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

Ashley V. Geerlinks, Division Hematology and Oncology, Children's Hospital at London Health Sciences Centre, Western University, London, ON, Canada.
Brooks Scull, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Christa Krupski, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Ryan Fleischmann, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Michael A. Pulsipher, Division of Hematology and Oncology, Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, UT.
Mary Eapen, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
James A. Connelly, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital and The George Washington University, Washington, DC.
Sung-Yun Pai, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD.
Christine N. Duncan, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, MA.
Leslie S. Kean, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, MA.
K Scott Baker, Clinical Research Division, Fred Hutchinson Cancer Center and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
Lauri M. Burroughs, Clinical Research Division, Fred Hutchinson Cancer Center and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
Jeffrey R. Andolina, Department of Pediatrics, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY.
Shalini Shenoy, Division of Pediatric Hematology-Oncology, Washington University School of Medicine, St. Louis, MO.
Philip Roehrs, Pediatric Hematology/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA.
Rabi Hanna, Department of Pediatric Hematology and Oncology and BMT, Cleveland Clinic, Cleveland, OH.
Julie-An Talano, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
Kirk R. Schultz, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
Elizabeth O. Stenger, Aflac Center and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA.
Howard Lin, Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, TX.
Adi Zoref-Lorenz, Hematology Institute, Meir Medical Center, Kfar Saba, Israel.
Kenneth L. McClain, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Michael B. Jordan, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Tsz-Kwong Man, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Carl E. Allen, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Rebecca A. Marsh, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Document Type

Journal Article

Publication Date

7-25-2023

Journal

Blood advances

Volume

7

Issue

14

DOI

10.1182/bloodadvances.2022009478

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.

Department

Pediatrics

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