Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies

Abstract

Summary:Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin's disease, 22 non-Hodgkin's lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m 2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52-289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P Ͻ 0.001) and BCV regimen (P Ͻ 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m 2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309-313. Keywords: carmustine; pulmonary toxicity; autologous peripheral blood progenitor cell transplantation There is evidence that several agents used in the preparative regimens for both autologous and allogeneic bone marrow transplantation may induce lung injury without evidence of infection. Agents that have been implicated include carmustine (BCNU), busulphan, cyclophosphamide (CY), and total body irradiation.1 BCNU causes toxic lung reactions characterized by chronic interstitial fibrosis, cough, dyspnea and decrease in lung diffusing capacity; toxicity related to the use of BCNU is suspected to be caused by damage to the glutathione system.2 BCNU has been included in highdose conditioning regimens for gliomas, breast cancer, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma. Toxic pulmonary reactions have been recognized in as many as 16-64% of patients; 3-13 onset generally occurs within 1 year of starting BCNU. Events occurring up to 17 years later have been reported.14 The drug seems to cause pulmonary damage in a dose-related manner: 5,10,11 Phillips et al 6 reported a 9.5% incidence of fatal pulmonary toxicity in patients receiving BCNU doses as high as 1.200 mg/m 2 as a single agent; another report suggests no pulmonary toxicity at doses of less than 1000 mg/m 2 . 7 The threshold dose for BCNU toxicity is still controversial: lung toxicity may occur at 600 mg/m 2 when the drug is associated with other toxic agents like CY. 1,15 This report deals with patients with hematological malignancies who received a carmustine-based preparative regimen; the drug was combined with cyclophosphamide and etoposide or with etoposide and melphalan and both regimens were followed by autologous peripheral blo...

High-dose CEB vs BEAM with autologous stem cell transplant in lymphoma

“…12 Risk factors favoring BCNU lung toxicity have been reported, including previous treatment with bleomycin or chest radiotherapy and the female gender. 1 Half (3/6) of our patients who developed BCNU pulmonary toxicity had previously received bleomycin, although it is unknown whether they had experienced any pulmonary complications at that time. The number of other patients who had received bleomycin as earlier treatment and had been spared toxicity with BCNU given presently is unknown.…”

“…Previous studies have included small numbers of patients but reported roughly 26-28% occurrence of post-transplant noninfective pulmonary complications with CEB. 1,[5][6] These studies used a BCNU dose of 600 mg/m 2 or higher. It is apparent from these studies that BCNU pulmonary toxicity is dose related, but it remains unclear why our study reports a low occurrence rate.…”

“…Doses greater than 600 mg/m 2 are not well tolerated with a higher risk of development of posttransplant noninfective pulmonary complications, marked mucositis, and increased cases of infection. [1][2][3][4][5][6] In terms of efficacy, whether CEB or BEAM produces better survival outcome is unclear. There is a wide range of percentages of patients achieving complete remission in both the CEB and BEAM.…”

Fatal pulmonary fibrosis associated with BCNU: the relative role of platelet-derived growth factor-B, insulin-like growth factor I, transforming growth factor-β1 and cyclooxygenase-2

“…3 Some risk factors, such as history of irradiation to lung, cigarette smoking, female gender and a dosage greater than 475 mg/m 2 , are known to be associated with BCNU-related pulmonary injury. 4,5 However, the pathogenetic mechanism of BCNU-associated pulmonary fibrosis has never been studied.…”

Outcomes of EAM conditioned autologous haematopoietic SCT for lymphoma. A matched pairs retrospective single-centre study analysis

“…However, BCNU is associated with potentially lethal pulmonary interstitial toxicity, in a dose-dependent manner. 3 The incidence of BCNU-associated pneumonitis in published trials has ranged from 3% (ref. 1) to 17% (ref.…”