title: Pulmonary arterial hypertension in patients treated by dasatinib.
abstract: BACKGROUND
  The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.
  
  
  RESULTS
  This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.
  
  
  CONCLUSIONS
  Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bergot
authors.forename: Sven
authors.initials: S
authors.lastname: Günther
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.forename: Anne
authors.initials: A
authors.lastname: Bergeron
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourdin
authors.forename: Helene
authors.initials: H
authors.lastname: Bouvaist
authors.forename: Matthieu
authors.initials: M
authors.lastname: Canuet
authors.forename: Christophe
authors.initials: C
authors.lastname: Pison
authors.forename: Margareth
authors.initials: M
authors.lastname: Macro
authors.forename: Patrice
authors.initials: P
authors.lastname: Poubeau
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.forename: Delphine
authors.initials: D
authors.lastname: Natali
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.forename: Dermot S
authors.initials: DS
authors.lastname: O'Callaghan
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.forename: Pascale
authors.initials: P
authors.lastname: Tubert-Bitter
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D000069439:Dasatinib; D004363:Drug Utilization / Q000706:statistics & numerical data; D065128:Endothelin Receptor Antagonists; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D012042:Registries; D013844:Thiazoles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C498826:nilotinib; D000069439:Dasatinib; D006918:Hydroxyurea