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Similar survival but increased toxicity with a sequential versus concurrent FluBu4 regimen

Bone Marrow Transplantation volume 53, pages 1221–1224 (2018)Cite this article

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Allogeneic hematopoietic stem cell transplantation (HSCT) using myeloablative-conditioning results in a reduced risk of relapse compared to reduced intensity regimens [1,2,3]. Fludarabine and intravenous (i.v.) busulfan (FluBu4) has been adopted as a myeloablative but limited toxicity conditioning regimen [4,5,6]. It has previously been shown that combined in vitro treatment with fludarabine and busulfan leads to synergistic cytotoxicity with maximal synergy being achieved when fludarabine is administered immediately prior to busulfan [5,6,7,8,9,10]. However, FluBu4 may be administered both as either a concurrent 5-day regimen or a 9-day sequential, non-overlapping schedule [4,5,6]. Clinical data suggest that sequential regimens have increased anti-leukemia activity as well as decreased toxicity which allows for application in elderly, co-morbid patients [11, 12]. Because the clinical impact of sequence and schedule of administration of FluBu4 conditioning on toxicity and transplant outcomes is unknown, we sought to compare toxicity, survival and relapse outcomes between patients receiving HSCT with a concurrent 5-day versus a sequential 9-day FluBu4 regimen.

At our institution, we initially administered FluBu4 in a sequential fashion over 9 days and subsequently shortened it to 5 days based on studies predominantly administering in a concurrent fashion [13]. We retrospectively analyzed consecutive adult patients who underwent FluBu4 and HSCT between January 2003 and December 2016. Approval of the University of Illinois at Chicago Institutional Review Board was obtained before study commencement. One-hundred and two patients who received FluBu4 prior to HSCT were included in the final analysis. Supportive care measures and graft versus host disease (GVHD) prophylaxis were as previously published. Briefly, GVHD prophylaxis consisted of standard tacrolimus and methotrexate. Patients undergoing HSCT from an unrelated donor additionally received rabbit anti-thymocyte globulin 4.5 mg/kg. For all patients, anti-microbial prophylaxis consisted of levofloxacin during neutropenia, fluconazole until Day + 90 and acyclovir until Day + 180. In addition, patients received Pneumocystis jiroveci prophylaxis with either sulfamethoxazole- trimethoprim or monthly pentamidine until day + 180. Acute and chronic GVHD were graded using standard criteria [14, 15]. Mucositis was graded according to the NCI-CTCAE version 4.0 criteria. In patients experiencing mucositis, specific attention was paid to methotrexate dose reductions and omissions. Categorical data were analyzed by chi-square test and Fisher’s exact test with cells < 5. Comparison of means and medians for continuous data were analyzed by the student’s t-test and Wilcoxon rank-sum test respectively. Equality of survivor functions for GVHD-free, relapse-free survival (GRFS), overall survival (OS), progression free survival (PFS), and cumulative incidence of aGVHD and relapse were assessed using the Kaplan–Meier method and log-rank test. In time-dependent Cox proportional hazards model, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between a 9-day regimen and overall and progression-free survival. We assessed proportional hazards by testing for interaction between regimen and person time at risk for each of the outcomes and found no evidence suggesting violation of the proportionality assumption. Analyses were performed using GraphPad Prism (GraphPad, La Jolla, CA, USA) or SAS (SAS Institute, Cary, NC, USA).

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Authors and Affiliations

  1. Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA

    Karen Sweiss

  2. Cancer Center, University of Illinois, Chicago, IL, USA

    Karen Sweiss, Damiano Rondelli & Pritesh Patel

  3. Division of Hematology/ Oncology, University of Illinois at Chicago, Chicago, IL, USA

    Annie Oh, Damiano Rondelli & Pritesh Patel

  4. Center for Pharmacoepidemiology and Pharmacoeconomic Research, Chicago, IL, USA

    Gregory Calip

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Correspondence to Karen Sweiss.

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Sweiss, K., Oh, A., Calip, G. et al. Similar survival but increased toxicity with a sequential versus concurrent FluBu4 regimen. Bone Marrow Transplant 53, 1221–1224 (2018). https://doi.org/10.1038/s41409-018-0195-4

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