Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT

• Type of Material: Article
• Authors: Ashley V Geerlinks, Western University; Brooks Scull, Baylor College of Medicine, Houston; Christa Krupski, University of Cincinnati; Ryan Fleischmann, Baylor College of Medicine, Houston; Michael A Pulsipher, University of Utah; Mary Eapen, Medical College of Wisconsin; James A Connelly, Vanderbilt University; Catherine M Bollard, George Washington University; Sung-Yun Pai, National Institutes of Health, Bethesda; Christine N Duncan, Dana-Farber Cancer Institute, Boston; Leslie S Kean, Dana-Farber Cancer Institute, Boston; K. Scott Baker, University of Washington; Lauri M Burroughs, University of Washington; Jeffrey R Andolina, University of Rochester; Shalini Shenoy, Washington University; Phili Roehrs, University of Virginia; Rabi Hanna, Cleveland Clinic; Julie-An Talano, Medical College of Wisconsin; Kirk R Schultz, University of British Columbia; Elizabeth O Stenger, Emory University; Howard Lin, Texas Children's Hospital, Houston; Adi Zoref-Lorenz, Tel Aviv University; Kenneth L McClain, Baylor College of Medicine; Michael B Jordan, Cincinnati Childrens Hosp Med Ctr; Tsz-Kwong Man, Baylor College of Medicine; Carl E Allen, Baylor College of Medicine; Rebecca A Marsh, University of Cincinnati
• Language: English
• Date: 2023-07-25
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2022009478
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 7
• Issue: 14
• Start Page: 3725
• End Page: 3734
• Grant/Funding Information: Support for this correlative biology study was provided by a grant from the Primary Immune Deficiency Treatment Consortium, the HistioCure Foundation, and the St. Baldrick’s Foundation Innovation Grant (C.E.A.). This work was supported in part by funding from the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: GAMMA; GRAFT FAILURE; Science & Technology; MIXED CHIMERISM; FLUDARABINE; PHARMACOKINETICS; DISEASE; STEM-CELL TRANSPLANTATION; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; Life Sciences & Biomedicine; IMPACT; Hematology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Health Sciences, Public Health; Health Sciences, Immunology

Abstract

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.