if you would like to support my site hosting fees and help keep Haembase #FOAMed forever you can do so here!

Systemic Mastocytosis (SM)

CD2+, CD25+ Mast Cells

KIT D816V mutation in >90% patient (or other exon 17)

 

WHO 2021 diagnostic Criteria (1 major + 1 minor, or 3 minor)

 

Major

Multifocal, dense infiltrates (>15 mast cells in aggregates) in marrow or extracutaneous organs.

 

Minor

>25% mast cells with spindled / atypical morphology

KIT point mutation at codon 816 (KIT D816V), or at other critical regions of KIT

CD25, CD2 and/or CD30 expression in mast cells

Serum tryptase >20 ng/ml, unless there is an associated clonal myeloid disorder

 

WHO-HAEM5 Classification of Systemic Mastocytosis

 

Bone marrow mastocytosis

Indolent systemic mastocytosis

Smouldering systemic mastocytosis

Aggressive systemic mastocytosis

Systemic mastocytosis with an associated haematologic neoplasm

Mast cell leukaemia

(WDSM - Well-differentiated systemic mastocytosis - is a morphological subtype occurring in any SM subtype. Most of these cases are CD25-, CD2-, CD30+ and are KITD816V negative)

 

Clinical Presentation

 

Features of mast cell degranulation (‘mediator’ symptoms)

  • Anaphylaxis, flushing, itch, N&V, diarrhoea, lightheadedness, severe hypotension, bone paine, neuropsychiatric distrubance

  • Often no identifiable triggers

 

Staging Work-Up

 

Serum total tryptase

BM Biopsy

Relevant organ biopsy

KITD816V mutation (or other exon 17)

CD2 / CD25 Mast cell expression

If eosinophilia, screen for FIP1L1-PDGFRA

 

Indolent / Smouldering / Advanced (as per who)

 

Indolent

  • No B or C findings

 

Smouldering = 2 or more B Findings

(B = Burden of disease)

  • BM >30% mast cells and/or Tryptase >200 ng/ml and/or KITD816V mutation with a variant allele frequency (VAF) of >10%

  • Signs of dysplasia or myeloproliferation without frank AHN, & normal FBC

  • Hepatomegaly without liver dysfunction and/or splenomegaly without hypersplenism and/or palpable lymphadenopathy >2cm

 

Advanced (ASM, MCL, SM-AHN with organ damage) = C Findings, ie organ damage

(C = Cytoreduction-requiring)

  • One or more cytopenias (Hb <100, Plt <100, Neut <1.0)

  • Hepatomegaly with liver dysfunction

  • Osteolytic lesions or fractures

  • Splenomegaly with symptomatic hypersplenism

  • Malabsorption with weight loss due to GI infiltration

 

Management

 

Avoidance of triggers

 

Treatment of mediator symptoms

  • EpiPen

  • H1 anti-histamines (Cetirizine, Fexofenadine, Hydroxyzine)

  • H2 antagonists (Ranitidine, Cimetidine)

  • Leukotriene antagonists (Montelukast)

  • Bisphosphonates for osteoporosis / bone pain / fractures

  • Mast cell stabilisers (ketotifen, cromolyn)

  • PUVA light therapy

  • NSAID - Aspirin

 

Cytoreductive Therapy

  • Steroids

  • PEG Interferon alpha - Variable outcomes reported in small case series. Low median treatment duration due to poor tolerance of side effects.

  • Cladribine - Approx. 50% response rate. Presence of KIT mutation predicts response. 30% cytopenias.

  • Multi-agent chemotherapy

  • Allogeneic Transplant - All patient 3yr OS 57% retrospective studies (74% for SM-AHN)

 

Targeted Therapies / Trials (Presence of KIT D816V confers resistance against many TKI’s)

  • Midostaurin (KIT inhibitor)

    • 60% ORR

    • SE: Gastrointestinal, Cytopenias, QT interval prolongation

  • Avapritinib (KIT + PDGFRA kinase inhibitor)

    • 75% ORR in PATHFINDER 2021

    • Large number or patients dose reduced or discontinued due to adverse events

    • SE: Gastrointestinal, Oedema, Cytopenias, Cognitive impairment (hair colour change in 20%!)

  • Dasatinib / Nilotinib

  • Mastinib

  • Imatinib

  • Everolimus

  • Mabs – Daclizumab, Omalizumab

  • Other Mabs to consider based on pt’s immunophenotype – CD30, CD33, CD52, CD123

 

Mast Cell Activation Syndrome (MCAS)

 

Meeting only 1 or 2 of the minor diagnostic criteria

Lack the characteristic BM mast cell aggregates

Episodic symptoms of mast cell degranulation