Systemic mastocytosis refers to a heterogenous group of uncommon clonal disorders characterized by the expansion and accumulation of neoplastic mast cells (MCs) in various organs and tissues (e.g., skin, bone marrow, liver, spleen, GI tract, etc.). The disease is usually limited to the skin in children (cutaneous mastocytosis) and often resolves spontaneously, while adults typically have systemic mastocytosis (SM), with or without cutaneous involvement. Within SM, five major entities are recognized: indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL).
Diagnostic Criteria & Disease Entities
The diagnosis of SM requires the presence of either the major criterion and one minor criterion, or three minor criteria. The major criterion is the presence of multifocal, dense infiltrates of MCs (>15 in aggregate) in sections of bone marrow and/or another extracutaneous organ. The minor criteria include the following:
- In biopsy sections of the bone marrow or another extracutaneous organ, >25 percent of the MCs in the infiltrate are spindle-shaped or have atypical morphology; or, of all the MCs in the bone marrow aspirate smears, >25 percent are immature or atypical (mostly spindle-shaped).
- Presence of an activating point mutation at residue D816 of KIT in bone marrow, peripheral blood, or another extracutaneous organ.
- Expression of CD2 and/or CD25 (by flow cytometry or immunohistochemistry, CD25 more reliable) by MCs in bone marrow, peripheral blood, or another extracutaneous organ.
- Serum tryptase persistently >20 ng/mL in the absence of an associated clonal myeloid disorder.
The distinction between ISM, SSM, ASM, and MCL has to do with the neoplastic MC burden and the absence or presence of organ damage. ISM is characterized by <2 B-findings (B for Borderline Benign) and SSM by 2-3 of these findings in the absence of C-findings (C for Consider Cytoreduction), while one or more C-findings are typical of ASM and MCL. The distinction between ASM and MCL is made by the percentage of MCs in bone marrow aspirate smears, with ≥20 percent making the diagnosis of MCL. The term ASM in transformation is used when there are 10-19 percent MCs in the bone marrow smears. Within MCL, cases with <10 percent circulating MCs are often referred to as aleukemic MCL. The AHN in SM-AHN is usually a myeloid malignancy, most commonly chronic myelomonocytic leukemia (CMML). B and C findings are listed in the Table.
KIT & Other Mutations
c-KIT (CD117), the receptor for stem cell factor (SCF), is universally expressed on MCs, and the differentiation of pluripotent hematopoietic progenitors into MCs is driven by SCF. KIT mutations, most frequently the activating kinase domain mutation D816V, are found in >80 percent of patients with SM (>90% in ISM, 70% in ASM). Other mutations in KIT also have been described, as compound mutations.
In patients with SM-AHN, KIT mutations are usually demonstrable in both the SM and the AHN clones. Recent work has demonstrated the additional presence of mutations in genes such as TET2, SRSF2, and ASXL1 among patients with SM-AHN, and that these mutations precede KIT D816V, acquisition of which may push the disease phenotype towards that of SM. The allelic burden of mutant KIT correlates with the neoplastic MC burden and with survival in SM. The presence and number of mutated genes within the S/A/R (SRSF2/ASXL1/RUNX1) “panel” have been associated with an adverse prognosis and inferior survival in KIT D816V SM. The genomic underpinnings of SM are only now beginning to be unraveled by the availability of next-generation sequencing, and the prognostic and predictive implications of these and other mutations continue to evolve.
Management of ISM & SSM
Patients with ISM have a normal life expectancy and do not generally require cytoreductive therapy. The main focus of treatment in this setting is on the management of mediator symptoms. This is typically achieved with the use of H1 and H2 blockers (with or without proton pump inhibitors), mast cell stabilizers (e.g., cromolyn sodium), and glucocorticoids. Coexistent allergies, with or without detectable IgE antibodies against specific allergens, can be a significant issue in these patients, some of whom may need to carry self-injectable epinephrine at all times. Immunotherapy (i.e., desensitization) may also be needed. Some patients may benefit from antileukotriene therapy such as with monteleukast or the anti-IgE monoclonal antibody omalizumab. In general, we defer to other specialists, allergists and dermatologists in the management of patients with ISM.
Bone loss is an important consideration in SM, and annual DEXA scans are advised in all patients. Bisphosphonates represent first-line therapy for osteoporosis, and denosumab may be a particularly helpful agent. Periodic bone marrow examinations are not routinely recommended in patients with ISM/SSM. Rather, changes in blood counts should prompt bone marrow examination when appropriate. More symptomatic patients with SSM and a high MC burden may be particularly well-served by chronic interferon therapy, with or without glucocorticoids, or single-agent cladribine.
Management of ASM, MCL & SM-AHN
There is no standard therapy for patients with advanced SM, and our preference is to enroll patients on clinical trials of novel agents whenever possible. In general, patients with SM-AHN should be managed so both the SM and the AHN are treated independently of each other's presence, keeping in mind drug-drug interactions, etc. However, the AHN in this setting is typically more drug-resistant and difficult to treat.
Imatinib is approved for use in adult patients with ASM without KIT D816V and in those in whom the mutational status of KIT is unknown. Given the high prevalence of this mutation in patients with SM, imatinib is not an option for the vast majority.
While cladribine or interferon alfa (with or without glucocorticoids) can lead to responses in a substantial proportion of patients with ASM, relapses are the norm and these agents are largely ineffective in patients with rapidly progressing ASM or MCL. Outside of clinical trials, the latter group of patients should be offered multi-agent AML-like cladribine-based regimens, with consideration of allogeneic hematopoietic stem cell transplantation in responders.
KIT D816V is a primary driver of disease pathogenesis and has been shown to be a bona fide therapeutic target in SM. The multi-kinase inhibitor midostaurin (100 mg twice daily), which inhibits KIT D816V was evaluated in 116 patients with SM, of whom 16 had ASM, 57 SM-AHN, and 16 MCL. The overall response rate was 60 percent, with a major response, defined as complete resolution of at least one type of SM-related organ damage, seen in 45 percent. Median overall survival was 28.7 months, and median progression-free survival 14.1 months. The median overall survival among the 16 patients with MCL was 9.4 months. This agent is under consideration for approval by the FDA. BLU-285 is a highly potent and selective KIT inhibitor currently in early clinical development for patients with SM and other mutant KIT-driven malignancies (e.g., gastrointestinal stromal tumors). Encouraging preliminary results in advanced SM were recently presented. DCC-2618 is a “switch control” inhibitor of KIT and PDFGR, also in early phase clinical trials.
PRITHVIRAJ BOSE, MD, is Assistant Professor in the Department Leukemia at the University of Texas MD Anderson Cancer Center, Houston. SRDAN VERSTOVSEK, MD, PHD, is Professor in the Department of Leukemia at University of Texas MD Anderson Cancer Center, Houston.
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