U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details


; .

Author Information and Affiliations

Last Update: October 17, 2022.

Continuing Education Activity

Busulfan is a medication used to manage and treat allogeneic hematopoietic progenitor cell transplantation, specifically for patients with chronic myelogenous leukemia. It is in the antineoplastic class of drugs, and it is defined as an alkylating agent. This activity reviews the indications, action, and contraindications for busulfan as a valuable agent in the therapy for allogeneic hematopoietic progenitor cell transplantation, specifically for patients with chronic myelogenous leukemia and other disorders when applicable. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional healthcare team in the management of patients with chronic myelogenous leukemia and other related conditions.


  • Identify the mechanism of action of busulfan.
  • Describe the adverse effects profile of busulfan.
  • Review select appropriate monitoring of busulfan.
  • Summarize team strategies for improving care coordination and communication to advance busulfan and improve outcomes.
Access free multiple choice questions on this topic.


Busulfan is an alkylating antineoplastic agent that has been in use since the 1950s. The FDA-approved indication for busulfan is for use with cyclophosphamide as part of the regimen before allogeneic hematopoietic progenitor cell transplantation, specifically for patients with chronic myelogenous leukemia. Non-FDA-approved indications for busulfan are for patients undergoing allogeneic hematopoietic progenitor cell transplantation, but for other malignancies, whether acute or chronic, and other nonmalignant disorders like hemoglobinopathies, congenital metabolic diseases, or inborn errors of the immune system.[1][2]

Mechanism of Action

Busulfan is an alkylating chemotherapeutic agent. Alkylating agents are a broad category of antineoplastic agents, but all have a similar mechanism of action. Alkylating agents work specifically by substituting alkyl groups for hydrogen atoms on the cancer cell DNA molecule; this results in cross-linkage within the DNA chain, inhibiting the transcription of DNA into RNA. The inhibition of DNA into RNA causes inhibition of protein synthesis and further results in cytotoxic, mutagenic, and carcinogenic effects.[3]

Busulfan works by having a hydrolysis reaction occur with the two easily displaced methanesulfonate groups located on opposite ends of a butane chain within the drug's chemical structure. This reaction creates positively charged carbonium ions that are highly reactive, which disrupts and damages the cancer cell's DNA. The reaction that occurs is a nucleophilic substitution reaction with the guanine molecules, which creates DNA intrastrand cross-links.

Another inhibitory effect that busulfan exerts on DNA is binding to the cysteine molecules of histone proteins, which leads to DNA-protein binding. Busulfan also disrupts the cellular redox equilibrium by interacting with the sulfhydryl groups of glutathione, resulting in increased oxidative stress in cancer cells.[4][5]


Patients can receive busulfan either orally or IV. For pre-transplantation, patients who are over 12 kg in weight receive busulfan at a rate of 0.8 mg/kg every six hours for a total of 4 days. Pre-transplantation treatment also includes cyclophosphamide. IV administration is preferable to oral administration because multiple studies show a sizeable therapeutic variability among patients receiving therapy with oral busulfan.[6][2]

Adverse Effects

There are side effects that commonly correlate with busulfan use and that are common among all alkylating agents. Common side effects associated with all alkylating agents include intestinal mucosal damage, alopecia, pancytopenia, anemia, amenorrhea, impaired spermatogenesis, and increased risk of malignancy.

Hepatic veno-occlusive disease is a side effect commonly associated with busulfan. It typically occurs 10 to 20 days after hematopoietic cell transplantation, but it can present as late as 30 to 75 days with newer therapeutic regimens. Frequency ranges from 20 to 50%, but the incidence has decreased due to better therapeutic regimens. Hepatic veno-occlusive disease typically presents with abdominal pain, liver tenderness, and jaundice. There is also associated with weight gain due to fluid accumulation. Serum enzyme and serum aminotransferase concentrations typically become elevated, with a minimal increase in alkaline phosphatase concentrations. If severe enough, it can cause hepatic failure. With the fatality rate being as high as 50%, it is important to bear in mind how much busulfan a patient is receiving because hepatic veno-occlusive disease is dose-dependent. Doses higher than 16 mg/kg, for instance, would put the patient at more risk of hepatic veno-occlusive disease.[2][3][7]

Other side effects of busulfan include interstitial pulmonary fibrosis. This side effect is commonly referred to as busulfan lung, and while it is rare, it is an important side effect to note. Research has not established the exact mechanism, but it is believed to be due to chemically induced inflammation of the alveoli. This inflammation then causes granular pneumocytes to proliferate, which causes the lungs to become fibrotic.[7][8][9]

Busulfan-induced seizure is also another side effect to note. The seizures are generally tonic-colonic. Incidence is reported to be 10% and is associated with high concentrations of busulfan. Busulfan has the capability of rapid distribution into the CSF. CSF concentration can be approximately equivalent to the concentration in plasma when using busulfan in high doses. It is highly recommended that physicians prophylactic treat patients with phenytoin. Other medications that have been useful as a prophylactic treatment for busulfan-induced seizures are clonazepam, lorazepam, valproic acid, and levetiracetam. Some physicians have chosen to use benzodiazepines like the antiseizure medications previously suggested because phenytoin can increase the metabolism of busulfan by upregulating many P450 enzymes. Further research into this area is underway.[4][10][11]

Other notable side effects of busulfan include hyperpigmentation, emesis, wasting syndrome, thrombocytopenia, and sometimes medullary aplasia.[7][8][12]


Busulfan or any of its dosage form components causing hypersensitivity is an absolute contraindication. Many cautions are necessary when using busulfan and all alkylating agents like pancytopenia, gonadal dysfunction, pubertal development in children, carcinogenicity, mutagenicity, infertility, and many other factors others.

The FDA has declared busulfan to be pregnancy category D medication. Breastfeeding is contraindicated when undergoing treatment with antineoplastic medications. Like many other antineoplastic medications, busulfan can impact the normal microbiome and chemical composition of breastmilk. There has been a case where a woman breastfeeding was taking 4 mg/day of busulfan for five weeks for myeloid leukemia that resulted in no adverse effects on her infant’s hemoglobin and leukocyte count.[13] Even with this case, there is still not enough information to say whether it is safe to take busulfan when breastfeeding. 


Optimal monitoring of busulfan uses the concentrations expressed as the area under the concentration-time curve (AUC). AUC has significantly helped clinicians monitor the therapeutic concentrations and correct them as needed for better outcomes after allogeneic hematopoietic cell transplantation. An AUC of 100 mg*h/L reaches optimal efficacy in most patients, but the optimal target varies due to factors that include age, diagnosis, and many others. Anything less than 100 mg*h/L increases the risk of graft rejection or disease relapse. Anything greater than 100 mg*h/L or 1500 microM for AUC increases a patient’s risk of hepatic venous-occlusive disease.[1][14] Other tests to use when analyzing the effects of busulfan on a patient include complete blood count, liver function tests, pulmonary function tests, and many others.


When using busulfan, toxicity concerns are mostly associated with hepatic venous-occlusive disease, acute graft-versus-host disease, and chronic graft-versus-host disease. Most research indicates that maintaining the AUC between 78 to 101 mg*h/L significantly increases the event-free survival for patients.[14]

Treatment for hepatic venous-occlusive disease (also known as hepatic sinusoidal occlusive syndrome) includes defibrotide. Defibrotide is an antiplatelet agent and antithrombotic agent. Research has shown that 25 mg/kg/day of defibrotide IV for 21 days has been effective in treating hepatic venous-occlusive disease.[15] Standard first-line therapy for both acute and chronic graft-versus-host disease is corticosteroids.[16]

Enhancing Healthcare Team Outcomes

Busulfan is a medication that can be helpful but has many side effects associated with its use. Busulfan should be used by experienced clinicians due to its vast aside effects profile. The interprofessional healthcare team, e.g., clinicians (MDs, DOs, PAs, NPs), nurses, pharmacists, etc., needs to effectively coordinate the treatment of patients with busulfan; it is important to monitor and repeat multiple labs. These laboratory tests include complete blood count, liver function test, pulmonary function test, and many others when the suspected side effect is suspected. When a suspected side effect seems to be present in a patient, especially during the period of allogeneic hematopoietic progenitor cell transplantation, nurses and other medical staff should relay this information to the doctor. Effective interprofessional communication is key in this situation because the sooner the adverse effect is identified, the easier it will be for the clinician to treat the problem or terminate its use, which will improve patient outcomes while mitigating adverse events. [Level 5]

It is also vital to enhance the care for the many people who survive allogeneic hematopoietic progenitor cell transplantation. Some predict that by the year 2030, hematopoietic cell transplantation survivors will surpass half a million in the United States. There are currently patient-centered delivery models for cancer survivors, but not for patients who have survived hematopoietic cell transplantation. This area should be a focus of research in the future with the increasing number of patients who survive hematopoietic cell transplantation, and clinicians and health care workers should always be working together to help in the survival of patients after undergoing chemotherapeutic treatments.[17]

Review Questions


Krivoy N, Hoffer E, Lurie Y, Bentur Y, Rowe JM. Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf. 2008 Jan;3(1):60-6. [PubMed: 18690982]
Buggia I, Locatelli F, Regazzi MB, Zecca M. Busulfan. Ann Pharmacother. 1994 Sep;28(9):1055-62. [PubMed: 7803883]
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Feb 13, 2023. Antineoplastic Agents. [PubMed: 31643354]
Myers AL, Kawedia JD, Champlin RE, Kramer MA, Nieto Y, Ghose R, Andersson BS. Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review. Expert Opin Drug Metab Toxicol. 2017 Sep;13(9):901-923. [PMC free article: PMC5584057] [PubMed: 28766962]
Iwamoto T, Hiraku Y, Oikawa S, Mizutani H, Kojima M, Kawanishi S. DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci. 2004 May;95(5):454-8. [PubMed: 15132775]
Madden T, de Lima M, Thapar N, Nguyen J, Roberson S, Couriel D, Pierre B, Shpall EJ, Jones RB, Champlin RE, Andersson BS. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007 Jan;13(1):56-64. [PubMed: 17222753]
Grigg A, Gibson R, Bardy P, Szer J. Acute portal vein thrombosis after autologous stem cell transplantation. Bone Marrow Transplant. 1996 Nov;18(5):949-53. [PubMed: 8932850]
Brisse H, Orbach D, Lassau N, Servois V, Doz F, Debray D, Helfre S, Hartmann O, Neuenschwander S. Portal vein thrombosis during antineoplastic chemotherapy in children: report of five cases and review of the literature. Eur J Cancer. 2004 Dec;40(18):2659-66. [PubMed: 15571949]
Littler WA, Kay JM, Hasleton PS, Heath D. Busulphan lung. Thorax. 1969 Nov;24(6):639-55. [PMC free article: PMC472068] [PubMed: 5260190]
Eberly AL, Anderson GD, Bubalo JS, McCune JS. Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy. 2008 Dec;28(12):1502-10. [PubMed: 19025431]
Akiyama K, Kume T, Fukaya M, Shiki I, Enami T, Tatara R, Shino M, Ikeda T. Comparison of levetiracetam with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic cell transplantation recipients. Cancer Chemother Pharmacol. 2018 Oct;82(4):717-721. [PMC free article: PMC6132870] [PubMed: 30083882]
HAYHOE FG, KOK D. Medullary aplasia in chronic myeloid leukaemia during busulphan therapy. Br Med J. 1957 Dec 21;2(5059):1468-71. [PMC free article: PMC1962898] [PubMed: 13489262]
Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Aug 16, 2021. Busulfan. [PubMed: 30000295]
Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, Bredius RG, Egberts AC, Bierings M, Kletzel M, Shaw PJ, Nath CE, Hempel G, Ansari M, Krajinovic M, Théorêt Y, Duval M, Keizer RJ, Bittencourt H, Hassan M, Güngör T, Wynn RF, Veys P, Cuvelier GD, Marktel S, Chiesa R, Cowan MJ, Slatter MA, Stricherz MK, Jennissen C, Long-Boyle JR, Boelens JJ. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016 Nov;3(11):e526-e536. [PMC free article: PMC5159247] [PubMed: 27746112]
Richardson PG, Triplett BM, Ho VT, Chao N, Dignan FL, Maglio M, Mohty M. Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Expert Rev Clin Pharmacol. 2018 Feb;11(2):113-124. [PubMed: 29301447]
Schneiderman J. Extracorporeal photopheresis: cellular therapy for the treatment of acute and chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2017 Dec 08;2017(1):639-644. [PMC free article: PMC6142534] [PubMed: 29222315]
Hashmi SK, Bredeson C, Duarte RF, Farnia S, Ferrey S, Fitzhugh C, Flowers MED, Gajewski J, Gastineau D, Greenwald M, Jagasia M, Martin P, Rizzo JD, Schmit-Pokorny K, Majhail NS. National Institutes of Health Blood and Marrow Transplant Late Effects Initiative: The Healthcare Delivery Working Group Report. Biol Blood Marrow Transplant. 2017 May;23(5):717-725. [PMC free article: PMC5378687] [PubMed: 27713091]
Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK555986PMID: 32310446


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

  • Rivastigmine.[StatPearls. 2023]
    Patel PH, Gupta V. StatPearls. 2023 Jan
  • Cisplatin.[StatPearls. 2023]
    Gold JM, Raja A. StatPearls. 2023 Jan
  • Cyanocobalamin.[StatPearls. 2023]
    Vasavada A, Sanghavi D. StatPearls. 2023 Jan
  • Bisoprolol.[StatPearls. 2023]
    Bazroon AA, Alrashidi NF. StatPearls. 2023 Jan
  • Omega-3 Fatty Acids.[StatPearls. 2023]
    Omega-3 Fatty Acids.
    Krupa K, Fritz K, Parmar M. StatPearls. 2023 Jan
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...