%A Merli,Pietro %A Algeri,Mattia %A Galaverna,Federica %A Milano,Giuseppe Maria %A Bertaina,Valentina %A Biagini,Simone %A Girolami,Elia %A Palumbo,Giuseppe %A Sinibaldi,Matilde %A Becilli,Marco %A Leone,Giovanna %A Boccieri,Emilia %A Grapulin,Lavinia %A Gaspari,Stefania %A Airoldi,Irma %A Strocchio,Luisa %A Pagliara,Daria %A Locatelli,Franco %D 2020 %J Frontiers in Immunology %C %F %G English %K TcRγδ+ lymphocytes,Zoledronic Acid,Acute leukemia,Children,TcRαβ/CD19 cell depleted haploidentical stem cell transplantation %Q %R 10.3389/fimmu.2020.00699 %W %L %M %P %7 %8 2020-May-12 %9 Original Research %# %! Zoledronic acid in TcRαβ/CD19-cell-depleted haplo-HSCT %* %< %T 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 %U https://www.frontiersin.org/articles/10.3389/fimmu.2020.00699 %V 11 %0 JOURNAL ARTICLE %@ 1664-3224 %X 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.