Myelofibrosis is a severe and very rare hematological disease for which treatment has only been partially effective to date. It is a Philadelphia chromosome-negative chronic myeloproliferative cancer clinically characterized by stem cell-derived clonal proliferation and a reactive cytokine-driven increase in bone marrow fibrosis. Patients with myelofibrosis have a poor prognosis and a median survival of 5.8 years. Myelofibrosis is characterised by the excess production of connective tissue that leads to fibrosis, and which eventually replaces stem cells in the bone marrow. This in turn forces blood cells to mature outside of the bone marrow, and immature cells can even migrate to other tissues such as the spleen or liver. The average age of patients at diagnosis is 65, although myelofibrosis also occurs in young people. Survival with treatment is around five years. Its low incidence rate is one of the reasons why effective therapies are still lacking. The year 2005 probably saw the most important advancement made until now in myelofibrosis research: the discovery of the JAK2 gene mutation, which, together with the finding of the CALR mutation in 2013, explain the molecular mechanism that causes this disease in 90% of patients. Thanks to that finding, a drug called ruxolitinib began to be used, which acts by inhibiting the activity of JAK2. This treatment has been shown to be fairly effective in polycythemia vera and essential thrombocythemia, pathologies that involve the JAK2 mutation but not as effective in myelofibrosis.
The H12O-CNIO Hematological Malignancies Clinical Research Unit at the Spanish National Cancer Research Centre (CNIO) has now reported a three-drug combination therapy, that pave the way for a substantial improvement in the treatment of myelofibrosis. A clinical trial involving patients is already up and running. The team published thefindings in the journal Haematologica. The research was led by Joaquín Martínez-López and coordinated by Miguel Gallardo, from this Unit. It is based on a pharmacological screening process in which cells taken from patients suffering from myelofibrosis are exposed to several drugs, including one of the treatments recommended against this disease, ruxolitinib. The results show that its beneficial effect is enhanced when combined with nilotinib and prednisone, which are currently used to treat other diseases. Ruxolitinib is one of the recommended treatments for myelofibrosis, but, although it is still too soon to evaluate its effectiveness in terms of survival, it has proved to be effective in only a proportion of patients, and even in these, only to treat certain symptoms. Faced with this situation, the team spent five years ago to explore the effectiveness of other drugs , alone or in combination with ruxolitinib. The group selected 17 compounds whose mechanism of action or therapeutic effects could provide potential treatments for myelofibrosis. The researchers conducted ex vivo tests on samples from patients with myelofibrosis and began to expose cells to the different compounds, either singly or in multiple combinations.
They then measured the effectiveness of each combination and studied the biological pathways on which each compound was acting. The results are starting to come in and are encouraging. They reveal that when therapy combines nilotinib, ruxolitinib and prednisone, the drugs potentiate each other enhancing the effectiveness of the therapeutic benefit of ruxolitinib. The authors attribute the improvement observed to the combination of the antifibrotic effect of nilotinib with the immunomodulatory action of ruxolitinib and the anti-proliferative action of prednisone against the myelofibrosis blast cell. Prednisone is a corticosteroid; and nilotinib is used for the treatment of chronic myeloid leukemia. In addition, this combination inhibited the synthesis of collagen in bone marrow mesenchymal cells, which is the important to achieve histopathological response. The antifibrogenic effect of nilotinib has been previously described in skin cells, liver and muscle, because blocks PDGF receptor, which is directly involved in the induction of collagen synthesis. Similar results are seen with prednisone, which decreases the levels of cytokines and proinflammatory growth factors including TGF-β. Based on the findings of the sinergic effect of the combination therapy on myelofibrosis, a phase I clinical trial has been launched in order to study whether the positive results observed in cell cultures are also seen in patients. Eight Spanish hospitals are taking part in this trial.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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