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Reduced-toxicity conditioning for allogeneic hematopoietic cell transplantation in elderly or comorbid patients with AML using fludarabine, BCNU and melphalan: disease stage at transplant determines outcome

Bone Marrow Transplantation volume 53, pages 94–96 (2018)Cite this article

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Patients with acute myeloid leukemia (AML) over the age of 60 have a poor outcome after conventional chemotherapy with only 10–20% becoming long-term survivors.1 Thanks to the introduction of a variety of reduced-intensity conditioning (RIC) regimens in the late 1990s, more elderly patients have proceeded to allogeneic hematopoietic cell transplantation (HCT). The available data suggest that 30–40% of patients transplanted in first complete remission (CR1) can be cured.2, 3 RIC has reduced the non-relapse mortality (NRM) compared with myeloablative condition but is often associated with an increased relapse rate.4 One promising RIC regimen is the FBM protocol which combines carmustine and melphalan with fludarabine. This approach was pioneered by the Freiburg group5, 6 and subsequently used by the Mayo Clinic.7 Both groups highlighted low toxicity and high cytoreductive potency especially in advanced disease. In the most recent publication of the Freiburg group, 68% of the 250 reported AML and MDS patients were pretreated prior to transplant and for ~32% of patients the FBM conditioning regimen was the primary treatment.8 A striking finding was that tumor load at the time of transplant did not impact on outcome, which is in contrast to previous publications.9

In the present study, 53 patients ⩾55 years and 4 comorbid patients <55 years of age (ntotal=57) diagnosed with AML (de novo AML n=45, secondary AML n=7, and therapy-related AML n=5) at the University Hospital Ulm and the Municipal Hospital of Karlsruhe, who received FBM followed by allogeneic HCT between 2009 and 2015 were included in this analysis. The median age of the group was 64 years. Fifty six out of 57 patients received at least one cycle of induction or salvage chemotherapy before starting the conditioning chemotherapy and 25 patients were treated within a study protocol of the German–Austrian AML study group (AMLSG). All patients gave written informed consent to be treated with this conditioning protocol and to prospective data collection. Relevant patient characteristics and transplant characteristics are included in Table 1. All patients received the FBM protocol consisting of fludarabine 5 × 30 mg/m2 from days −9 to −5, BCNU 2 × 150 mg/m2 from days −7 to −6, and melphalan 110 mg/m2 on day −4.5 GvHD prophylaxis consisted of tacrolimus (n=29) or ciclosporine (n=28) starting on day −1 prior to transplant plus mycophenolate mofetil (MMF) 720 mg orally or 1000 to 1500 mg IV twice a day starting on the day of transplant. MMF was tapered from day 30 and tacrolimus or ciclosporine from day 100 after transplantation in the absence of GvHD. In addition, all patients with unrelated donor and two patients with MRD received rabbit-ATG (ATG-F, Fresenius) 10 mg/kg or 20 mg/kg for 3 days (n=39) or alemtuzumab 20 mg total dose (n=10) prior to transplantation. Statistical analyses evaluating relapse-free survival (RFS), overall survival (OS) by Kaplan–Meier analysis as well as cumulative incidence of relapse (CIR) and death (CID) as competing risk analysis were performed with the R software package using the EZR Module 1.30.10

Table 1 Patient characteristics
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Acknowledgements

We thank the nursery staff of both BMT wards for their outstanding patient care. Special thanks to Julie Schieffer for her help in completing the data set. F.K. was supported by grants from Deutsche Krebshilfe grant 109420 (Max-Eder program); fellowship 2010/04 by the European Hematology Association; and by the Deutsche Forschungsgemeinschaft (DFG) (SFB 1074, project A5) and the Wilhelm Sander Stiftung (2015.153.1). V.W. was supported by the Else Kröner-Forschungskolleg.

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  1. F Kuchenbauer and M Ringhoffer: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    V Wais, S R Bohl, S von Harsdorf, R F Schlenk, K Döhner, V Teleanu, L Bullinger, T M Nguyen, H Döhner, D Bunjes & F Kuchenbauer

  2. Department of Internal Medicine III, Municipal Hospital of Karlsruhe, Karlsruhe, Germany

    L Kündgen, K Drognitz, J-C Moulin, M Binnenhei, M Bentz & M Ringhoffer

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Correspondence to F Kuchenbauer or M Ringhoffer.

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Wais, V., Kündgen, L., Bohl, S. et al. Reduced-toxicity conditioning for allogeneic hematopoietic cell transplantation in elderly or comorbid patients with AML using fludarabine, BCNU and melphalan: disease stage at transplant determines outcome. Bone Marrow Transplant 53, 94–96 (2018). https://doi.org/10.1038/bmt.2017.211

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