Mastocytosis Becomes a 'Disease You Don't Want to Miss'

Zosia Chustecka

December 10, 2017

ATLANTA — Most hematologists and oncologists will not have come across systemic mastocytosis, but a new targeted drug that homes in on the underlying defect will help put this disease on physicians' radar, says an expert.

"Once you have a therapy, patients will come," said Daniel DeAngelo, MD, PhD, director of clinical and translational research, adult leukemia, Dana-Farber Cancer Institute, Boston, Massachusetts.

From the clinician's point of view, "once there's an effective therapy, this is a disease you don't want to miss," he told Medscape Medical News.

Speaking here at a press briefing at the American Society of Hematology (ASH) 2017 Annual Meeting, Dr DeAngelo was presenting the clinical data with a novel agent, avapritinib (BLU-285, Blueprint Medicines), which targets a specific mutation found in 90% of cases of mastocytosis.

The results, from an early dose-escalation trial, show impressive activity, with disease control seen in all patients, and improvements in clinical symptoms seen quickly. "The rapidity of the improvement is extremely dramatic," he commented.

Dr De Angelo noted that there has already been an increase in the attention being paid to systemic mastocytosis, and the last year saw the first-ever approval of a drug for this indication midostaurin (Rydapt, Novartis).

In an interview, Dr DeAngelo said that when he first became interested in this condition, "almost as a hobby," he was seeing one or two patients a year. Now he sees one to two patients a week.

There are an estimated 2000 mastocytosis cases per year in the United States, which is about half that for chronic myeloid leukemia, but he suggests that this is an underestimate, as the disease is often unrecognized, and is certainly underdiagnosed.

At present, the most common way hematologists get to see patients with mastocytosis is from referrals by dermatologists, who find these patients when they present with skin lesions, or from referrals by allergists/immunologists, who see patients with recurring severe anaphylactic reactions. Both of these are presenting symptoms for an underlying disorder in which mast cells are proliferating at pathological rate.

In a normal bone marrow, mast cells will account for only one or two cells in 1000, but in a patient with mastocytosis, some 10% of the bone marrow, and sometimes as much as 50%, is filled with mast cells, he explained.

This growing mass of mast cells distorts body organs, causing swelling of the spleen and leaving little room for the stomach, which can cause problems with eating, or the mast cells accumulate in the small intestine and colon and lead to malnutrition and weight loss. Other symptoms include disruption of liver function and low blood counts, and in some cases, the mast cells become malignant and transform into mast cell leukemia.

Until recently, there was no treatment for mastocytosis, and clinicians would try cladribine (Leustatin, Janssen Pharmaceuticals, Inc) or other chemotherapies or alpha interferon, but with limited success.

In the last year, midostaurin was approved by the US Food and Drug Administration for systemic mastocytosis, as well as for use in acute myeloid leukemia, having shown clinical efficacy in a phase 2 trial published in the New England Journal of Medicine, as reported by Medscape Medical News at the time. Midostaurin is a multitargeted kinase inhibitor, and its product labeling states that it achieved a complete response plus partial response rate of 17% (as measured according to International Working Group [IWG] criteria).

The preliminary results now reported for the new therapy avapritinib look much better, although they come from a small phase 1 study that was not designed to assess efficacy. In that study, among the 18 evaluable patients with aggressive systemic mastocytosis, 72% had an overall response and 100% had disease control. In addition, the complete response and partial response rate was 56% (according to IWG criteria).

Most patients showed a rapid improvement in clinical symptoms, Dr DeAngelo reported. Ten of 12 patients showed marked reductions of urticarial pigmentosa lesions. There were also improvements in malabsorption (n = 30), with a median weight gain of 5 kg (−3.7 to 16.3 kg).

The reductions in mast cell burden and D816V mutant allele fraction were durable, the researchers reported. As of the data cutoff, 30 of 32 patients remained in the avapritinib study, with a median duration of treatment of 9 months. Importantly, marked reductions in mast cell burden were noted in 2 patients with mast cell leukemia who had progressed on midostaurin, and also in 2 patients with advanced systemic mastocytosis who were intolerant to midostaurin, the researchers noted.

These results come from a phase 1 dose-escalation study, which concluded that the dose to be used clinically is 300 mg daily.

This dose will now be tested in a larger number of patients in a phase 2 trial.

Dr DeAngelo noted that most patients showed an improvement in clinical symptoms that was both rapid and striking, and he attributes this activity to the precise nature of the drug's targeting. Avapritinib BLU-285 was designed specifically designed to target the KIT D816V mutation, which is found in 90% of mastocytosis.

Commenting on this study, ASH Secretary Robert A. Brodsky, MD, professor of medicine and oncology and the director of the Division of Hematology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the drug shows marked clinical efficacy, and it also targets a known defect. "This is so exciting, as it is reminiscent of the Gleevec [imatinib] story in chronic myeloid leukemia from 20 years ago," he said.

The study was sponsored by Blueprint Medicines. Dr DeAngelo reports the following disclosures Consultancy: BMS, Incyte, ARIAD, Novartis Pharmaceuticals Corporation, Amgen, Pfizer Inc, and Takeda Pharmaceuticals USA, Inc; honoraria: Incyte, Immunogen, Blueprint Medicines, Shire, Novartis Pharmaceuticals Corporation, and Pfizer Inc; research funding: Immunogen, Blueprint Medicines; ARIAD, Glycomimetics, Celgene, Novartis Pharmaceuticals Corporation, Amgen, and Pfizer Inc.

American Society of Hematology (ASH) 2017 Annual Meeting: Abstract 2. Presented December 10, 2017.

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