“Solving the problem of anemia and having fewer patients with myelofibrosis who are transfusion-dependent could certainly have a great impact on their quality and quantity of life, because the transfusion-independent patient lives longer and better” and this “is a extremely important data.” This was stated by Francesco Passamonti, full professor of Hematology, University of Milan and director of Complex Structure, Department of Oncology and Onco-Hematology of the Milan Polyclinic, speaking this morning in Verona in a meeting with journalists organized by GSK, in where the latest therapeutic innovations for the treatment of this bone marrow neoplasm characterized by the proliferation of abnormal red blood cells and the accumulation of fibrous tissue were presented.
“The main problems of the patient with myelofibrosis are splenomegaly”, enlargement of the spleen, “the presence of systemic symptoms and anemia or thrombocytopenia – explains Passamonti – The drugs currently used for the treatment of myelofibrosis, the Jak inhibitors ruxolitinib and fedratinib , approved in Italy and reimbursed for the first line ruxolitinib and for the first and second line fedratinib, reduce splenomegaly and improve systemic symptoms, but can also worsen anemia. Recently, a new one has received approval, also in Europe Jak inhibitor, “momelotinib, for the patient with anemic myelofibrosis because this molecule has been shown to improve not only splenomegaly, but also anemia”.
“We ask the new molecules for the treatment of myelofibrosis – explains the professor – to also address the problem of anemia, because 20% of these patients require transfusions and must go to hospital initially once a month, then every 3 weeks, then every 2, every once and even 2 times a week, because obviously over time there is a minimum of refractoriness to transfusions and, above all, the disease progresses”. When accessing the hospital, the patient often has to “be accompanied by a caregiver”, which entails a “loss of working days for both and an extremely important social impact”. Furthermore, on a clinical level, “there is above all an accumulation of iron in the heart, in the kidneys, in the liver. This does not cause problems in 6 months, but in years. Therefore a chronic transfusion-dependent anemia can have a series of problems”.
“Myelofibrosis, which can be defined as rare given the incidence of 1.2-1.4 new cases in 100 thousand inhabitants/year – continues Passamonti – has aspects that we call myelopolyferative such as leukocytosis, splenomegaly, the presence of systemic symptoms such as fever, sweating and weight loss and, in many patients, it is also accompanied by the effects of cytopenia, i.e. anemia and thrombocytopenia, which represent 'unmet medical needs', i.e. areas in which today we have no therapies”. Of course, “the pathophysiology of myelofibrosis is not entirely defined – adds the specialist – but it involves the activation of a cellular pathway, the Jak-Stat pathway, which plays an essential role because it is involved in metabolic and immune functions and in hematopoiesis. From 2005 onwards we also understood the pathogenesis of this disease”, which in 85% of cases presents mutations in at least one of 3 genes: Jak2 (prevalence 50-60%); Mpl (prevalence 5-9%); Calr (prevalence 20-35%). “When the Jak2 gene is overactive, the production of white blood cells hemoglobin and platelets is activated.”
Jak inhibitor drugs “are able to slow down the pathway, the cellular Jak-Stat pathway, hyperactivated by the Jak2, Mpl and Carl genes. Obviously, all these Jak inhibitor molecules, by acting on Jak-Stat, can improve splenomegaly and symptoms systemic, but also cause anemia and thrombocytopenia”. Momelotinib has also been shown to improve anemia. The drug, in fact – it was recalled during the event – in addition to inhibiting Jak1 and Jak2 also inhibits another target (Acvr1), effectively reducing the production of hepcidin, restoring iron homeostasis and increasing hemoglobin levels, improving constitutional symptoms, splenomegaly and cytopenias”.
Jak inhibitors “do not represent the only therapeutic option we have in myelofibrosis – concludes the hematologist – Allogeneic bone marrow transplant is the only procedure we have today to cure, but it may be indicated in 10-15% of patients and it is a highly life-threatening procedure.”
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