Twenty Thousand Tomorrows

Growing up in Mexico, young Rodrigo Nunez had no idea he would one day help make medical history.

He was 17 when he crossed into the U.S. to do farm work, mostly picking grapes. Separated from his family and speaking no English, Nunez nevertheless fared well - until one day in 1977 when he fainted.

Rodrigo Nunez

More symptoms followed. Bruises. Nosebleeds. Intense fatigue. Blood transfusions helped, but only for a little while. Tests revealed the cause: aplastic anemia, a rare but serious condition in which the bone marrow stops producing blood cells. Alone in the hospital, he got the news through a translator.

"I felt really scared," he recalled.

It was a different story for Clarice Moore, a retired schoolteacher and principal from Temecula, California. Back in 2019, Moore, already in her eighth decade, was a remarkably fit gym rat ("four miles on the treadmill, five times a week" she said proudly). Then, she suddenly collapsed and fell off her machine, not just once but several times, the worst incident landing her in the hospital for a week.

It took some time for doctors to figure out what was wrong, and the news was not good. Moore had a form of leukemia called myelodysplastic syndrome (MDS) in which the bone marrow produces blood cells that don't mature.

She began chemotherapy, which helped for a short time. When the chemo stopped working, Moore was left with just one option. But her local oncologist wouldn't hear of it. "He said I was too old," she recalled.

Hope Is the Answer

Ultimately, though separated by decades, both Nunez and Moore found their way to City of Hope, where doctors saved their lives with bone marrow transplants. Nunez was among the first to undergo the then-experimental procedure and, 47 years later, is one of the longest-surviving transplant patients. Moore, who received her transplant in 2023 at the age of 80, is possibly the oldest City of Hope patient to do so. Together, they bookend an amazing era that is still unfolding: this March, City of Hope performed its 20,000th bone marrow/stem cell transplant.

The contrast between "then" and "now" is nothing short of staggering. Stephen J. Forman, M.D., remembers.

"We knew a lot less then," recalled Dr. Forman, director of the Hematologic Malignancies Research Institute and a professor in the Department of Hematology & Hematopoietic Cell Transplantation. He joined City of Hope in 1978, two years after the transplant program began. "In that first year, we performed six transplants for patients with advanced leukemia," he said. "We now perform over 750 per year, helping to cure people suffering from the full spectrum of hematologic malignancies."

Stephen J. Forman, M.D.

In those early days, oncologists believed their only chance was to match the patient with a bone marrow donor from his or her own family - preferably a sibling - who displayed an identical array of human leukocyte antigen (HLA) proteins, key markers in the immune system. This kept the potential donor base painfully low. If none of your relatives matched, you were out of luck and likely out of time.

Even when a match could be found, there was no guarantee of success. Young Rodrigo Nunez was told that even with a perfectly matched donor, there was a 50% chance he wouldn't survive. The transplant process was grueling - it required intense chemotherapy to destroy the diseased marrow - and it was fraught with possible complications and side effects, most notably graft versus host disease (GVHD), in which the newly transplanted cells attack the patient's tissues.

Nunez didn't worry about the odds. He wanted to live.

"Back then," he remembered, "if you had told me I had just a 1% chance, I would have said, 'OK, so I'll be the first one.' I was scared, but also determined to see my family again."

Decades of painstaking research and clinical trials changed everything.

"Today," said Dr. Forman, "we have successfully crossed the HLA barrier so that cells from unrelated donors can be used for the benefit of patients. Advances now enable us to also use half-matched family members as donors." (This is also referred to as "haploidentical.")

Broadening the Donor Base

In fact, what was then impossible is now nearly routine - and even has its own department.

"What makes me happy," said Monzr Al Malki, M.D., director of the Haploidentical Transplant Program and the Unrelated Donor BMT Program, "is no longer having to say to a patient, 'Sorry, we don't have a donor for you.'"

Crossing that HLA barrier has brought down racial barriers as well. Most people with European ancestry have a better than 50-50 chance of finding a match. The odds drop to 3 in 10 for people of Hispanic origin and are even lower for African Americans. With exact matches no longer needed, more people of color can benefit from the transplant procedure.

Monzr Al Malki, M.D.

"At City of Hope," continued Dr. Al Malki, "we have performed over 600 haploidentical transplants as well as 400 mismatched unrelated donor transplants, and the outcomes have been comparable to traditional transplants. This approach has opened new doors for patients from diverse backgrounds who might otherwise struggle to find a fully matched donor."

In 1976, it was unheard of to even consider subjecting anyone older than 30 to the rigors of a transplant. But by the time Clarice Moore was diagnosed, doctors had learned to refine the process and make it far less harsh. The reduced intensity, or "mini" transplant, relies less on heavy doses of chemotherapy and radiation and more on the anti-tumor effects of the graft itself. City of Hope also pioneered the use of CAR T cells - re-engineered immune cells - as a way to prepare the body for transplant when heavy chemotherapy may not be appropriate.

Sitting in Dr. Al Malki's office, the 80-year-old Moore rejoiced when he told her, "You're not too old."

"It was like I had found a miracle," she said.

Her miracle stretched across the globe. While Nunez had to hope for a matching relative (two of his six siblings in Mexico matched), doctors found an unrelated but appropriate donor for Moore in Germany, a 20-year-old woman whom they chose over Moore's own 67-year-old sister because, in this new age of haplo and unrelated donors, younger is better.

Other advances at City of Hope have made the post-transplant recovery period much easier. In Nunez's time, prednisone and cyclosporine were the drugs of choice for GVHD, and he took them for five years. He also required immunosuppressant drugs - necessary until the body adapts to the grafted cells - for an equal period. Newer and better treatments, such as cyclophosphamide, have lessened GVHD's severity, and the latest crop of immunosuppressants did their job for Moore in just one year.

Clarice Moore with her husband Ed.

City of Hope even developed a vaccine, called Triplex, that combats cytomegalovirus (CMV), a potentially deadly post-transplant complication. And in 2019, a stem cell transplant involving a donor with a rare genetic mutation resistant to most HIV strains cured a man in his sixties not only of his leukemia but also erased his HIV - just the fifth such case ever documented.

"I feel so lucky," said Moore, reflecting on her case and all the progress that preceded it, "to be living in a time when this is possible, and I'm grateful to all before me who paved the way."

So grateful was Nunez that he went to school, became a registered nurse and joined the City of Hope staff, working with many of the people who had treated him. He's been there 37 years. Does he call himself a pioneer? "Sure!" he said. "But all I really did was be in the right place with the right people."

One of those people, Dr. Forman - he's Nunez's doctor - wants to someday be able "to transplant anybody to anybody," and though it's been a remarkable half-century, there's much more to do.

Looking toward the next 20,000 procedures, "our largest obstacle," he explained, "is relapse of the original disease. Leukemia cells, for example, have a way of getting around everything we do. So we have to improve our regimens and aim for zero recurrence.

There is much reason for hope, as scientists remain focused on tackling every remaining obstacle. "Patients need to know that we know what we're doing," he continued. "No resting on laurels here. No pats on the back. We go right back to work the next day."

Main image: Stem cells.