Due to the severe side effects, a particularly careful risk-benefit assessment must be carried out here.