Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2–1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1–1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2–1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1–1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99–1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4–2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.

[1]  A. Pettitt,et al.  Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. , 2010, Blood.

[2]  M. Sanz,et al.  Effect of CD8⁺ cell content on umbilical cord blood transplantation in adults with hematological malignancies. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  Harriet Noreen,et al.  High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. , 2007, Blood.

[4]  G. Fahle,et al.  CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML , 2013, Bone Marrow Transplantation.

[5]  C. Craddock,et al.  Cytomegalovirus seropositivity adversely influences outcome after T‐depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft‐versus‐host disease prophylaxis , 2001, British journal of haematology.

[6]  K. Matsuo,et al.  Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. , 2015, Blood.

[7]  M. Copland,et al.  In a 12-allele analysis HLA-DPB1 matching is associated with improved OS in leukaemic and myelodysplastic patients receiving myeloablative T-cell-depleted PBSCT from unrelated donors , 2014, Bone Marrow Transplantation.

[8]  J. Goldman,et al.  CYTOTOXIC T LYMPHOCYTE PRECURSOR FREQUENCY ANALYSES IN BONE MARROW TRANSPLANTATION WITH VOLUNTEER UNRELATED DONORS VALUE IN DONOR SELECTION , 1995, Transplantation.

[9]  E. Thiel,et al.  Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation , 2007, Bone Marrow Transplantation.

[10]  A. Gratwohl The EBMT risk score , 2012, Bone Marrow Transplantation.

[11]  J. Stockman Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients , 2013 .

[12]  J. Cayuela,et al.  Patterns of cytomegalovirus reactivation are associated with distinct evolutive profiles of immune reconstitution after allogeneic hematopoietic stem cell transplantation. , 2008, The Journal of infectious diseases.

[13]  Medhat Askar,et al.  Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. , 2014, Blood.

[14]  P. Veys,et al.  Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis , 2016, Bone Marrow Transplantation.

[15]  J. Klein,et al.  HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[16]  P. Ljungman,et al.  Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT , 2007, Bone Marrow Transplantation.

[17]  S. Mackinnon,et al.  CMV-specific cellular therapy for acute myeloid leukemia? , 2012, Blood.

[18]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[19]  E. Jaskuła,et al.  CMV Serostatus of Donor-Recipient Pairs Influences the Risk of CMV Infection/Reactivation in HSCT Patients , 2012, Bone marrow research.

[20]  Effie W Petersdorf,et al.  Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. , 2012, The Lancet. Oncology.

[21]  H. Einsele,et al.  Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[22]  M. Lindemann,et al.  Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors. , 2003, Blood.

[23]  M. Pini,et al.  The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors , 2015, American journal of hematology.

[24]  M. Hughes,et al.  IMMUNE DONORS CAN PROTECT MARROW-TRANSPLANT RECIPIENTS FROM SEVERE CYTOMEGALOVIRUS INFECTIONS , 1987, The Lancet.

[25]  H. Einsele,et al.  Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. , 2003, Blood.

[26]  J. Zaia,et al.  Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. , 2008, Blood.

[27]  L. Jardine,et al.  A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants , 2015, British journal of haematology.

[28]  B. Sandmaier,et al.  CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. , 2013, Blood.

[29]  S. Quezada,et al.  CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status. , 2015, Blood.

[30]  C Anasetti,et al.  Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. , 2001, Blood.

[31]  B. Sarina,et al.  Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[32]  S Mackinnon,et al.  Diverging effects of HLA–DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles , 2010, Leukemia.

[33]  A. Begovich,et al.  The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. , 2007, Blood.

[34]  M. Balestreri,et al.  CMV infections following allogeneic BMT: risk factors, early treatment and correlation with transplant related mortality. , 1992, Haematologica.

[35]  J. Dipersio,et al.  The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. , 2016, Blood.

[36]  D. van Baarle,et al.  Influence of donor cytomegalovirus (CMV) status on severity of viral reactivation after allogeneic stem cell transplantation in CMV-seropositive recipients. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.