Pulmonary hypertension associated with busulfan

Abstract

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin’s disease, Ewing’s sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow-up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases.

Progression of pulmonary veno‐occlusive disease without pulmonary hypertension

“…Our patient was recently treated with cyclophosphamide and was likely culprit factor in her case. PVOD induced by alkylating agents, bone marrow transplantation, and occupational exposure to organic solvents is very well reported 4,5,11,12 . This case raised management questions, as she neither had hemodynamically confirmed PH nor was eligible for lung transplantation due to recent diagnosis of lymphoma.…”

“…PVOD induced by alkylating agents, bone marrow transplantation, and occupational exposure to organic solvents is very well reported. 4 , 5 , 11 , 12 This case raised management questions, as she neither had hemodynamically confirmed PH nor was eligible for lung transplantation due to recent diagnosis of lymphoma. We possibly, diagnosed her early in the disease course due to early referral to a PH center and availability of lung biopsy findings.…”

Pulmonary Veno-Occlusive Disease after Autologous Stem Cell Transplantation

“…Contrary to the significant efficacy of selective pulmonary vasodilators for patients with PAH, the role of these agents is limited in patients with PVOD. Specifically, responses to endothelin receptor antagonists or phosphodiesterase type 5 inhibitors in patients with chemotherapy-associated PVOD have been reported in small case series with various outcomes [10, 11]. Such vasodilators should be used under careful monitoring in highly experienced treating centers since these agents may induce severe pulmonary edema in patients with PVOD [5].…”

“…Such vasodilators should be used under careful monitoring in highly experienced treating centers since these agents may induce severe pulmonary edema in patients with PVOD [5]. In addition, immunosuppressive treatment with corticosteroids has a potential role in drug-induced PVOD, as well as in inheritable PVOD [10, 11, 17].…”

“…For instance, one study reported that 12 of 14 (86%) patients who failed to respond to PAH-specific treatments were ultimately revealed to have PVOD based on lung pathology results at explant for lung transplantation or postmortem findings [9]. The possible causes of PVOD include chemotherapy such as alkylating agents (e.g., cyclophosphamide and busulfan) or mitomycin C [5, 10, 11], collagen diseases such as scleroderma [6], viral infections such as human immunodeficiency virus (HIV) infection, exposure to toxic substances such as tobacco and organic solvents, and chemotherapeutic agents [7]. Because of the lack of evidence-based treatments, most patients with PVOD have a poor prognosis and die within 2 years of their diagnosis.…”