Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy: Short report

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA.
British Journal of Haematology (Impact Factor: 4.71). 07/2010; 150(2):196-9. DOI: 10.1111/j.1365-2141.2010.08216.x
Source: PubMed


In severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We have reported the early pattern of evolution to MDS/AML, but the long-term risk remains uncertain. We updated a prospective study of 374 SCN patients on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after 10 years). This risk now appears similar to, rather than higher than, the risk of AML in Fanconi anaemia and dyskeratosis congenita.

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    • "Recently, several other mutations in genes including HAX1, G6PC3, GFI1, GATA2, and WASP have all been implicated in SCN (reviewed by Klein) [Klein, 2011]. The latest data on the long-term risk of developing a myeloid malignancy in this population is 2.3% per year after the first decade [Rosenberg et al. 2010]. "
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    ABSTRACT: While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.
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    • "Simulation-estimation experiment outlined in the Methods demonstrates that distribution of simulated times (counting form initiation of CGSF treatment) at sAML (Rosenberg et al., 2010) is reproduced by our model. Figure 4A cumulative distribution "
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    ABSTRACT: We present a stochastic model of driver mutations in the transition from severe congenital neutropenia to myelodysplastic syndrome to acute myeloid leukemia (AML). The model has the form of a multitype branching process. We derive equations for the distributions of the times to consecutive driver mutations and set up simulations involving a range of hypotheses regarding acceleration of the mutation rates in successive mutant clones. Our model reproduces the clinical distribution of times at diagnosis of secondary AML. Surprisingly, within the framework of our assumptions, stochasticity of the mutation process is incapable of explaining the spread of times at diagnosis of AML in this case; it is necessary to additionally assume a wide spread of proliferative parameters among disease cases. This finding is unexpected but generally consistent with the wide heterogeneity of characteristics of human cancers.
    Full-text · Article · Apr 2013 · Frontiers in Oncology
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    • "In our study no patient has died of infections, while SCNIR reported a 10% septicaemia-related mortality (Rosenberg et al, 2010) and the French Severe Chronic Neutropenia Registry reported six septic deaths out of 101 patients with SCN, although none of these patients received G-CSF (Donadieu et al, 2005). These differences compared to our study might be due to our more uniform patient population and that more of our patients are on G-CSF. "
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    ABSTRACT: Severe congenital neutropenia (SCN) is characterized by low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. As yet, no population-based incidence estimates of SCN have been reported. Children less than 16 years of age with SCN were sought in Sweden during the 20-year period 1987-2006 by a questionnaire to all Swedish Departments of Paediatrics and by reviewing the Swedish Health and Welfare Statistical Databases. Thirty-two patients were diagnosed with congenital neutropenia during this period. All received treatment with recombinant granulocyte-colony stimulating factor (G-CSF). Twenty-one patients were diagnosed as SCN or probable SCN, corresponding to 1·0 per 100,000 live births. Nine (43%) had ELANE mutations, four (19%) HAX1 mutations and eight (38%) were children with disease of unknown genetic aetiology. Four out of 21 patients (19%) developed myelodysplastic syndrome/leukaemia and three (14%) died, all with leukaemia. The cumulative incidence of myelodysplastic syndrome/leukaemia was 31%. The observed incidence of SCN in this population-based study was higher than previously estimated, possibly because genetic testing now can identify SCN cases previously thought to be idiopathic or benign neutropenia. The risk of developing myelodysplastic syndrome/leukaemia is considerable. ELANE mutations are the most commonly identified genetic defects.
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