Chemistry:Treosulfan

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Treosulfan, sold under the brand name Trecondi among others, is an alkylating medication given to people before they have a bone marrow transplant from a donor known as allogeneic hematopoietic stem cell transplantation. It is used as a 'conditioning' treatment to clear the bone marrow and make room for the transplanted bone marrow cells, which can then produce healthy blood cells.[1][2] It is used together with another medicine called fludarabine in adults and children from one month of age with blood cancers as well as in adults with other severe disorders requiring a bone marrow transplant.[1] It belongs to the family of drugs called alkylating agents.[1] In the body, treosulfan is converted into other compounds called epoxides which kill cells, especially cells that develop rapidly such as bone marrow cells, by attaching to their DNA while they are dividing.[1] DNA cross-linking is considered a primary mechanism underlying the pharmacological action of treosulfan, and epoxides formed from treosulfan may cross-link DNA via at least two chemical pathways.[3]

Preclinical studies in animal models have shown that treosulfan is widely distributed to the liver, lungs, bone marrow, and skeletal muscle, with tissue-to-plasma ratios of 0.96, 0.82, 0.82, and 0.77, respectively. Lower biodistribution was observed in the brain and the aqueous humor of the eye (both 0.10). [4][5] In juvenile rats with an immature blood–brain barrier, brain exposure was higher (0.15) than in young adult rats. The monoepoxide of treosulfan (EBDM) exhibited greater brain penetration than the parent compound, with tissue-to-plasma ratios of 0.25 in young adult rats and 0.50 in juvenile rats.[6]

The elimination half-life of treosulfan in patients is short, averaging 1.5–2.0 h. The apparent elimination half-life of the biologically active epoxides is similar to that of treosulfan, reflecting the phenomenon of formation rate-limited elimination.[2][7]

The most common side effects include infections, nausea (feeling sick), stomatitis (inflammation of the lining of the mouth), vomiting, diarrhea, and abdominal pain (belly ache).[1] Tiredness, febrile neutropenia (low white blood cell counts with fever) and high blood levels of bilirubin (a breakdown product of red blood cells) are also seen in more than 1 in 10 adults, and rash also affects more than 1 in 10 children.[1] The most common adverse reactions include musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.[8] Selected grade 3 or 4 nonhematological laboratory abnormalities include increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine.[8]

Treosulfan was authorized for medical use in the European Union in June 2019,[1] and approved for medical use in the United States in January 2025.[8][9]

Medical Uses

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation in adults with malignant and non malignant diseases, and in children older than one month with malignant diseases.[8][1]

History

Two main studies showed that treosulfan is at least as effective as busulfan, another medicine used to prepare people for haematopoietic stem cell transplantation.[1]

In one of the studies, involving 570 adults with acute myeloid leukaemia (a blood cancer) or myelodysplastic syndromes (conditions in which large numbers of abnormal blood cells are produced), 64% of patients given treosulfan (with fludarabine) had a successful transplant and were alive and disease-free after 2 years, compared with 51% of patients given busulfan (with fludarabine).[1]

In an additional study in 70 children with blood cancers, 99% of children given treosulfan (with fludarabine) were alive three months after their transplant.[1]

Efficacy was evaluated in MC-FludT.14/L Trial II (NCT00822393), a randomized active-controlled trial comparing treosulfan to busulfan with fludarabine as a preparative regimen for allogeneic transplantation. Eligible patients included adults 18 to 70 years old with AML or MDS, Karnofsky performance status ≥ 60%, and age ≥ 50 years or hematopoietic cell transplantation comorbidity index [HCTCI] score > 2. There were 570 patients randomized to treosulfan (n=280) or busulfan (n=290).

Society and culture

Treosulfan was authorized for medical use in the European Union in June 2019,[1] and approved for medical use in the United States in January 2025.[9][10][11]

The US Food and Drug Administration granted orphan drug designation to treosulfan in 1994, for the treatment of ovarian cancer;[12] and in 2015, for conditioning treatment prior to hematopoietic stem cell transplantation in malignant and non-malignant diseases in adults and pediatric patients.[13]

In February 2004, orphan designation (EU/3/04/186) was granted by the European Commission to medac Gesellschaft fuer klinische Spezialpräparate mbH, Germany, for treosulfan for the conditioning treatment prior to haematopoietic progenitor cell transplantation.[14]

Names

Treosulfan is the international nonproprietary name.[15]

Treosulfan is sold under the brand names Trecondi[1], Grafapex[8] and Ovastat[16].

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Trecondi EPAR". 11 December 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/trecondi.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ↑ 2.0 2.1 "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". Clinical Pharmacokinetics 57 (10): 1255–1265. October 2018. doi:10.1007/s40262-018-0647-4. PMID 29557088. 
  3. ↑ "Kinetics of in Vitro Guanine- N7-Alkylation in Calf Thymus DNA by (2 S,3 S)-1,2-Epoxybutane-3,4-diol 4-methanesulfonate and (2 S,3 S)-1,2:3,4-Diepoxybutane: Revision of the Mechanism of DNA Cross-Linking by the Prodrug Treosulfan". Molecular Pharmaceutics 16 (6): 2708–2718. June 2019. doi:10.1021/acs.molpharmaceut.9b00251. PMID 31013419. 
  4. ↑ "Disposition of treosulfan and its active monoepoxide in a bone marrow, liver, lungs, brain, and muscle: Studies in a rat model with clinical relevance". European Journal of Pharmaceutical Sciences 16 (6): 616–623. November 2017. doi:10.1016/j.ejps.2017.09.011. PMID 28916482. 
  5. ↑ "Ocular disposition of treosulfan and its active epoxy-transformers following intravenous administration in rabbits". Drug Metabolism and Pharmacokinetics 31 (5): 356–362. October 2016. doi:10.1016/j.dmpk.2016.07.001. PMID 27662779. 
  6. ↑ "Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats". Drug Metabolism and Disposition 43 (12): 1946–1954. December 2015. doi:10.1124/dmd.115.066050. PMID 26428246. 
  7. ↑ "Formation Rate-Limited Pharmacokinetics of Biologically Active Epoxy Transformers of Prodrug Treosulfan". Journal of Pharmaceutical Sciences 105 (5): 1790–1797. May 2016. doi:10.1016/j.xphs.2016.03.001. PMID 27044946. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Cite error: Invalid <ref> tag; no text was provided for refs named Grafapex FDA label
  9. ↑ 9.0 9.1 "FDA approves treosulfan with fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients with AML or MDS". 6 February 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-treosulfan-fludarabine-preparative-regimen-allohsct-adult-and-pediatric-patients-aml-or.  Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ "Novel Drug Approvals for 2025". 21 February 2025. https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2025. 
  11. ↑ "Medexus Announces FDA Approval of Grafapex (treosulfan) for Injection and Provides Business Update" (Press release). Medexus Pharmaceuticals. 22 January 2025. Retrieved 25 January 2025 – via Newsfile.
  12. ↑ "Treosulfan Orphan Drug Designations and Approvals". 16 May 1994. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=81294. 
  13. ↑ "Treosulfan Orphan Drug Designations and Approvals". 8 April 2015. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=468014. 
  14. ↑ "EU/3/04/186". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu304186.  Public Domain This article incorporates text from this source, which is in the public domain.
  15. ↑ "International nonproprietary names for pharmaceutical substances (INN). recommended INN: list 12". WHO Chronicle 26 (10). 1972. https://www.who.int/publications/m/item/inn-rl-12. 
  16. ↑ , Ashwani Kumar; Saurabh Upadhyay & Heena Dua et al."A process for the preparation of treosulfan" patent WO2019043587A2, issued 2019-03-07



  1. ↑ "Treosulfan (Code C1257)". 25 November 2024. https://evsexplore.semantics.cancer.gov/evsexplore/concept/ncit/C1257. 
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