NEWS

A Brief History of the Brief History of Low-Dose Transplants

Brian Vastag

There have been few steps forward in the realm of allogeneic transplants since their inception as a treatment for leukemia more than 30 years ago. Stepwise advances have widened the pool of potential donors for each patient, nudged downward the incidence of graft-versus-host disease, and gone a long way toward eliminating post-transplant viral infections, once a major problem.

Despite this progress, allogeneic transplants are still like "playing Russian roulette. There’s a pretty fair chance you’ll die from it," said Robert Collins, M.D., director of bone marrow transplantation at the University of Texas Southwestern Medical Center, Dallas.

So a few years back when researchers from three major cancer centers began touting less toxic transplants that would leave patients’ bodies in better shape to fight side effects as well as disease, the whole field listened.

Two advances primed the field for this arrival. The first, an advanced immunosuppressant that doubles as an anti-leukemia drug, fludarabine, was brought to market in 1991. Bone marrow and stem cells transplants are like any other transplant: If the recipient’s immune system is fully functional, it will simply reject the new tissue, rendering the entire procedure moot. By whacking the recipient’s immune T cells, fludarabine gives the donor’s cells a fighting chance to engraft. Unlike high doses of total body irradiation—the conventional method for beating back the immune system—fludarabine does not cause hair loss, sterility, or other serious side effects.

The second advance drew on research that fleshed out an immunologic curiosity called the graft-versus-tumor or graft-versus-leukemia effect. The flip side of graft-versus-host disease, graft-versus-tumor ends on a happier note, with the donor’s T cells mopping up renegade tumor cells inside the recipient. Both phenomena occur only when the donor’s immune cells carry genetic ID tags that differ from those on the host’s cells.

Controversial when first proposed, the graft-versus-tumor theory gained weight after 1979, when a group of Seattle transplanters reported on patients who received marrow from identical twins. Twins were seen as ideal donors because their immune cells were genetically identical to the host’s. That translated into less graft rejection and no graft-versus-host disease. But another finding emerged: Patients who received identical twin transplants had relapse rates twice as high as those seen in non-twin transplants. Why? Because the twin recipients did not get the benefit of graft-versus-tumor.

The old school, which saw marrow transplants as simply an immune system rescue after the pre-transplant chemotherapy and radiation knocked out the cancer, was forced to reconsider. The new thinking was radically different: The transplant itself could fight cancer. By the late 1980s, researchers were looking for ways to boost the graft-versus-tumor effect by adding extra donor T cells to the transplant mix. Evidence of graft-versus-tumor mounted, and by the mid-1990s a flurry of reports had firmly established its existence.

The result of all this: Transplanters began thinking that maybe, just maybe, they could reduce the amount of pre-transplant treatment, and that it was not necessary to wipe out the entire tumor up front. Rather, suppressing the recipient’s immune system just enough might enable the graft to settle in and beat back the cancer. The question of how well this will ultimately work remains open.



             
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