Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Intravenous Busulfan, Dimethylacetamide and neurotoxicity after high-dose pretransplant conditioning chemotherapy

Bone Marrow Transplantation volume 58, pages 635–638 (2023)Cite this article

Subjects

Pursuing more efficacious and less toxic allogeneic stem-cell transplant (allo-SCT) conditioning therapy, intravenous (IV) Busulfan, Busulfex™, (Bu) was introduced in 1999 [1]. Its combinations with Cyclophosphamide (Cy) or with the nucleoside analog Fludarabine (Flu), have led for more than a decade high-dose chemotherapy for allo-SCT for patients with acute and chronic myeloid leukemia (AML, CML) and myelodysplastic syndrome (MDS) [2,3,4]. It is increasingly being advocated in high dose chemotherapy (HDC) with autologous SCT for relapsed Hodgkin and non-Hodgkin lymphomas and myeloma [5,6,7,8], where it may confer an advantage over previous standard of care with BCNU, etoposide, cytarabine and melphalan (BEAM) and high-dose Melphalan, respectively [6, 7]. Regarding allo-SCT for AML and MDS, Bu-based conditioning results in better overall survival than Cy-total body irradiation (TBI) [9, 10], and yields lower risk for severe graft versus host disease [11]. While IV Bu represents an improvement over TBI, there remain concerns with the formulation, initially expressed by the FDA expert reviewer in 1999 [1]. These concerns were not related to busulfan itself, but rather to its solvent vehicle including N,N-dimethylacetamide (DMA) [12, 13]. In contrast, the sponsor, Orphan Medical Inc. (OMI) (Minnetonka, MN), claimed a DMA-based solvent to be safe, based on a published trial using DMA as an anti-cancer agent [14]. However, in his review of the phase II data underlying the approval of Busulfex, the FDA expert examiner surmised that the total amount of DMA given in HDC may be enough to cause significant toxicities [1]. Occupational DMA exposure was associated with both neurological and hepatic toxicity, and in experimental systems it also caused reproductive toxicity [14,15,16].

In reference to possible DMA toxicity, the phase II study report submitted by OMI listed a high incidence of neurological toxicities: 84% insomnia, 72% anxiety, 30% dizziness and 23% depression following IV Bu infusion. Fewer patients suffered more serious problems, including delirium (2%), agitation (2%), confusion (11%), hallucinations (5%) and encephalopathy (2%) [1]. In our use of IV Bu-based conditioning, we recorded six patients who developed hallucinations, agitation, delirium, and in two cases deep stupor. These neurologically deranged states lasted for almost 2 months in one patient before he recovered, while in one patient it deteriorated into an encephalopathy with progressive, irreversible coma before he expired 5 weeks post-SCT. Two patients recovered within 10 days from the onset of the problems; in two patients altered mental status started days after recovery from treated bacteremia (Table 1).

Table 1 Clinical characteristics and risk factors that may promote neurotoxicity.
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Data availability

Raw data were generated at the University of Texas MD Anderson Cancer Center. Derived data supporting the findings of this study are available from the corresponding author JLR upon reasonable request.

References

  1. Orphan Medical Inc. (1999, February 4). Drug Approval Package, Busulfex (Busulfan Infusion). https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20954.cfm.

  2. Andersson BS, Valdez BC, Jones RB. Pharmacologic Basis for High-dose Chemotherapy, in Thomas’ Hematopoietic Cell Transplantation. 4th Edition. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG, editors. John Wiley & Sons, Ltd.; 2016. p. 211–24.

  3. Center for International Blood and Marrow Transplantation Research, 2022. Summary slides and reports. https://cibmtr.org/CIBMTR/Resources/Summary-Slides-Reports.

  4. Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transpl. 2002;8:493–500.

    Article  CAS  Google Scholar 

  5. Nieto Y, Thall PF, Ma J, Valdez BC, Ahmed S, Anderlini P, et al. Phase II trial of high-dose Gemcitabine/Busulfan/Melphalan with autologous stem-cell transplantation for primary refractory or poor-risk relapsed Hodgkin’s Lymphoma. Biol Blood Marrow Transpl. 2018;24:1602–09.

    Article  CAS  Google Scholar 

  6. Nieto Y, Valdez BC, Thall PF, Ahmed S, Jones RB, Hosing C, et al. Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas. Biol Blood Marrow Transpl. 2015;21:1914–20.

    Article  CAS  Google Scholar 

  7. Nieto Y, Valdez BC, Pingali SR, Bassett R, Delgado R, Nguyen J, et al. High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan. Lancet Haematol. 2017;4:e283–e292.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bashir Q, Thall PF, Milton DR, Fox PS, Kawedia JD, Kebriaei P, et al. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol. 2019;6:e266–e275.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bredeson C, LeRademacher J, Kato K, DiPersio JF, Agura E, Devine SM, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122:3871–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, et al. Better Leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013;122:3863–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nagler A, Rocha V, Labopin M, Unal A, Ben Othman T, Campos A, et al. Allogeneic hematopoietic Stem-Cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen – A report from the acute leukemia working party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2013;31:3549–56.

    Article  CAS  PubMed  Google Scholar 

  12. Bhagwatwar HP, Phadungpojna S, Chow DS, Andersson BS. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharm. 1996;37:401–08.

    Article  CAS  Google Scholar 

  13. Dwivedi AM. Residual solvent analysis in pharmaceuticals. Pharmaceut Technol. 2002;26:42–46.

  14. Weiss AJ, Jackson LG, Carabasi RA, Mancall EL, White JC. A Phase I study of Dimethylacetamide. Cancer Chemother Rept. 1962;16:477–85.

    CAS  Google Scholar 

  15. Choi TS, Woo KH, Kim JS, Park WS, Ham JH, Jung SJ, et al. Toxic hepatitis induced by occupational dimethylacetamide exposure. Korean J Occup Environ Med. 2001;13:164–70.

    Article  Google Scholar 

  16. Solomon HM, Ferenz RL, Kennedy GL Jr, Staples RE. Developmental toxicity of dimethylacetamide by inhalation in the rat. Fundam Appl Toxicol. 1991;16:414–22.

    Article  CAS  PubMed  Google Scholar 

  17. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–22.

    Article  CAS  PubMed  Google Scholar 

  18. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–83.

    Article  CAS  PubMed  Google Scholar 

  19. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Andersson BS, et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transpl. 2002;8:468–76.

    Article  CAS  Google Scholar 

  20. de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–64.

    Article  PubMed  Google Scholar 

  21. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, et al. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transpl. 2008;14:672–84.

    Article  CAS  Google Scholar 

  22. Andersson BS, Thall PF, Valdez BC, Milton DR, Al-Atrash G, Chen J, et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transpl. 2017;52:580–87.

    Article  CAS  Google Scholar 

  23. Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transpl. 2008;14:220–8.

    Article  CAS  Google Scholar 

  24. U.S. Food and Drug Administration. 2010. Drug-Induced Liver Injury Severity and Toxicity (DILIst) Dataset. https://www.fda.gov/science-research/liver-toxicity-knowledge-base-ltkb/drug-induced-liver-injury-severity-and-toxicity-dilist-dataset.

  25. VICH Steering Committee, VICH GL 18 (R)-Intl. Coop. Harmonisation of Tech. for Registration of Veterinary Medicinal Products. 2010; Rev. 9. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-vich-gl-18-residual-solvents-new-veterinary-medicinal-products-active-substances-excipients_en.pdf.

  26. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Step 4, April 2021. https://database.ich.org/sites/default/files/ICH_Q3C-R8_Guideline_Step4_2021_0422_1.pdf.

Download references

Author information

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX, USA

    J. Ramdial, K. H. Chan, G. Sanchez Petitto, B. Valdez, B. S. Andersson & Y. Nieto

Authors
  1. J. Ramdial
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. H. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Sanchez Petitto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Valdez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. S. Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JLR contributed to writing in each section of the paper. GSP contributed in summarizing the reports and table. KHC contributed in verifying and summarizing the reports. YN, BV, and BSA have made a substantial contribution to the concept and design of the paper.

Corresponding author

Correspondence to J. Ramdial.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Informed consent was obtained from patient and family prior to publishing the cases.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramdial, J., Chan, K.H., Sanchez Petitto, G. et al. Intravenous Busulfan, Dimethylacetamide and neurotoxicity after high-dose pretransplant conditioning chemotherapy. Bone Marrow Transplant 58, 635–638 (2023). https://doi.org/10.1038/s41409-023-01964-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-023-01964-y

Search

Advanced search

Quick links