Systemic Mastocytosis Responds to New Drug


ALBUQUERQUE, New Mexico ─ June 29, 2016 ─ Patients with a group of rare blood disorders known as advanced systemic mastocytosis have few treatment options. A drug called midostaurin showed promise in an international clinical trial coauthored by University of New Mexico and TriCore Reference Laboratories’ pathologist, Tracy George, MD.
A global trial of an oral medication called midostaurin indicates that the drug can produce partial or complete resolution of organ damage in 60 percent of patients with advanced systemic mastocytosis which includes mast cell leukemia, aggressive systemic mastocytosis, and systemic mastocytosis with an associated hematologic neoplasm.
The results of the open-label, phase-2 trial will be published June 30 in the New England Journal of Medicine. Jason Gotlib, MD, an associate professor of medicine at Stanford, led a team of international investigators that conducted the study, which enrolled 116 patients at 29 sites around the world. Tracy George, MD, an associate professor of pathology at the University of New Mexico, evaluated the pathology of the patients along with Hans-Peter Horny, a professor of pathology at the University of Munich. Andreas Reiter, MD, of the University of Heidelberg, is the senior author of the study. The study was funded by Novartis Inc., which manufactures midostaurin.
 “There is currently no effective therapy for patients with advanced systemic mastocytosis,” said George. “Midostaurin shows not only clinical improvement, but actual reduction of mast cells in the blood and bone marrow of patients. These include patients with mast cell leukemia that with currently available drugs have an expected life span of less than 6 months.”
What is systemic mastocytosis?
Systemic mastocytosis (SM) is caused by the accumulation of neoplastic mast cells in the bone marrow, spleen, liver, lymph nodes, skin and intestine. Normal mast cells mediate allergic and inflammatory responses in the human body and play a role in defending the body against organisms such as bacteria, fungi and viruses. Patients with systemic mastocytosis can experience flushing, itching, abdominal pain and diarrhea, and in some cases, anaphylaxis, when the mast cells release inflammatory mediators such as histamine. In mast cell leukemia and other advanced forms of the disease, neoplastic mast cells infiltrate organs leading to low blood counts, malabsorption, weight loss, bone fractures, splenomegaly and other organ enlargements, and liver dysfunction abnormalities.

A majority of patients with advanced SM have a mutation in the KIT gene (D816V) that controls the growth of mast cells. The KIT gene encodes the tyrosine kinase KIT protein, which in turn controls the activity for many different signaling pathways within cells. The D816V KIT mutation turns on and abnormally keeps on the KIT protein which results in systemic mastocytosis. Drugs known as tyrosine kinase inhibitors can be used to block the activity of the mutant protein to slow or eliminate disease progression. The only FDA approved drug for advanced SM is a tyrosine kinase inhibitor, imatinib, but it is not active against the D816V KIT mutation; thus, is not effective in most patients with advanced SM.
The search for an effective treatment

More than a decade ago, Dr. Gotlib and Dr. George worked together at Stanford diagnosing patients with hematologic malignancies. “Dr. Gotlib asked me to take a look at the blood of a patient with mast cell leukemia, a highly fatal variant of advanced systemic mastocytosis,” said Dr. George. “He recognized the significance of research by investigators at Harvard showing that a cell line with the mutant D816V KIT gene responded to midostaurin.” Dr. Gotlib petitioned Novartis for compassionate use of the drug in this patient with mast cell leukemia. Amazingly, the patient who was near death, had an incredible response to the drug, leaving the hospital and going shopping. Drs. George and Gotlib published this dramatic response in the journal Blood in 2005.
This single patient’s response resulted in an investigator -initiated clinical trial of midostaurin in the United States by Gotlib with George reviewing all diagnostic material for the trial and evaluating response to therapy in the patient’s blood and bone marrow. “The diagnosis of systemic mastocytosis is tricky,” noted George. “The disease is extraordinarily rare and can mimic other disorders. Many pathologists have never seen a case in their practice and the classification of the disease into subtypes requires specialized studies not performed in many centers.”
Promising results from the investigator-initiated trial prompted this current international multi-site clinical trial, launched in 2009.
Clinical trial results
Sixty percent of patients experienced complete or partial resolution of organ damage related to their disease in the current trial. Patients’ blood cell counts improved and they were less likely to need transfusions. Almost 80 percent of patients saw a reduction in their spleen size. There was also a significant decrease in the number of mast cells in bone marrow of patients (-59%, median change) and a significant decrease in serum tryptase level (-58%, median), which is a marker of mast cells.
The overall survival of patients was 28.7 months (median). Patients treated with midostaurin who experienced improvement in organ damage or a decrease in the percentage of mast cells in the bone marrow (e.g. responders) survived significantly longer than those who did not respond as well. The median survival of patients with mast cell leukemia was 9.4 months, compared to less than 6 months survival typically seen with this disease. Of 8 patients with mast cell leukemia who had a response, seven patients had a major response; four major responses were ongoing for 8, 19, 33, and 49 months at the time of data cut-off for the study. Hence, median survival for responders in the mast cell leukemia group has not been reached.
Side effects of midostaurin were low-grade nausea, vomiting and diarrhea. Patients reported a significant improvement in quality of life and disease-related symptoms.
At the current time, midostaurin is available on a compassionate-use basis for patients with advanced SM. Investigators hope that this drug will be approved by health authorities around the world.

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Dr. Tracy George is associate professor of pathology at the University of New Mexico School of Medicine. In addition, she serves as division chief of hematopathology and director of the Hematopathology Fellowship Program. Her research interests are in myeloproliferative neoplasms, with a focus on mastocytosis, and laboratory hematology. She has served in several education and leadership roles with the College of American Pathologists, and she is Vice President of Scientific Communications for the International Society for Laboratory Hematology.
For more information about the Department of Pathology at the University of New Mexico, please visit
For more information about TriCore Reference Laboratories, please visit
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