Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis

Summary

Background

Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate.

Methods

We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively).

Findings

Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18–2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19–2·39; p=0·003). Grades 2–4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42–0·77; p=0·002 and HR 0·38, 0·27–0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44–0·90; p=0·01).

Interpretation

These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently.

Funding

National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease (U24-CA76518); Health Resources and Services Administration (HHSH234200637015C); Office of Naval Research, Department of Navy (N00014-08-1-1207); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.

Introduction

Treatment of high-risk acute leukaemia by allogeneic haemopoietic stem-cell (HSC) transplantation is an accepted therapeutic strategy. However, the scarcity of HLA-compatible sibling donors limits its application in around 70% of patients who could otherwise benefit from this treatment. An unrelated HLA-matched adult donor is generally considered to be the next-best alternative if an HLA-matched sibling is not available.¹ HSCs can be harvested from bone marrow or, after stimulation of the donor with haemopoietic growth factors, from peripheral blood. Over the past decade, peripheral blood progenitor cells (PBPCs) have surpassed bone marrow as the preferred source of allogeneic HSCs for adults. In 2008, worldwide PBPC collections from unrelated donors numbered 7260 (69%), compared with 3221 (31%) bone-marrow collections.²

As of 2008, over 14 million potential unrelated adult donors were registered with the unrelated-donor registries worldwide.² Still, only around 50% of patients of white ethnic origin will have an HLA-matched unrelated donor available. The chance of finding an available and fully HLA-matched unrelated adult donor is even lower for patients of non-white ethnic origin. Additionally, the search and procurement process for adult donors can take weeks or months; consequently, umbilical-cord blood (UCB) is increasingly attractive as an alternative to HLA-matched PBPC or bone marrow.2, 3

Many studies have clearly established the limitations and advantages of UCB, particularly in children.4, 5, 6, 7 We previously did a comparative analysis of UCB and bone marrow in children with acute leukaemia,⁷ and showed that 4–6/6 HLA-matched UCB (HLA-A and HLA-B matching at intermediate resolution, and HLA-DRB1 matching at allele level) provided a similar probability of leukaemia-free survival (LFS) to matched bone marrow (HLA-A, HLA-B, HLA-C, and HLA-DRB1 matched at allele level). As a result, we concluded that there was no reason to delay transplantation if a 4–6/6 HLA-matched UCB unit with an adequate cell dose was available, especially if an allele-matched unrelated adult donor could not be readily identified. The logical next step was to do a similar analysis in adults with acute leukaemia. Although several previous reports have compared outcomes after UCB and bone marrow transplantation in adults,8, 9 these studies were based on less rigorous historical, rather than current, donor-selection practices. Specifically, adult donors are now selected on the basis of HLA matching using allele-level typing at HLA-A, HLA-B, HLA-C, and HLA-DRB1,¹⁰ and a cell-dose threshold of 2·5×10⁷ total nucleated cells per kg of the recipient's bodyweight is considered a standard for UCB grafts. The findings of these early reports differed in that one showed higher transplant-related mortality (TRM) and lower LFS after UCB compared with matched bone-marrow transplants,⁸ whereas the other⁹ showed similar TRM and LFS after UCB and matched bone-marrow transplants. Additionally, these studies did not compare UCB with PBPC transplants. In the absence of a prospective clinical trial, which would be logistically challenging, we used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), the European Group for Blood and Marrow Transplantation (EBMT), the Eurocord-Netcord Registry, and the National Cord Blood Program (NCBP) at the New York Blood Center, for adults with acute leukaemia who were transplanted with unrelated donor bone marrow, PBPC, or UCB. By assessing LFS and other transplant outcomes for UCB relative to 8/8 HLA-matched bone marrow or PBPC as the gold standard, we sought to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia.