Allogeneic bone marrow (hematopoietic stem cell) transplantation as curative therapy (Thomas)

Before E. Donnall Thomas's work in Seattle, acute leukemia that no longer responded to chemotherapy and severe aplastic anemia were usually fatal. Chemotherapy could produce remissions, but in leukemia the disease arises in the bone marrow itself. Destroying the marrow with high-dose chemoradiotherapy and replacing it with a donor's cells had been explored in animals since the 1950s, but early attempts in humans failed because graft rejection and graft-versus-host disease were not yet understood. Thomas's first human report, in 1957, described only one transient graft.

Thomas and his colleagues spent years refining the method in dogs, starting at Cooperstown, New York, in 1955. The advances that mattered were better tissue typing to find HLA-matched sibling donors and methotrexate given after the graft to reduce graft-versus-host disease, an approach first reported in mice and worked out in dogs. Their 1975 review in the New England Journal of Medicine, published in two parts, set out the experimental background, the early clinical successes and the problems still unsolved. As follow-up of patients transplanted for end-stage leukemia lengthened, their survival curve reached a plateau, and by 1977 the group could speak of cure.

Graft-versus-host disease remained the central danger. Donor T cells attacking host tissue could produce a severe, sometimes fatal syndrome affecting the skin, gut, and liver. In the early sibling trials it developed in almost half of the patients despite methotrexate. Rainer Storb, working with Thomas, was first author of the 1986 trials that combined methotrexate with cyclosporine, still among the most widely used ways to prevent it. Seattle papers in 1979 and 1981 showed that the same donor immune reaction also attacked leukemia.

Skepticism ran deep: after the failures of the 1950s and 1960s, prominent immunologists doubted that the immune barrier between two people could be crossed. Transplanting leukemia patients earlier, while the disease burden was low, cut relapses. The first successful transplant from an HLA-matched unrelated donor was done in 1979, for a patient with acute lymphoblastic leukemia. Volunteer donor registries followed in the 1980s, first the Anthony Nolan register in Britain and then a national registry in the United States.

Thomas shared the 1990 Nobel Prize in Physiology or Medicine with Joseph Murray. Allogeneic transplantation is now a standard treatment for otherwise fatal blood diseases, including the acute leukemias and aplastic anemia. By 2020 close to 1.5 million hematopoietic cell transplants had been performed in more than 1,500 centers, and stem cells can now be collected from a donor's blood after G-CSF injections instead of from the marrow.