NEWS

Mixed Moniker: ‘Mini’ Marrow Transplants Fuel Excitement, Concern

Brian Vastag

With traditional allogeneic bone marrow and stem cell transplants, toxic pre-transplant treatments wipe out patients’ immune systems and cause severe side effects. Post transplant, the dual threats of unchecked infection and graft-versus-host disease kill as many matched sibling transplant recipients—between 20% and 40%, depending on age and other factors—as the underlying cancer will, according to the International Bone Marrow Transplant Registry.

People who survive the ordeal would cheer the chance to get through it without traveling to the brink and back. They would also meet the suggestion of transplants as an outpatient treatment with scoffs of incredulity.

Yet these are the aspirations of a movement among bone marrow transplant specialists. Across the globe, these researchers are developing what they call low-dose, "mini" transplants, soothing terms that conjure images of a quick trip to the clinic for a shot or two. Growing in popularity, these procedures deliver to leukemia and lymphoma patients decreased doses of pre-transplant radiation and chemotherapy. Long a goal for transplanters, this toxicity reduction drives the optimistic monikers. It is a hard-earned optimism, because there have been few advances in allogeneic transplants since their inception as a treatment for leukemia in the late 1960s (see sidebar, p. 1201).

The subsequent enthusiasm has researchers foreseeing more patients as eligible for, and surviving, transplants. But the movement has also fueled concerns that too much is being promised too quickly. Little is truly "mini" about the transplants. (Except perhaps the amount of data available; reports on variations on the theme are just now reaching journal editors.) Patients still spend weeks with suppressed immunity. They still receive a full infusion of bone marrow or blood stem cells from matched siblings, or, less frequently, unrelated donors. These foreign cells carry with them the same potential for graft-versus-host disease as seen in traditional transplants, say the clinical researchers working on the procedures. These physicians also worry that relapse rates will be unacceptably high and that cutting pre-transplant treatment will hinder chances for a cure.

"If we have the capacity to do a transplant with a lot less up-front mortality, that would be a great leap forward," said Daniel Weisdorf, M.D., who is starting a study of low-dose transplants as director of the adult blood and marrow transplant program at the University of Minnesota, Minneapolis. "But if we lose control of the disease and have a relapse rate that’s way high 2 years down the road, then we haven’t taken a step forward at all."



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Dr. Daniel Weisdorf

 
A Plethora of Protocols

The idea of lowering toxicity for transplant recipients was so attractive when first proposed that, like a good graft, it quickly took hold. By 1997, low-dose protocols were popping up across the world, with three major cancer centers established as heavyweights. Fred Hutchinson Cancer Research Center, Seattle, long a pioneer in transplant research, moved completely to outpatient procedures with no up-front chemotherapy. The University of Texas M. D. Anderson Cancer Center, Houston, and the Hadassah University Hospital, Jerusalem, took more conservative approaches, offering reduced pre-transplant regimens that include chemotherapy.

Other centers are aligning behind the powerhouses, jumping toward one treatment philosophy or another. Yet others are developing their own treatment routines for phase II studies. Still more are offering unproven low-dose regimens outside clinical trials.

With only a slim folder of conference abstracts and the wispy beginnings of a journal literature as back up, the trend hardly seems the cautious stuff of medical science.

"People are jumping on it much faster than they should be. It looks easy, but it isn’t," said Karl Blume, M.D., professor of medicine and transplant specialist at Stanford University, Palo Alto, Calif. He added that coordinated clinical trials are needed to test the various approaches.

Daniel Fowler, M.D., a transplant researcher at the National Cancer Institute, Bethesda, Md., agreed. "There’s a lot of empiricism about it. People from all over the world go to the transplant meetings, and they’ll hear someone present data from a certain center, and then they’ll go home and start to do the same thing. They don’t ask the biological questions. You end up with people repeating other people’s work, to a large extent, without . . . trying to figure out if they can make it better," he said.

For some involved, this wildfire enthusiasm harkens to a recent transplant fiasco. In the early 1990s, a swell of interest in high-dose chemotherapy and stem cell transplants for breast cancer washed over the transplant community. That wave broke before much data had been collected, with hospitals promoting the unproven procedure off-study against a backdrop of vocal patient activists. Centers offered the unproven treatment as if it were standard care and it subsequently took years to accrue patients to clinical trials. These large, crucial studies are just now weighing in, and most have been disheartening, reporting little survival advantage for the transplant recipients.

While worrying that low-dose transplants could suffer a similar fate, some researchers note an irony: the drop in interest in transplants for breast cancer appears to be driving the low-dose bandwagon. "A lot of people who were in the breast cancer transplant field, which is temporarily inactive, are using this as an opportunity to increase their activity," said Blume.

However, others say the swell of early interest is vital to building a critical mass of research. Mary Horowitz, M.D., scientific director of the International Bone Marrow Transplant Registry, housed at the Medical College of Wisconsin, Milwaukee, said, "If you don’t get a little bit of bandwagon effect in the beginning, you don’t get enough data. It’s not unreasonable for people to try the approach instead of waiting for years to see what’s going to happen," provided that the transplants are not offered in place of standard therapy, Horowitz said, but are given instead to people who have run out of options.

A Misleading Moniker

And indeed, all of the researchers interviewed said that their lower-dose transplants are offered to older and sicker patients who would not qualify for a conventional transplant. But more and more young people are asking for the procedure. Some hospitals are complying with, or even encouraging, these requests.

Rainer Storb, M.D., of Fred Hutchinson Cancer Research Center in Seattle, is generally credited with starting the movement toward low-dose transplants. His center offers a completely outpatient transplant. "This is a dilemma that’s coming up more and more," said Storb, referring to requests from younger patients. "I had a long talk recently with a patient who is 55 and is clearly a perfect candidate for a conventional transplant from her healthy sister," he said, going on to state that if the woman insisted on a low-dose transplant, he would not turn her away.

The University of Texas Southwestern Medical Center’s Robert Collins, M.D., does not like the trend. "I think it’s being a bit oversold right now. Recently, I heard a doctor describe it as a ‘chip shot’ to a patient. That’s the wrong thing to say." Collins, who heads his hospital’s transplant unit, said he talked to an oncologist in Australia who is recommending that all patients with a certain form of adult lymphocytic leukemia receive low-dose transplants. "Why is he doing that? There’s no data," said Collins.

That will be changing soon. A paper from Storb, Blume, and colleagues in Europe will be published soon. Results of a few other studies presented at recent oncology meetings are also awaiting journal publication. In addition, several multicenter trials testing various low-dose regimens head-to-head are in the works.

These larger studies will go a long way toward determining if low-dose transplants find a permanent place in oncology wards, either as a niche treatment or a true breakthrough. "If the problems can be worked out, it has enormous potential," said Collins. "But right now, there’s a lack of appreciation for how many problems remain. The fact that we’ve lessened the toxicity doesn’t mean we’ve removed the immunological barriers that have existed in bone marrow transplants since we started doing them."

In the next issue of the Journal: How low can the doses go? The News looks at variations on the low dose transplant theme.



             
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