Regular article
Cardiovascular, pulmonary, and renal pathology
Chemotherapy-Induced Pulmonary Hypertension: Role of Alkylating Agents

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Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

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Supported by Agence National de la Recherche grant ANR-13-JSV1-0011, Labex LERMIT (B.R.), Association HTAPFrance grant (S.G. and D.M.), Aviesan [Institut Thématique Multi-Organismes Immunologie, Hématologie et Pneumologie (ITMO IHP)] post-doctoral grant (F.A.), a Bayer Investigator Sponsored Study grant (F.P.), and Fonds de Dotation Recherche en Santé Respiratoire (S.J.D.). The French pulmonary hypertension pharmacovigilance network VIGIAPATH is chaired by M.H. and supported by the Agence Nationale de Sécurité du Médicament et des Produits de Santé.

B.R. and S.G. contributed equally to this work.

D.M. and F.P. contributed equally to this work as senior authors.

Disclosures: L.S., X.J., O.S., G.S., M.H., and D.M. have received speaker fees or honoraria for consultations from Actelion, Bayer, Bristol-Myers-Squib, GSK, Lilly, Novartis, Pfizer, and United Therapeutics Corporation; received reimbursement from Actelion and Lilly for attending French and international meetings; and received fees from Bristol-Myers-Squib and Lilly for participating to advisory boards.

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