Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15–0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15–0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5–0.6 mcg/kg divided over days –14 to –12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day –5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual “top-up” dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.
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Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P. et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood. 2010;116:3080–8. https://doi.org/10.1182/blood-2010-05-286856.
Marsh RA, Kim MO, Liu C, Bellman D, Hart L, Grimley M. et al. An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis. Biol Blood Marrow Transpl. 2013;19:1625–31. https://doi.org/10.1016/j.bbmt.2013.09.001.
Gartner F, Hieke S, Finke J, Bertz H. Lowering the alemtuzumab dose in reduced intensity conditioning allogeneic hematopoietic cell transplantation is associated with a favorable early intense natural killer cell recovery. Cytotherapy. 2013;15:1237–44. https://doi.org/10.1016/j.jcyt.2013.05.016.
Lane JP, Evans PT, Nademi Z, Barge D, Jackson A, Hambleton S. et al. Low-dose serotherapy improves early immune reconstitution after cord blood transplantation for primary immunodeficiencies. Biol Blood Marrow Transpl. 2014;20:243–9. https://doi.org/10.1016/j.bbmt.2013.11.005.
Marsh RA, Lane A, Mehta PA, Neumeier L, Jodele S, Davies SM. et al. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT. Blood. 2016;127:503–12. https://doi.org/10.1182/blood-2015-07-659672.
Marsh RA, Fukuda T, Emoto C, Neumeier L, Khandelwal P, Chandra S. et al. Pretransplant Absolute Lymphocyte Counts Impact the Pharmacokinetics of Alemtuzumab. Biol Blood Marrow Transpl. 2017;23:635–41. https://doi.org/10.1016/j.bbmt.2017.01.071.
Morris EC, Rebello P, Thomson KJ, Peggs KS, Kyriakou C, Goldstone AH. et al. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood. 2003;102:404–6. https://doi.org/10.1182/blood-2002-09-2687.
Holford N, Ma G, Metz D. TDM is dead. Long live TCI! Br J Clin Pharmacol. 2020. https://doi.org/10.1111/bcp.14434
Dong M, Emoto C, Fukuda T, Arnold DE, Mehta PA, Marsh RA. et al. Model-informed precision dosing for alemtuzumab in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation. Br J Clin Pharmacol. 2021. https://doi.org/10.1111/bcp.14955
This work was supported by a Cincinnati Children’s Research Foundation GAP award.
SMD receives research funding from Alexion and is a consultant with Novartis Pharmaceuticals. KCM is a consultant with Novartis Pharmaceuticals. The remaining authors have no relevant conflicts of interest to disclose.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Arnold, D.E., Emoto, C., Fukuda, T. et al. A prospective pilot study of a novel alemtuzumab target concentration intervention strategy. Bone Marrow Transplant 56, 3029–3031 (2021). https://doi.org/10.1038/s41409-021-01460-1