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Oncology Times:
doi: 10.1097/01.COT.0000389882.98089.59
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Myelofibrosis: Promising Results with Oral INCB018424 JAK Inhibitor

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An oral medication produced “significant and lasting relief” for patients with myelofibrosis in a study reported in the September 16th issue of the New England Journal of Medicine.

Myelofibrosis...
Myelofibrosis...
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Myelofibrosis is caused by the accumulation of malignant bone marrow cells that trigger an inflammatory response, scarring the bone marrow and limiting its ability to produce blood, causing anemia, principal investigator Srdan Verstovsek, MD, PhD, Associate Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, explained in a news release.

“The problem with myelofibrosis is the lack of available therapies for patients—there are none approved for this disease today,” and available therapies approved for other diseases provide little response and are mainly palliative.

“This experimental drug is the first to target one of the underlying abnormalities in the malignant cells that cause myelofibrosis,” he continued. “It provides unprecedented reduction of enlarged spleens that are a central characteristic of the disease, and relieves pain, fatigue, and other symptoms, improving quality of life.

“Interestingly, other organs, mainly the spleen, attempt to take over the production of blood cells….The growing spleen causes significant problems for the patient, and not just because it's painful. It compresses the stomach and bowels, so patients suffer malnutrition and lose weight. The ability to walk and to bend is affected, and the body deteriorates overall.”

INCB018424, a JAK1 and JAK2 inhibitor developed by Incyte Corp., targets abnormal signaling caused by a mutation in the JAK2 gene that was discovered in 2005 in patients with myelofibrosis. The Phase I/II trial began in 2007 at MD Anderson and the Mayo Clinic and enrolled 153 patients, all of whom had either advanced disease or were newly diagnosed with high intermediate- or high-risk myelofibrosis.

Clinical responses have been maintained and 115 patients (75%) remain on the trial, the researchers reported. All patients benefited, with those on optimal doses experiencing:

SRDAN VERSTOVSEK, MD...
SRDAN VERSTOVSEK, MD...
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* A median reduction in spleen volume, as measured by MRI, of 33% at six months, with 48% showing reductions of at least 35%.

* “Swift and lasting spleen reduction”—70% to 82% of patients on the three optimal-dosing regimens had spleen reductions of at least 25% that occurred within the first two months of therapy and lasted more than a year.

* Rapid and lasting improvement in symptom score, with 51% of patients achieving a 50% reduction at one month, and 58% maintaining that at six months.

* Greater exercise capacity as measured in a six-minute walk. Patients increased their distance by a median of 34 meters at one month and 71 meters at six months.

* Median weight gain of 14.5 to 20.6 pounds after one year.

Symptom improvement coincided with a quick and sustained reduction in a variety of inflammatory cytokines involved in disease biology, the researchers noted, and the main side effect is lowered blood cell counts in some patients, which can be remedied by lower doses or temporarily halting therapy.

Dr. Verstovsek explained that the JAK2V617F mutation is the most prevalent involved in myelofibrosis, found in about half of patients, but it is not the sole cause of the disease—“Myelofibrosis is too complex to be eliminated by a single drug. It will probably take combination therapies to cure it.”

Normally, JAK2 is turned on by various growth factors to make new blood cells as needed. The JAK2V617F mutation leaves the JAK2 enzyme permanently turned on, which causes the overgrowth of bone marrow cells at the heart of myelofibrosis.

The drug worked in the study whether or not patients had the mutation—“suggesting that patients who do not have specific mutations still have a very active JAK signaling pathway and can benefit from JAK inhibition,” Dr. Verstovsek said. “However, because the drug also inhibits normal JAK2, it can lead to low blood counts that can limit dosing.”

Pivotal Phase III studies for INCB018424 in myelofibrosis are now under way in the United States, Canada, Australia, and Europe, the news release notes. The Phase I/II trial was the largest ever conducted for the disease and was funded by Incyte Corporation.

Dr. Verstovsek's coauthors for the study were Hagop Kantarjian, MD, Deborah Thomas, MD, Zeev Estrov, MD, and Jorge Cortes, MD, of MD Anderson; Ruben Mesa, MD, of Mayo Clinic Scottsdale; Animesh D. Pardanani, MBBS, PhD, and Ayalew Tefferi, MD, of Mayo Clinic Rochester; and Edward C. Bradley, MD, Susan Erickson-Viitanen, PhD, Kris Vaddi, PhD, and Richard Levy, MD, of Incyte.

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Hear More!

Dr. Verstovsek discusses more about his study in an OT Broadcast News podcast, recorded at the most recent ASH Annual Meeting, where he presented an abstract of the research.

Click on “Podcasts” on oncology-times.com

© 2010 Lippincott Williams & Wilkins, Inc.

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