Neutrophil Elastase Mutations and the Risk of Leukemia In Patients with Cyclic and Congenital Neutropenia.

Abstract 3786

Mutations in the gene for neutrophil elastase (ELANE) are the cause for the majority of cases of cyclic and congenital neutropenia. More than 50 different mutations of ELANE have been identified in patients with these disorders. It is not known whether specific ELANE mutations predispose patients to the risk of myelodysplasia (MDS) and acute myeloid leukemia (AML).

We have investigated the relationships of ELANE mutations to the risk of MDS/AML in a population of 208 patients with cyclic (N=92) and congenital neutropenia (N=116) having ELANE mutations and receiving granulocyte colony-stimulating factor (G-CSF) therapy for up to 22 years. In the congenital group there were 52 different mutations occurring with increasing frequency from exon 1 (2 mutations) to exon 5 (17 different mutations). In the cyclic group there was a narrower spectrum of mutations; these mutations clustered in exon 4, intron 4 and exon 5. There were 13 different mutations in this group. Mutations P110L, S97L, R191Q, and splice site mutations in intron 4: +5 SD G>A, and +1 SD G>T were observed both in patients with the cyclic and congenital neutropenia.

Sixteen congenital neutropenic patients developed MDS/AML. There were 15 different mutations associated with these transformations. There are also 15 congenital patients who have not evolved to develop leukemia who have the same mutations as in the MDS/AML group. In three families with autosomal dominant congenital neutropenia attributed to ELANE mutations, one affected member has developed AML the other has not. The pairs are: father no, daughter yes; father yes, daughter no; and one identical twin yes, other twin no. One patient with a clinical diagnosis of cyclic neutropenia who had received long term immunosuppressive therapy also developed MDS and had a stem cell transplant. There were no MDS/AML transformations in the other 91 cyclic patients. For the overall population of cyclic and congenital patients, missense mutations in ELANE were most commonly found. In the 16 congenital neutropenia patients evolving to MDS/AML by category the mutations were: missense (8), deletion (2) termination (4) intronic (2), a pattern similar to those of the congenital patients who have not evolved to develop MDS/AML: missense (79) deletion (7) termination (8) intronic (6).

The 16 patients with congenital neutropenia who developed MDS/AML were treated with G-CSF for a median of 8.6 years (range 3.3 – 15.2). The mean of the median G-CSF dose for patients with MDS/AML transformation was 14.6 mcg/kg/day (range 2–43 mcg/kg/day) and the mean of the median dose of G-CSF for the population not developing MDS/AML was 13.7 mcg/kg/day (range 0–183 mcg/kg/day) (p=0.89). However, a higher proportion of the AML group (69%) were receiving G-CSF at > 8mcg/kg than the non MDS/AML group (40%). The median duration of G-CSF treatment was significantly less (p=0.009) in the MDS/AML group than the group not developing MDS/AML. The mean cumulative G-CSF exposure was not significantly different (p=0.54) for the two groups.

These data indicate that there are no specific ELANE mutations or specific types of ELANE mutations predisposing patients with congenital neutropenia to development of MDS or AML. The data confirm previous reports that patients requiring higher daily doses of G-CSF may be at somewhat greater risk of MDS/AML, but there is no distinct dose predicting risk and no association with total G-CSF exposure and the risk of MDS/AML. The specific cause for the high risk of MDS and AML in congenital neutropenia remains unknown.