LONDON — Myelodysplastic syndromes (MDS), a condition linked to contaminated water at Camp Lejeune for some veterans, are the second common indication for an allogeneic hematopoietic stem cell transplant (Allo-HCT.)
An international study led by UK researchers from University College London compared the outcomes of 1,414 matched siblings (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017.1
The participants’ median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD — 20 vs 16 days for MSD (p < 0.001).
“Two-year overall survival (OS) and PFS (progression-free survival) with MSD were significantly better at 58% compared with 50%, p ≤ 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016),” the researchers wrote in the Blood Cancer Journal. “Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5-4.48) p < 0.001] and was also higher at two years being 30% for HD and 20% for MSD, p ≤ 0.001.”
Researchers determined that the incidence of acute GVHD grade II-IV and III-IV at 100 days was comparable for MSD and HD. Still, chronic GVHD at two years was significantly higher with MSD — 44% vs 32% for HD (p < 0.001).
After multivariable analysis, the study found that OS and primary graft failure were significantly worse for HD, especially before six months [HR 1.93(1.24-3.0)], and HR [3.5(1.5-8.1)]. “The median age of HD 37 (IQR 30-47) years was significantly lower than sibling donors 56 (IQR 49-62 years) p < 0.001,” the authors added. “However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying its use when no better donor is available.”
Background information in the article advised that the myelodysplastic syndromes are a heterogenous cluster of clonal stem cell disorders that occur in the older adult; those manifest as either bone marrow failure and or a progression towards acute leukemia.
“Allogeneic hematopoietic cell transplantation (allo-HCT) is the only option that offers the potential for long-term disease-free survival in 30–50% of recipients,” according to the study team. “ Both conditioning intensity and donor type affect outcomes”.
Past research has suggested comparable outcomes in patients who received allo-HCT from a human leukocyte antigen (HLA)-matched sibling donor (MSD) with those from an HLA-matched unrelated donor (10/10). “More recently the donor pool has been extended to the use of haploidentical donors (HD) particularly utilizing T-replete stem cells with post-transplant cyclophosphamide (PTCy) GVHD (graft versus host disease) prophylaxis,” the authors pointed out.
They said that trend was confirmed in an analysis of HD for MDS in Europe, with outcomes improving with reduced intensity conditioning and the use of PTCy as GVHD prophylaxis. Additionally, a comparison of HD with PTCy and mismatched unrelated/cord blood (MMUD/CB) donors “showed lower non-relapse mortality, acute GVHD, and better overall survival for HD when compared to both MMUD and CBD,” the authors advised.
“In older recipients with MDS/AML who were transplanted with MUD or Haplo donor, overall survival was similar with lower GVHD among Haploidentical recipients,” the researchers explained. “Recipient age, however, remains the most important prognostic factor predicting outcomes in HD transplant.”
The report went on to note, “Recently, a comparison of Haplo stem cell transplants in patients with acute leukemia from sibling or offspring donors showed that in patients younger than 55, the outcomes from MSD were similar to the Haplo recipients conditioned with PTCy. Conversely, older recipients who predominantly had offspring donors had higher graft failure, NRM and overall mortality compared to MSD.”
The authors suggested that with a median age of presentation of MDS in the 6th–7th decade and haplo-HCT across the EBMT registry increasing, it was important to compare the outcomes of MSD and an alternative albeit family HD. The study also addressed “the debatable issue as to whether readily available younger family mismatched donor should be a preferred choice over older MSD in older patients receiving allo-HCT.”
They said “it is unclear whether we can extrapolate from reports focused on AML, regarding selection between an older MSD or a younger HD (easily available for all patients) transplanted with PTCy.” The researchers said their data from a recent cohort of patients with MDS who underwent Haploidentical transplants with post-transplant cyclophosphamide, however, showed that results for HD are inferior to MSD transplants due to the increased NRM, especially in the first six months.
“In comparison with MSD, as expected, the relapse rate with HD is relatively lower,” they added. “This may be due to a higher graft versus leukemia effect attributed to HD.”,
The authors also advised that they identified significantly lower relapse rates and NRM for transplants from female to male donors, positing that that might be related to enhanced graft vs leukemia effects without GVHD (non-tolerized donor T cells) against SMCY, which might have translated into survival/PFS benefit.
They also found lower relapse rates among untreated patients as compared to patients who received treatment; that was irrespective of response and disease status-blast count and “might be due to inability of treatment such as azacytidine to eliminate founder precursor clones, and emergence/selection of resistant clones while on treatment,” the researchers said.
The data suggested that matched siblings are the optimal donor in MDS, “however in their absence, despite the higher early NRM and primary graft failure, HD transplantation is a reasonable option,” the study concluded, adding that more MDS studies on donor kinship are needed.
- Raj K, Eikema DJ, Sheth V, Koster L, et. al. Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT. Blood Cancer J. 2022 Sep 28;12(9):140. doi: 10.1038/s41408-022-00729-y. PMID: 36167679; PMCID: PMC9515068.
