Lower Risk of GVHD With Parous Female Sibling Donors Than With Male Unrelated Donors

Donor’s sex and number of previous pregnancies are well established risk factors for graft-versus-host disease (GVHD) in hematopoietic cell transplantation (HCT), with male sibling donors typically associated with a lower incidence of GVHD than other donors.

According to results from a study published in Blood Advances, patients who received HCT from male unrelated donors, though, are more likely to experience acute GVHD compared with HCT from parous female sibling donors. However, the study did not demonstrate a difference between the two options with respect to survival, relapse, or transplant-related mortality (TRM; defined as any death within a 28- day period following transplantation or death in continuous remission).

“The findings from this study may help guide transplant providers in selecting donors for their patients,” lead author Anita J. Kumar, MD, MS, assistant professor at Tufts University School of Medicine in Boston, told ASH Clinical News. “While the ideal donor may be a young human leukocyte antigen (HLA)–identical male sibling, difficult decisions may arise for patients whose only available sibling donor is a sister with previous pregnancies.”

Investigators retrospectively reviewed patient data from the Center for International Blood and Marrow Transplant Research from adults with acute myeloid leukemia, acute lymphocytic leukemia, and myelodysplastic syndromes. All underwent T-cell replete myeloablative, non-myeloablative, or reduced-intensity conditioning prior to HCT.

Patients received HCT from what the authors considered “higher-risk” donor groups:

  • parous female sibling donors (n=892)
  • matched male unrelated donors (n=1,921)

HCT recipient characteristics were similar between each group: The median age was 49 and 50 years, respectively (ranges not provided), though donor age was higher in the parous female sibling group (48 years vs. 32 years; p<0.001).

For this analysis, researchers compared rates of the following primary outcomes between the two donor groups: grade 2-4 acute GVHD, grade 3-4 chronic GVHD, and overall survival (OS).

After adjusting for multiple donor-, recipient-, and transplant-related variables (including age, ABO match, cytomegalovirus serology, disease refractory status, and time from diagnosis to HCT), the authors reported that recipients of male unrelated donor grafts had a significantly higher risk of grade 2-4 acute GVHD (relative risk [RR] = 1.56; p<0.0001; see TABLE).

Univariable analyses showed similar rates of chronic GVHD at six months (33% vs. 30%) and 1 year (50% vs. 50%; p values not reported) for recipients of male unrelated donor grafts and parous female donor grafts. In the multivariable analyses, however, women had a significantly higher risk for chronic GVHD with HCT with male unrelated donors, compared with parous female sibling grafts (adjusted RR=1.43, p<0.0001).

“This study appears to provide a clear answer about donor selection for allogeneic stem cell transplantation and will definitely affect our decision-making process [in this setting],” wrote Dennis Kim, MD, PhD, when asked to comment on the study’s findings. For more from Dr. Kim, see Perspectives at the end of this article.

“Although parous female siblings more frequently donated peripheral blood stem cells [vs. bone marrow cells] (87% vs. 76%; p<0.001), a product known to increase chronic GVHD, the effect was preserved even when controlling for this variable,” according to the researchers. “When evaluating only the most severe acute GVHD (grade 3/4) this increased risk may have persisted, but our results no longer demonstrated statistical significance, possibly because of a relatively low incidence of severe acute GVHD in the study sample.”

The investigators also compared rates of disease-free survival (DFS; defined as time to treatment failure), TRM, and relapse between the two groups.

At 100 days post-HCT, a smaller proportion of male unrelated donor recipients were still alive, compared with recipients of parous female sibling transplants (82% vs. 88%, respectively; p<0.001). This difference dissipated at one-year post-HCT. Similarly, although the TRM rate was significantly higher among recipients of male unrelated donor grafts at 100 days (11% vs. 8%, respectively; p=0.003), these differences were resolved by six-month follow-up.

There also were no significant differences in OS benefit (RR=1.10; 99% CI 0.99-1.26; p=0.07) or five-year DFS rates (33% vs. 34%, respectively; p=0.52) between male unrelated donors and parous female sibling donors.

Relapse rates were also similar between the two cohorts at all time points following transplant (p=0.59).

As the study authors relied on a registry for a retrospective review of patient data, it is possible that the inclusion of misclassified GVHD incidences occurred, which they noted was a limitation of this analysis. In addition, the findings may not be generalizable to individuals receiving in vivo or ex vivo T-cell–depleted transplants, as only T-cell replete transplants were included in the analysis.

“Our study suggests that, when faced with the options of an HLA-identical female sibling donor with prior pregnancies or a male unrelated donor, providers should opt for the parous sibling donor to reduce the risk of acute and chronic GVHD,” Dr. Kumar concluded.

The corresponding authors report no financial conflicts.

Reference

Kumar AJ, Kim S, Hemmer MT, et al. Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants. Blood Advances. 2018;2:1022-31.

“Bone marrow transplant physicians typically prefer male donors over parous female donors, but it was debatable if a parous, related female donor should be deferred in favor of an unrelated male donor.

The findings from the study clearly provide answers to this question: For acute GVHD, unrelated male donors showed a 56-percent higher risk of acute GVHD and for chronic GVHD, at least, the parous female donor does not have increased risk of chronic GVHD compared with the unrelated male donor. The latter finding implies minor histocompatibility antigen mismatch may be more important than H-Y mismatch.

Also, donor type does not affect long-term outcomes, including overall survival, relapse, or transplant-related mortality between the two groups. However, when physicians are faced with a choice between a male unrelated donor or parous female sibling donor, parous female sibling donor should be favored to reduce the risk of acute and chronic GVHD.

From these results, we do not know if this information is applicable in the setting of transplantation with T-cell–repleted stem cells. Further investigation is warranted to determine whether the source of cells (peripheral blood or bone marrow) from parous female siblings or male unrelated donors affects risks of GVHD, relapse, and transplant-related mortality.”

Dennis Kim, MD, PhD
Allogeneic Blood & Marrow Transplant Program
Princess Margaret Cancer Centre
Toronto, Ontario

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