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Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment.
- Source :
-
PloS one [PLoS One] 2016 Oct 20; Vol. 11 (10), pp. e0165336. Date of Electronic Publication: 2016 Oct 20 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-α (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Adult
Alleles
Blood Cell Count
Female
Follow-Up Studies
Gene Frequency
Genotype
Humans
L-Lactate Dehydrogenase blood
Male
Middle Aged
Mutation
Myeloproliferative Disorders diagnosis
Myeloproliferative Disorders genetics
Prognosis
Thrombocythemia, Essential diagnosis
Thrombocythemia, Essential drug therapy
Thrombocythemia, Essential genetics
Treatment Outcome
Calreticulin genetics
Interferon-alpha therapeutic use
Myeloproliferative Disorders drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27764253
- Full Text :
- https://doi.org/10.1371/journal.pone.0165336