Early peripheral blood and T-cell chimerism dynamics after umbilical cord blood transplantation supported with haploidentical cells

Abstract

Single-unit umbilical cord blood (CB) SCT is limited by low total nucleated cell (TNC) dose. Co-infusion of CD34 þ cells from a third party HLA-mismatched donor, known as dual or haplo-cord transplant, reduces the period of post-transplant neutropenia and related complications. The aim of this study was to analyze the value of early post-transplant peripheral blood (PB) and T cell chimerism after 28 dual transplants regarding CB engraftment. Cumulative incidence of myeloid engraftment at 30 days was 93% with a median time to engraftment of 14 days (10-29). Patients who developed CB graft failure (n ¼ 5) showed very low percentages of CB cells on days þ 14, þ 21 and þ 28 with decreasing dynamics. On the other hand, percentages of CB cells in patients who achieved CB engraftment increased over time. Interestingly, such patients showed two distinct chimerism dynamics in PB, but all of them showed a predominance of CB T cells early after SCT with increasing dynamics over time. Early post-transplant chimerism dynamics in PB and T cells predicts CB graft failure enabling rapid therapeutic measures to be applied. On the other hand, early increasing percentages of CB T cells correlates with ultimate CB engraftment.Bone Marrow Transplantation (2014) 49, 212-218; doi:10.1038/bmt.2013.177; published online 11 November 2013Keywords: cord blood transplantation; haploidentical donor; chimerism; graft failure INTRODUCTION Unrelated umbilical cord blood (CB) has been increasingly used as an alternative stem cell source for adult patients eligible for allogeneic SCT, but lacking HLA-matched adult donors. [1][2][3] However, one of the main limitations of CB transplantation is the late engraftment related to low total nucleated cell (TNC) dose, with the subsequent increased risk of serious early neutropenia-related infections and high non-relapse mortality. 2,4 Single CB transplantation supported by mobilized and selected CD34 þ cells from a HLA-mismatched third party donor (TPD), known as dual or haplo-cord SCT, has shown to reduce the period of post-transplant neutropenia and related early morbidity and mortality associated with single CB transplantation. [5][6][7][8] This strategy offers a rapid neutrophil recovery at the expense firstly of TPD cells with subsequent replacement and long-term engraftment of CB cells.Graft failure and graft rejection are major complications after allogeneic SCT, with a frequency as high as 23% using CB transplants. 9-11 Outcome of patients who develop graft failure without a second transplantation is dismal with survival rates lower than 10%; 12 however, survival rates improve significantly to 30-60% after salvage transplantation using reduced intensity conditioning regimens. [13][14][15] From the extensive experience with CB transplantation, various risk factors have been associated with CB graft failure. [16][17][18] Once transplantation has been performed, early detection of graft failure is important to start rapid therapeutic measures such as immunomodulation and to launch a second transplan...

Frequency and Risk Factors Associated with Cord Graft Failure after Transplant with Single-Unit Umbilical Cord Cells Supplemented by Haploidentical Cells with Reduced-Intensity Conditioning

“…This suggests that assessing chimerism before day 60 may indicate impending CGF. This is in line with that reported by the Spanish group in the haplo-cord transplant setting [42]. They found that the dynamics of UCB chimerism over time at days 14, 21, and 28 predicts for CGF, which they defined as absence of UCB-specific alleles by short tandem repeat PCR at day 30.…”

“…These rates of CGF after haplo-cord HSCT appear on par to the reported rates of 4% to 20% in the myeloablative setting and 6% to 12% in the RIC setting using single and double UCB approaches, with variable graft-versus-host-disease prophylaxis [40–42]. Brunstein et al [43] reported a 10% rate of CGF in a multi-institutional protocol using a RIC double UCB approach.…”

“…The Spanish group pursued second transplant for most patients with CGF after myeloablative haplo-cord HSCT [39,42]. We have not standardly pursued a second transplant after CGF in our haplo-cord approach in the absence of inadequate hematopoietic function or relapse.…”

Haplo-Cord Transplantation Using CD34+ Cells from a Third-Party Donor to Speed Engraftment in High-Risk Patients with Hematologic Disorders

“…On the other hand, TNC content showed influence on myeloid engraftment, only in a minority of the cases included in this analysisdthose achieving engraftment beyond day 16. This group of patients may have experienced an early CB graft dominance, which leads to a relatively lower contribution of the TPD cells, as previously described [23]. Also, HLA matching had no impact on longterm CB engraftment.…”

“…The third-party cells infused in this procedure contribute to the fast neutrophil recovery after transplantation [23]. However, the role of the third-party cells might exceed the sole function of providing a bridge engraftment.…”