Francis A. Ayuk, Dietrich W. Beelen, Martin Bornhäuser, Matthias Stelljes, Tajana Zabelina, Jürgen Finke, Guido Kobbe, Daniel Wolff, Eva Maria Wagner, Maximilian Christopeit, Christoph Schmid, Hellmut Ottinger, Christoph Groth, Christoph Faul, Hartmut Bertz, Elena Rachlis, Christine Wolschke, Nicolaus Kröger, Wolfgang Bethge
- Introduction:
Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions.
Patients and methods:
We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST),Introduction:
Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions.
Patients and methods:
We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST), 2) age >/= 18 years, 3) availability of high-resolution typing for HLA-A, -B, C, DRB1 and DQB1 in case of unrelated donor. Patients with ex-vivo T cell depletion were excluded.
3215 patients with AML (n = 2648) or MDS (n = 567) were included in the study. Donors were matched related (MRD, n =872), matched unrelated (MUD, n = 1553) or mismatched unrelated (9/10 MMUD, n= 620; 8/10 MMUD n = 137; <8/10 MMUD n = 33). Remission status at transplant was CR (49%), not in CR (40%) or untreated (11%). The vast majority of patients (96%) received peripheral blood stem cell grafts. Conditioning was reduced intensity (51%) or myeloablative (49%) according to EBMT criteria. ATG (56%) or alemtuzumab (8%) were used for in vivo T cell depletion. Median patient age was 56 (18-79) years. Median donor age was 38 (12-80) years. Median follow-up was 54 months (34-81 months). Primary endpoint was overall survival (OS) at 3 years.
Results:
Kaplan-Meier estimates for OS at 3 years was similar after transplants from MRD = 55% (95%CI 51-59%) compared to MUD = 53% (95%CI 51-59%), p = 0.26. OS at 3 years was worse for 9/10 MMUD with 45% (95% CI 41-49%, p<0.001), for 8/10 MMUD with 35% (95% CI: 27%-43%, p < 0.001) and for <8/10 MMUD with 29% (95% CI 13%-45%, p = 0.005) (figure 1).
In recipients of unrelated donor transplants, multivariate cox regression analysis revealed significant negative impact of increasing patient age, increasing donor age, sex-mismatch (male patient/female donor), CMV-mismatch (patient pos/ donor neg), diagnosis of AML or sAML compared to MDS, lack of complete remission at transplant, abnormal cytogenetics and HLA-mismatching (table 1a).
In a subgroup analysis restricted to patients transplanted from unrelated donors after myeloablative conditioning and T cell depletion, 3 years OS was better after 10/10 MUD: 60% (55-65%) compared to 9/10 MMUD: 49% (41-57%), p = 0.02. This was also true after reduced intensity conditioning and T cell depletion with ATG, with 3 year OS after 10/10 MUD: 49% (45-53) compared to 9/10 MMUD: 37% (31-43%), p = 0.001. Excluding HLA-DQB1-mismatches and HLA-C0303/0304-mismatches from the 9/10 MMUD group did not significantly alter results.
Acknowledging the negative impact of both HLA and CMV-mismatching, we sought to determine which of these two parameters is of higher relevance for donor selection. For this purpose subgroup analyses were performed including only CMV-positive patients who received transplants from an unrelated donor (10/10 MUD or 9/10 MMUD). HLA-DQB1-mismatches and HLA-C0303/0304-mismatches were excluded. For this subgroup of n = 1167 patients multivariate cox regression analysis revealed better outcome after 10/10 MUD from CMV neg. donors compared to 9/10 MMUD from a CMV pos. donors (RR: 1.31, p = 0.04, table 1b and figure 2). Restricting the analysis only to patients who received T cell depletion with ATG did not significantly alter these findings.
Conclusions:
In this large multicenter cohort of recently transplanted patients, we find similar survival outcomes for matched related and fully matched unrelated donor transplants. We confirm the negative impact of HLA-mismatching on survival outcome, irrespective of conditioning intensity. Our results show that though CMV-mismatching is associated with poorer outcome, its relevance is secondary to HLA-mismatching.…
