EDUCATION
TABLE 1 . 2016 World Health Organization Diagnostic Criteria for Systemic Mastocytosis *
Major
Multifocal , dense infiltrates of mast cells ( ≥15 mast cells in aggregates ) detected in sections of bone marrow and / or other extracutaneous organ ( s )
Minor
In biopsy sections of bone marrow or other extracutaneous organs , > 25 % of the mast cells in the infiltrate are spindle shaped or have atypical morphology , or > 25 % of all mast cells in bone marrow aspirate smears are immature or atypical .
Detection of an activating point mutation at codon 816 of KIT in bone marrow , blood , or another extracutaneous organ .
Mast cells in the bone marrow , blood , or another extracutaneous organ express CD25 , with or without CD2 , in addition to normal mast cell markers .
Serum total tryptase persistently > 20 ng / mL , unless there is an associated myeloid neoplasm . * A diagnosis of SM requires 1 major + 1 minor criteria , or > 3 minor criteria
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 .
References
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
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 openlabel 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 .
TABLE 2 . World Health Organization-Defined B and C Findings in Systemic Mastocytosis **
B findings
High mast cell burden ( shown on bone marrow biopsy ): > 30 % infiltration of cellularity by mast cells and serum total tryptase > 200 ng / mL
Hepatomegaly without impairment of liver function , palpable splenomegaly without hypersplenism and / or lymphadenopathy on palpation or imaging
Signs of dysplasia or myeloproliferation in non – mast cell lineage ( s ), but criteria are not met for definitive diagnosis of an associated hematologic neoplasm , with normal or only slightly abnormal blood counts
C findings
Bone marrow dysfunction caused by neoplastic mast cell infiltration , manifested by ≥1 cytopenia : absolute neutrophil count < 1.0 × 10 9 / L , hemoglobin level < 10 g / dL , and / or platelet count < 100 × 10 9 / L
Palpable hepatomegaly with impairment of liver function , ascites and / or portal hypertension
Skeletal involvement , with large osteolytic lesions with or without pathological fractures ( pathological fractures caused by osteoporosis do not qualify as a C finding )
Palpable splenomegaly with hypersplenism Malabsorption with weight loss due to gastrointestinal mast cell infiltrates
** Indolent systemic mastocytosis is defined by 0 or 1 B finding , whereas 2 or more B findings define smoldering systemic mastocytosis . One or more C findings define aggressive systemic mastocytosis .
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 . ●
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