Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
The National Comprehensive Cancer Network (NCCN) has developed a set of guidelines and recommendations for the diagnosis and management of systemic mastocytosis (SM).1 The guidelines are based on the latest research and the recommendations of specialists from NCCN cancer centers with years of experience in treating SM. A diagnostic algorithm is included in the guidelines, as well as workup algorithms for patients with signs and symptoms of the disease.1
Diagnostic Classification and Clinical Presentation
The diagnostic criteria for SM established by the World Health Organization (WHO) are based on the presence of a major criterion and minor criteria. A diagnosis is reached when both the major criterion, which is the presence on a biopsy specimen of multifocal and dense aggregates of mast cells (≥15 mast cells per aggregate) in the bone marrow and/or other extracutaneous organs, and at least 3 minor criteria (atypical mast cells in lesional tissues, KIT D816V gene mutation, aberrant expression of CD25 on neoplastic mast cells with or without CD2, elevated serum tryptase level of >20 ng/mL) are observed simultaneously.2 Depending on the mast cell burden and the extent to which different organs are affected and damaged, SM is classified in 5 subvariants: indolent SM (ISM); smoldering SM (SSM); aggressive SM (ASM); SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).1
The clinical signs of SM vary according to the organs involved and damaged and are classified as B findings and C findings. B findings, which include an elevated mast cell burden and hepatomegaly, indicate a relatively high SM burden, whereas C findings, which include cytopenia(s) and liver malfunction, are linked to organ damage from mast cell infiltration.2,3 Observation of these findings is crucial for determining the subtype of SM.
A physical evaluation, including examination of the skin to detect cutaneous lesions, palpation of the spleen and liver, and the patient’s medical history, should be performed. A laboratory study, including measurement of the serum tryptase level and a peripheral blood smear, should also be performed.1 Other studies included in the diagnostic workup are bone marrow biopsy, biopsy of the organ(s) potentially involved in the disease, imaging studies to detect B and/or C findings, mast cell immunophenotyping, and molecular testing to identify gene mutations that may underlie the disease. The KIT D816V mutation is observed in more than 90% of patients with SM; however, prognostically relevant mutations in genes other than KIT (TET2, JAK2, RAS, SRSF2, ASXL1, CBL, and RUNX1) may be identified during the diagnostic process.4,5
The management of SM requires a multidisciplinary care team that includes dermatologists, immunologists, hematologists, and medical staff with other specialties, such as pathologists. The NCCN guidelines recommend that patients be referred to centers with expertise in treating mast cell disorders.1 Symptoms can be evaluated at baseline and monitored in patients with ISM or SSM with the mastocytosis quality-of-life questionnaire (MQLQ) and the mastocytosis symptom assessment form (MSAF). The MQLQ is a disease-specific questionnaire for mastocytosis, complemented by the MSAF, a short and convenient symptom scoring form.6
The NCCN guidelines recommend anti-mediator drug therapy for all patients with SM. Histamine receptor type 1 and type 2 blockers can help control skin, gastrointestinal, neurological, cardiovascular, pulmonary, and naso-ocular symptoms.7 Cromolyn sodium can be used to manage cutaneous, gastrointestinal, and neurological symptoms.8 Other anti-mediator drugs include corticosteroids and leukotriene receptor antagonists for refractory symptoms. Epinephrine should be used as a first-line treatment for anaphylaxis, and the anti-immunoglobulin E monoclonal antibody omalizumab (Xolair®) can be used for unprovoked anaphylaxis.1 Patients should be aware of the signs and symptoms of mast cell activation and the factors that trigger activation, and they should carry 2 auto-injectors with epinephrine for managing anaphylaxis.1
The NCCN guidelines have categorized treatment regimens for cytoreductive therapy. The categories correspond to preferred regimens (which include avapritinib [Ayvakit™] and midostaurin [Rydapt®]), other recommended regimens (which include cladribine [Mavenclad®] and peginterferon alfa-2a), and regimens that are useful under certain circumstances (including imatinib [Gleevec®]).1 Interferon alfa may be used with or without prednisone to reduce symptoms associated with the release of mast cell mediators in patients with slowly progressive disease. Cladribine and peginterferon alfa-2a can be useful in patients with ISM or SSM who have severe and refractory symptoms.
Allogeneic hematopoietic cell transplant (HCT) should be considered for patients with ASM or MCL when an adequate response to cytoreductive treatment is observed. For patients with SM-AHN, HCT may be considered after the SM and AHN components have been evaluated.
Patients with SM undergoing surgery should be managed by a multidisciplinary team that includes surgical, anesthesia, and perioperative specialists. Perioperative drugs are not contraindicated for patients with SM; however, opioid analgesics should be administered with care.1
For patients who are pregnant, a high-risk obstetrician and an anesthesiologist should be members of the medical team. Triggers of mast cell mediator release should be avoided, and anti-mediator drug therapies should be used prophylactically. Avapritinib, midostaurin, cladribine, and imatinib are not recommended. Patients should also avoid agents that precipitate mediator releases such as codeine, thiamine, quinine, decamethonium, procaine, radiographic dyes, dextran, polymyxin B, and D-tubocurarine.1
2. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (revised 4th edition). Lyon, France: International
Agency for Research on Cancer; 2017.
3. Jennings S, Russell N, Jennings B, et al. The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions. J Allergy Clin Immunol Pract. 2014;2(1):70-76. doi:10.1016/j.jaip.2013.09.004
4. Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009;23(5):900-904. doi:10.1038/leu.2009.37
5. Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122(14):2460-2466. doi:10.1182/blood-2013-04-496448
6. van Anrooij B, Kluin-Nelemans JC, Safy M, Flokstra-de Blok BM, Oude Elberink JN. Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis. Allergy. 2016;71(11):1585-1593. doi:10.1111/all.12920
7. Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother. 2013;14(15):2033-2045. doi:10.1517/14656566.2013.824424
8. Edwards AM, Stevens MT, Church MK. The effects of topical sodium cromoglicate on itch and flare in human skin induced by intradermal histamine: a randomised double-blind vehicle controlled intra-subject design trial. BMC Res Notes. 2011;4:47. doi:10.1186/1756-0500-4-47
Reviewed by Debjyoti Talukdar, MD, on 4/26/2022.