A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαβ+ and CD19+ Cell-Depleted Stem Cell Transplantation in Patients with Wiskott-Aldrich Syndrome

Abstract

Our initial experience with hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n = 12) or a haploidentical related donor (n = 6) with T cell receptor (TCR)αβ/CD19 graft depletion in patients with Wiskott-Aldrich syndrome (WAS) (n = 18) showed a dramatic decrease in the incidence of graft-versus-host disease (GVHD) and transplantation-related mortality, with an increased overall survival (OS) of 88.9%. Unfortunately, the treatment was associated with mixed myeloid donor chimerism and secondary graft dysfunction (severe thrombocytopenia, n = 2; graft rejection, n = 5). To improve the outcome, we hypothesized that the addition of G-CSF and plerixafor to the conditioning chemotherapy would result in more complete donor stem cell engraftment. This trial was registered at www.clinicaltrials.gov (NCT03019809). A study group of patients with WAS (n = 16) underwent TCRαβ/CD19-depleted HSCT (MUD, n = 6; haploidentical, n = 10). The conditioning regimen was treosulfan-fludarabine-rabbit antithymocyte globulin-melphalan (or thiophosphamide in 1 patient) with G-CSF (10 µg/kg/day for 5 days starting on day -8) and plerixafor (240 µg/kg/day for 3 days starting on day -6). The clinical outcomes in this study were compared to those in a historical dataset (n = 18). No patients had grade III/IV acute GVHD in either the study or the historical control group. Importantly, in the patients with WAS, there was no statistical significance in OS between those who underwent HSCT from haploidentical donors and those who underwent HSCT from MUDs (93.8% versus 88.5%; P = .612). All patients in the study group had full donor chimerism in whole blood and in the CD3 compartments. The OS was 93.8%, and there were no cases of graft dysfunction. This study demonstrates the efficacy of adding G-CSF/plerixafor to the conditioning regimen before HSCT with TCRαβ/C D19 graft depletion in patients with WAS.

Get Outta Here! Addition of Mobilizing Agents to Conditioning Regimen Improves Donor Engraftment after Allogeneic Hematopoietic Stem Cell Transplantation for Wiskott-Aldrich Syndrome

“…Similar to the WAS patients in this study by Balashov et al [2], Konopleva et al [15] recently found that leukemic patients treated with G-CSF and plerixafor during pretransplant myeloablative conditioning for alloHCT also had increased donor myeloid chimerism and lower rates of GVHD compared with historical controls not receiving mobilizing agents. Because cohorts of conditioned patients were not treated with only 1 of the mobilizing agents in either of these studies, it is unclear whether both G-CSF and plerixafor are required to enhance donor engraftment and reduce subtransplant complications after alloHCT.…”

“…Therefore, increasing donor engraftment so as to minimize mixed chimerism could increase the efficacy of alloHCT for WAS. In this study, Balashov et al [2] report increased donor engraftment and event-free survival following addition of G-CSF and plerixafor to the conditioning regimen of WAS patients undergoing alloHCT with TCR αβ/CD19-depleted haploidentical or matched unrelated grafts. Patients underwent a reduced toxicity myeloablative conditioning regimen consisting of treosulfan (days -5 to -3), fludarabine (days -6 to -3), and melphalan (day -2) with the addition of G-CSF (days -8 to -4) and plerixafor (days -6 to -4).…”

“…While UCB can achieve reasonable per-kilogram cell doses in pediatric HCT, adults undergoing HCT may suffer from inadequate cell numbers. Recently, methodology to overcome the cell dose limitation have been pursued in a variety of ways: infusion of 2 UCB units [2], increasing homing efficiency of UCB cells [3], and expanding the UCB in vitro [4]. HSC expansion technologies have relied on the use of cytokines combined with mesenchymal stromal cells (MSCs), proteins, or small molecules.…”

“…Specifically, removal of T cells bearing the αβ receptor (TCR αβ), which are implicated in causing GVHD, and CD19 + B cells, which can harbor Epstein-Barr virus, allows infusion of the remaining CD34 + stem cell inoculum, including natural killer cells, myeloid cells, dendritic cells, and T cells bearing the γδ T cell receptor, which have antiviral activity [6][7][8]. This refined T and B cell depletion technique was used by Balashov et al [2] and has improved the overall survival of WAS children undergoing alloHCT with mismatched grafts to >80% [2,6,8]. However, despite myeloablative conditioning, a small fraction (~10%) of WAS patients reject their first transplants and a substantial proportion (up to~30%) exhibit long-term mixed chimerism [9][10][11].…”

Hematopoietic Stem Cell Transplantation for Combined Immunodeficiencies, on Behalf of IEWP-EBMT

“…In the absence of a matched-donor, decision to transplant needs to be balanced. Transplantation from an alternative donor is more challenging even though most recent results show increasingly successful survival, allowing to consider transplant early in the disease course (43)(44)(45)(46). At the end, the final decision about transplant will depend on a conjunction of factors such as immunological parameters, the severity of past and current clinical manifestations, i.e., severity of infections, autoimmunity, need of immunosuppressive treatment to control the manifestations related to immune dysregulation and donor compatibility.…”