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Researchers Uncover Potential New Therapy Combo for Rare Blood Disease

MADRID (ESP), December 2018 — Myelofibrosis is a severe and very rare hematological disease for which treatment has only been partially effective to date. Its low incidence rate is one of the reasons why effective therapies are still lacking. But a new study by researchers from the Spanish National Cancer Research Centre (CNIO) and the Hospital 12 de Octubre shows how a three-drug combination therapy paves the way for a substantial improvement in the treatment of myelofibrosis.

A clinical trial involving patients is already up and running.

The research, published in Haematologica, was led by Joaquín Martínez-López, M.D., Ph.D., and coordinated by Miguel Gallardo, Ph.D., from the CNIO’s H12O-CNIO Haematological Malignancies Clinical Research Unit. It is based on a pharmacological screening process in which cells taken from patients suffering from myelofibrosis are exposed to several drugs, including ruxolitinib, one of the treatments recommended for this disease. The results show that its beneficial effect is enhanced when combined with nilotinib and prednisone. Prednisone is a corticosteroid and nilotinib is used for the treatment of chronic myeloid leukemia.

Myelofibrosis affects bone marrow stem cells, which are responsible for making all blood cells. It is characterized by the excess production of connective tissue that leads to fibrosis and 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.

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, explains the molecular mechanism that causes this disease in 90 percent of patients.

Thanks to that finding, ruxolitinib began to be used as a treatment. This drug, which acts by inhibiting the activity of the JAK2 molecule, 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.

Dr. Gallardo explained, “Ruxolitinib is one of the recommended treatments for myelofibrosis. 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 lead author of the paper, Alicia Arenas, Ph.D., from the Hospital 12 de Octubre, began five years ago to explore the effectiveness of other drugs already in use for other ailments, alone or in combination with ruxolitinib.

Her team 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, prednisone and ruxolitinib, "the drugs potentiate each other," explained Dr. Gallardo, thereby "enhancing the effectiveness" of the therapeutic benefit of ruxolitinib.

The researchers attribute the improvement 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.

Based on the findings of the synergetic effect of the combination therapy on myelofibrosis, a phase I clinical trial has been launched to study whether the positive results observed in cell cultures are also seen in patients. Eight Spanish hospitals are taking part in this trial.

Comparison of myelofibrosis models by collagen staining. Untreated cells (left) show the presence of fibrosis, while (right) cells that have undergone the three-pronged therapy exhibit reduced fibrosis. Image courtesy of CNIO.

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DOI: 10.3324/haematol.2018.201038