In the fall of 2021, Gabriel Arias felt like his body was “rotting from the inside.” He was diagnosed with acute myeloid leukemia. This is a type of blood cancer, and it was so aggressive that the doctors admitted her to the hospital on the day of the biopsy. In cases like his, the ideal treatment is a transplant. Arias’ cancer-prone blood cells had to be destroyed and replaced with healthy blood cells taken from bone marrow or the blood of a biologically matched donor. Fortunately, doctors found a match for him in the volunteer donor registry – a man living in Poland. Unfortunately, Arias’ worldwide singles matches are no longer available for donation.
In the past, the road to transplantation might have ended here, but medical advances have dramatically expanded the pool of donors for patients like Arias. With the right medicine, Arias could receive a partially matched graft from his brother or, as he ultimately chose, a stranger who shares only eight of the 10 markers used in the bone. You can also participate in a clinical trial in which someone becomes a donor. -Bone marrow transplantation. Under this relaxed criteria, Arias’ registry matches increased from her one match to her more than 200 matches. “This is truly a game changer,” says Steve Devine, chief medical officer at NMDP, the nonprofit organization that runs the donor registry. Today, the struggle to find a compatible donor is almost a thing of the past.
The drug that powers this breakthrough is actually very old. Cyclophosphamide was first developed for chemotherapy in the 1950s. 50 years later, Started by researchers at Johns Hopkins University It is used to prevent a common and sometimes fatal complication of bone marrow transplants called graft-versus-host disease, in which the donor’s white blood cells, which form the recipient’s new immune system, attack the rest of the body as foreign. We are researching whether it can be reused. . The greater the mismatch between donor and recipient, the more likely this is to occur. Cyclophosphamide worked surprisingly well against graft-versus-host disease. The drug reduced the incidence of acute and serious complications by more than 80%.
Cyclophosphamide has made bone marrow transplants available to more patients than ever before, with more than 7,000 people receiving bone marrow transplants last year, according to the NMDP. (Bone marrow transplantation Although “” is still used as an umbrella term, many of these procedures now use cells collected from blood rather than bone marrow and can be performed without surgery. Both versions are also more accurately known as hematopoietic transplants or blood stem cell transplants. ) The field essentially overcomes the problem of donor matching, which is a major barrier to transplantation, said Johns Hopkins University oncologist Ephraim Fuchs. Fuchs could not remember the last time a patient was unable to receive a blood stem cell transplant because a donor could not be found.
It was not clear whether cyclophosphamide would be as effective. “I’m just going to come clean,” Divine told me. “Back in 2003 and his 2005, we thought this was crazy.” The drug, derived from a relative of mustard gas, is known to be highly toxic to various blood cells. . In fact, doctors have long used it to kill diseased bone marrow in patients before transplants. Why would anyone want to administer such a drug after a transplant when new donor cells were still precious and scarce? It defied a certain logic.
But in the 1960s, researchers realized that administering high doses of cyclophosphamide after transplantation might prevent graft-versus-host disease in mice, even if they didn’t know why. was. Over the next several decades, scientists working in the lab learned that cyclophosphamide did not carpet bomb the blood. In fact, it preserves the most important stem cells for a successful transplant. (Blood stem cells differentiate into all the types of red and white blood cells a patient needs.) It is still unclear why cyclophosphamide works so well against graft-versus-host disease, but the drug Also, selectively kill White blood cells are active during illness, but spare them It is what calms the immune system.
By the late 1990s, doctors clearly recognized the need to expand the search for donors. Bone marrow transplants are most successful when donor and recipient share the same markers. HLA, this is a protein tag that our cells use to distinguish between self and non-self. We inherit her HLA markers from our parents, so the chance that a sibling will be an exact match is about 1 in 4. However, as families became smaller in the 20th century, siblings became less likely to match. Donor registries such as the NMDP, although imperfect, were created to fill the gap.
Doctors soon began to coalesce around the idea of taking advantage of just a family. Haploidentical or half-identicalThat is, they shared at least 5 out of 10 HLA markers. Every child is half like its parent, and every parent is half like its child. He also has a 50% chance of half-matching siblings. But when doctors first tried these transplants, “the results were terrible,” said Leo Ruznick, a medical oncologist at Johns Hopkins University. Patients suffered from frighteningly high rates of graft-versus-host disease, and more than half died within three years.
Based on their lab results, Ruznik, Fuchs, and other colleagues at Johns Hopkins wondered if post-transplant cyclophosphamide might help. The drug company that made it wasn’t interested in funding any research because “it was an old and very cheap drug,” Rzunik said. However, with a government grant, the research team was able to demonstrate that cyclophosphamide could be obtained in a graft-to-graft ratio.disease As low as its corresponding sibling port. By the late 2000s, transplants in half-same-sex families had become routine.
Still, not all patients have siblings, parents, or children who can donate. Doctors began to wonder if cyclophosphamide might also be effective in unrelated donors. If he only needs to match 8 out of 10 markers, almost everyone will find a donor, including multiple donors. This was especially important for patients of mixed ancestry and non-European descent, where finding unrelated donors was difficult. This is because people from such backgrounds make up a lower proportion of registered donors and may carry more diverse HLA markers. two-thirds of white people Although it is possible to find an exact match registry donor, that number drops to 23 percent for Black Americans and 41 percent for Asians or Pacific Islanders.
Amelia Johnson, who is half Indian and half Black, was one of the first children to receive a transplant from a mismatched related donor in a 2022 clinical trial. Her mother, Salome Sukdiopersad, remembers being told: A bone marrow donor can help increase your chances. ” When that still did not yield an ideal match, Ms. Sukhdiopersad prepared to donate her half as a match to her daughter. But then Amelia was offered a place in a clinical trial, and they decided to take it. Transplants with mismatched unrelated donors have already been tried in adults, which Arias did, and offered other potential benefits as well. For example, younger donors have younger cells. significantly improved than the old one. Amelia eventually developed graft-versus-host disease. Cyclophosphamide reduces the risk, but does not eliminate it. Still, her mother pointed out that a transplant was necessary to save her life, and that regardless of the type of donor, some risk is inevitable. Amelia’s friend underwent a graft-versus-host transplant, even with a perfectly matched donor. Her doctors were able to treat Amelia’s complications, and she returned to school last August.The pediatric clinical trial she participated in was Ongoing.
In adults, where more data Despite the availability of drugs, doctors are already accepting mismatched and unrelated donors. Between this family and a semi-identical family, patients who may once have had no donor now find themselves with multiple possibilities. Doctors will also have more choice. For example, you can select the youngest donor or select donors according to characteristics such as blood type. The larger pool of donors also prevents situations like Arias, where matched donors who registered years ago are no longer available, which occurs with some regularity. Cyclophosphamide is now also routinely used in matched transplants to further reduce the risk of graft-versus-host disease.
Arias’ unmatched unrelated donor at trial was an anonymous 22-year-old man living somewhere in the United States. When Arias and I spoke last month, it had been almost exactly two years since his transplant. He doesn’t have cancer. He and his wife just had a baby girl. None of this would likely have been possible without transplants, donors, and cleverly repurposed 70-year-old drugs.
