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Impact of frailty, melphalan pharmacokinetics, and pharmacogenetics on outcomes post autologous hematopoietic cell transplantation for multiple myeloma

Bone Marrow Transplantation volume 54, pages 2088–2095 (2019)Cite this article

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Abstract

Autologous hematopoietic cell transplantation (auto-HCT) using melphalan is the standard of care in the management of myeloma. Auto-HCT is a safe procedure with tolerable toxicity except in Asian-Indians. We hypothesized either one or a combination of factors: (1) frailty (assessed by IMWG frailty score), (2) generic melphalan pharmacokinetic area under the curve (AUC) assessed by high-performance liquid chromatography, and (3) pharmacogenetics of glutathione S-transferase (GSTP1) assessed by Sanger sequencing, to be associated with toxicity and survival outcomes post auto-HCT. Disease response was evaluated by IMWG response criteria at day +100 post auto-HCT. Gastrointestinal (GI) toxicity, infections, hospital stay, progression-free survival (PFS) were also recorded. A total of 35 patients were evaluated over 2 years (2016–2018). Frailty, not HCT-comorbidity index correlated with GI toxicity and infections. Overall there was an 11-fold variation in melphalan AUC with a median of 27.88 mg h/L (10.06–110.26). Patients with AUC more than the median had more GI toxicity and infections. Patients with wild-type GSTP1 polymorphism had more GI toxicity and infections. Frailty, AUC, or GSTP1 polymorphism did not impact hospitalization duration or PFS. A combination of the factors frailty, melphalan pharmacokinetics, and pharmacogenetics impacts GI toxicity and infections after auto-HCT in myeloma.

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Acknowledgements

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.

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  1. These authors contributed equally: Ram V. Nampoothiri, Kripa Shanker Kasudhan

Authors and Affiliations

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

    Ram V. Nampoothiri, Pankaj Malhotra, Alka Khadwal, Gaurav Prakash, Arihant Jain, Subhash Varma & Deepesh P. Lad

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

    Kripa Shanker Kasudhan, Amol N. Patil & Samir Malhotra

  3. Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Savita Verma Attri

  4. Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Neelam Varma

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Contributions

RVN and KSK contributed equally to the manuscript. DPL, ANP, PM, and SV conceived and designed the study. RVN, DPL, PM, AK, GP, AJ, and SV were involved in patient recruitment and clinical care of the patients. KSK, ANP, SM, SA, and NV analyzed the lab data. DPL, RVN, ANP, and PM drafted the manuscript. All authors revised 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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Clinical trials registry of India Identifier CTRI/2018/08/015354

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Nampoothiri, R.V., Kasudhan, K.S., Patil, A.N. et al. Impact of frailty, melphalan pharmacokinetics, and pharmacogenetics on outcomes post autologous hematopoietic cell transplantation for multiple myeloma. Bone Marrow Transplant 54, 2088–2095 (2019). https://doi.org/10.1038/s41409-019-0631-0

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