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Genetic variants may improve bone marrow transplant donor selection, outcomes in ALL
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Certain genetic variations in the DNA of patients with acute lymphoblastic leukemia who underwent unrelated donor bone marrow transplant appeared associated with poor outcomes, according to study results.
“We believe that these findings will lead to a better understanding of the biology of this disease,” Theresa Hahn, PhD, of the department of medicine at Roswell Park Cancer Institute, said in a press release. “Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”
Disease relapse is the most common cause of early mortality after human leukocyte antigen (HLA)–matched unrelated donor bone marrow transplant.
Hahn and colleagues previously performed a genome-wide association study — known as DISCOVeRY-BMT — that included 3,532 patients treated for ALL, acute myeloid leukemia or myelodysplastic syndrome.
In their latest study, Hahn and colleagues assessed outcomes among the 577 patients with ALL.
The researchers identified three linked variants on chromosome 8 — rs79853417, rs6990973 and rs145488394 — and a single nucleotide polymorphism — rs60640657 — on chromosome 2 that appeared significantly associated with death due to ALL. A region on chromosome 3 that contained MLH1 also was significantly associated with PFS.
HemOnc Today spoke with Hahn about the study results, their clinical implications and the directions that future research may take.
Question: What prompted you and your co lleagues to conduct this study?
Answer: Outcomes after unrelated donor transplant have significantly improved during the past 20 years. Yet, there is still a 40% mortality rate 1 year after transplant. Although we have made many improvements in the areas of patient and donor selection, we want to address that high mortality rate. Therefore, we sought to investigate the underlying genetics of recipients and their donors to find out if there is a genetic risk that influences mortality among these patients.
Q: How did you conduct the study?
A: The Center for International Blood and Marrow Transplant Research has a repository of biospecimens, as well as clinical data. All unrelated donor transplants in the United States are required to be reported to this resource. Patients and donors can provide their consent to allow their samples and data to be used in research. The entire population of our study included patients with AML, ALL and myelodysplastic syndrome who underwent unrelated donor transplant between 2000 and 2011 at one of more than 150 U.S. centers. In the most recent study, we looked at inherited genetic variants and risk for leukemia relapse among patients with ALL to see if patients with variations in their DNA were more likely to relapse within 1 year of transplant. Our final analysis included 577 patients with ALL and their matched unrelated donors. We performed a genome-wide association study that genotyped patients’ genetic code at more than 700,000 different markers within the genome. Based upon what we know about the genetic code, we were able to impute about 9 million single-nucleotide polymorphisms.
Q: What did you find?
A: Two regions on different chromosomes of unrelated donors had several variants associated with ALL-related death among recipients. This is where the donors’ genome is influencing the patients’ outcomes. This means we could potentially select different donors based upon their genotype in addition to their HLA, which is how they are matched and selected now. Also, among patients with leukemia, we identified three chromosomes associated with increased risk for relapse. One of them — MLH-1 — is associated with DNA mismatch repair, a natural process through which errors in DNA replication can be repaired. Understanding how these regions in recipients are related to outcomes can give us more information about leukemia biology, and it may help us understand how and why ALL relapses after transplant.
Q: What are the potential clinical implications of these findings?
A: After further evaluation and testing of our findings, we potentially could include some of these loci as additional tests to match and select donors. If we can better understand disease biology, there may be better treatments or additional treatment that we can give to patients that can reduce their risk for relapse.
Q: What are the next steps in research?
A: We are trying to renew the funding that supports our research so we can validate our work. We are pursuing genotyping in other cohorts via collaborators at other institutions.
Q: Is there anything else that you would like to mention?
A: The broader implications of the data are in trying to improve outcomes after transplant to reduce mortality. In science, small steps accumulate into a large leap. This is one of many studies that need to be conducted to advance the matching and selection of unrelated donors and patients. Many more studies need to be conducted before we incorporate this information into the donor selection process. – by Jennifer Southall
Reference:
Hahn T, et al. Abstract S-BestAb. Presented at: BMT Tandem Meetings; Feb. 22-26, 2017; Orlando, Florida.
For more information:
Theresa Hahn, PhD, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: theresa.hahn@roswellpark.org.
Disclosure: Hahn reports no relevant financial disclosures.