Researchers have identified oncogenic mutations in the CSF3R gene that appear to be "the defining molecular abnormality" of both chronic neutrophilic leukemia and atypical chronic myeloid leukemia, according to a report published online May 8 in the New England Journal of Medicine.
Testing patients for these mutations will aid in the diagnosis of these two rare diseases, and also may prove useful in assessing other disorders of unknown etiology that are characterized by neutrophilia. Genetic testing should also "help refine the molecular classification of myeloproliferative neoplasms," said Julia E. Maxson, Ph.D., of the division of hematology and medical oncology, Oregon Health and Science University, Portland, and her associates.
Dr. Julia Maxson
Discovering the mutations allowed the investigators to test tissue samples for susceptibility to different anticancer drugs. Then, administering the likeliest candidate drug – the JAK-family tyrosine kinase inhibitor ruxolitinib – to one CML patient produced a marked decrease in the total number of white cells and the absolute neutrophil count, and complete normalization of the platelet count.
This excellent clinical response "constitutes a proof of concept. Although anecdotal, this observation provides an impetus for further investigation of tyrosine kinase inhibitors for the treatment of patients with neutrophilic leukemia who have CSF3R (colony-stimulating factor 3) mutations," Dr. Maxson and her colleagues said.
The researchers began with the hypothesis that patients with CNL or atypical CML may carry oncogenes that could be sensitive to small-molecule kinase inhibitors. They screened cell samples from 27 patients with the two diseases and from more than 300 patients with other hematologic cancers including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia. Regions from 1,862 candidate genes known to be involved with cancer signaling, such as those related to kinases, phosphatases, and nonkinase growth factor or cytokine receptors, were sequenced.
Sixteen of the 27 CNL or atypical CML patients (59%) were found to carry certain novel CSF3R mutations, which were present in less than 1% of the other study subjects. The finding suggests that these CSF3R mutations were specific for the two diseases. No other genetic markers specific to these myeloid neoplasms have been previously identified, the investigators said (N. Engl. J. Med. 2013 May 8 [doi:10.1056/NEJMoa1214514]).
They then assessed whether specimens harboring the CSF3R mutations were sensitive to either chemical kinase inhibitors or small interfering RNA directed against kinases. One set of mutations – frameshift or nonsense mutations that truncated the cytoplasmic tails of CSF3R – were sensitive to the multikinase inhibitor dasatinib. Another set of mutations – membrane proximal mutations – were susceptible only to inhibitors such as ruxolitinib that target JAK family kinases.
In vitro colony-forming assays confirmed that the two types of mutation had different transformation capacities and that they were susceptible to different drugs.
A patient who had CNL and carried the CSF3R membrane proximal mutations, had cells that were hypersensitive in vitro to ruxolitinib. The patient was given oral ruxolitinib at a dose of 10 mg twice per day, which induced a marked decrease in white cells and in the absolute neutrophil count. Raising the dose to 15 mg twice daily further decreased both white cells and the absolute neutrophil count, normalizing the platelet count.
These CSF3R mutations "define a new molecular subset of hematologic cancers," and point the way toward new therapeutic approaches, Dr. Maxson and her colleagues said.
This study had no industry support and was funded by the Leukemia and Lymphoma Society, the National Cancer Institute, the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, and several others. Dr. Maxson reported no ties to industry sources; her associates reported numerous ties to industry sources.