title: Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia.
abstract: About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being "triple negative." Furthermore, CALR mutations in ET are structurally classified as type 1/type 1-like or type 2/type 2-like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis-free (MFFS), thrombosis-free, and leukemia-free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple-negative. Among the 109 CALR-mutated cases, 52% were classified as type 1/type 1-like and 48% as type 2/type 2-like. In univariate analysis, triple-negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL-mutated patients on both univariate and multivariable analyses (age-adjusted P = 0.02; HR 7.9, 95% CI 2.0-31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1-3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yoseph C
authors.initials: YC
authors.lastname: Elala
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Terra L
authors.initials: TL
authors.lastname: Lasho
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Naseema
authors.initials: N
authors.lastname: Gangat
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christy
authors.initials: C
authors.lastname: Finke
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barraco
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mahnur
authors.initials: M
authors.lastname: Haider
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ahmed K
authors.initials: AK
authors.lastname: Abou Hussein
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota.|Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Hanson
authors.affiliation: Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.|Division of Cytogenetics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.|Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D012189:Retrospective Studies; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000401:mortality; D055815:Young Adult
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2