Ongoing Study of First-Ever Drug Therapy for Myelofibrosis

Zosia Chustecka

December 08, 2009

December 8, 2009 (New Orleans, Louisiana) — An experimental oral compound that could be the first-ever drug therapy for myelofibrosis has shown benefits in an ongoing open study, with unprecedented reductions of enlarged spleens, improvements in quality of life, and durable responses. "The results are amazing," said lead researcher Srdan Verstovsek, MD, PhD, associate professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Srdan Verstovsek

"The results are intriguing, but it is early days yet," countered another researcher involved in myelofibrosis, Karen Ballen, MD, director of the leukemia program at Massachusetts General Hospital in Boston.

Speaking here at the American Society of Hematology (ASH) 51st Annual Meeting, Dr. Verstovsek said there is no standard approved therapy for myelofibrosis. This is a rare syndrome, affecting about 1 in 100,000 people, so many hematologists and oncologists may not have come across these patients, he noted.

Myelofibrosis is among the worst of the myeloproliferative disorders, and is both debilitating and fatal, he explained. It causes fibrosis of the bone marrow, which limits blood production, causing anemia. "The spleen and other organs attempt to take over the production of blood cells, which causes massive swelling of the spleen. Patients have poor quality of life, with fatigue, weight loss, abdominal, bone, and muscle pain, night sweats, and sometimes severe itching." End-stage patients look as if they are severely malnourished, with thin limbs and a swollen abdomen, and usually die in a hospice. The average survival is about 5 to 7 years, but in about 20% of patients, the disease transforms to acute myeloid leukemia (AML) and they die within 4 to 6 months, he said.

The new drug resulted in a "massive reduction in spleen and liver organomegalopathy," as well as an improvement in quality of life, with patients able to eat more and walk further, Dr. Verstovsek told Medscape Oncology.

Benefits were seen in patients regardless of whether or not they had the mutation.

The drug is an experimental JAK inhibitor, known as INBC018424, under development by Incyte Corporation. It was tested in myelofibrosis after the discovery, in 2005, that these mutations in the JAK2 gene are seen in many patients with myeloproliferative disorders. Dr. Verstovsek noted that about 50% of patients with myelofibrosis have a JAK2 mutation, but he emphasized that the drug "benefits were seen in patients regardless of whether or not they had this mutation."

The drug is also an inhibitor of JAK1, which leads to myelosuppression as an adverse effect, but this can be controlled by "selectively targeting the dose," Dr. Verstovsek explained. The drug was originally used at a dose of 25 mg twice daily, but this led to thrombocytopenia in about 30% of patients, so the dose being used now is 15 mg twice daily, with individual dose optimization from 10 to 25 mg twice daily. "This has improved the safety while maintaining the efficacy of 25 mg twice daily, the maximum tolerated dose," he told the meeting.

The open study was conducted in 153 patients, and all of the patients benefited, he said. Patients who were receiving an optimized dose of the drug showed a median reduction of 33% in spleen volume, as measured by magnetic resonance imaging, a 50% reduction in symptom score, and an improvement in the 6-minute walk test by a median of 33 meters at 1 month and 70 meters at 6 months.

"There are also indications that there might be an impact on survival, but more follow-up is necessary,"Dr. Verstovsek said. So far, 115 of the 153 patients (90%) who were enrolled in the trial remain alive, at an average follow-up of 16 months, he said. Patients with high-risk disease, the majority of patients in this trial, generally have an average survival of about 2 years, he added.

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Dr. Srdan Verstovsek

"There is also a suggestion — but again, only a suggestion — that the drug may be reducing the risk of transformation to AML," he added. So far, there have been 3 transformations to AML among the 153 study participants, a rate of 0.016 per patient-year, which compares with a historic-control rate of 0.056 per patient-year from 2 different studies in the literature.

Randomized Trials in Progress

Two randomized trials are now in progress, with a view to gathering data for registration. These data might be available for next year's ASH meeting, and the drug could be on the market by 2011, Dr. Verstovsek said.

One of the studies, known as COMFORT-1, will enroll 240 patients in the United States, Canada, and Australia, and will be a placebo-controlled trial of INCB018424, but patients in the placebo group who are not responding and/or who have an increase of 25% or more in their spleen size will be allowed to crossover, Dr. Verstovsek said. The other study, known as COMFORT-2, will be conducted in Europe; it will involve 150 patients and will be randomized in a 2:1 manner to INCB018424 or to standard of care, where physicians can use whatever therapies they choose. Details are available at

Currently, treatment of myelofibrosis consists of treating the signs and symptoms of the disease, Dr. Verstovsek explained. The anemia is tackled with erythropoietin, the poor quality of life with steroids, and the cachexia with testosterone-like drugs such as danazol. The large spleen is sometimes treated with oral chemotherapy, such as hydroxyurea, and in selected cases it can be removed surgically, but he noted that this has a 9% mortality rate, even in specialist centers. There is also the option of bone marrow transplantation, but that carries a 15% mortality rate and "we don't know the benefit yet," he said.

In patients who are eligible, transplant can cure the disease.

Dr. Ballen, who has been involved in trials of bone marrow transplantation in myelofibrosis, disagreed, and said that allogeneic bone marrow transplantation offers a curative treatment. Dr. Ballen told Medscape Oncology that, "in patients who are eligible, transplant can cure the disease." She acknowledged that many of these patients are too sick and too frail to undergo such a procedure, and so many more would be eligible for treatment with an oral drug, but she emphasized that the results so far are "preliminary."

Currently, allogeneic stem cell transplantation is the only known curative treatment, she said.

"Myelofibrosis is too complex to be eliminated by a single drug," Dr. Verstovsek said in a statement. JAK mutation is one of the underlying abnormalities, but it's not the sole cause of the disease. The new JAK inhibitor appears to "control the disease very well in most patients," he said, but "it will probably take combination therapies to cure myelofibrosis."

Dr. Verstovsek reports receiving research funding from Incyte.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 756. Presented December 7, 2009.


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