How I treat myelofibrosis

Abstract

Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK)2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. However, although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

Aktualitások a primer myelofibrosis ellátásában

“…A betegség kifejlődését eredmé-nyező és a konstitutív JAK/STAT aktivációhoz vezető, úgynevezett szomatikus drivermutációk közül a PMF esetében a betegek ~50%-ában mutatható ki a JAK2V617F-mutáció, 30-35%-ában a calreticulingén (CALR) különböző mutációi és körülbelül 5%-ában az MPLW515L/K-mutáció, míg mintegy 10%-ban ezen mutációk egyike sincs jelen, ezek a betegek az úgyneve-zett "triple negative" csoportba tartoznak [8,9]. Ritkábban más (szubklonális) mutációk is megfigyelhetők (például: TET2, ASXL1, IDH1/2, EZH2, DNMT3A, TP53, SRSF2, SF3B1 stb.…”

“…Egyéb esetekben a kezelés elsődleges célja a tünetek (hepatosplenomegalia, anaemia, fatigue, viszketés, korai teltségérzet, aktivitási tünetek stb.) és így az életminőség javítása [8,10,18,29,30].…”

“…Amennyiben progresszió észlelhető (aktivitási tünetek, panaszokat okozó splenomegalia, progresszív leukocytosis, transzfúzióigény megjelenése stb. ), úgy a kezelés megkezdése javasolt [8,10,29].…”

JAK inhibitors truly changing the therapeutic paradigm in myelofibrosis

“…MF, however it arises, is characterized by abnormalities of the blood counts, especially anemia; circulating immature cells (leukoerythroblastosis), progressive splenomegaly, and a variety of symptoms affecting quality-of-life (QoL) 1 . Such symptoms include unexplained fever, drenching night sweats, and weight loss (often termed 'constitutional symptoms'), abdominal discomfort, and pain due to massive spleen enlargement, bone, muscles or joint pain, pruritus, and profound fatigue.…”

Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response

“…2 With the exception of allogeneic hematopoietic stem cell transplant, therapies for myelofibrosis have targeted symptoms but have not modified the natural history of the disease. 9 The recent introduction of the JAK1/2-inhibitor ruxolitinib has partially changed the therapeutic landscape, as it has been shown to reduce splenomegaly and myelofibrosis-related constitutional symptoms. Recent evidence may suggest an improved overall survival, but this is questioned by others.…”