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Nitrosoureas, triazenes, alkyl sulfonates, aziridines and related alkylatorsIn useDerivative of an earlier drugNeeds review

Treosulfan

Also known as Trecondi, Grafapex, dihydroxybusulfan, dihydroxybusulphan, L-threitol 1,4-dimethanesulfonate, NSC-39069

A water-soluble dihydroxy derivative of busulfan that acts as a prodrug. National authorisations for ovarian cancer date from 1973 in several European countries; it was authorised in the EU in 2019 and in the US in 2025 for transplant conditioning.

From discovery to approval

  1. c. 1964 · Earliest report found

    A 2018 review describes treosulfan as a water-soluble dihydroxy derivative of busulfan. The earliest paper found is Loeb's 1964 report on dihydroxybusulfan (NSC-39069) in chronic myeloid leukaemia and other cancers (title only; no PubMed abstract). As a clinical report it postdates the synthesis, whose date and laboratory were not found.[2][3][4][1]

  2. 2019-06-20 · EMA regular · 55 years after first description

    Marketing authorisation date 20 June 2019 (EPAR page). The CHMP-approved indication: treosulfan in combination with fludarabine as part of conditioning treatment before allogeneic haematopoietic stem cell transplantation in adults with malignant and non-malignant diseases and in paediatric patients older than one month with malignant diseases (assessment report). The page does not describe the authorisation as conditional or exceptional, so regular is an inference.[5]

  3. 2025-01-21 · FDA regular · 61 years after first description

    In combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients 1 year of age and older with acute myeloid leukemia or myelodysplastic syndrome (approval letter, NDA 214759; Drugs@FDA lists standard review, orphan, new molecular entity). The letter has no accelerated-approval wording, so regular is an inference.[6]

How it works

A prodrug that converts spontaneously under physiological conditions, without enzymes, to a monoepoxide and then to diepoxybutane. These epoxides alkylate DNA and can form DNA cross-links, which are considered responsible for its stem-cell-depleting and antineoplastic effects.[1]

Where it came from and why

No cited source states why it was made. A 1970 paper by Feit and colleagues (title only) concerns epoxide formation from threitol 1,4-bismethanesulfonate; the EMA assessment cites it for treosulfan's conversion to epoxides.

Cancers

  • Ovarian cancer

    In a 1977 series of 36 patients with ovarian carcinoma the author reported complete responses in 30.5 per cent, lasting a mean of 19.0 months, and partial responses in 33.3 per cent (the abstract prints the decimal points as hyphens). The EMA assessment says treosulfan has had national authorisations for ovarian cancer in several EU countries since 1973.[7]

  • Conditioning before allogeneic stem cell transplantation

    Authorised in the EU (2019) and the US (2025) with fludarabine as part of conditioning before allogeneic transplantation; the US indication is acute myeloid leukemia or myelodysplastic syndrome in adults and children aged 1 year and older.[8]

Family and partners

Derived from: Busulfan

Worth knowing

  • The EMA assessment report states that treosulfan has been granted national authorisations for ovarian cancer in Germany, Denmark, Ireland, the Netherlands and the UK since 1973.[1]
  • In the randomised trial behind the 2025 US approval (570 patients, fludarabine with treosulfan or busulfan), the label reports an overall-survival hazard ratio of 0.67 (95% CI 0.51 to 0.90) for treosulfan versus busulfan.[8]
  • In a randomised phase III trial of 274 women with ovarian cancer relapsing within 12 months of platinum and paclitaxel, topotecan gave longer overall survival than treosulfan (median 55.0 versus 41.0 weeks, P = 0.0023) and a higher response rate (27.5% versus 16.0%).[9]
  • Eight women developed acute non-lymphocytic leukaemia after long-term treosulfan for ovarian carcinoma; seven arose among 553 patients treated from 1970 to 1977, which the authors report as a 175-times increased risk against the expected 0.04 cases of acute myeloblastic leukaemia.[10]
  • The EMA assessment reports almost no conversion of treosulfan to its active epoxides at pH below 6 at 20 degrees C in vitro, but spontaneous conversion at pH 7.4 and 37 degrees C.[1]

References

  1. European Medicines Agency. Trecondi: CHMP assessment report, 13 December 2018 (EMA/903773/2019), procedure EMEA/H/C/004751/0000. Source
  2. Romański M, Wachowiak J, Główka FK. Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives. Clin Pharmacokinet. 2018;57(10):1255-1265. PubMedDOI
  3. LOEB V Jr. DIHYDROXYBUSULFAN (NSC-39069) IN CHRONIC MYELOCYTIC LEUKEMIA AND MISCELLANEOUS MALIGNANT NEOPLASMS. Cancer Chemother Rep. 1964;42:39-43. PubMed
  4. Feit PW, Rastrup-Andersen N, Matagne R. Studies on epoxide formation from (2S,3S)-threitol 1,4-bismethanesulfonate. The preparation and biological activity of (2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate. J Med Chem. 1970;13(6):1173-5. PubMedDOI
  5. European Medicines Agency. Trecondi (treosulfan): EPAR medicine page (authorisation details). Page read 2026-10-26. Source
  6. U.S. Food and Drug Administration. Approval letter, NDA 214759, Grafapex (treosulfan) for injection, medac GmbH, 21 January 2025. Source
  7. Fennelly J. Treosulfan (dihydroxybusulphan) in the management of ovarian carcinoma. Br J Obstet Gynaecol. 1977;84(4):300-3. PubMedDOI
  8. U.S. Food and Drug Administration. Grafapex (treosulfan) for injection: prescribing information (NDA 214759, original approval, January 2025). Source
  9. Meier W, du Bois A, Reuss A, Kuhn W, Olbricht S, Gropp M, et al. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol. 2009;114(2):199-205. PubMedDOI
  10. Pedersen-Bjergaard J, Nissen NI, Sørensen HM, Hou-Jensen K, Larsen MS, Ernst P, et al. Acute non-lymphocytic leukemia in patients with ovarian carcinoma following long-term treatment with Treosulfan (= dihydroxybusulfan). Cancer. 1980;45(1):19-29. 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 214759 (Grafapex, treosulfan). Page read 2026-10-26. Source