Stem cell transplantation does not increase risk for clonal hematopoiesis
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Key takeaways:
- Clonal hematopoiesis occurred at similar rates among donors and recipients over decades.
- Findings suggest older individuals may be more suitable donors for stem cell transplantation than previously thought.
Clonal hematopoiesis did not occur significantly more often among patients who received hematopoietic stem cell transplantation than their donors, according to findings of a correlative laboratory study.
The results support use of older donors when younger donors are not available, Masumi Ueda Oshima, MD, MA, associate professor in the clinical research division at Fred Hutch Cancer Center, told Healio.
“Our findings highlight how wonderful our blood-forming system is, and that it doesn’t go awry even after many decades of transplanted donor cells making blood cells every day,” Ueda Oshima said. “It provides reassurance that these stem cells transplanted from the donor can carry on normal hematopoiesis for many, many years, and that the DNA doesn’t change dramatically as a result of the transplant process.”
Background and methods
Clonal hematopoiesis most commonly occurs among adults aged at least 70 years. Prior studies have showed between 10% to 20% of that population undergoes DNA changes, according to study background.
Most of those mutations are “benign,” but clonal hematopoiesis has been linked to hematologic cancers, cardiovascular disease and overall mortality, Ueda Oshima said.
Additionally, other researchers found transplant recipients who got clonal hematopoiesis from donors had a higher risk for graft-versus-host disease, she added.
Individuals who undergo HSCT receive a small number of donor stem cells to rebuild their hematopoietic system.
“[The concern has been] that with more replication going on, there would be more clonal hematopoiesis happening in the recipient, and over time this would make the donor at higher risk for blood cancers,” Ueda Oshima said.
Ueda Oshima and colleagues had a unique opportunity to investigate this theory due to Fred Hutch’s extensive follow-up of transplant recipients dating back to the 1970s, when Fred Hutch researchers were working to establish HSCT as a life-saving therapy.
Researchers evaluated contemporary blood samples from 16 donor-recipient pairs (median time since HSCT, 33.8 years; range, 6.6-45.7). Recipients received HSCT between 1971 and 2010 at Fred Hutch.
The cohort included “the longest surviving [recipients of HSCT] in the world,” Ueda Oshima and colleagues wrote.
Mutation frequency among donors and recipients served as the primary endpoint.
Results and next steps
Researchers observed clonal hematopoiesis in all 16 donor samples, which included individuals aged 12 years to 84 years.
Older donors had higher rates of mutation.
Investigators had donor samples from the time of transplant in 11 of the 16 donor-recipient pairs analyzed.
Analysis showed no significant difference in mutation rate in genes “recurrently mutated in myeloid malignancies” (2% per year in donors vs. 2.6% per year in recipients), they wrote.
Only 5.6% of 393 shared variants between pairs expanded at least 10-fold in the recipient.
“We expected to see more mutations and more frequent mutations in the recipient — and to our surprise, that’s not what we found,” Ueda Oshima said.
Researchers acknowledged study limitations, including the small sample size and the inherent selection bias in a cohort consisting of long-term survivors.
Future research could examine if multiple mutations occur in the same cell, they wrote.
Ueda Oshima also wants to investigate how clonal hematopoiesis changes over time.
“We now have more gene therapies available for treatment of things like thalassemia and sickle cell disease,” she said. “In that setting, we use the patient’s own cells, but it’s the same process of taking out stem cells and restarting the blood system with a small number of cells that then have to divide for decades. I think this same study could be done in those settings.”
‘A lot more to understand’
NMDP — formerly Be The Match & National Marrow Donor Program — recruits individuals aged 40 years or younger to be donors, Ueda Oshima said.
She does not expect that to change based on these results.
“There are probably other biological reasons for that,” Ueda Oshima said. “There are advantages to using younger donors.”
However, these findings do suggest that using healthy, older donors, such as those for haploidentical transplants using a parent as a donor, could be done without added risk for clonal hematopoiesis.
“Our data does provide reassurance that we don’t have to worry about mutations in a healthy donor putting the recipient at higher risk for donor-derived malignancies,” Ueda Oshima said.
“We don’t understand the complete picture of how blood cancers develop because these mutations are happening in genes that are associated with myelodysplastic syndrome and acute myeloid leukemia, and they can exist throughout one’s lifespan and not cause any issues,” she added. “I think it shows us that we have a lot more to understand about how normal blood cells become cancerous.”
For more information:
Masumi Ueda Oshima, MD, MA, can be reached at mueda@fredhutch.org.
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