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Higher CD8 T-cell dose from younger donors improves allogeneic HSCT outcomes
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A higher graft CD8 dose from younger donors — even if they are not related to the patient — predicted improved survival in patients with hematologic malignancies undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation, according to study results.
Further, a blood test to measure the T lymphocyte count in donors may help identify the best donor match for patients undergoing hematopoietic stem cell transplant (HSCT), the researchers found.
Ran Reshef
Ran Reshef, MD, an assistant professor in the division of hematology/oncology and a member of the hematologic malignancies research program at the Abramson Cancer Center of the University of Pennsylvania, and colleagues conducted this study to see if older patients who received stem cells from younger, unrelated donors with a higher number of “killer T-cells” (CD8 cells) would have a reduced risk for disease relapse and improved survival outcomes compared with patients who received grafts from donors — including matched siblings — with lower CD8-cell counts.
“As we all know, the number one cause of death after reduced intensity allogeneic transplant is disease relapse, and there is interest in identifying modifiable factors that could reduce relapse risk and improve survival,” Reshef told HemOnc Today. “In this study, we focused on the doses of T cells, the primary mediators of the graft-vs.-tumor response in peripheral blood stem cell grafts. An impact of T-cell doses on patients’ survival has not been shown previously.”
Because older patients receive lower doses of chemotherapy and/or radiation when they undergo reduced-intensity conditioning for HSCT, there is more of an onus on the donor T cells to kill the cancer cells.
“Developing better tools to identify ideal donors is an exciting prospect and fundamental to improving transplant outcomes,” Reshef said in a press release. “There are many suitable donors out there who are overlooked because they are considered a poorer match by today’s donor selection algorithms. Refining the screening method could greatly increase the chances of finding the most appropriate donor, one that will induce the most potent graft-vs.-tumor response.”
Reshef and colleagues retrospectively evaluated the association between T-cell doses and outcomes in 200 patients (median age, 62 years) who underwent reduced-intensity conditioning allogenic HSCT at Abramson Cancer Center between 2007 and 2014. Researchers then evaluated data from 21 stem-cell donors to identify predictors of optimal graft T-cell content.
Forty-seven percent (95% CI, 40-55) of patients experienced disease relapse by 5 years.
Results of a multivariable analysis indicted higher CD8 cell doses reduced the risk for disease relapse (HR = 0.43; 95% CI, 0.23-0.81) and improved RFS (HR = 0.5; 95% CI, 0.3-0.82) and OS (HR = 0.57; 95% CI, 0.33-0.97). Further, higher CD8 cell doses did not significantly increase the risk for acute graft-versus-host disease (GVHD; HR = 0.96; 95% CI, 0.55-1.65), chronic GVHD (HR = 1.84; 95% CI, 0.89-3.78) or nonrelapse mortality (HR = 0.8; 95% CI, 0.36-1.76).
Researchers noted total CD3, CD4 and CD34 cell doses did not significantly impact outcomes.
Using classification and regression tree analysis, researchers identified a cutoff level of 0.72 x 108 CD8 cells/kg to define the high-dose level at which patients experienced benefit.
The researchers also noted that high CD8 cell counts were more common among young donors. Only 13% donors aged older than 50 years and no donors aged older than 60 years provided a graft at the high CD8 cutoff. Fifty-three percent of donors aged younger than 30 years had high CD8-count grafts.
Further, with 4-year OS rates of 59% (95% CI, 39-74) for patients with younger, unrelated donors with high CD8 cell counts, 18% (95% CI, 7-33) for patients with younger, unrelated donors with low CD8 cell counts and 33% (95% CI, 20-47) for patients with older sibling donors, the researchers concluded that it would be better to use a younger, unrelated donor graft with high CD8 cells instead of a matched sibling.
The CD8 cell content of a specific graft can be predicted by measuring the proportion of CD8 cells in a blood test from potential stem cell donors. This would allow a simple blood test to determine the best match for stem-cell transplant before the grafts are even collected.
“I feel that these results may ultimately change the way we pick donors for allogeneic stem-cell transplantation, in particular in older individuals who receive reduced intensity transplants that are becoming more and more common,” Reshef said. “Since this is a major conceptual change in the way that donors are selected, the plan for the near future is to examine these findings in a prospective clinical trial.” – by Anthony SanFilippo
For more information: Ran Reshef, MD, can be reached at the Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; email: ran.reshef@uphs.upenn.edu
Disclosure: Reshef reports research funding from Tobira Therapeutics and consultant/advisory roles with Celgene, Spectrum Pharmaceuticals, Teva and Tobira. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Nelli Bejanyan, MD
Malignancy relapse is the major cause of treatment failure after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplant (allo-HCT), leading to dismal survival. Therefore, interventions directed toward prevention of relapse and enhancing graft-versus-tumor response after RIC allo-HCT are in great demand. Reshef and colleagues recently examined the impact of T-cell subsets (CD3+, CD8+ and CD4+) on the clinical outcomes of 221 adult recipients of 7/8 to 8/8 HLA-matched sibling or adult unrelated donor RIC allo-HCT for hematological malignancies. Higher dose of CD8+ T-cell subset (≥ 0.72 x 108 cell dose/kg) predicted reduced rate of malignancy relapse and better DFS and OS after RIC allo-HCT without affecting the risk of graft-versus-host disease. In addition, donor age was inversely correlated with CD8+ T-cell dose, and OS was significantly better in patients with a younger unrelated donor (age < 50 years) with high CD8+ T-cell dose than in patients with an older (age ≥ 50 years) HLA-matched sibling donor or younger unrelated donor with low CD8+ T-cell dose. This is a very informative clinical observation emphasizing the importance of both preferential selection of younger donors with high baseline CD8+ T-cell proportion and large blood volume aphereses (>15 liter) for optimal CD8+ T-cell dose collection in order to improve the survival of patients undergoing 7/8- to 8/8-matched adult donor RIC allo-HCT. Since increasing numbers of alternative donor RIC transplantations are being performed for older patients in most recent years, this study also sets the stage to investigate the impact of CD8+ T-cell dose on clinical outcomes after RIC allo-HCT using umbilical cord blood or haploidentical donor types.
References:
Bejanyan N, et al. Biol Blood Marrow Transplant. 2015;doi:10.1016/j.bbmt.2014.11.007.
Schmid C, et al. Blood. 2012;doi:10.1182/blood-2011-08-375840.
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