Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Busulfan-induced pulmonary injury

Erich W Russi, MD
Robert S Negrin, MD
Section Editors
Kevin R Flaherty, MD, MS
James R Jett, MD
Deputy Editors
Helen Hollingsworth, MD
Diane MF Savarese, MD


Busulfan is an alkylating agent that was previously used for treatment of chronic myelogenous leukemia, but is now used exclusively as a component of a preparative regimen prior to hematopoietic stem cell transplantation (HCT). Busulfan was the first cytotoxic drug reportedly associated with pulmonary toxicity [1]. The reported patterns of pulmonary toxicity include acute lung injury, chronic interstitial fibrosis, and alveolar hemorrhage. Busulfan is often used in combination with other drugs, many of which cause pulmonary toxicity, which can make it difficult to ascertain which drug is the culprit. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Chemotherapy without radiation'.)

The clinical characteristics of busulfan-induced pulmonary injury will be reviewed here. Pulmonary toxicity caused by other chemotherapeutic agents is discussed separately. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)


Symptomatic pulmonary injury is thought to occur in fewer than 8 percent of patients who receive busulfan; the incidence of pulmonary toxicity appears to be similar in children and adults [2-16]. However, the true incidence is unknown; most of the early data in patients treated with busulfan alone for chronic myelogenous leukemia (CML) consisted of single case reports [3-7,9,10]. Such treatment is no longer considered a standard approach since the introduction of oral tyrosine kinase inhibitors. (See "Overview of the treatment of chronic myeloid leukemia".)

At present the utility of busulfan is limited to preparative regimens prior to hematopoietic cell transplantation (HCT). Modern data examining the risk of pulmonary toxicity in such patients are derived from series in which patients received busulfan in addition to other myelosuppressive chemotherapy agents and/or radiation therapy prior to HCT. The incidence has been variable, and interpretation complicated by competing causes of pulmonary toxicity [14,16-21], particularly cytomegalovirus (CMV) pneumonitis:

In one report, 2 of 78 patients (2.5 percent) who received a conditioning regimen of busulfan and cyclophosphamide prior to autologous HCT developed pulmonary fibrosis [14].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Oct 03, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. OLINER H, SCHWARTZ R, RUBIO F, DAMESHEK W. Interstitial pulmonary fibrosis following busulfan therapy. Am J Med 1961; 31:134.
  2. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 1986; 133:321.
  3. Smalley RV, Wall RL. Two cases of busulfan toxicity. Ann Intern Med 1966; 64:154.
  4. Heard BE, Cooke RA. Busulphan lung. Thorax 1968; 23:187.
  5. Burns WA, McFarland W, Matthews MJ. Busulfan-induced pulmonary disease. Report of a case and review of the literature. Am Rev Respir Dis 1970; 101:408.
  6. Podoll LN, Winkler SS. Busulfan lung. Report of two cases and review of the literature. Am J Roentgenol Radium Ther Nucl Med 1974; 120:151.
  7. Hankins DG, Sanders S, MacDonald FM, Drage CW. Pulmonary toxicity recurring after a six week course of busulfan therapy and after subsequent therapy with uracil mustard. Chest 1978; 73:415.
  8. Schallier D, Impens N, Warson F, et al. Additive pulmonary toxicity with melphalan and busulfan therapy. Chest 1983; 84:492.
  9. Pearl M. Busulfan lung. Am J Dis Child 1977; 131:650.
  10. Oakhill A, Green ID, Knowlson GT, et al. Busulphan lung in childhood. J Clin Pathol 1981; 34:495.
  11. Jochelson M, Tarbell NJ, Freedman AS, et al. Acute and chronic pulmonary complications following autologous bone marrow transplantation in non-Hodgkin's lymphoma. Bone Marrow Transplant 1990; 6:329.
  12. Fernandez HF, Tran HT, Albrecht F, et al. Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation. Biol Blood Marrow Transplant 2002; 8:486.
  13. Hänel M, Kröger N, Sonnenberg S, et al. Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma. Ann Hematol 2002; 81:96.
  14. Ulrickson M, Aldridge J, Kim HT, et al. Busulfan and cyclophosphamide (Bu/Cy) as a preparative regimen for autologous stem cell transplantation in patients with non-Hodgkin lymphoma: a single-institution experience. Biol Blood Marrow Transplant 2009; 15:1447.
  15. Brockstein BE, Smiley C, Al-Sadir J, Williams SF. Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant 2000; 25:885.
  16. Crilley P, Topolsky D, Styler MJ, et al. Extramedullary toxicity of a conditioning regimen containing busulphan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogenic bone marrow transplantation. Bone Marrow Transplant 1995; 15:361.
  17. Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309:1347.
  18. Copelan EA, Hamilton BK, Avalos B, et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 2013; 122:3863.
  19. Bredeson C, LeRademacher J, Kato K, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood 2013; 122:3871.
  20. Orchard PJ, Fasth AL, Le Rademacher J, et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood 2015; 126:270.
  21. Peters C, Schrappe M, von Stackelberg A, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol 2015; 33:1265.
  22. Ringdén O, Remberger M, Ruutu T, et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood 1999; 93:2196.
  23. Ginsberg SJ, Comis RL. The pulmonary toxicity of antineoplastic agents. Semin Oncol 1982; 9:34.
  24. Sostman HD, Matthay RA, Putman CE. Cytotoxic drug-induced lung disease. Am J Med 1977; 62:608.
  25. Perkins JB, Kim J, Anasetti C, et al. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:1099.
  26. Vergnon JM, Boucheron S, Riffat J, et al. [Interstitial pneumopathies caused by busulfan. Histologic, developmental and bronchoalveolar lavage analysis of 3 cases]. Rev Med Interne 1988; 9:377.
  27. Limper AH. Chemotherapy-induced lung disease. Clin Chest Med 2004; 25:53.
  28. Cleverley JR, Screaton NJ, Hiorns MP, et al. Drug-induced lung disease: high-resolution CT and histological findings. Clin Radiol 2002; 57:292.
  29. Worth L, Tran H, Petropoulos D, et al. Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide. Bone Marrow Transplant 1999; 24:947.
  30. Lund MB, Brinch L, Kongerud J, Boe J. Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide. Eur Respir J 2004; 23:901.
  31. Padley SP, Adler B, Hansell DM, Müller NL. High-resolution computed tomography of drug-induced lung disease. Clin Radiol 1992; 46:232.
  32. Lund MB, Kongerud J, Brinch L, et al. Decreased lung function in one year survivors of allogeneic bone marrow transplantation conditioned with high-dose busulphan and cyclophosphamide. Eur Respir J 1995; 8:1269.
  33. Bruno B, Souillet G, Bertrand Y, et al. Effects of allogeneic bone marrow transplantation on pulmonary function in 80 children in a single paediatric centre. Bone Marrow Transplant 2004; 34:143.
  34. Lund MB, Brinch L, Kongerud J, Boe J. Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide. Eur Respir J 2004; 23:901.
  35. Costabel U, Uzaslan E, Guzman J. Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med 2004; 25:25.
  36. Ito K, Iwabe K, Okai T, et al. Rapidly progressive pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. Intern Med 1994; 33:710.
  37. Aymard JP, Gyger M, Lavallee R, et al. A case of pulmonary alveolar proteinosis complicating chronic myelogenous leukemia. A peculiar pathologic aspect of busulfan lung? Cancer 1984; 53:954.
  38. Tsushima K, Koyama S, Saitou H, et al. Pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. Respiration 1999; 66:173.
  39. Ohmachi K, Ogiya D, Morita F, et al. Secondary pulmonary alveolar proteinosis in a patient with chronic myeloid leukemia in the accelerated phase. Tokai J Exp Clin Med 2008; 33:146.
  40. Kobayashi S, Ishikawa M, Wakabayashi Y, et al. [Busulfan lung exacerbated during steroid therapy: a review of Japanese literature]. Rinsho Ketsueki 1990; 31:1884.
  41. Korbitz BC, Reiquam CW. Busulfan in chronic granulocytic leukemia, a spectrum of clinical considerations. Clin Med 1969; 76:16.