As a hematologist-oncologist in Miami, Mikkael Sekeres always hopes his patients will find a perfect match for the bone marrow transplant they need to save their lives — but he doesn’t expect it. Most of his patients are Latino or African American, and rates of perfect matches are much lower for racial or ethnic minorities.
That gloomy picture could soon change. A study published Wednesday in the Journal of Clinical Oncology found that certain unmatched donors, or people whose bone marrow does not as closely resemble that of the patient’s, provided similar outcomes to matched donors so long as patients receive a key drug called cyclophosphamide to prevent dangerous complications. That suggests that patients who need a transplant might be able to safely consider both matched and some unmatched donors, vastly expanding the pool of potential acceptable donors for all patients, though particularly those of African, Latino, or Asian ancestry.
“It’s much harder to find a match for most of my patients. Looking to people who are donor unrelated and aren’t a perfect match for my patients has become the norm,” said Sekeres, who is the chief of hematology at Sylvester Cancer Center at the University of Miami and did not work on the study. “That’s why this study really resonated with me. The classic teaching is you want a perfect match as opposed to less than perfect. What this study suggests is, if you use the right drugs after transplant, it may not be as big of a deal.”
If so, up to roughly 84% of African American patients might have a potential donor in the national registry. Currently, less than 30% of African American patients have a potential match in the NMDP registry, previously called the National Marrow Donor Program.
Bone marrow transplants, also called hematopoietic cell or blood stem cell transplants, are essentially immune system transplants, and often represent a patient’s last chance for a cure for blood cancers like leukemia and lymphoma. Oncologists give chemotherapy first to put the cancer in remission, but the chemotherapy also does substantial damage to healthy bone marrow, where stem cells that give rise to blood and immune cells reside. The transplanted immune system would then replenish the lost stem cells as well as attack any remaining cancer in the patient.
The trouble is that the grafted immune system can also reject its new home, attacking healthy tissues in a potentially fatal complication known as graft versus host disease. Your native immune system avoids this by using a system of proteins called HLAs or human leukocyte antigens. Every cell carries these proteins like a security badge, identifying itself as part of your own body to patrolling immune cells. A matched donor would thus carry the same eight major HLA markers as the recipient — or be an eight of eight match — to make it more likely the transplanted immune system will settle into the new host without much fuss.
“For many years, it was known having a donor whose immune system is matched to yours conferred a better outcome. Back when I was a fellow, outcomes were dismal when patients got an unmatched donor,” said Brian Shaffer, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center and the lead author on the study.
Then, several years ago, scientists at Johns Hopkins University showed that cyclophosphamide could lower the risk of these complications for half-matched first-degree relative donors. Blood stem cells are resistant to this particular chemotherapy, but not so much immune cells like T and B cells that drive graft versus host disease. These immune cells are particularly vulnerable to the toxin if they’re activated and in the process of proliferating, Shaffer said.
That means when the transplanted immune system goes into the patient, some of these T and B cells will recognize they’re in the wrong body and begin lashing out against the recipient, but make themselves more vulnerable to cyclophosphamide in doing so. That means the drug can selectively delete the immune cells that are most likely to cause dangerous complications.
“Other T cells will remain quiet, because they’re happy with the host,” Shaffer said. “These angry T cells will go into cell division, and they’re more exposed to cyclophosphamide.”
Some of the first indications that this strategy would work to ease even unrelated and unmatched immune systems into patients came in 2021. A team of researchers saw no significant difference in the overall survival of about 80 patients who received either an unmatched or matched unrelated transplant after one year. This study expands those findings with data collected from approximately 10,000 patients treated for acute leukemia or myelodysplastic syndromes.
The study was possible partly because so many patients, particularly those with non-European ancestry, cannot find an 8/8 match in the registry. So, their only option is to go down to a 7/8 or lower mismatched donor. Some centers were already using cyclophosphamide to prevent graft versus host disease, though others use another drug called a calcineurin inhibitor. Shaffer and his colleagues collected data from 153 centers comparing patients who received either an 8/8 or 7/8 match and either cyclophosphamide or a calcineurin inhibitor.
“The major finding is that the patients who had post-transplant cyclophosphamide had no differences in survival or any other sort of key clinical outcome, freedom from graft versus host disease and other complications, from matched or mismatched donors,” Shaffer said. That wasn’t true for the patients who received calcineurin inhibitors. These patients also had worse survival, relapse occurrence, and graft versus host disease compared to those who received cyclophosphamide.
“I was pleased to read this article,” said Warren Fingrut, a transplant and cell therapy physician and MD Anderson Cancer Center who did not work on the study. “Allowing seven of eight mismatched unrelated donors will extend access to many more patients, especially those from racial, ethnic minority groups to receive transplantation.”
While the study was specifically on patients with acute leukemia or myelodysplastic syndromes, the findings are of “great interest for patients who have other hematologic malignancies and nonmalignant conditions who also receive transplants,” Fingrut said. Though, he added, it may still be important to replicate the work in other indications.
According to the analysis, broadening the pool of bone marrow donors to include 7/8 mismatched transplants increases the potential match rate for Asians and Hispanics from less than 50% to close to 90%. The potential match rate for African Americans rises to 84%. The potential match rate for white Americans also goes up from about 79% to 99%.
Those are enormous gains and would likely help substantially in reducing health disparities in these cancers, Fingrut said, though it wouldn’t solve all the disparities in transplant access. One problem is even if a potential donor exists in the registry for a patient, many of these donors cannot actually donate. That might be because their contact information changed and aren’t reachable, they have new health conditions that preclude them from donating, or they may no longer be interested.
“About half of donors are unavailable overall for confirmatory typing. When you zoom in on African ancestry, it’s less than one third that are available,” Fingrut said. “That’s not improving over time, and it’s not just due to the Covid-19 pandemic.”
This study opens an avenue to getting around that problem, Fingrut said. Transplant doctors could consider 7/8 unmatched donors alongside matched donors for patients who have worse chances of finding a match in the registry. “If you go after the few unrelated donors that never show up, and only then you switch to mismatched donors or alternatives like cord blood donors, it in fact impacts overall survival,” Fingrut said. “These patients cannot wait months and months for a donor that never materializes.”
Dropping down to a four, five, or six out of eight match would further increase the match rate to nearly 100% for all patients, although it’s still unclear if using more heavily mismatched donors would worsen outcomes. “Everyone is eagerly awaiting that data,” Fingrut said.
But there is also another way to improve the match rate without resorting to more heavily mismatched donors, he pointed out. More people could join the donor registry.