The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease - PubMed (original) (raw)

The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease

G Hoermann et al. Allergy. 2014 Jun.

Abstract

KIT D816V is present in a majority of patients with systemic mastocytosis (SM). We determined the KIT D816V allele burden by quantitative real-time PCR in bone marrow and peripheral blood of 105 patients with mastocytosis. KIT D816V was detected in 92/105 patients (88%). Significant differences in the median allele burden were observed between disease subgroups: cutaneous mastocytosis (0.042%), indolent SM (0.285%), smoldering SM (5.991%), aggressive SM (9.346%), and SM with associated hematologic non-mast cell lineage disease (3.761%) (P < 0.001). The KIT D816V burden also correlated with serum tryptase (R = 0.5, P < 0.005) but not with mast cell infiltration in bone marrow or mediator symptoms. Moreover, the allele burden was of prognostic significance regarding survival (P < 0.01). Patients responding to cytoreductive therapy showed a significant decrease in KIT D816V (P < 0.05). To conclude, the KIT D816V burden correlates with the variant of mastocytosis, predicts survival, and is a valuable follow-up parameter in SM.

Keywords: KIT D816V; allele burden; mastocytosis; survival; treatment response.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

P.V. is a consultant in a global Novartis trial investigating the effects of PKC412 in patients with advanced systemic mastocytosis. In addition, P.V. received honoraria and a research grant from Novartis. The authors declare no other competing financial interests.

Figures

Fig. 1

Fig. 1. KIT D816V allele burden in different WHO-subtype of mastocytosis and its impact on survival.

(A) Highly significant differences in the KIT D816V allele burden were found between patients with cutaneous mastocytosis (CM), mastocytosis in the skin (MIS), indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and systemic mastocytosis with an associated hematologic non-mast cell lineage disease (SM-AHNMD) (P<0.001, Kruskal Wallis test). (B) Kaplan-Meier plot for overall survival of mastocytosis patients with a KIT D816V mutation burden <2% and patients with a KIT D816V burden of ≥ 2% at diagnosis. The difference in the probability of survival was significant (_P_=0.001).

Fig. 2

Fig. 2. KIT D816V allele burden during the follow-up.

Change in KIT D816V mutation positive allele fraction during the follow-up in patients without (A; _N_=19) and with cytoreductive treatment (B; _N_=11). The allele burden was normalized to the mutant burden at diagnosis. The value of 1 corresponds to no change in allele fraction over time and the values of 0.1 and 10 (dotted lines) correspond to 10 fold decreases and increases. (C-F) Follow-up of KIT D816V allele burden (blue) and serum tryptase (black) in individual mastocytosis patients with an uneventful course (C, ISM; D, SSM), a patient initially diagnosed as ISM with disease progression to ASM-CMML and response to cytoreductive therapy with cladribine (2-CDA) (E), and a patient with SSM receiving cytoreductive therapy due to recurrent episodes of life threatening vascular instability requiring epinephrine support (F).

Similar articles

Cited by

References

    1. Longley BJ, Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA. 1999;96(4):1609–1614. - PMC - PubMed
    1. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995;92(23):10560–10564. - PMC - PubMed
    1. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37(6):435–453. - PubMed
    1. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et al. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013;121(13):2393–2401. - PMC - PubMed
    1. Kristensen T, Vestergaard H, Moller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn. 2011;13(2):180–188. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources