Life can change heartbreakingly fast. Early last year, Dr. Felipe-Andres Ramirez-Weber was busy teaching developmental biology courses and running his lab at San Francisco State University. The 42-year-old had some lingering cold and flu symptoms — annoying remnants of the season, he thought. Then he got his first-ever gum infection. Antibiotics cleared that, but another began on its heels. Ramirez-Weber's doctor thought the string of illnesses warranted some blood work, which led to an unexpected midnight phone call from a local hospital a few days later.
"They said, 'There's something wrong with your blood work, and we need you to come to the emergency room right now,'" he said. "I was a little upset because I felt sick, but it's not like I needed to go to the emergency room."
His trek that night brought more blood tests and a frightening diagnosis: acute myelogenous leukemia, a fast-growing cancer of the blood and bone marrow. The next five months brought hospitalizations and rounds of chemotherapy to get the cancer in remission while a search began for a bone-marrow donor so Ramirez-Weber could have a transplant, his only chance at a lasting cure for his leukemia.
The first transplantation choice for someone with leukemia is always bone marrow from a sibling. However, only one patient in three or four has a sibling who is a match. The next option is the National Marrow Donor Program, but this avenue offers less hope for people of color because most of the donors in the registry are white and of Western-European descent. Ramirez-Weber is Latino, and he became one of 16,000 leukemia patients diagnosed each year who can't find a match.
Ramirez-Weber was exactly the kind of patient sought by Dr. Colleen Delaney.
Delaney, an oncologist and researcher in Dr. Irwin Bernstein's Clinical Research Division lab, offered Ramirez-Weber a tentative ray of hope. She recently opened a unique clinical trial using two units of cord blood, the stem-cell-rich blood remaining in the umbilical cord and placenta after childbirth. The ability of cord-blood stem cells to differentiate, or change, into other types of cells in the body holds significant promise for improving the treatment of health conditions besides cancer. However, cord-blood stem cells are not the same as embryonic stem cells, which have the potential to become life.
Two-unit cord-blood transplants are fairly common, but the stem cells in one of the units in Delaney's protocol were dramatically increased through a technique pioneered in the Bernstein Lab. Ramirez-Weber fit the protocol's criteria, and Delaney hoped he would become her first patient.
Cord blood has advantages as a stem-cell source: it is readily available, fewer viral infections are transmitted with it, and it is immunologically naÏve, so it doesn't require the extremely close tissue-type matching of bone-marrow transplants, which increases the donor pool and extends the option of transplant for those patients, especially people of color and those of mixed ethnicity, who cannot find a conventional donor.
But it has a major disadvantage. Each unit has fewer stem cells than contained in a unit of bone marrow or peripheral blood. Because of this low number, engraftment (the birth of a new immune system following transplantation) in adults from a cord-blood transplant takes about 25 days, compared to 15 for a bone-marrow transplant. Patients can die from infections while waiting for engraftment.
Five years ago, researchers in the Bernstein Lab found a way to jump-start cord-blood stem cells. They rapidly grow the cells on a protein called Delta, which activates a gene that keeps the cells from maturing into more specific cells.
"Other research centers are trying to expand these cells, and at best, they've increased the number of cells by about fourfold," Delaney said. "We increase ours by 150-fold."
Benefits outweighed risks
Being first is often advantageous, but it isn't an easy place to be in a clinical trial. Without other patients' outcomes upon which to base a decision, inaugural study participants are foot soldiers in uncharted territory. Fortunately, Ramirez-Weber's scientific background and his knowledge of the Center made the decision to participate in the trial a bit easier.
"Given my ethnicity, I knew a cord-blood transplant was my best option. After consulting with my doctors and colleagues, Fred Hutchinson was my first choice for the transplant," Ramirez-Weber said. "By reputation, I knew that the Center did impressive science and was one of the best places for the type of cancer I had."
"Still, deciding to be the first patient on this protocol was a very difficult decision for me. But in the end, the solid science behind the trial and the charismatic presence of Dr. Delaney really convinced me that the benefits outweighed the risks. I had a lot of confidence that it would help me."
Initially, Ramirez-Weber had trouble convincing his doctor of Delaney's preclinical success in expanding the cells. "Felipe's doctor told him that he must have heard wrong when Felipe explained our 150-fold expansion," Delaney said. "So the doctor called me and I said, 'No, he didn't hear wrong — that really is what we get.' That's when I realized that even I was taking these tremendous numbers for granted."
Ramirez-Weber and his wife left their Berkeley home for Seattle last June. About two weeks before the transplant, he started high-dose chemotherapy followed by total-body radiation while the cord-blood cells were increased in the laboratory.
Transplant birth day
On July 27, surrounded by Delaney and a hospital room full of friends and family, Ramirez-Weber had his transplant, the first with Delta-expanded stem cells anywhere in the world.
"If we had given him a conventional two-unit transplant that day, he would have received a dose of about 200,000 stem cells per kilogram of body weight. After we expanded them, he received a dose of 13 million stem cells per kilogram, so he had a huge boost," Delaney said.
That increase paid off. Ramirez-Weber's blood work showed white blood cells just four days after his transplant, and on the ninth day, he officially engrafted. He had the makings of a new blood system in almost half the time of a standard bone-marrow transplant.
"Dr. Delaney was very, very excited when she told me I had engrafted, and so was I," Ramirez-Weber said. "It was amazing news."
He had some typical post-transplant infections, but Ramirez-Weber said he's been relatively healthy since the procedure, and he's slowly gaining back weight and strength. "It's a long process of recovery, but so far it's been going really well," he said.
"It's great work," said Bernstein, head of the Center's Pediatric Oncology program and Delaney's mentor. "Colleen really took our basic-science findings and effectively translated them into the clinic — a true bench-to-bedside success story. And others — including lab members Carrie Stein, Barbara Varnum-Finney, Koshi Oishi and Mari Dallas — have spent many years doing the work that allowed Colleen to pick up the project."
Before Ramirez-Weber and his wife left Seattle, they toured the Bernstein Lab and the cell-processing facility and met the devoted team behind his cure. "I thought Felipe would be interested in seeing the lab, but I also wanted the people who have put years of effort into this project to meet him. They don't normally get to see the profound impact of their work," Delaney said.
"That was an amazing visit for me," Ramirez-Weber said. "It was very emotional for me to meet the people who labored on this protocol from the basic-science end. It was just great to be able to thank them for saving my life."
Delaney's second patient in the clinical trial also did astoundingly well. She engrafted quickly, too, and had no early post-transplant complications whatsoever. The patient was released from the hospital only 15 days after her transplant. "Right before she was discharged, she called me and said, 'Colleen, are you sure I got a transplant, are you sure I got the radiation, because I haven't had any problems!'" Delaney said.
"To my knowledge, these two patients are the first to have shown any clinical benefit from expanded cord-blood cells. No one else has decreased the time to engraftment at all. To show any benefit — let alone these tremendous results — is really quite a big deal."
Delaney expects enrollment for the first phase of her NHLBI-funded trial will take two to three years, and if the positive outcomes continue, she hopes to expand the protocol into a phase II trial. "I'm excited to take this to the national level," she said. "So far, we're hitting a home run on this, and if we can keep doing it, it will be great. I believe our expertise in cord-blood transplantation will bring people to the Center."
Procedure holds great potential
"There are lots of advantages to using cord blood for donors and patients. There is absolutely no risk to donor and essentially no donor attrition. If we can perfect the outcomes associated with cord-blood transplants, one can imagine certain future scenarios where cord blood becomes the preferred source of donor stem cells. There are a lot of patients, especially people of color, who come to the Center needing a transplant but they can't find a donor. The potential for this to help so many people is definitely there, so we've got lots to do."
"If this continues to work," Delaney said, "our long-term goal is to create a shared resource. We're developing a technology for the world to use."