Our study is the largest to date of ELA2
mutations and clinical outcomes in SCN. It is well known that almost all SCN patients respond to G-CSF, but there is considerable heterogeneity in the dose of G-CSF required to obtain a haematological response. In this study, we observed that patients with mutant ELA2
usually responded with higher ANC values at lower doses of G-CSF than patients with wild-type ELA2
. As an exception to this general trend, we observed a particularly severe course in the four patients in our study with the ELA2
mutation Gly185Arg, consistent with the report from the French Neutropenia Registry that also had four SCN patients with this mutation (Bellanne-Chantelot et al, 2004
Notwithstanding these differences in response to therapy, an important finding was that patients with or without mutations in ELA2 were at extraordinary risk of MDS/AML. Indeed, there was no significant difference in risk between the two groups. In all patients combined, the cumulative incidence of MDS/AML was 34% after 15 years on G-CSF.
We do not believe that selection or referral bias had a major impact on our analysis. Considering patients who enroled during the same calendar periods, we found no differences in the rates of loss-to-follow-up according to ELA2 mutation status (data not shown). Furthermore, the incidence of MDS/AML was similar in the patients included here, compared to other SCN patients in the SCNIR who were not included. Together, these observations suggest that our analyses of MDS/AML are statistically valid.
In contrast to our results, the French Neutropenia Registry reported a significantly reduced
leukaemia risk in patients with wild-type ELA2
, based on their observation that no patient with wild-type transformed (Bellanne-Chantelot et al, 2004
). Our study was larger, with 20 MDS/AML events versus
three MDS/AML events, and one acute lymphoblastic leukaemia event in the French study. We attribute the divergent results to statistical heterogeneity, and possibly, genetic heterogeneity between ELA2
wild-type patients in the respective studies. Our results suggest that it is the marrow disorder that leads to leukaemia, not simply the presence of an ELA2
mutation, and leads to the prediction that patients with wild-type ELA2
who develop leukaemia may ultimately be found to harbour mutations in a number of other causative genes.
Although the average incidence of MDS/AML in our cohort was similar in patients with and without ELA2
mutations, exploratory analysis supports the concept that susceptibility to MDS/AML varies by mutation. The subgroup of SCN patients with the Gly185Arg missense mutation may be at increased risk, given our findings and the leukaemias in this group reported by the French Neutropenia Registry (Bellanne-Chantelot et al, 2004
). In addition, in our data, SCN patients with the Pro110Leu or Ser97Leu missense mutations were at significantly decreased risk. Interestingly, these specific ELA2
mutations are among the limited number associated with both SCN and cyclic neutropenia (Horwitz et al, 2007
From the clinical perspective, SCN patients with a wide diversity of ELA2
mutations, and SCN patients without ELA2
mutations, have been observed to transform to leukaemia. Therefore, the average risk is extraordinarily high. Until more refined predictions are available, all SCN patients should be considered at high risk. Our data also suggest that patients with wild-type ELA2
who do not respond to standard doses of G-CSF are comparatively unlikely to respond to high doses. These patients should be considered for early haematopoietic stem cell transplantation, because they may be at high risk of mortality from sepsis. It is now essential to develop new practice guidelines for SCN (Touw & Bontenbal, 2007
). These guidelines will need to carefully weigh the potential risks and benefits of G-CSF therapy versus
transplantation, and specify the appropriate role and timing of genetic and molecular tests in counselling and decision-making.