Professor Marie Robin
HLA-mismatched donors continue to be associated with poorer outcomes than matched donors for myelodysplastic syndrome (MDS), according to long-term registry data.
The study showed that outcomes following allogeneic haematopoietic stem cell transplantation (allo-HSCT) have improved over time and identified several risk factors, such as MDS with excess blasts (EB) and cytomegalovirus (CMV) positivity.
HLA-matched donors remained associated with the best outcomes overall. However, the data suggested that the overall survival (OS) advantage compared to mismatched-related donors has diminished in recent years.
“How HLA-mismatched unrelated donor or mismatched-related donor (MMRD) should be incorporated into donor choice algorithm remains debated,” wrote the authors led by Professor Marie Robin of the Hôpital Saint-Louis in Paris, France.
“The study still shows higher mortality and worse progression-free survival (PFS) using HLA-mismatched donor, including during the last period, in contrast to other registry studies reporting a similar OS between matched-related donor and haplo-identical donors,” they added.
The study, published in the American Journal of Haematology [link here], analysed outcomes of 18,710 MDS patients from across 368 EBMT centres who underwent allo-HSCT between 2000 and 2022.
Compared with the earliest study period (2000-2004), the most recent period (2018-2022) saw a higher number of transplants (6,943 vs 1,614), older transplanted patients (median age 62 vs 50 years), and greater use of hypomethylating agents before transplantation (28% vs 0.3%).
HLA-mismatched related donors were also more common in the most recent versus earliest period (15% vs 3%) and HLA-matched related donors were less frequent (20% vs 54%), while donors were younger (median 33 vs 43 years).
Four-year OS and PFS increased progressively over the study, with a roughly 8-9% gain from the first to last period (OS: 44% to 53%, PFS: 39% to 47%).
However, the relapse rate remained stable over time. “Despite efforts made to reduce relapse risk, such as posttransplant maintenance, that is not converted to a reduced relapse risk,” the authors noted.
Factors associated with increased risk of relapse were poor or very poor IPSS-R cytogenetic risk, MDS with EB, treated patients not in CR, CMV positivity, the combination of female donor to male recipient, and reduced intensity conditioning regimen.
PFS was significantly better for untreated patients compared to those in complete remission following pretransplant therapy, although the authors noted the possibility of treatment selection bias and incomplete information in the registry.
“Moreover, new therapies or combination may have different effects compared with intensive chemotherapy or hypomethylating agents alone which were predominantly used in this study,” they added.
Adjusted PFS was significantly worse for MDS with EB, suggesting that “while EB increases relapse risk, reducing marrow blast percentage before transplantation does not modify this risk,” the authors wrote.
Positive cytomegalovirus (CMV) serology in the patients was also associated with significant increased mortality risk which did not decrease over time.
“More focused studies are needed to assess the impact of letermovir CMV prophylaxis on mortality; letermovir data are lacking in the current study,” the authors noted.
HLA-matched related donors resulted in the best OS outcomes throughout the study, but in the last period outcomes were similar with HLA-matched unrelated donors (interaction test with time, p = 0.009), and both were better than HLA-mismatched-related or unrelated donors.
Non-relapse mortality (NRM) decreased over time, with higher HCT-CI and lower performance status associated with increased NRM, while myeloablative conditioning was no longer significantly associated with increased NRM in the most recent period.
Rates of grade 2–4 acute GVHD and chronic GVHD fell over time, with matched-related donors lowering the risk of acute GVHD and MMRD reducing the risk of chronic GVHD (vs matched-related donor).
In a final analysis, acute GVHD increased the risk of death or NRM, but the impact did not change over time, suggesting that “improved management of acute GVHD alone may not explain survival gains over the last two decades,” the authors wrote.
“This large study provides a comprehensive overview of outcome after transplantation in MDS patients and identifies major risk factors, including age, comorbidities, MDS with EB, poor cytogenetics, and donor type,” noted the authors.
“It also highlights that the impact of established risk factors may change over time with medical progress,” they added.