Myeloproliferative diseases D46.9

From both a pathogenetic and therapeutic perspective, it is useful to subdivide the group of chronic myeloproliferative neoplasms (MPNs) into:

I. BCR-ABL-positive chronic myeloproliferative diseases

• Chronic myeloid leukemia (CML)

II. BCR-ABL negative chronic myeloproliferative disorders

• Primary myelofibrosis (osteomyelofibrosis)
• Polycythaemia vera (PV)
• Essential thrombocythemia (ET)
• Chronic neutrophil leukemia
• Chronic eosinophil leukemia, not otherwise specified (NOS)
• Myeloproliferative neoplasms, unclassifiable (MPN, U)

Typical, but not necessarily obligatory, common features of chronic myeloproliferative neoplasias are an increase in one or more of the three cell lines of the blood(leuko-, erythro-, thrombocytosis) and a relatively characteristic increase in basophilic granulocytes. Splenomegaly is also typical and frequently diagnosed (exception: essential thrombocytosis). In the course of the disease, there is often a tendency to fibrosis and sclerosis of the bone marrow and reactive extramedullary haematopoiesis (especially in primary myelofibrosis).

The diagnosis of the individual entities is based on diagnostic criteria (see for the respective clinical picture), which, especially in the case of the main entities(chronic myeloid leukaemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis), rely heavily on the detection of clonal markers. These include the BCR-ABL fusion gene in chronic myeloid leukemia and the JAK2 (Janus kinase), CALR (calreticulin) and MPL (thrombopoietin receptor) mutation in the BCR-ABL negative entities mentioned above. The other entities (see classification) are diagnosed with the exclusion of the above-mentioned and with the exclusion of reactive alterations with corresponding diagnostic criteria. A clear differentiation from reactive changes in haematopoiesis is much more difficult with these.

The therapeutic procedure depends on the respective disease entity, whereby the therapeutic approaches differ particularly between the BCR-ABL positive and negative entities (see classification). Especially in BCR-ABL-negative chronic myeloproliferative neoplasias, the primary therapeutic approaches are predominantly palliative in nature, whereby the only curative therapeutic approach is usually allogeneic stem cell transplantation. Primary therapeutic goals, particularly in polycythemia vera and essential thrombocythemia, are the reduction of arterial and venous thromboses and the reduction of disease symptoms (see Clinical) by means of drug therapy.

I. Chronic myeloid leukaemia (BCR-ABL-positive)

Besides an initial cytoreductive therapy with hydroxyurea , if necessary, the long-term treatment with tyrosine kinase inhibitors such as imatinib (first-generation inhibitor), bosutinib, dasatinib and nilotinib (second-generation inhibitors) is in the foreground. However, at the stage of the blast crisis, similar treatment regimens are used as in acute leukemia, with the choice of chemotherapeutic agents depending, among other things, on whether the blast crisis is myeloid or lymphatic.

II BCR-ABL negative chronic myeloproliferative neoplasia

Especially in the case of polycythemia vera and essential thrombocythemia, depending on the risk constellation, therapy with ASA and, if necessary, cytoreductive therapy are in the foreground. In polycythemia vera, cytoreduction is primarily achieved by bloodletting therapy, in essential thrombocythemia by hydroxyurea, pegylated interferon α or anagrelide as required. The Janus kinase inhibitor Ruxolitinib is available as a second line therapy, if a corresponding mutation is detectable.

I. Chronic myeloid leukaemia (BCR-ABL positive)

Initially, the chronic form of the disease is mostly asymptomatic (median: 3-5 years), followed by the accelerated phase, which finally leads to the blast crisis, the picture of which is similar to that of acute leukemia and is determined with a survival time of a few months to a maximum of 1 year. Signs of the accelerated phase: clonal evolution in cytogenetics, increase in blasts (> 15%), and/or of blasts and promyelocytes (> 30%), and/or of basophils (> 20%) in the blood, and/or the development of thrombopenia (< 100,000/µl). By definition, a blast crisis is present when the blast percentage in blood or bone marrow is > 30%.

II BCR-ABL negative chronic myeloproliferative neoplasia

a) Polycythaemia vera: The mean survival time is about 19 years under therapy, without treatment about 1.5 years. In the chronic (polycythemic) phase, which usually lasts for years, the greatest risk is the occurrence of arterial and venous thrombus embolisms, which occur in up to 40% of patients and are the most frequent cause of death in untreated patients, accounting for over 60% of deaths. The late phase (also called "Spent Phase") of the disease is characterized by a decrease in erythrocytosis accompanied by corresponding changes in the bone marrow and an increase in splenomegaly. The transition to post-PV myelofibrosis occurs after 10 years of disease progression in 15% of patients, after 20 years in about 50%. Even though polycythaemia vera can directly change into acute leukaemia in the late phase (approx. 4% of patients), this usually occurs on the basis of post-PV myelofibrosis (20% of cases!).