title: Impact of JAK2(V617F) mutation status on treatment response to anagrelide in essential thrombocythemia: an observational, hypothesis-generating study.
abstract: A JAK2(V617F) mutation is found in approximately 55% of patients with essential thrombocythemia (ET), and represents a key World Health Organization diagnostic criterion. This hypothesis-generating study (NCT01352585) explored the impact of JAK2(V617F) mutation status on treatment response to anagrelide in patients with ET who were intolerant/refractory to their current cytoreductive therapy. The primary objective was to compare the proportion of JAK2-positive versus JAK2-negative patients who achieved at least a partial platelet response (≤600×10(9)/L) after anagrelide therapy. Of the 47 patients enrolled, 46 were included in the full analysis set (JAK2-positive, n=22; JAK2-negative, n=24). At 12 months, 35 patients (n=14 and n=21, respectively) had a suitable platelet sample; of these, 74.3% (n=26) achieved at least a partial response. The response rate was higher in JAK2-positive (85.7%, n=12) versus JAK2-negative patients (66.7%, n=14) (odds ratio [OR] 3.00; 95% confidence interval [CI] 0.44, 33.97). By using the last observation carried forward approach in the sensitivity analysis, which considered the imbalance in patients with suitable samples between groups, the overall response rate was 71.7% (n=33/46), with 77.3% (n=17/22) of JAK2-positive and 66.7% (n=16/24) of JAK2-negative patients achieving at least a partial response (OR 1.70; 95% CI 0.39, 8.02). There was no significant change in median allele burden over 12 months in the 12 patients who achieved a response. In conclusion, the overall platelet response rate was high in both JAK2-positive and JAK2-negative patients; however, a larger study would be required to confirm the differences observed according to JAK2(V617F) mutation status.
authors.affiliation: Division of Hematology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cascavilla
authors.affiliation: Institute of Hematology, Catholic University, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: De Stefano
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pancrazzi
authors.affiliation: Oncohematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iurlo
authors.affiliation: IRCCS AOU San Martino, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Department of Specialistic, Diagnostic and Experimental Medicine, St Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Palandri
authors.affiliation: Unit of Hematology with Transplantation, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.affiliation: Ospedale Santa Maria, Terni, Italy.
authors.forename: A Marina
authors.initials: AM
authors.lastname: Liberati
authors.affiliation: Division of Hematology, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: D'Adda
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Rajmonda
authors.initials: R
authors.lastname: Fjerza
authors.affiliation: Research and Development, Shire GmbH, Eysins, Switzerland.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Achenbach
authors.affiliation: Shire Pharmaceutical Development Ltd, Basingstoke, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Smith
authors.affiliation: Shire Pharmaceutical Development Ltd, Basingstoke, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Wilde
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001792:Blood Platelets / Q000187:drug effects; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C021139:anagrelide
keywords: JAK2; allele burden; anagrelide; essential thrombocythemia; mutation; treatment response