American Society of Hematology

Ask the Hematologist January February 2013

Jason Gotlib, MD, MS
Stanford University School of Medicine, Stanford, CA

Published on: January 01, 2013

Dr. Gotlib is the chairman of the Study Steering Committee for the Novartis-sponsored global trial of midostaurin in advanced systemic mastocytosis. He also receives funding for administration of the clinical trial and payment for travel expenses from Novartis. Dr. Gotlib will also serve as the principal investigator on a forthcoming trial of brentuximab vedotin in advanced systemic mastocytosis.

Associate Professor of Medicine (Hematology) & Director, Hematology Fellowship Program, Stanford University School of Medicine and Stanford Cancer Institute

The Question

What is your approach to the diagnosis and management of mastocytosis?

Defining Mastocytosis

Mastocytosis is characterized by the accumulation and proliferation of neoplastic mast cells in one or more organs (e.g., skin, bone marrow, spleen, lymph nodes, liver, and gastrointestinal tract). Flushing, diarrhea, anaphylaxis, and neuropsychiatric symptoms resulting from mast cell release of bioactive molecules such as histamine, leukotrienes, and various inflammatory cytokines can impose a significant burden on a patient’s quality of life. Such mediator symptoms may be triggered by physical stimuli, exercise, alcohol, NSAIDs, opioids, insect stings, or certain foods. In advanced disease, mast cell infiltration of tissues can lead to organ damage and shortened survival.

The World Health Organization (WHO) includes mastocytosis within the category of myeloproliferative neoplasms (MPN) and divides these disorders into cutaneous and systemic forms.1 The diagnosis of systemic mastocytosis (SM) is based on consensus diagnostic criteria (Table) and requires one major plus one minor criterion or three minor criteria. Clinicopathologic criteria are used to further classify SM into subtypes that generally reflect clinical severity and prognosis. In indolent SM (ISM), where bone marrow mast cell burden is relatively low, survival is similar to age-matched populations, and clinical issues are usually related to mediator symptoms.2 Smoldering SM (SSM) is a subtype of ISM that reflects SM in transition toward more advanced disease and is characterized by two or more so-called “B-findings” (Figure), including organomegaly, and indicators of a relatively higher mast cell burden (e.g., > 30% bone marrow mast cells and serum tryptase level > 200 ng/ml). Advanced SM collectively refers to SM subtypes in which organ damage (referred to as “C” findings) is present. This includes the WHO-defined subtypes aggressive SM (ASM), mast cell leukemia (MCL), and SM with an associated hematologic non-mast cell lineage disease (SM-AHNMD). Approximately 90 percent of AHNMDs represent a myeloid neoplasm such as myelodysplastic syndrome (MDS), MPN, MDS/MPN (e.g., chronic myelomonocytic leukemia), eosinophilic disorders, or acute myeloid leukemia (AML). Rarely, a lymphoid neoplasm may be concurrently diagnosed with SM.

Mastocytosis is a challenging disease for many reasons. In the normal state, mast cells are not identified on the peripheral blood differential and represent a small fraction of the myeloid lineage on visual inspection of the marrow aspirate. The idiom “out of sight, out of mind” is apt in the case of SM and, together with its rare incidence, tests the physician to think about this neoplasm in the first place. If present, prototypic mediator symptoms such as flushing, diarrhea, and anaphylaxis may make this task easier. In advanced disease, organ damage such as cytopenias, liver dysfunction, ascites, lytic bone lesions, and hypoalbuminemia with weight loss due to mast cell infiltration of the gastrointestinal tract are sufficiently protean to conceal a unifying diagnosis. Because SM often partners with a myeloid disease, immunohistochemical (IHC) stains (e.g., tryptase, CD117 [KIT], and CD25) are necessary to identify and quantify neoplastic mast cells in trephine biopsies and can additionally help unmask SM when it lives in the shadow of other neoplasms. Clinical and biologic heterogeneity, even within specific SM disease subtypes, can make it difficult to gauge disease trajectory and prognosis. In patients with an AHNMD, prognosis is usually related to the associated myeloid neoplasm, highlighting the need to fully characterize and stage the concomitant disease.

Diagnosis

In addition to a high index of suspicion, obtaining the expertise of a cadré of subspecialists (hematologists, dermatologists, and allergists/immunologists) as well as hematopathologists versed with the nuances of mast cell disease is important in establishing the correct diagnosis. A combination of clinical, morphologic, immunophenotypic, and molecular studies is required to establish the diagnosis of SM and its subtype. Bone marrow mast cell burden is best quantified by morphologic analysis, and use of the aforementioned IHC stains on the core biopsy is essential. The major criterion for SM requires demonstration of multifocal mast cell aggregates in the bone marrow (or other extracutaneous organ), of which > 25 percent are atypical, often spindle-shaped mast cells. In MCL, mast cells account for > 20 percent of nucleated cells on the BM aspirate and form a diffuse infiltrate on the core biopsy with or without circulating mast cells. Multi-parameter flow cytometry of the BM aspirate can also be used to quantify mast cells in the marrow and complements morphologic evaluation. The overwhelming majority of SM patients (> 80%) carry the activating KIT D816V mutation, which should be obtained from the bone marrow aspirate or from a core biopsy that is preserved in formalin to avoid degradation of DNA for PCR analysis. Determination of KIT D816V mutation status is critical to the diagnostic evaluation of SM, but it also guides treatment decisions. Although KIT D816V is an imatinib-resistant mutation, this tyrosine kinase inhibitor has been reflexively misapplied and overused in the treatment of SM. However, a small minority of patients (< 5%) may exhibit juxtamembrane KIT mutations, which exhibit sensitivity to imatinib in vitro as well as in clinical practice. Such cases illustrate that sequencing the remainder of the KIT gene in SM patients who are negative for codon 816 mutations may prove fruitful. Total serum tryptase levels generally reflect the increased burden of mast cells in patients with SM. A serum tryptase level > 20 ng/ml is an additional minor criterion for the diagnosis of SM. Although not always concordant, it is the most useful blood marker to assess changes in mast cell burden in response to cytoreductive therapy. In advanced disease, staging studies include CT of the abdomen to assess hepato/splenomegaly, lymphadenopathy, and ascites; metastatic skeletal survey to evaluate osteolyses and/or pathologic fractures; and DEXA scans to follow osteoporosis, which is common in SM. Some patients with mediator symptoms who do not fulfill criteria for SM (e.g., only one or two minor criteria and/or exhibit a low burden of atypical mast cells without aggregates on biopsy) have been given the provisional diagnosis of mast cell activation syndrome (MCAS).2 The diagnostic criteria for this mast cell disorder are still evolving and its natural history is not well-defined.

Treatment

Individuals with symptomatic skin-only disease or SM with mediator symptoms are educated to avoid known triggers and are encouraged to carry an Epipen®, particularly those with a history of anaphylaxis or anaphylactoid symptoms. Antihistamines (H1- and H2-blockers) serve as the foundation for symptom palliation; leukotriene antagonists (e.g., monteleukast) and mast cell stabilizers (e.g., cromolyn sodium) are typically used for refractory mediator symptoms. Osteoporosis is treated with conventional approaches, and radiotherapy and/or IV bisphosphonates may be used to treat osteolyses or pathologic fractures. Patients with advanced SM exhibit shortened survival, and cytoreductive therapy is used in an attempt to reverse organ damage. Interferon-α with or without corticosteroids and 2-chloro-deoxyadenosine demonstrate overall response rates in the range of 30 to 60 percent, including major responses denoting normalization of organ dysfunction.3 Intensive chemotherapy has been used in MCL with modest benefit, and there is a paucity of published data regarding the utility of stem cell transplantation for advanced SM. The generally short-lived responses and tolerability of these approaches have reinforced the need to enroll patients in clinical trials evaluating novel agents. The tyrosine kinase inhibitors dasatinib and midostaurin exhibit in vitro activity against D816V-mutated KIT, with the latter demonstrating encouraging activity in an ongoing international, multi-center clinical trial.4 In patients with SM-AHNMD, the clinical approach for such patients has been to treat the SM component as if the myeloid neoplasm were not present and to treat the myeloid neoplasm as if SM were not present. However, in clinical practice, priority should be given to treating the disease component that is contributing to the most urgent clinical concerns. Because KIT D816V or other pathogenetic abnormalities may reside in both the abnormal mast cell and associated myeloid clonal cell populations, the future availability of agents that inhibit shared therapeutic targets may make the distinction between the two disease compartments less relevant. Next-generation sequencing approaches of sorted cell populations should inform this approach. The recent identification of CD30 expression on neoplastic mast cells5 also provides an opportunity for testing anti-CD30 antibody approaches (e.g., brentuximab vedotin) in advanced SM.

1. Horny HP, Akin C, Metcalfe DD, et al. Mastocytosis. In: Swerdlow S, Campo E, Lee Harris N, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press. 2008:53-63.

2. Akin C, P, Metcalfe DD. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126:1099-1104.

3. L im KH, Pardanani A, Butterfield JH, et al. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009;84:790-794.

4. Gotlib J, Kluin-Nelemans, George TI, et al. KIT inhibitor midostaurin in patients with advanced systemic mastocytosis: Results of a planned interim analysis of the global CPKC412D2201 trial. Blood. ASH Annual Meeting Abstracts. 2012;120:799.

5. Sotlar K, Cerny-Reiterer S, Petat-Dutter K, et al. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol. 2011;24:585-595.

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