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Nitrosoureas, triazenes, alkyl sulfonates, aziridines and related alkylatorsIn useSyntheticNeeds review

Busulfan

Also known as Myleran, Busulfex, Busilvex, busulphan, 1,4-butanediol dimethanesulfonate

A bifunctional alkylating drug of the alkyl sulfonate type, given as tablets and, since 1999 in the US, as an injection. The 2003 US tablet label lists palliative treatment of chronic myelogenous leukemia; the injection is approved for transplant conditioning.

From discovery to approval

  1. 1953 · First described

    Two consecutive papers in The Lancet of 1953 are titled "Myleran in chronic myeloid leukaemia": Haddow and Timmis on chemical constitution and biological action, and Galton on results of treatment. Both are cited by title only; PubMed has no abstract for either. The 2003 US label credits Galton with the first report of activity in this disease.[2][3][4][5]

  2. 1954-06-26 · FDA regular · 1 years after first description

    Busulfan tablets (Myleran), NDA 009386, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label and letter are not available there, so the indication at approval is not stated here; the 2003 label lists palliative treatment of chronic myelogenous leukemia. The type regular is an inference: no accelerated-approval wording was found.[6]

  3. 1999-02-04 · FDA regular · 46 years after first description

    Use in combination with cyclophosphamide as a conditioning regimen before allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (approval letter, NDA 20-954; the date is the Drugs@FDA original-approval date, listed as priority review and orphan, new dosage form). The letter has no accelerated-approval wording, so regular is an inference.[7]

  4. 2003-07-09 · EMA regular · 50 years after first description

    Marketing authorisation issued 9 July 2003 (CHMP opinion 19 March 2003; dates from the EPAR page). The scientific discussion states the initial indication: conditioning treatment before haematopoietic progenitor cell transplantation in adults when busulfan with cyclophosphamide is considered the best available option. The EPAR page, as last revised, also lists busulfan after fludarabine in adults eligible for reduced-intensity conditioning and use in paediatric patients. Neither document describes the authorisation as conditional or exceptional, so regular is an inference.[8]

  5. 2023-01-09 · EMA withdrawn · 70 years after first description

    On 9 January 2023 the European Commission withdrew the Busilvex marketing authorisation at the request of the holder, Pierre Fabre Medicament, which permanently discontinued marketing for commercial reasons (EPAR page). The page notes that busulfan generic medicines remain authorised in the EU.[8]

How it works

Reacts with guanine in DNA to form a four-carbon crosslink between two guanines, which a European assessment says causes misreading of the DNA code and single-strand breaks. The degree of crosslinking is reported to be proportional to dose and cytotoxicity.[1]

Where it came from and why

No cited source states the reasoning, and neither the 1953 papers nor a 1951 paper by Haddow and Timmis have an abstract in PubMed. The 1951 title refers to bifunctional sulphonic acid esters with radiomimetic activity; the 1953 title links chemical constitution to biological action. The US label notes that busulfan is not a structural analogue of the nitrogen mustards.

Cancers

  • Chronic myeloid leukaemia

    Galton reported results of treatment in chronic myeloid leukaemia in 1953 (no abstract in PubMed). The 2003 US Myleran label lists palliative treatment of chronic myelogenous leukemia and describes the drug as not curative.[5]

  • Conditioning before haematopoietic cell transplantation

    The 1999 US approval of busulfan injection covered use with cyclophosphamide as a conditioning regimen before allogeneic transplantation for chronic myelogenous leukemia. The 2003 EU authorisation of Busilvex (later withdrawn) was for conditioning in adults when busulfan with cyclophosphamide was considered the best available option; the EPAR page, as last revised, also lists paediatric use.[7]

Family and partners

Drugs derived from it: Treosulfan

Worth knowing

  • The 2003 US label states that busulfan is not a structural analogue of the nitrogen mustards, and that in phage T7 DNA it produced intrastrand crosslinks but no interstrand links.[5]
  • In the German CML Study Group's randomised comparison of 441 patients (1983 to 1991), median survival of Philadelphia-positive patients was 45.4 months with busulfan and 58.2 months with hydroxyurea (P = .008); the authors concluded that hydroxyurea should be first-line treatment.[9]
  • A 2010 historical review says that in the first half of the 20th century patients with chronic myeloid leukaemia were treated mainly with radiotherapy, and later with busulfan, hydroxycarbamide or interferon-alfa.[10]
  • A 2013 review calls busulfan, combined with other alkylating agents or nucleoside analogues, the cornerstone of high-dose chemotherapy before haematopoietic stem cell transplantation, and describes treosulfan as its hydrophilic analogue.[11]
  • The Busilvex authorisation in the EU, issued in 2003, was withdrawn on 9 January 2023 at the holder's request for commercial reasons; generic busulfan products remain authorised.[8]

On this site

References

  1. European Medicines Agency. Busilvex: EPAR scientific discussion (initial authorisation). Document footer reads EMEA 2005. Source
  2. HADDOW A, TIMMIS GM. Myleran in chronic myeloid leukaemia; chemical constitution and biological action. Lancet. 1953;264(6753):207-8. PubMedDOI
  3. GALTON DA. Myleran in chronic myeloid leukaemia; results of treatment. Lancet. 1953;264(6753):208-13. PubMedDOI
  4. HADDOW A, TIMMIS GM. Bifunctional sulphonic acid esters with radiomimetic activity. Acta Unio Int Contra Cancrum. 1951;7(3):469-71. PubMed
  5. U.S. Food and Drug Administration. Myleran (busulfan) 2-mg scored tablets: prescribing information, GlaxoSmithKline, 2003 (NDA 009386, supplement 23, 24 December 2003). Source
  6. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history for NDA 009386 (Myleran, busulfan tablets). Page read 2026-10-26. Source
  7. U.S. Food and Drug Administration. Approval letter, NDA 20-954, Busulfex (busulfan) Injection, Orphan Medical, Inc., 1999. Source
  8. European Medicines Agency. Busilvex (busulfan): EPAR medicine page (authorisation details, withdrawal). Page read 2026-10-26. Source
  9. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, et al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood. 1993;82(2):398-407. PubMed
  10. Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin Hematol. 2010;47(4):302-11. PubMedDOI
  11. Galaup A, Paci A. Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Expert Opin Drug Metab Toxicol. 2013;9(3):333-47. PubMedDOI
  12. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history for NDA 020954 (Busulfex, busulfan injection). Page read 2026-10-26. Source