Top

Published in:

12-11-2023 | Original Article

Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis

Authors: Akanksha Chichra, Lingaraj Nayak, Rushabh Kothari, Siddhesh Kalantri, Avinash Bonda, Anant Gokarn, Sachin Punatar, Sumeet Mirgh, Nishant Jindal, Bhausaheb Bagal, Sadhana Kannan, Libin Mathew, Navin Khattry

Published in: International Journal of Hematology | Issue 1/2024

Abstract

Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8 years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.

Available only for authorised users

Vriesendorp HM. Aims of the conditioning regimen. Exp Hematol. 2003;31:844–54.CrossRefPubMed

Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.CrossRefPubMedPubMedCentral

Lioure B, Béné MC, Pigneux A, Huynh A, Chevallier P, Fegueux N, Blaise D, Witz B, Delain M, Cornillon J, Luquet I, Blanchet O, Cornillet-Lefebvre P, Carré M, Hunault M, Larosa F, Lamy T, Randriamalala E, Ojeda-Uribe M, Berthou C, Fornecker L, Harousseau JL, Bouscary D, Ifrah N, Cahn JY, GOELAMS. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood. 2012;119(12):2943–8.CrossRefPubMed

Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13:1035–44.CrossRefPubMed

Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transpl. 2020;55:1114–25.CrossRef

Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97:631–7.CrossRefPubMed

Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756–63.CrossRefPubMed

Munkelt D, Koehl U, Kloess S, Zimmermann SY, Kalaaoui RE, Wehner S, et al. Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. Cancer Chemother Pharmacol. 2008;62:821–30.CrossRefPubMed

Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transplant. 2012;47:5–14.CrossRefPubMed

10.

Sjoo F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M, Aschan J, Concha H, Gaughan U, Hassan M. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol. 2006;34:115–21.CrossRefPubMed

11.

Shimoni A, Hardan I, Shem-Tov N, et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007;21:2109–16.CrossRefPubMed

12.

Baron F, Labopin M, Peniket A, et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121:1048–55.CrossRefPubMed

13.

Damlaj M, Alkhateeb HB, Hefazi M, et al. Fludarabine-busulfan reduced intensity conditioning in comparison with fludarabine-melphalan is associated with increased relapse risk in spite of pharmacokinetic dosing. Biol Blood Marrow Transplant. 2016;22:1431–9.CrossRefPubMed

14.

Kekre N, Marquez-Malaver FJ, Cabrero M, et al. Fludarabine/busulfan versus fludarabine/melphalan conditioning in patients undergoing reduced intensity conditioning hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant. 2016;22:1808–15.CrossRefPubMed

15.

Shimoni A, Shem-Tov N, Volchek Y, Danylesko I, Yerushalmi R, Nagler A. Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity versus reduced intensity. Bone Marrow Transplant. 2012;47:1274–82.CrossRefPubMed

16.

Schmitt M, Trenschel R, Sayer HG, Schneider C, Glass A, Hilgendorf I, et al. Conditioning with treosulfan and fludarabine for patients with refractory or relapsed non-Hodgkin lymphoma. Mol Clin Oncol. 2014;2:773–82.CrossRefPubMedPubMedCentral

17.

Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Reményi P, Wagner-Drouet E-M, Hauptrock B, Dreger P, Luft T, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2019;7:e28–39.CrossRefPubMed

18.

Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.CrossRefPubMedPubMedCentral

19.

Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012;47(6):749–56.CrossRefPubMed

20.

Wang HT, Chang YJ, Xu LP, Liu DH, Wang Y, Liu KY, Huang XJ. EBMT risk score can predict the outcome of leukaemia after unmanipulated haploidentical blood and marrow transplantation. Bone Marrow Transplant. 2014;49(7):927–33.CrossRefPubMed

21.

Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP, Ritz J, Sorror ML, Lee SJ, Deeg HJ, Storer BE, Appelbaum FR, Antin JH, Soiffer RJ, Kim HT. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120(4):905–13.CrossRefPubMedPubMedCentral

22.

Trehan A, Totadri S, Gautam V, Bansal D, Ray P. Invasive bacterial infections in a pediatric oncology unit in a tertiary care center. Indian J Cancer. 2014;51(4):428–31.CrossRefPubMed

23.

Chandy M, Das A, Bhattacharyya A, Banerjee S, Dhar K, Goel G, Bhattacharya S. Colistin-resistant Klebsiella infections among pediatric oncology and hematopoietic stem cell transplantation patients in eastern India. Infect Control Hosp Epidemiol. 2018;39(1):118–21.CrossRefPubMed

24.

Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. Bone Marrow Transplant. 2002;29:545–52.CrossRefPubMed

25.

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.PubMed

26.

Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9(4):215–33.CrossRefPubMed

27.

Kulkarni U, George B. Access to hematopoietic stem-cell transplantation in India. J Postgrad Med. 2019;65(1):1–4.CrossRefPubMedPubMedCentral

28.

Ganapule A, Nemani S, Korula A, Lakshmi KM, Abraham A, Srivastava A, Balasubramanian P, George B, Mathews V. Allogeneic stem cell transplant for acute myeloid leukemia: evolution of an effective strategy in India. J Glob Oncol. 2017;3(6):773–81.CrossRefPubMedPubMedCentral

29.

Zhou Z, Nath R, Cerny J, et al. Reduced intensity conditioning for acute myeloid leukemia using melphalan- versus busulfan-based regimens: a CIBMTR report. Blood Adv. 2020;4(13):3180–90.CrossRefPubMedPubMedCentral

30.

Koenigsmann M, Casper J, Kahl C, Basara N, Sayer HG, Behre G, et al. Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial. Bone Marrow Transplant. 2014;49:410–5.CrossRefPubMed

31.

Yerushalmi R, Shem-Tov N, Danylesko I, Avigdor A, Nagler A, Shimoni A. Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies. Bone Marrow Transplant. 2015;50:1526–35.CrossRefPubMed

32.

Duque-Afonso J, Finke J, Labopin M, Craddock C, Protheroe R, Kottaridis P, Tholouli E, Byrne JL, Orchard K, Salmenniemi U, Hilgendorf I, Hunter H, Nicholson E, Bloor A, Snowden JA, Verbeek M, Clark A, Savani BN, Spyridonidis A, Nagler A, Mohty M. Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation—a registry study on behalf of the EBMT Acute Leukemia Working Party. Bone Marrow Transplant. 2022;57(8):1269–76.CrossRefPubMedPubMedCentral

33.

Batra A, Perumal Kalaiyarasi J, Kannan K, Mehra N, Ganesan P, Karunakaran P, Dhanushkodi M, Selvarajan G, Rajan AK, Kesana S, Ganesan T, Sagar TG, Radhakrishnan V. Haploidentical hematopoietic stem cell transplantation in leukemia’s: experience from a cancer center in India. Indian J Hematol Blood Transfus. 2021;37(3):463–71.CrossRefPubMed

34.

Sharma SK, Choudhary D, Doval D, Khandelwal V, Setia R, Dadu T, Handoo A. Hematopoietic stem cell transplant for hematological malignancies: experience from a tertiary care center in northern India and review of Indian data. South Asian J Cancer. 2021;11(1):62–7.PubMedPubMedCentral

Title: Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis
Authors: Akanksha Chichra
Lingaraj Nayak
Rushabh Kothari
Siddhesh Kalantri
Avinash Bonda
Anant Gokarn
Sachin Punatar
Sumeet Mirgh
Nishant Jindal
Bhausaheb Bagal
Sadhana Kannan
Libin Mathew
Navin Khattry
Publication date: 12-11-2023
Publisher: Springer Nature Singapore
Published in: International Journal of Hematology / Issue 1/2024
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-023-03674-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Clonal hematopoiesis of a novel dic(18;20) clone following allogeneic hematopoietic stem cell transplantation

Real-world data of AML in Japan: results of JALSG clinical observational study-11 (JALSG-CS-11)

Contribution of post-transplantation therapy to sustained MRD negativity in multiple myeloma: a retrospective analysis

Reference guide for the diagnosis of adult primary immune thrombocytopenia, 2023 edition

Association of physical activity with bleeding events and safety in patients with haemophilia A starting emicizumab prophylaxis: an interim analysis of the TSUBASA study

Negative impact of immunoparesis in response to anti-SARS-CoV-2 mRNA vaccination of patients with multiple myeloma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer