Clinical Trials

Novel Therapy for Myelofibrosis

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Myelofibrosis is an incurable blood disease characterized by symptoms related to lack of blood production and enlarged internal organs, especially the liver and spleen. Its hallmark is scarring (fibrosis) of the bone marrow (myelo-), hence the name “myelofibrosis”. As the disease progresses the marrow becomes obliterated by fibrosis seriously impairing its ability to produce blood. Paradoxically marrow elements appear in the liver and spleen, both of which enlarge greatly. The spleen may become especially massive compressing the stomach impairing eating, and also causing abdominal pain. The average survival of high risk cases is only 5-8 years, and there are no approved therapies. Surgical removal of the enlarged spleen is very problematic, and the disease can transform into acute leukemia in 5-20% of patients. Obviously, some sort of treatment besides supportive care is urgently needed.

A very exciting research development occurred in 2005. Four independent research groups almost simultaneously discovered a main molecular abnormality in myelofibrosis and two other closely related diseases, polycythemia vera and essential thrombocythemia. The same genetic mutation was found in all three conditions, providing confirmatory evidence that these diseases not only were related, but also may have the same fundamental genetic cause. This mutation was discovered in a gene called JAK2, which controls the production of a cell enzyme known as JAK kinase, important in regulating bone marrow and blood production. When the JAK2 gene is altered (mutated), it causes JAK kinase to be activated all the time sending unregulated signals to DNA, and promoting abnormal growth of bone marrow elements.

After discovering that the JAK signaling pathway was abnormally activated in myelofibrosis, it was logical to presume that a drug that inhibits JAK kinase might reverse this disease. Many JAK inhibitors have been developed, but the most widely tested is ruxolitinib, an oral agent which has completed two phase III trials. Tower Cancer Research Foundation has been a participating site, and our results pooled with other sites were just presented at the June, 2011 ASCO meeting. The data showed that the effects of ruxolitinib occur rapidly; it significantly reduces spleen size and facilitates eating and weight gain, reduces itching, and improves fatigue. In a significant percentage of patients this drug seems to offer unequivocal relief of symptoms and improved quality of life, although it is too soon to evaluate its effect on long-term survival. The data from this trial have just been submitted to the FDA with a request for priority review.

The development of this drug illustrates the importance of basic research focused on understanding the molecular genetics of a disease. Research identified an overactive cellular pathway, after which a drug was developed to target it. This agent now seems to be an important advancement for the treatment of myelofibrosis, as it provides relief of symptoms and a degree of control for a previously untreatable condition.

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