Discovered nearly 45 years ago in the volcanic soils of fabled Easter Island in the Pacific, a drug first thought of as an antifungal agent has found a new purpose by boosting the survival of leukemia patients after blood stem cell transplants.
In a clinical trial conducted by Fred Hutchinson Cancer Research Center, the addition of a third drug, sirolimus, to a standard two-drug regimen effectively cut in half the incidence of acute graft-vs.-host disease, or GVHD, a common and dangerous complication of these lifesaving procedures.
So convincing were the early results of the trial that the independent Data Safety and Monitoring Board, which advises such studies, halted it in July. The new combination using sirolimus saved lives, so it was considered unethical to withhold it any longer from the patients in the control arm of the trial who were taking only the standard two-drug therapy.
At the American Society of Hematology annual meeting in San Diego, Fred Hutch physician/researcher Dr. Brenda Sandmaier on Sunday presented the interim study results that led to the decision, which in turn has already changed how patients at Fred Hutch’s clinical care partner, Seattle Cancer Care Alliance, and other participating hospitals are being treated.
“I do a lot of studies. It is not often you get to see an exciting result like this one,” said Sandmaier in an interview prior to her trip to the San Diego conference.
Ever since Fred Hutch scientists developed bone marrow transplants to cure blood cancers more than 40 years ago, GVHD has proven to be the most stubborn of side effects. In a transplant, the leukemia patient’s cancerous immune system — its army of infection-fighting white blood cells — is essentially swapped for that of a healthy donor. GVHD is caused when the donated immune cells (the graft) begin to attack the healthy tissues of the patient (the host). While years of careful adjustment have significantly trimmed the risk of GVHD, it still affects about half of leukemia patients who receive blood stem cells or marrow from a donor. The symptoms of rashes, blisters, liver damage and nausea are often temporary, but they can also become chronic, debilitating and deadly.
The key findings Sandmaier described from the trial were that patients taking the triple-drug combination containing sirolimus not only had a lower rate of acute GVHD, but scored substantially better on survival measures:
- Just 25 percent of those taking sirolimus as a third drug had moderate to severe GVHD, compared to 53 percent of those taking the two-drug combination.
- Rates of worrisome stage 3 or stage 4 GVHD fell fourfold, to 2 percent from 8 percent, in the triple-combo group.
- Deaths unrelated to leukemia relapse (and therefore most likely a result of GVHD) after one year fell to 5 percent from 15 percent.
- Overall survival one year after transplant rose to 85 percent from 72 percent in the sirolimus group.
According to Dr. Rainer Storb, a founding member of Fred Hutch and one of the early pioneers of bone-marrow transplants in the 1970s, the last time a bone marrow transplant clinical trial was halted for a good reason like this was in 1985. That’s when his own study found that combining two immune suppressants, methotrexate and cyclosporine, worked better lowering the risk of GVHD than either drug alone.
Sirolimus is the name for a drug formerly known as rapamycin. That moniker is derived from Rapa Nui, the Polynesian name for the mysterious Easter Island. One of the most isolated places on Earth, Rapa Nui rises alone in the Pacific Ocean, about 2,000 miles west of Chile. This is the Easter Island famous for its giant moai statues: 887 elongated human heads with straight noses and pursed lips, monoliths carved of stone in a bygone era and set in the ground, staring cryptically out to sea.
A multipurpose drug
Researchers half a century ago scraped out of the Rapa Nui soil a bacterium, Streptomyces hygroscopicus, which attracted attention because it left a circle of dead fungi around it in a petri dish. Scientists then discovered that the substance secreted by the bacteria, which was dubbed rapamycin, not only killed fungi but reduced the proliferation of human immune cells. Eventually it was approved as an immunosuppressant to prevent rejection of transplanted kidneys. Now sold as sirolimus, it is also used today to coat arterial stents, and it is the subject of research for its potential as an anti-aging drug.
Sandmaier was intrigued by preclinical studies that confirmed sirolimus’ value in preventing GVHD. “A lot of progress in GVHD is incremental,” she said. “You can fix GVHD with strong immune suppression, but it comes with a price: it can raise the risk of relapse.” In searching for ways to tinker with that delicate balance, research pointed to adding sirolimus to the gold standard in Fred Hutch transplantation practice since Storb adopted it in 1997: a two-drug combination of the immune suppressant cyclosporine and mycophenolic acid, or MMF, another anti-rejection drug.
Everyone who participated in the shortened clinical trial received a gentler type of transplant designed for older leukemia patients thought to be too frail for the conditioning regimen used in the majority of transplants. Hardier patients first receive very high doses of chemotherapy and radiation that essentially obliterate their immune system, leaving a tabula rasa for the donor’s cells. The trial patients received a lighter dose of chemotherapy that still leaves some of the old immune system intact. Developed by Storb and called a mini-transplant, this strategy is aimed at older patients. The median age of study participants was 62; the oldest, 79. Future studies will explore the use of the triple-drug combo to prevent GVHD in younger patients, but mini-transplants actually account for about 40 percent of blood cancer transplant procedures performed today at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner.
The results of the sirolimus trial have been particularly gratifying to Storb. A native of Essen, Germany, he immigrated to Seattle from Paris in 1965 to research bone marrow transplantation. His career spans from the days when transplants were desperation measures with low odds of success. He has worked closely with Sandmaier since she was a Fred Hutch fellow in the late 1980s.
“To be honest, I thought we might see something good,” said Storb, who still rows across Lake Union to run his lab at Fred Hutch at the age of 81. “But I wasn’t prepared to see such an impressive effect: Non-relapse mortality down to 5 percent! … That’s why I came to the United States. I wanted to improve clinical outcomes.”
To read more about Fred Hutch at ASH 2016, visit our page here.
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health, and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at srussell@fredhutch.org.
