CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 12, 2022
Expiration: April 11, 2023
Prithviraj Bose, MD:
Systemic mastocytosis is a clonal proliferation and activation of mast cells across multiple extracutaneous tissues that can include BM, the gastrointestinal (GI) tract, liver, spleen, and skin.1 There are multiple subtypes, although the most common is indolent SM, which has a near-normal life expectancy. By contrast, advanced SM is associated with median survival of 1.9 to 5.7 years.2 Presentation is heterogeneous, ranging from mild symptoms that resemble allergic reactions through to organ dysfunction and mast cell leukemia (MCL). This challenging entity is not made any easier by its rarity, with prevalence estimated at 5.2 cases in 1 million people.3
Prithviraj Bose, MD:
The transmembrane receptor KIT plays a vital role in SM. KIT interacts with stem cell factor, an important growth factor for mast cells.1,4 KIT mutations result in constitutive activation of KIT and oncogenesis. A specific point mutation at KIT D816V is present in >90% of patients with SM and affects treatment sensitivity. Patients harboring KIT D816V have disease resistant to imatinib, but several multikinase and selective kinase inhibitors are active against this mutant, as we will discuss later.
Prithviraj Bose, MD:
The World Health Organization (WHO) has established pathologic diagnostic criteria for SM.5 The diagnosis relies on several criteria, requiring fulfilment of either the major criterion and at least 1 minor criterion or ≥3 minor criteria.
The major criterion is detection of multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in BM or in any other extracutaneous organ. This distinguishes SM from cutaneous mastocytosis.
The first minor criterion is that at least 25% of the mast cells should be spindled or atypical in morphology. The other 3 minor criteria are somewhat more objective. These include either a serum total tryptase value >20 ng/mL, detection of a KIT mutation at codon 816, or the aberrant expression of CD25 ± CD2 on mast cells in addition to normal mast cell markers.
Again, meeting the major criterion and at least 1 minor criterion or meeting at least 3 minor criteria without the major criterion will suffice to make the diagnosis.
Prithviraj Bose, MD:
Now, classifying SM into subtypes is a little more challenging and depends on the treating healthcare professional (HCP), rather than the pathologist.
Patients with SM are classified into indolent, smoldering, and advanced SM subtypes based on clinicopathologic signs and symptoms known as B-findings and C-findings.5 “B” stands for “burden of disease” and “C” for “cytoreductive therapy requiring”—meaning organ dysfunction is present.6 B-findings include a high mast cell burden on BM biopsy and elevated serum total tryptase level; dysplasia or myeloproliferation in nonmast cell lineage(s) that do not meet the diagnostic criteria for myelodysplastic syndrome or myeloproliferative neoplasm; and hepatomegaly without impairment of liver function, palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging.
C-findings include BM dysfunction caused by neoplastic mast cell infiltration, manifested by cytopenia; palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension; large lytic bone lesions or pathologic fractures; palpable splenomegaly with hypersplenism; and malabsorption with weight loss due to GI mast cell infiltrates.
Prithviraj Bose, MD:
Indolent SM is, by far, the most common subtype. The hallmark of indolent SM is a lack of organ damage.7 There should be no C-findings, usually no evidence of associated hematologic neoplasm (AHN), and typically a low mast cell burden. Skin lesions may also be present in indolent SM.
The diagnostic criteria for smoldering SM (SSM)—a rare subtype—are 2 or more B-findings without C-findings.
C-findings are a defining feature of advanced SM, which includes SM with AHN (SM-AHN), aggressive SM (ASM), and MCL. The SM-AHN subtype must meet criteria for an AHN (eg, myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia AML, lymphoma). ASM includes ≥1 C-finding not meeting criteria for MCL, which is diagnosed where BM aspirate smears show ≥20% mast cells. In classic MCL cases, mast cells account for ≥10% of white blood cells (WBC) in peripheral blood but <10% in the aleukemic variant, which is the more common variant.
Prithviraj Bose, MD:
The most common subtype, indolent SM, has a good prognosis, with near-normal survival and a 5% to 10% chance of progression to more advanced forms.8 The prognosis of SSM is not well defined, as this is an extremely rare subtype.9
Patients with advanced SM have markedly shorter survival than those with the indolent subtype. An analysis of patients with SM receiving treatment at the Mayo Clinic reported a median survival of 24 months for SM-AHN, the most common form of advanced SM. The median survival was 41 months for those with ASM and only 2 months for those with MCL.10 A more recent study from the European Competence Network on Mastocytosis (ECNM) Registry observed a slightly longer median survival of 2.9 years for SM-AHN, 5.7 years for ASM, and 1.9 years for MCL.2
Prithviraj Bose, MD:
Patients with SM may present with a range of dermatologic, GI, cardiovascular, neurologic, constitutional, and bone-related symptoms, as well as with anaphylaxis.5 Organopathy becomes more prominent with more aggressive subtypes. It is important to ascertain that the cause of any organ dysfunction is mast cell infiltration.
Because SM has such a varied presentation, patients may be referred to treatment centers from many different sources. My colleague Caitlin Rausch and I practice at MD Anderson, a standalone cancer center, whereas Ilene Galinsky likely sees different referral patterns at Dana Farber Cancer Institute.
Ilene A. Galinsky, NP:
We have an allergy service at Dana Farber Cancer Institute, which refers patients with possible SM to us. It is notable that people who have anaphylaxis to bee or hornet stings are at an increased risk for having mastocytosis.7 We also receive referrals from primary care, often for patients who have had a GI workup for unexplained GI symptoms. Some providers will have already taken a biopsy and tested for tryptase and the KIT mutation as part of the workup for SM.
Because we have been participating in clinical trials, we also see people with advanced SM who are looking for better treatment options than what we had before the approval of avapritinib. Patients with advanced SM often have quite poor quality of life and are looking for anything that can help.
Prithviraj Bose, MD:
Most referrals that I see are from other heme-oncologists who may not be as comfortable managing patients with this rare entity and prefer to refer them to us. We occasionally will be referred patients who are interested in enrolling in clinical trials or receiving newer agents like avapritinib, which we will discuss later.
Do you ever see patients who are ultimately diagnosed with other mast cell diseases such as mast cell activation syndrome or hereditary α-tryptasemia?
Ilene A. Galinsky, NP:
Rarely. When we do, we send those patients to the allergy team for management.
Prithviraj Bose, MD:
Patients with SM can experience mast cell activation triggered by many different environmental and individual factors.7,11 These potential triggers include sudden changes in temperature, pollen, pet dander, venoms, infections, emotional and/or physical stress, medications, and even surgery and medical procedures (eg, colonoscopy, endoscopy). Triggers of mast cell activation vary between patients and can vary over time for a specific patient.
Prithviraj Bose, MD:
As I mentioned earlier, diagnosing SM requires measuring the patient’s serum tryptase level and performing a BM biopsy to examine mast cell markers.5,7 KIT D816V should be tested for in BM, blood, or another extracutaneous lesion specimen. It is preferred to test for this mutation using ASO-qPCR or digital droplet PCR.
If patients are negative for KIT D816V and have eosinophilia, then their BM or blood should be screened for FIP1L1-PDGFRA, which is associated with response to imatinib.
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Prithviraj Bose, MD:
To summarize, patients who meet WHO criteria for SM on the basis of pathology and molecular testing should then be subtyped according to WHO criteria for AHN, the presence of C-findings, and based on mast cell measurement on BM aspirate smear.5
We will now discuss the first part of a case study to help illustrate the challenges in referral and diagnosis of advanced SM.
Ilene A. Galinsky, NP:
I would like to present the first of 2 case studies involving patients from my own practice. This patient is a 75‑year‑old man who initially presented with a 3‑month history of fatigue, abdominal distention, and lower extremity edema. These symptoms became more pronounced while he was tapering off steroid treatment prescribed by his local doctor for pruritis and vague constitutional symptoms.
When we saw the patient, his WBC count was 27,000 cells/μL, hemoglobin was 8.2 g/L, and platelet count was 64 x 109/L. His WBC differential showed 76% neutrophils, 9% band neutrophils, 8% lymphocytes, and 3% monocytes with 1 nucleated red blood cell. Imaging conducted before referral showed a pleural effusion, some ascites, and splenomegaly. Endoscopy was negative. His biopsies had not been stained for mast cells, which is unsurprising because SM is such a rare condition that many HCPs do not even consider it as a potential cause of symptoms.
We measured his serum tryptase level, which was elevated to 187 ng/mL (normal: <11.4 ng/mL).12 A BM exam showed hypercellular marrow with 40% mast cells, and flow cytometry detected the mast cell markers CD117, CD2, and CD25. His cytogenetics were normal. The molecular sequencing panel was positive for KIT D816V as well as mutational abnormalities in SRSF2, TET2, and CUX1. A diagnosis of SM-AHN was made based on his BM and molecular results.
Prithviraj Bose, MD:
This case raises a number of important points. First, the patient had fairly nonspecific symptoms at presentation, which is often a feature of SM. Second, the high tryptase measurement was clearly a tipoff that the patient might have SM. However, ordering the tryptase test requires the provider to have SM in mind as a potential diagnosis.
We will continue our discussion of this case later, focusing on how his advanced SM was managed.
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