You Make the Call: How would you treat a patient with aggressive systemic mastocytosis?

This month, William Shomali, MD, discusses treatment of bone manifestations and transplantation for systemic mastocytosis.

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I am treating a 40-year-old female patient with a new diagnosis of aggressive systemic mastocytosis. She had a years-long history of progressive back pain, further exacerbated by a motor vehicle accident in January 2020.

A CT scan of her chest, abdomen, and pelvis showed subcentimeter left axilla nodes and dense, diffuse, bony sclerosis with small areas of lysis. A bone scan revealed diffuse increased bony remodeling in the distribution of the adult red marrow; metastatic or metabolic bony disease was felt to be unlikely based on lack of heterogeneity and peripheral involvement. Her complete blood cell, metabolic, and liver profile were within normal limits.

The patient had no complaints aside from back pain and no unusual allergic reactions or sensitivities. She has a reported history of blotchy erythema to the thighs when exposed to the cold (a dermatologist diagnosed telangiectasia macularis eruptiva perstans (TMEP) on skin biopsy years ago.

Her past medical history included TMEP and chronic back pain, and she has no family history of blood disorders. She was not taking any medications and has no known drug allergies. She reports that she does not smoke and occasionally consumes alcohol. The exam revealed no rashes and no organomegaly.

Subsequent bone marrow analysis was normocellular for her age, revealing many aggregates/clusters of CD117+ mast cells and areas of densely packed spindle-shaped mast cells that account for 30-40% of the marrow. There was minimal surrounding fibrosis. Karyotype was normal, molecular testing was positive for KIT D816V although at low variant allele frequency. Her tryptase level was 73.7 ng/mL.

The patient meets the major and three minor criteria for aggressive systemic mastocytosis, with one B finding (bone marrow mast cells >30%) and one C finding (lytic lesions). She is starting on midostaurin 100 mg orally twice daily.

Given her young age, would you consider allogeneic hematopoietic cell transplantation? If so, what timing would you recommend? Is there a particular bisphosphonate you would recommend? We have access to zoledronic acid and pamidronic acid in our medical day unit. Would you suggest cromolyn sodium for her bone pain?

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

In contrast to pediatric cases, most adult patients with cutaneous mastocytosis (e.g., TMEP and urticaria pigmentosa, which are now referred to as maculopapular cutaneous mastocytosis, will also have evidence of bone marrow (BM) involvement, and will meet the World Health Organization (WHO) criteria for systemic mastocytosis (SM; TABLE 1).^1,2

Reticulin fibrosis surrounding BM mast cell aggregates is a common finding in SM, whereas more diffuse fibrosis in conjunction with a mutation such as JAK2 V617F would be more suggestive of an associated hematologic neoplasm (AHN), such as myelofibrosis or another myeloproliferative neoplasm.

It is important to note that next generation sequencing (NGS) has lower sensitivity for detecting the KIT D816V mutation compared to allele-specific polymerase chain reaction, especially in the absence of a high mast cell burden or an AHN/multilineage involvement.³

This patient meets the diagnostic criteria for indolent SM (ISM) as she does not exhibit the two or more B-findings that are required for a diagnosis of smoldering SM (TABLE 2).² In SM, bone lesions are notoriously challenging to use as a basis for subtyping disease. While the WHO defines large osteolytic lesions with or without pathologic fractures as a “C finding” (a term used to denote SM-related organ damage), the size of such lesions is not specified. However, general consensus among mast cell investigators is that areas of osteolysis ≥2 cm should define this C finding, which is not present in this patient.

Although SM can cause both lytic and sclerotic bone lesions, I would further work up the breast nodule (e.g., biopsy if palpable or detected by ultrasound) and consider a bone biopsy of one of the innumerable lytic lesions before ascribing the bone changes to SM. Sclerotic bone lesions can be present across the spectrum of SM variants and do not signify advanced disease.

It is important to assess the blood count differential for the presence of eosinophilia or monocytosis, which can suggest the presence of an AHN, such as chronic eosinophilic leukemia or chronic myelomonocytic leukemia, respectively. An AHN might only show subtle changes in the marrow and/or be masked by the SM component. Review of the marrow by an experienced pathologist and looking for concomitant myeloid mutations by NGS can help uncover such cases.

Musculoskeletal symptoms are common in SM, and patients with SM are also at increased risk of osteoporosis.⁴ Bone density evaluation by DEXA scan is part of the diagnostic workup for SM. In a small phase II trial, midostaurin improved musculoskeletal symptoms in patients with indolent SM,⁵ but the drug is only currently approved for patients with advanced SM. Nevertheless, no data are currently available to indicate that midostaurin can ameliorate bone lesions or decrease the risk of fractures.

Clinical trials with new KIT inhibitors (e.g., avapritinib) are assessing changes in bone density and results from those studies are awaited. Bisphosphonates can help improve bone pain and density in patients with SM-related osteoporosis.^4,6,7 Both zoledronic acid and pamidronate have been successfully used in this setting, but data are not available to suggest a preferred agent.^6,7

Screening for vitamin D deficiency and appropriate replacement is also advised. Case reports and small series indicate a potential role for denosumab or interferon-alfa (off-label) in patients not responding to bisphosphonates.^8,9 Cromolyn sodium is poorly absorbed from the gastrointestinal tract and mostly helps with gastrointestinal symptoms. All patients with SM should carry two epinephrine auto-injectors in case of future episodes of anaphylaxis. In this regard, education of the patient and his or her health care team regarding severe mediator symptoms/anaphylaxis in anticipation of taking new medications or procedures/surgery should be undertaken. For symptoms related to mast cell activation, the National Comprehensive Cancer Network (NCCN) guidelines for SM list a stepwise approach for anti-mediator therapies.

In a recent cohort, patients with ISM had a 10-year overall survival of 93.5%, median survival of 28.4 years, and <5% of patients progressed to a more advanced form of SM or developed another hematological neoplasm.¹⁰ Hence, hematopoietic stem cell transplantation is not recommended in ISM.

References

1. Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1):35-45.
2. Horny HP, Akin C, Arber D, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2017:61-69.
3. Shomali W, Gotlib J. The new tool “KIT” in advanced systemic mastocytosis. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):127-136.
4. Barete S, Assous N, de Gennes C, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis. 2010 Oct;69(10):1838-41.
5. Van Anrooij B, Oude Elberink JNG, Span LFR, et al. Midostaurin in patients with indolent systemic mastocytosis: An open-label phase 2 trial. J Allergy Clin Immunol. 2018 Sep;142(3):1006-1008.e7.
6. Rossini M, Zanotti R, Viapiana O, et al. Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med. 2014 Nov;127(11):1127.e1-1127.e4.
7. Marshall A, Kavanagh RT, Crisp AJ. The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis. Br J Rheumatol. 1997 Mar;36(3):393-6.
8. Orsolini G, Gavioli I, Tripi G, et al. Denosumab for the treatment of mastocytosis-related osteoporosis: a case series. Calcif Tissue Int. 2017 Jun;100(6):595-598.
9. Lehmann T, Beyeler C, Lämmle B, et al. Severe osteoporosis due to systemic mast cell disease: successful treatment with interferon alpha-2b. Br J Rheumatol. 1996 Sep;35(9):898-900.
10. Sperr WR, Kundi M, Alvarez-Twose I, et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019 Dec;6(12):e638-e649.

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I am treating a 20-year-old male patient who is COVID-19 positive and developed acute pain in his arm. On presentation to the emergency room, he was found to have a subclavian deep vein thrombosis and bilateral pulmonary emboli. What duration of anticoagulation would you recommend? He was initiated and remains on apixaban. What would you recommend regarding testing?

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.