title: Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment.
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.
authors.affiliation: Department of Haematology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Kjær
authors.affiliation: Department of Haematology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cordua
authors.affiliation: Department of Haematology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Morten O
authors.initials: MO
authors.lastname: Holmström
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Torben A
authors.initials: TA
authors.lastname: Kruse
authors.affiliation: Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Pallisgaard
authors.affiliation: Department of Haematology, Odense University Hospital, Odense, Denmark.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Larsen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: de Stricker
authors.affiliation: Department of Haematology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Vibe
authors.initials: V
authors.lastname: Skov
authors.affiliation: Department of Haematology, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hasselbalch
mesh_terms: D000328:Adult; D000483:Alleles; D001772:Blood Cell Count; D037282:Calreticulin / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D013920:Thrombocythemia, Essential / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D037282:Calreticulin; D016898:Interferon-alpha; D007770:L-Lactate Dehydrogenase