Busulfan

Article Author:
Raj Patel
Article Editor:
Prasanna Tadi
Updated:
4/1/2020 10:22:23 AM
PubMed Link:
Busulfan

Indications

Busulfan is an alkylating antineoplastic agent that has been in use since the 1950s. The FDA approved indication for busulfan in 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 DNA molecule; this results in cross-linkage within the DNA chain, which inhibits 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 chemical structure of the drug. This reaction creates positively charged carbonium ions that are highly reactive, which disrupts and damages the DNA. The reaction that occurs is a nucleophilic substitution reaction with the guanine molecules, which creates DNA intrastrand cross-links.

Other inhibitory effects that busulfan has 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 oxidative stress.[4][5]

Administration

Patients can receive busulfan either orally or IV. For pretransplantation, 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. Pretransplantation treatment also includes cyclophosphamide. IV administration is preferred over oral administration because multiple studies show a sizeable therapeutic variability among patients taking 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 that are 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 10-20 days after hematopoietic cell transplantation, but with newer therapeutic regimens, it can present as late as 30 to 75 days. 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 levels typically become elevated, with a minimal increase in the levels of alkaline phosphatase. 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][3]

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 levels 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. Recommended, many physicians have used prophylactic treatment with phenytoin. Other medications have been useful as a prophylactic treatment for busulfan induced seizures like clonazepam, lorazepam, valproic acid, and levetiracetam. Some physicians have chosen to use benzodiazepines like the ones 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]

Contraindications

Busulfan or any of its components causing hypersensitivity is an absolute contraindication. Many cautions are necessary when using not only busulfan but all alkylating agents like pancytopenia, gonadal dysfunction, and pubertal development in children, carcinogenicity, mutagenicity, infertility, and many others.

The FDA has declared busulfan to be pregnancy category D. Breastfeeding is contraindicated when undergoing treatment with antineoplastic medications. Busulfan, like many other antineoplastic medications, can have an impact on 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. 

Monitoring

Optimal monitoring of busulfan uses the levels expressed as the area under the concentration-time curve (AUC). AUC has significantly helped clinicians monitor the therapeutic levels 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 optimal target varies due to factors like 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.

Toxicity

Concerns for toxicity when using busulfan is 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 78-101 mg*h/L significantly increases the event-free survival for patients. [14]

Treatment for hepatic venous-occlusive disease 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 the treatment for 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 that are associated with its use. Busulfan should be used by experienced clinicians due to its vast aside effects profile. For clinicians and other health professionals working alongside the physician in treating a patient 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 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.

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. We currently have patient-centered delivery models for cancer survivors, but we do not have them for patients who have survived hematopoietic cell transplantation. This area should be a focus of research in the future with the increasing amount of people who survive hematopoietic cell transplantation, and clinicians and health care workers should always be thinking about what will help in the survival of patients after undergoing such hazardous treatments.[17]


References

[1] 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. Current drug safety. 2008 Jan;     [PubMed PMID: 18690982]
[2] Buggia I,Locatelli F,Regazzi MB,Zecca M, Busulfan. The Annals of pharmacotherapy. 1994 Sep;     [PubMed PMID: 7803883]
[3] Antineoplastic Agents 2012;     [PubMed PMID: 31643354]
[4] Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review., Myers AL,Kawedia JD,Champlin RE,Kramer MA,Nieto Y,Ghose R,Andersson BS,, Expert opinion on drug metabolism & toxicology, 2017 Sep     [PubMed PMID: 28766962]
[5] 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 science. 2004 May;     [PubMed PMID: 15132775]
[6] 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. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2007 Jan;     [PubMed PMID: 17222753]
[7] Grigg A,Gibson R,Bardy P,Szer J, Acute portal vein thrombosis after autologous stem cell transplantation. Bone marrow transplantation. 1996 Nov;     [PubMed PMID: 8932850]
[8] 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. European journal of cancer (Oxford, England : 1990). 2004 Dec;     [PubMed PMID: 15571949]
[9] Littler WA,Kay JM,Hasleton PS,Heath D, Busulphan lung. Thorax. 1969 Nov;     [PubMed PMID: 5260190]
[10] Eberly AL,Anderson GD,Bubalo JS,McCune JS, Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy. 2008 Dec;     [PubMed PMID: 19025431]
[11] 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 chemotherapy and pharmacology. 2018 Oct;     [PubMed PMID: 30083882]
[12] HAYHOE FG,KOK D, Medullary aplasia in chronic myeloid leukaemia during busulphan therapy. British medical journal. 1957 Dec 21;     [PubMed PMID: 13489262]
[13] Busulfan 2006;     [PubMed PMID: 30000295]
[14] 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. The Lancet. Haematology. 2016 Nov;     [PubMed PMID: 27746112]
[15] 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 review of clinical pharmacology. 2018 Feb;     [PubMed PMID: 29301447]
[16] Schneiderman J, Extracorporeal photopheresis: cellular therapy for the treatment of acute and chronic graft-versus-host disease. Hematology. American Society of Hematology. Education Program. 2017 Dec 8;     [PubMed PMID: 29222315]
[17] 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. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2017 May;     [PubMed PMID: 27713091]