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Still learning the right way to administer melphalan in autologous transplantation

Bone Marrow Transplantation volume 55, pages 2357–2358 (2020)Cite this article

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Al Saleh et al. recently reported on the differences in transplant outcomes using day-1 compared with day-2 high-dose melphalan in autologous stem cell transplant for multiple myeloma [1]. The elimination half-life (t1/2 β) of melphalan is reported to be around 17–75 minutes with significant inter-patient variation and is dose dependent [2]. High dose melphalan on day-1 is considered safe on the presumption that there is no residual melphalan on day 0 to affect the infused stem cells. In this retrospective study, patients who received melphalan conditioning on day-2 had less incidence of fever, earlier platelet engraftment, and shorter hospital stay than those who received melphalan on day-1. Patients who received melphalan on day-1 had a minimum of 18 hours between melphalan and stem cell infusion. The authors have hypothesized that there may be some residual melphalan even after 18 hours to affect the infused stem cells to explain the differences observed in their study. We and others have previously shown that the melphalan area under the curve (AUC) has an association with the severity of mucositis post autologous transplant [3,4,5,6]. We and Nath et al. have also shown an association of melphalan AUC with the duration of hospital stay [3, 4]. Our study had shown time to platelet engraftment (>20 × 109/L) difference of 1 day, which was not significant, compared with the significant 2-day difference (>50 × 109/L) observed in this paper by Al Saleh et al. [1]. Of these studies, only the older study, which used a higher dose of melphalan 220 mg/m2, showed a significant delay in platelet engraftment (>25 × 109/L) with higher melphalan AUC [6]. Our study also showed an association with increased infections with melphalan AUC [3]. That melphalan AUC is positively associated with toxicity post transplant is biologically plausible. To explain the impact of melphalan pharmacokinetics on the infused stem cells, we looked at the melphalan volume of distribution (Vd) and clearance (CL) as melphalan is highly protein-bound. Just like AUC, there is a 3–30 fold variation in the CL and Vd of melphalan (Table 1). The half-life of a drug is directly related to the Vd and inversely related to its CL. As a result, the t1/2 β in our study showed a 40-fold variation from 10 to 410 min. This high variation might be explained by the inclusion of some patients with impaired creatinine CL and has been described previously [2]. Renal CL of bound and unbound melphalan has been estimated from population pharmacokinetic studies to be around 40% [4]. Therefore, given these considerable variations in the pharmacokinetic parameters of melphalan, it would be safest to administer melphalan on day-2 as shown by Al Saleh et al. [1] or at least 24 h before the infusion of stem cells, to minimize its impact on the infused stem cells and ultimately transplant outcomes.

Table 1 Melphalan pharmacokinetic parameters and its association with transplant toxicity and short term outcomes.
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References

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Authors and Affiliations

  1. Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Deepesh P. Lad & Pankaj Malhotra

  2. Department of Clinical Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Amol N. Patil

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  1. Deepesh P. Lad
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  2. Amol N. Patil
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Contributions

DPL, ANP, and PM conceived the study, drafted the manuscript and, approved the final version. DPL and ANP confirm full access to the data in the study and final responsibility for the manuscript.

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Correspondence to Deepesh P. Lad.

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Part of this work was funded by the Science and Engineering Research Board, Department of Science and Technology, Government of India (file number ECR/2016/000884) grant to ANP and DPL. All the other authors have no competing financial interests to disclose.

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Lad, D.P., Patil, A.N. & Malhotra, P. Still learning the right way to administer melphalan in autologous transplantation. Bone Marrow Transplant 55, 2357–2358 (2020). https://doi.org/10.1038/s41409-020-0971-9

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