Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia: Frontiers in Immunology

P. Merli, M. Algeri, F. Galaverna, G.M. Milano, V. Bertaina, S. Biagini, E. Girolami, G. Palumbo, M. Sinibaldi, M. Becilli, G. Leone, E. Boccieri, L. Grapulin, S. Gaspari, I. Airoldi, L. Strocchio, D. Pagliara, F. Locatelli

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Abstract

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24–48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1–2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM. © Copyright © 2020 Merli, Algeri, Galaverna, Milano, Bertaina, Biagini, Girolami, Palumbo, Sinibaldi, Becilli, Leone, Boccieri, Grapulin, Gaspari, Airoldi, Strocchio, Pagliara and Locatelli.
Original languageEnglish
JournalFront. Immunol.
Volume11
DOIs
Publication statusPublished - 2020

Keywords

  • acute leukemia
  • children
  • TcRαβ/CD19 cell depleted haploidentical stem cell transplantation
  • TcRγδ+ lymphocytes
  • zoledronic acid
  • antivirus agent
  • CD19 antigen
  • corticosteroid
  • steroid
  • T lymphocyte receptor alpha chain
  • T lymphocyte receptor beta chain
  • T lymphocyte receptor delta chain
  • T lymphocyte receptor gamma chain
  • acute graft versus host disease
  • acute lymphoblastic leukemia
  • acute myeloid leukemia
  • adenovirus infection
  • antiviral therapy
  • arthralgia
  • Article
  • asymptomatic disease
  • cancer survival
  • child
  • childhood leukemia
  • childhood mortality
  • chill
  • chronic graft versus host disease
  • clinical article
  • controlled study
  • corticosteroid therapy
  • cytomegalovirus infection
  • extracorporeal photopheresis
  • female
  • fever
  • follow up
  • haploidentical transplantation
  • human
  • hypocalcemia
  • immunomodulation
  • leukemia remission
  • malaise
  • male
  • peripheral blood stem cell
  • photopheresis
  • recurrence free survival
  • single drug dose
  • stem cell transplantation
  • systemic therapy
  • topical treatment
  • tumor engraftment
  • virus reactivation

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