Stem cell transplants can be effective for treating blood cancers, but treatments carry risks. Donor stem cells may be rejected leading to graft-versus-host disease and other complications can arise. New research conducted at Washington University suggests that complications can arise from rare genetic mutations in donors, which are not detected using standard sequencing techniques.
Stem cell transplants involve taking bone marrow from a donor and transplanting it into a patient after chemotherapy or radiation therapy has been administered to kill the cancer cells. Patients are then provided with immunosuppressive drugs.
The study found that rare genetic mutations in the donors are passed on to the patient and the conditions created through immunosuppression and cancer treatment create an environment where cells containing the mutations can proliferate.
The donor may not experience any symptoms of these genetic mutations and they may not be detectable using genome sequencing techniques, but they can still cause severe health problems in patients receiving the transplant, such as heart damage or graft-versus-host disease.
The Washington University study involved an analysis of samples taken from 25 patients with acute myeloid leukemia (AML) and their stem cell donors. The researchers developed a new technique for identifying rare mutations, called error-corrected sequencing. The next generation sequencing techniques now being used are able to detect a single mutation in 100 cells, but the new technique allowed the researchers to identify a mutation in 10,000 cells and also distinguish between real mutations and errors made during the sequencing process.
This allowed the researchers to identify mutations that are very rare. Using their new technique, the researchers found that even young donors that were healthy had harmful, rare genetic mutations. 44% of the donors had a mutation that was potentially harmful for the AML patients and they found that those mutations persisted over time and were even amplified in some cases after the transplant.
“There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didn’t have a way to identify them because they are so rare,” explained Todd E. Druley, MD, Ph.D., associate professor of pediatrics at Washington University and senior author of the study. “This study raises concerns that even young, healthy donors’ blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further.”
Young donors are usually sought for bone marrow transplants as they are less likely to have mutations that could cause complications, but the study shows that even young donors can have mutations that can cause problems for patients receiving the transplant.
“We didn’t expect this many young, healthy donors to have these types of mutations,” said Druley. “We also didn’t expect 100% of the harmful mutations to be engrafted into the recipients. That was striking.”
While the study size was small, the researchers found that 75% of patients who received at least one harmful mutation from the donor went on to develop chronic graft-versus-host disease. 50% of patients who did not receive a mutation developed graft-versus-host disease.
The researchers are now planning further studies into mutations passed over from donors and graft-versus-host disease, as the findings from their research were not statistically significant.
You can read more about the study in the paper – Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation – which was recently published in the journal Science Translational Medicine. DOI: 10.1126/scitranslmed.aax6249