NEWS

How Low Can the Doses Go? Transplanters Look To Less Toxic Future

Brian Vastag

This is the second of a two-part series.

When the first scientific papers describing less toxic bone marrow transplants for leukemia and lymphoma appeared in the journal Blood in 1997 and 1998, they sparked a movement that spread across the transplant community and gave rise to dozens of variations on the procedure. (See News, Aug. 2, p. 1200.) But the goal for all of these treatments—called low-dose, mini, or in scientific parlance, non-myeloablative transplants—is the same: minimize side effects while harnessing a phenomenon called the graft-versus-tumor effect to fight the cancer.

Slowly, information is emerging about when and where to use these transplants. The toxicity reduction means that older, sicker patients who would not do well with conventional transplants can tolerate the procedures. And evidence is mounting that because the graft-versus-tumor phenomenon takes months to build strength, slow-growing or indolent diseases like chronic myelogenous leukemia and chronic lymphocytic leukemia make better candidates than fast-growing or bulky tumors.

But just how potent can the graft-versus-tumor effect really be? The question lingers, leading researchers down the dual tracks of intensive laboratory immunology and empiric clinical experimentation. New approaches strive to reduce serious side effects, treat broader groups of patients with transplants, and expand the donor pool to include unrelated or mismatched donors.

While this research matures, leading centers are refining their day-to-day transplant protocols. These studies all incorporate some form of immune suppression to prepare the patient for the graft and include drugs like cyclosporine to help prevent the sometimes-serious side effect known as graft-versus-host disease. But a dearth of solid data has spawned a healthy debate over other tools and techniques.

How Much Chemo?

One discussion focuses on how much chemotherapy to give up front. "People are split into camps, modest chemotherapy dose de-escalation versus just immune suppression to get the graft in," said Mary Horowitz, M.D., scientific director of the International Bone Marrow Transplant Registry at the Medical College of Wisconsin, Milwaukee. At the vanguard of the "just immune suppression" camp is the Fred Hutchinson Cancer Research Center, Seattle. The Seattle protocol, based on extensive dog research, discards upfront chemotherapy, relying on immune suppressants and low doses of radiation to prepare the recipient for the graft. These outpatient procedures, which carry few side effects—no hair loss or sterility from the radiation, for instance—became derisively known as "drive-through transplants" in some research circles.

"Other centers are still pursuing to an extent the idea of having to reduce the tumor burden," said Hutchinson’s Rainer Storb, M.D. "We deliberately cut that out and are testing the hypothesis of less is more."



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Dr. Rainer Storb

 
But the "pendulum is swinging back," said Michael Bishop, M.D., a senior researcher in the National Cancer Institute’s Department of Experimental Transplantation and Immunology. More and more, researchers are realizing that some upfront chemotherapy is needed to reduce the tumor burden prior to transplant. Bishop pointed out that the graft-versus-tumor effect can only do so much against advanced lymphomas and leukemias. "A simple analogy is ants working against a mountain," he said. "If there’s just a little pile of dirt, they can move it. But if there’s a great big pile, they can’t."



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Dr. Michael Bishop

 
Bishop and other researchers at NCI, along with transplanters at the University of Texas M. D. Anderson Cancer Center, Houston, and the Hadassah University Hospital, Jerusalem, have subscribed to the "some treatment up front" philosophy since the beginning of the debate. These centers all use reduced- or intermediate-dose chemotherapy regimens that require inpatient stays. The tradeoff is clear: more initial cancer fighting potential, but a larger side effect burden.

Although data are sparse, early reports suggest that both approaches result in high rates of durable engraftment, the first goal of any bone marrow transplant. But whether they will ultimately bring lower relapse rates and fewer complications remains to be seen.

Allogeneic Transplants

Another debate revolves around strategies to squash graft-versus-host disease and achieve long-term remissions. Unique to allogeneic marrow and stem cell transplants, and caused when the donor’s T cells attack the host’s tissues, graft-versus-host disease develops in about half of all transplants, usually in mild form. However, even with prophylactic drugs it can be deadly, claiming up to 20% of graft recipients.

In response, researchers are testing advanced approaches to amelioration. Some protocols deliberately delay full engraftment—usually by depleting the donor’s T cells prior to transplant—in an attempt to stave off the disease. Others try to outrun it by getting the new graft to take as quickly as possible.

The first approach is built on years of mouse modeling that shows, according to Megan Sykes, M.D., professor of surgery at Harvard Medical School, Boston, that graft-versus-host disease occurs when the patient’s tissues are damaged. "With any of these [pre-transplant] conditioning regimens, you’re going to have some tissue damage," said Sykes, who performs transplants at the Massachusetts General Hospital. The donor’s T cells naturally migrate to these wounded areas, sparking the reactions that lead to severe rashes, jaundice, and organ damage.

To avoid this, Sykes’ protocol delivers a stem cell transplant minus the donor’s T cells, giving the patient time to heal. But that creates a catch-22: the T cells also bestow the desired graft-versus-leukemia effect. So the Harvard protocol (and others) delivers the donor’s T cells back to the patient 35 or more days post-transplant, in what is called a donor lymphocyte infusion. (These infusions caught on in the late 1980s and were essential in establishing the existence of the graft-versus-tumor effect. Researchers in Germany and elsewhere reported that relapsed leukemias could be coaxed back into remission simply by infusing patients with loads of T cells from the original marrow donors. These infusions are now standard with most allogeneic transplants.)

Sykes says that although her approach "worked perfectly" in mice, eliminating graft-versus-host disease, it "isn’t there yet" in human trials. The reason? She says that the drug used to deplete the T cells, a polyclonal antibody, is not as effective as it needs to be. Her hospital’s next protocol will use a more advanced monoclonal antibody.

But this technique, which leads to a state of "mixed chimerism" where the donor’s and patient’s immune cells co-exist, is controversial. Before receiving a marrow or stem cell transplant, a patient’s immune system—namely, T cells—is knocked down to low levels. However, some T cells and other blood stem cells remain and end up in a turf battle with the new immune system. This state—mixed chimerism—is generally viewed as unstable, eventually resolving to 100% donor cells—engraftment—or 100% host cells—rejection. How long this should take for optimal treatment is unknown.

Sykes and others see a state of mixed chimerism as a goal, saying that the two immune systems can peacefully coexist, at least temporarily, and that the lymphocyte infusions will have a better chance with this state of tolerance. But other groups, such as the one at NCI, seek to quickly induce a full graft—that is, convert the patient to 100% donor cells with only a brief period of mixed chimerism.

In fact, the NCI protocol, based on extensive mouse modeling by Ronald Gress, M.D., and Daniel Fowler, M.D., explicitly lists fleetness as a goal. There is some evidence to back this approach. Patients in a state of mixed chimerism who are then taken off graft-versus-host disease prophylaxis tend to have a high transplant-related death rate. That suggests a benefit to achieving quicker upfront donor engraftment, said Fowler. Early data from the NCI study shows the goal is attainable; many of the patients had nearly 100% donor T cells within 2 weeks after transplant.

But again, the field is too young for experts to decide which schemes, if any, will ultimately result in fewer transplant-related deaths. A multicenter, head-to-head trial of various transplant protocols is being planned by the International Bone Marrow Transplant Registry and the University of Texas Southwestern Medical Center, Dallas. Until more data are in, researchers will continue exploring variations on the low-dose theme.



             
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