Quizzed in Ansbach, then key to a drug trial for mast cell disease

By the time of these presentations, planning had already begun for the international trial and Dr. George had already been “tested” in Ansbach. During that December 2007 weekend, “Professor Horny picked up slide after slide of various types of mast cell disease. He looked at these slides with a microscope that was hooked up to a monitor—video microscope—and I could see the monitor. While he drove the microscope and asked questions over two days, I answered the questions as best I could.”

Says Dr. Horny, “We had an open and highly fruitful discussion, finally resulting in the starting point of the trial when we contacted Dr. Gotlib and Dr. [Peter] Valent of the University of Vienna on Saturday evening.”

During planning for the trial, Dr. George says, “What became increasingly clear was that pathologists were incredibly important. I could interpret lab values, I could look at bone marrows and peripheral blood. It wasn’t just mast cells decreasing; it was also eosinophils and monocytes in some patients. I talked with Jason Gotlib about how often to do bone marrows, what samples we should look at. Because we were so thorough, we have a robust understanding of how this drug works for this disease.”

The trial was conducted in patients with advanced systemic mastocytosis, which is an umbrella term for three distinct histologic entities: aggressive systemic mastocytosis (ASM); mast cell leukemia (MCL), defined by a bone marrow aspirate with at least 20 percent mast cells; and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). All can be fatal, owing to mast cell invasion of bone marrow, spleen, liver, gastrointestinal tract, and lymph nodes.

In addition to the clinical improvements already mentioned, Dr. Gotlib shared ad hoc survival data. “Survival is clearly short in patients with mast cell disease,” he tells CAP TODAY. In MCL, for example, survival is typically less than six months. In the trial, eight of 16 patients with MCL responded, and seven of those eight had major responses. “While median survival for the entire 16 MCL patients [including the responders] was 9.4 months, median survival for the eight responders had not been reached at the time of data cutoff,” Dr. Gotlib says. Median survival for those who did not have a response was 7.6 months, significantly less than for responders. Although the trial was not powered to look at survival, he called this finding “encouraging.”

Discussion is ongoing about a possible trial with combination therapy, perhaps midostaurin plus cladribine, Dr. Gotlib says, cautioning: “We must be circumspect about using the two drugs together, since it has never been done.”

In the Netherlands, a trial is already underway of midostaurin in patients with so-called indolent disease, those without frank organ damage. It is being directed by Hanneke C. Kluin‑Nelemans, MD, PhD, of the University of Groningen, one of the participants in the advanced systemic mastocytosis trial. Patients with indolent disease have medical symptoms such as flushing, diarrhea, and possibly ulcers. The most serious is anaphylaxis.

Midostaurin is also being submitted to the FDA for treatment of FLT3/internal tandem duplication acute myeloid leukemia. A large, collaborative trial was presented at the 2015 meeting of the American Society of Hematology, Dr. Gotlib says (http://bit.ly/midostaurin-ratify).

One reason that pathologists were so crucial to the trial is that mast cell disease is difficult to diagnose. “It is a rare disease,” Dr. Gotlib says, “both from the clinician’s and the pathologist’s standpoint. Not many people have experience with it unless they are at an academic center that tends to see a lot of cases.

“Also, if you don’t think about mastocytosis, you are not going to find it. It has pleiotropic symptoms and pathology, and it often occurs with other myeloid neoplasms,” he says. Like their initial patient, many patients with systemic mastocytosis have an associated MDS or MDS/MPN such as chronic myelomonocytic leukemia (CMML). That makes it hard to decide what disease component is causing symptoms and laboratory abnormalities—the mast cell disease or the associated myeloid neoplasm. Without special stains, such as tryptase or CD25, it is difficult to see the mast cells.

“I say that mast cell disease lurks in the shadows,” Dr. Gotlib says. He cites a patient with CMML who developed liver disease. Upon biopsy the liver was full of mast cells.
Dr. George has been working with The Mastocytosis Society, a group of patients with possible mast cell disease. (She and Dr. Gotlib are on the group’s medical advisory board.) It has become clear to her that many patients are dealing with clinicians who are not familiar with the disease and not comfortable making the diagnosis, especially in children, who typically have a more benign form of the condition. Often insurance carriers won’t pay for a proper workup. Dr. George has been doing pro bono reading of slides for some patients. “I have seen cases where pathologists have called the bone marrow normal and when I look at it I see abnormal mast cells. That gives me an opportunity to educate pathologists.”

One of the important diagnostic clues, she says: “Neoplastic mast cells don’t look like normal mast cells.” They have a different morphology and can mimic other cells. “I clearly recall a case of a five-year-old girl with primary GI symptoms whose bone marrow was called normal. Yet it was obvious to me on the bone marrow aspirate smear that there were abnormal spindle-shaped mast cells. The referring pathologist had never seen this before. Once you see it you can do ancillary studies to prove they are there.”

Dr. Horny agrees that mastocytosis can mimic other diseases, clinically and morphologically. “Morphologically, aggressive systemic mastocytosis may perfectly mimic bland bone marrow fibrosis,” he says. “And mast cells express various markers or antigens that are usually related to other hematological malignancies, such as CD14, CD25, CD30, CD68, and others. Mast cells, especially in mucosal layers, may even lose expression of tryptase, the antigen most commonly related to mast cells, resulting in an incomplete-aberrant immunophenotype.” This adds to the difficulty.

Dr. George calls being involved in the study the high point of her academic career. “It has been exciting to be on the cutting edge of diagnosing such a rare disease and being involved in finding effective therapy.”

For Dr. Horny, there has been an added professional benefit that can best be appreciated by other pathologists. “This was the first time for me to be involved as a consultant in an international trial. Never before was it possible for me to see so many cases of the rare category of advanced systemic mastocytosis. Until 2008 I had seen about 40 cases of mast cell leukemia over almost 30 years. Since then,” he says with excitement, “I have seen more than 100.”n

William Check is a writer in Ft. Lauderdale, Fla.