●Comprehensive clinical update covering WHO classification, molecular risk stratification
●Identification of ASXL1/RUNX1/SRSF2/NRAS as poor-risk mutations
●Treatment algorithm for ISM through MCL

Details DOI ↗

Grade Anarrative review

Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management

Pardanani A · Am J Hematol · 2019

●ISM median survival 198 months (near-normal)
●ASM median survival 41 months
●SM-AHN median survival 24 months
●MCL median survival 2 months

Details DOI ↗

Grade Anarrative review

Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts

Valent P, Akin C, Metcalfe DD · Blood · 2017

●Updated WHO classification overview
●CD2, CD25, CD30 as aberrant MC markers
●Potential therapeutic targets including CD30, CD33, CD123

Details DOI ↗

Grade Bnarrative review

Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future

Valent P, Akin C, Hartmann K, et al. · Cancer Res · 2017

●Classification refinements from consensus group, WHO, and ECNM
●New treatment options including allogeneic HSCT and KIT D816V inhibitors

Details DOI ↗

genetics

3 sources

Grade Bnarrative review

KIT Mutations and Other Genetic Defects in Mastocytosis

Chantran Y, Valent P, Arock M · Immunol Allergy Clin North Am · 2023

●Comprehensive review of KIT mutations and additional genetic defects in SM
●KIT D816V present in >90% of adult SM when sensitive assays used

Details DOI ↗

Grade Bcohortn=70

Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis

Jawhar M, Schwaab J, Schnittger S, et al. · Leukemia · 2016

●S/A/R gene panel: SRSF2/ASXL1/RUNX1 mutations predict inferior OS in AdvSM
●3-year OS: 90% (0 mutations), 73% (1 mutation), 42% (>=2 mutations)
●SRSF2 HR 5.9, ASXL1 HR 3.4, RUNX1 HR 2.4 for mortality

Details DOI ↗

Grade Bcohort

ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis

Pardanani A, Lasho TL, Finke CM, et al. · Br J Haematol · 2016

●ASXL1 and CBL mutations independently predict inferior survival in AdvSM

Details DOI ↗

treatment

10 sources

Grade ARCTn=212

Avapritinib versus Placebo in Indolent Systemic Mastocytosis

Gotlib J, Castells M, Engelbrecht ME, et al. · NEJM Evidence · 2023

●PIONEER trial: avapritinib superior to placebo in ISM
●TSS decrease: -15.6 vs -9.2 points (P<0.003)
●54% achieved >=50% tryptase reduction vs 0% placebo
●First FDA-approved treatment for ISM (May 2023)

Details DOI ↗

Grade Acohort

Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis

DeAngelo DJ, Radia DH, George TI, et al. · Blood · 2022

●Avapritinib induced 30% molecular response (KIT D816V undetectable) in AdvSM
●Deep responses across ASM, SM-AHN, and MCL subtypes

Details DOI ↗

Grade Bnarrative review

Treatment of Indolent and Advanced Systemic Mastocytosis

Castells M, Butterfield J · J Allergy Clin Immunol Pract · 2022

●Stepwise treatment: H1/H2 antihistamines, cromolyn, leukotriene antagonists, then cytoreductive therapy
●Anaphylaxis prevention paramount in ISM management

Details DOI ↗

Grade Acohortn=86

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Reiter A, George TI, Engelbrecht ME, et al. · Nat Med · 2021

●EXPLORER phase 1: avapritinib safety and dose-finding in AdvSM
●Established recommended phase 2 dose

Details DOI ↗

Grade Bnarrative review

Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap

Frost MJ, Ferrao PT, Hughes TP, Ashman LK · Front Pharmacol · 2020

●TKI roadmap from imatinib to selective KIT D816V inhibitors
●Only rare KIT D816V-negative cases initially responsive to early TKIs

Details DOI ↗

Grade Aregulatory review

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis

Gotlib J, Reiter A, DeAngelo DJ · Oncologist · 2018

●FDA approval summary for midostaurin in ASM/SM-AHN/MCL (April 2017)
●56% dose modifications for toxicity; 21% treatment discontinuation

Details DOI ↗

Grade Bcohort

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial

DeAngelo DJ, George TI, Hirshberg B, et al. · Leukemia · 2018

●Long-term midostaurin efficacy confirmed with 10-year median follow-up

Details DOI ↗

Grade Bcohortn=10

Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations

Akin C, Fumo G, Yavuz AS, et al. · Haematologica · 2017

●Imatinib efficacy in SM lacking exon 17 KIT mutations
●Complete remission in 1 patient with K509I mutation

Details DOI ↗

Grade ARCTn=116

Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis

Gotlib J, Kluin-Nelemans HC, George TI, et al. · N Engl J Med · 2016

●Overall response rate 60% in AdvSM
●45% major response (complete resolution of organ damage)
●Median OS 28.7 months; median PFS 14.1 months
●Median 59% reduction in MC burden and 58% reduction in serum tryptase

Details DOI ↗

Grade Bcohort

Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis

Lim KH, Pardanani A, Butterfield JH, et al. · Blood · 2009

●Confirms imatinib ineffective in D816V+ SM
●May benefit occasional D816V-negative patients

Details DOI ↗

diagnostics

4 sources

Grade Aexpert opinion

Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal

Valent P, Akin C, Hartmann K, et al. · HemaSphere · 2021

●CD30 expression added as minor SM criterion
●BMM defined as distinct subtype
●Hereditary alpha-tryptasemia recognized as confounder

Details DOI ↗

Grade Aexpert opinion

Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria

Valent P, Akin C, Escribano L, et al. · Eur J Clin Invest · 2007

●Standardized application of diagnostic tests
●Treatment recommendations and response criteria (Valent criteria)
●Patient selection guidance for interventional therapy

Details DOI ↗

Grade Bcohort

Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease

Akin C, Metcalfe DD · Int Arch Allergy Immunol · 2002

●Serum tryptase correlates with MC burden (r=0.8)
●Median tryptase 67 ng/mL in SM patients
●Tryptase helps distinguish SM categories

Details DOI ↗

Grade Aexpert opinion

Diagnostic criteria and classification of mastocytosis: a consensus proposal

Valent P, Horny HP, Escribano L, et al. · Leuk Res · 2001

●Established original WHO-adopted diagnostic criteria for SM
●Defined major criterion (multifocal dense MC aggregates) and 4 minor criteria
●Classification into ISM, ASM, SM-AHNMD, MCL

Details DOI ↗

pathophysiology

3 sources

Grade Bnarrative review

Systemic Mastocytosis: Molecular Landscape and Implications for Treatment

Chatterjee A, Ghosh J, Bhatt N · Cancers · 2021

●Comprehensive review of KIT D816V downstream signaling: STAT5-PI3K-AKT-mTOR axis
●PI3K, STAT5, NF-kB, mTORC2, PKCdelta as key mediators of oncogenic KIT signaling

Details DOI ↗

Grade Bbasic research

Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis

Hoermann G, Gleixner KV, Dinu GE, et al. · eBioMedicine · 2019

●D816V mutation arises in early hematopoietic stem/progenitor cells
●Mutation burden is low in progenitors but increases in mature mast cells

Details DOI ↗

Grade Bbasic research

Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade

Growney JD, Clark JJ, Adelsperger J, et al. · Blood · 2005

●STAT5-PI3K cascade essential for KIT D816V-mediated MC growth and survival
●Knockdown of Stat5 or Akt inhibits neoplastic KIT D816V+ MC growth

Details DOI ↗