The clinical and prognostic relevance of driver mutations in 203 Taiwanese patients with primary myelofibrosis.

AIMS

We investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF).

METHODS

Pyrosequencing was used to detect mutational status and measure allele burden, while (exon 10) mutations were analysed by PCR assay and then by direct sequencing. exon 9 mutations were first screened for length changes by GeneScan followed by sequencing. The allele burden of the mutated gene was measured by pyrosequencing. The EEC assay was conducted using a serum-free culture system.

RESULTS

The frequencies of the three driver mutations and triple-negative status were similarly distributed between pre-PMF and overt PMF patients, except that pre-PMF patients had a higher incidence of type 2/type-2 like mutations and a lower allele burden. EEC growth and mutations conferred favourable overall survival (OS). A lower allele burden and grade 3 bone marrow fibrosis were associated with shorter OS and decreased leukaemia-free survival (LFS). Type 2/type 2-like mutations were associated with better LFS compared with type1/type 1-like mutations. Patients with triple-negative mutation status had significantly worse OS and LFS. The allele burden of mutations remained unchanged, while some mutations showed clonal expansion in patients during secondary acute myeloid leukaemia transformation.

CONCLUSIONS

Our study showed that EEC growth, a higher allele burden and mutations, especially type 2, were independent predictors for better outcomes in PMF. The allele burden of mutations remained stable, but the allele burden of mutations was variable during leukaemia transformation.