Dr. Fred Appelbaum was a medical student in 1970 when he stumbled upon Dr. E. Donnall Thomas’ initial description of bone-marrow transplantation in a medical journal and was transfixed.
“I thought it was so cool that this was even possible,” said Appelbaum, now deputy director and executive vice president of Fred Hutchinson Cancer Research Center. In 1978, he leapt at the chance to work alongside Thomas at Fred Hutch, helping to refine the pioneering technique that transformed leukemia and related cancers, once thought incurable, into highly treatable diseases.
Today more than 1 million people around the globe have received blood stem cell transplants to treat dozens of different diseases, and researchers at Fred Hutch continue to build on that work to find innovative new treatments. Transplants are one of the most significant advances in the history of cancer treatment, which is chronicled in the Pulitzer Prize-winning book “The Emperor of All Maladies: A Biography of Cancer” by Dr. Siddhartha Mukherjee. The book has been made into the six-hour documentary, “Cancer,” by Ken Burns and Barak Goodman and will air on PBS Monday, Tuesday and Wednesday.
Recently, Appelbaum sat down to talk about 40 years of transplants at Fred Hutch, from the early, heart-wrenching challenges to the latest innovations in immunotherapy, which harnesses the body’s own immune system to fight cancer.
FRED HUTCH: You’ve described the early days of transplantation as both incredibly difficult and incredibly exhilarating. Can you tell me about that time?
DR. FRED APPELBAUM: In the early- to mid-1970s, the very first patients being transplanted were patients whose life expectancy was measured in weeks to months. These end-stage patients were already very sick, they had very advanced leukemia, and so the cure rates were very low, in the range of 15 percent. That meant that eight or nine out of 10 patients would not be cured. So time and again you’d have patients come in with hopes that they could be saved, and their family hoped that they could be saved, and unfortunately the toxicity of the transplant caused them to die or the disease came back. That was really, really hard. It was hard on the nurses. It was hard on the docs. It was obviously horribly difficult for the families.
But we had some patients who went into remission – there was no leukemia there. And they came back [to the Hutch] in six months, they came back in a year, and they came back at two years. Oh my God, this patient was really cured. That was incredibly exhilarating. They’d been brought back literally from the jaws of death.
FRED HUTCH: How did you stay optimistic when so many patients didn’t survive?
APPELBAUM: It was hard because you failed so many times in a row, but the successes just pumped you up and kept you going. And of course Don Thomas was just a giant of a man in both his personality and his vision, and having a leader like that was absolutely instrumental. If Don didn’t have that kind of presence, I think it might not have happened. There’s a reason he got the Nobel Prize. He deserved it.
FRED HUTCH: You’ve talked before about how advances in nausea control, infection control and pain control have improved outcomes.
APPELBAUM: These things are amazingly important. You might think of an antiemetic – a medicine that keeps you from vomiting – as trivial. Nobody likes throwing up, but it’s more than that. The drugs we were using were so nauseating and the vomiting was so severe that people would aspirate some of the vomitus and bring it back into their lungs, which would set them up for pneumonias. Just a thing that seems a minor advance really made a huge difference in the ability of people to tolerate the transplant procedure.
And it wasn’t just that. It was also [Dr. Robert] Hickman's [a founding member of the Hutch transplant team] ability to figure out a way to place catheters so you could give intravenous alimentation [nutrition] throughout the procedure. People would lose so much weight until Bob figured out a way to allow us to give those fluids through a central vein. People would lose 10 percent, 15 percent of their body mass during this procedure. With Bob’s advance, they wouldn’t.
You have better pain control so people could get out of bed, be up and around and exercise throughout the procedure. All these things added up to much better supportive care that allowed people to get through this very difficult procedure.
FRED HUTCH: And infection control?
When we started, I remember going on rounds and seeing a patient who was otherwise looking fine, listening to their lungs and hearing a few crackles in their lung. It would be CMV [cytomegalovirus, a type of herpesvirus that can be fatal in people with compromised immune systems]. And that patient was almost certainly going to die. They went from healthy to dead in a matter of weeks.
Then we developed ways to protect against CMV by giving people blood that didn’t [test positive] for CMV. Just by changing transfusion policies we were able to save patients from dying of CMV. Then we developed [anti-viral medication] to treat them. Then we started giving it prophylactically. Those kinds of things happened time and again to boost our cure rates in transplantation.
FRED HUTCH: What has changed in terms of how you screen stem cell donors?
APPELBAUM: Before 1980, the only people who could donate were essentially brothers and sisters who matched. An occasional father or mother or child was also able to be used. We weren’t doing any unrelated transplants. Only about a third of the population has a matched sibling. So for two-thirds of patients, we couldn’t even do a transplant because we didn’t have a donor.
Then we did the first matched unrelated transplant [for a patient with leukemia] in the late 1970s. We showed that that could be done, and that opened up a whole new world of donors. We started to develop these large unrelated donor banks. Today there are over 21 million individuals worldwide who have been HLA-typed [human leukocyte antigens used for determining a match] to serve as unrelated donors.
FRED HUTCH: Tell me about the first unrelated transplant.
APPELBAUM: That was an incredible story. A 10-year-old girl, Laura Graves, had acute lymphocytic leukemia and had already failed first-line chemotherapy. Her dad was [Dr. Robert] Graves [from Fort Collins, Colorado.] Bob had done enough reading that he knew that Laura’s HLA type was a common one. There are lots of differences in HLA types among humans – some are very rare, some are more common. He came here and said, “You know, I’ll bet you could find a donor for my daughter.” [There were no matches within the family.]
We hadn’t done unrelated donor transplants, but we had done lots of platelet transfusions. We kept the records for our platelet donors. Our files at the time were actual files – they were in a 3-by-5 file box, like where you have your recipes, and lo and behold, one of our technicians matched Laura Graves. So we then talked to the Institutional Review Board, and everyone said this is not unreasonable and to go ahead. We did the transplant. Laura went into complete remission and did very well for about two years. Unfortunately, her leukemia came back, and she did eventually die. But the transplant itself, the nuts and bolts of the transplant, actually went very, very well.
Bob Graves realized that HLA typing is so variable that you’d need a really large registry if you’re going to make this more generally available. So Bob developed the Laura Graves Foundation to help support development of such a registry. And eventually, Bob Graves and Don Thomas met Admiral E.R. [Elmo] Zumwalt Jr., whose son came here for a transplant. Elmo helped get funding for the national marrow donor program [now called Be The Match] that provides all these unrelated donors.
FRED HUTCH: Can you walk me through what a transplant in, say, 1980 would be like, and what it would be like today?
APPELBAUM: In 1980 or 1981, patients would get intensive chemo-radiotherapy. They would be so sick from the drugs that we would give them sedatives so they weren’t consistently throwing up. They would be not quite comatose, but they would be sleeping through the day and night in bed because we’d be trying to keep them from being dehydrated from nausea and vomiting. Even so, when they’d wake up, they’d roll over to throw up. This would go on for several days while they’re getting their chemo-radiotherapy. Finally the stem cells would be brought in from the donor, usually bone marrow at that time, and the bone marrow would be infused intravenously. From the time of the transplant, they would have very low blood counts that would last for, on average, about three weeks, and they would have to be on high doses of antibiotics and getting platelets and getting red-cell transfusions during that entire three-week period, and we would be monitoring them with our fingers crossed that they didn’t develop either pneumocystis or CMV infection. And finally after three or four weeks, their blood counts would start to come up, and after a month of being near death’s door, they’d start to feel a little better. At 28 to 35 days, we might think about discharging them from the hospital. It was a harrowing period of time.
We’ve learned an awful lot in the interim. Now, the chemotherapy, while still very intense, doesn’t have as many side effects as the chemotherapy/radiation therapy we gave back then. Now, with antiemetics, many patients have no nausea or vomiting. They would be eating during that period. If they were hospitalized, they would be doing their laps around the ward every day. They would be on exercise bikes. It’s a world of difference from what it was.
If we were doing an unrelated transplant, we would probably be using, instead of bone marrow, peripheral blood as the source of stem cells. During the post-transplant period, the patients’ blood counts would be down for 10 days instead of three weeks. Their counts would be coming back up much more rapidly, and often times they’d be out of the hospital by day 14 – if they had to be hospitalized at all.
FRED HUTCH: So the time needed to undergo a transplant and the time spent in a hospital has really changed.
APPELBAUM: It depends on the kind of transplant. We do so-called autologous transplants, where we use one’s own stem cells. Those we can do in a much more abbreviated time. For allogenic [donor] transplants, we have about a two-week period [pre-transplant] in which the patients are evaluated. We want to find out everything about them and their health and their disease before we go into a transplant.
Then we start the transplant. Depending on the regimen that we use, we can give a lot of drugs in the outpatient department. We have essentially a day hospital here. You can spend almost all day in the clinic and get your medications, but you don’t have to necessarily be admitted to a hospital and stay overnight. Almost everyone’s more comfortable at home than they are in a hospital. They sleep better, they eat better, and they’re not exposed to as many opportunistic infections. We joke that a hospital’s no place for a sick person. There’s some truth to that.
We only hospitalize them when they need hospitalization – because they are so sick they are on multiple drugs or they’re not taking any fluid by mouth and they need the hydration. But we don’t hospitalize people just for the sake of hospitalization. Some patients can go through the entire transplant in the outpatient setting and never have to be hospitalized.
FRED HUTCH: How did transplantation lead to today’s advances in immunotherapy?
Early in the days of doing transplants we saw that if we did a transplant between identical twins, the chance that the leukemia would come back was much higher than if we did it between siblings who were not identical. That was the first demonstration that the human immune system could actually eradicate malignancies.
When you do a transplant, you’re putting a new immune system into the patient, and this new immune system from the [non-identical twin] donor can see the leukemia cells as being foreign and reject them. And then our task became, OK, can we, in fact, identify the cells that are doing that and can we augment that effect?
One of the problems with transplantation is that, yes, the new immune system can come in and see the leukemia and get rid of it. But that new immune system also could react against other tissues in the patient’s body. When that happens it is called graft-vs.-host disease. Our task over the last 30 years has been to try and segregate the graft-vs.-leukemia effect from the graft-vs.-host effect. Right now we are, for the first time, able to do that very, very effectively. The trick in doing that is to find targets that are expressed by the leukemic cells but not by other tissues in the body.
That’s the first thing – you have to find the [cancer] targets. The second thing you have to do is find cells from the donor that can see those targets and react against them. We can find some of them but oftentimes there are too few or they react too weakly or they survive for too short a period of time. So now we’re able to take cells from the donor and genetically manipulate them to specifically see that target on the leukemic cell. And we can expand them into large numbers and watch as they go back into the patient, see the leukemia, react against it, kill the leukemic cells and watch those patients go into remission or stay in remission and potentially be cured.
That’s happening today. The number of targets that we’ve been able to identify on leukemic cells is still limited in number, but some of the results that we’re seeing are absolutely remarkable. We can take patients who have acute lymphocytic leukemia who have failed all standard chemotherapy and we can take these genetically engineered T cells and give them to those patients and we’re seeing the leukemia melt away.
Of course there’s no reason you can’t take [these T cells] from the patients themselves [instead of from donors]. So you can get rid of the whole idea of the transplant now and do these so-called adoptive immunotherapies, where we’re taking out these T cells from the patient and giving them back to the patient, eradicating their leukemia. It’s amazing how far we’ve come.
These are still clinical trials. We have a long way to go, but it is really incredibly exciting.
This all began as the observation of a graft-vs.-tumor effect in transplantation. It has evolved into this approach of adoptive T-cell transfer for the treatment of leukemia and lymphoma. But impressively, we also have data that what we’re doing in leukemia and lymphoma may not be restricted to leukemia and lymphoma, that we may be able to do this in the common solid tumors – including diseases like breast cancer and lung cancer and melanoma – and even the deadliest of the diseases like pancreatic cancer. If that happens, then the legacy of transplantation will be absolutely astounding.
FRED HUTCH: How do you see transplantation changing in the next 10 to 20 years? Will transplants continue, or will they be replaced by immunotherapy?
APPELBAUM: We’d sure like that. I can think of nothing better than being involved with the development of transplantation early in my career to save tons of lives and the development of techniques which do away with transplantation at the end of my career. It would put nice bookends on it.