Boost for bone marrow transplants

October 17, 1994

Clinical trial tests new method to speed recovery, prevent infections, for patients transplanted for advanced breast cancer

Physicians at the University of Chicago Medical Center, working in cooperation with the Immunotherapy Division of Baxter Healthcare Corporation's Biotech Group, have begun the first U.S. clinical trial of an experimental technique that may reduce the risks and costs of bone-marrow transplantation for breast cancer.

By growing billions of infection-fighting white blood cells in the laboratory and allowing them to mature before being given to the patient, the researchers hope to reduce the eight-to-fourteen day period when bone-marrow transplant patients are at greatest risk for life-threatening infections to as little as three to five days.

This trial combines conventional techniques of harvesting and freezing "stem" cells--immature cells, found in bone marrow and blood, that have the potential to develop into the many types of cells that make up the blood--with a novel system that stimulates some of those cells to multiply and mature before being infused into the patient.

"The goal is to determine whether we can make bone-marrow transplantation safer and less expensive by hastening the functional recovery of the patient's immune system," said Stephanie Williams, MD, associate professor of medicine at the University of Chicago and director of the trial. "That would allow us to reduce the number and severity of infections, cut antibiotic use, lessen the need for transfusions, and shorten the average hospital stay. Bone marrow transplantation will eventually become an outpatient procedure."

The trial will involve 20 women with metastatic breast cancer. Conventional therapies for breast cancer that has spread to the liver or lungs are not effective; there are essentially no long-term survivors. By using very high doses of chemotherapy, however, physicians are now reporting disease-free survival rates of 15 to 20 percent five or more years after treatment. For patients in complete remission at the beginning of the therapy, the success rate climbs to 35 to 40 percent.

"It's far from a panacea," stressed Williams, "but even 15 percent is a lot better than zero."

Because it is so common, advanced breast cancer surpassed leukemia and lymphoma as the most frequent diagnosis treated with bone-marrow transplantation in 1993.

In order to survive high-dose chemotherapy, which destroys the bone marrow, such patients undergo an autologous marrow transplant. In this type of transplant, some of the patient's own bone marrow is removed and frozen before chemotherapy begins. After high-dose therapy is completed, the stored marrow is thawed and returned to the patient, where it gradually takes hold and begins to make all of the different types of blood cells, which transport oxygen, control clotting, and fight off infections.

The greatest short-term risk for the autologous-transplant patient comes in the weeks following chemotherapy, before the reinfused marrow can produce the mature immune cells that combat infection. Medications, called growth factors, that speed maturation of stem cells can shorten this high-risk period to 12 to 16 days. Transplanting "peripheral stem cells"--marrow-derived cells collected from the blood stream rather than from bone marrow--can further shorten this period to eight to 14 days.

That high-risk period, the eight to 14 days when the patient has too few infection fighting white blood cells, is the minimum time required for the transplanted cells to repopulate the bone marrow and mature into effective infection-fighting cells. But by collecting extra stem cells, freezing and storing three-quarters of them and enticing the remaining one-quarter to multiply and mature in culture, physicians hope to supplement the transplanted stem cells with large numbers of more mature immune cells, which would begin to function almost immediately.

However, stem cells account for less than two percent of cells found in peripheral blood or bone marrow. The technical aspects of isolating those cells and growing them in culture combines the wonders of cutting-edge biotechnology with the mechanical imagination of a Rube Goldberg.

First, the coveted cells are labelled with monoclonal antibodies that recognize CD-34, a molecular marker that appears on the surface of stem cells. A second set of antibodies next serves to attach minute magnetic beads to the labelled cells. The solution is then passed through Baxter's Isolex 300 Magnetic Cell Selection Device, an instrument manufactured for this procedure, that consists of a sterile tubing system with a long plastic chamber adjacent to a group of moveable magnets. The magnetic beads, with stem cells attached, are attracted to the magnet and held in the chamber while the other blood cells are washed away.

After exposure to chymopapain--an enzyme, derived from papaya sap, which dissolves the bond between the stem cells and the magnetic beads--the stem cells are allowed to flow out of the plastic chamber, past a second magnet that removes any remaining magnetic beads that might have escaped the first magnet.

Next, the stem cells are incubated for several days in culture medium (in Baxter gas-permeable bags) and stimulated by an investigational growth factor--PIXY 321, supplied by Immunex Corporation--that promotes proliferation and differentiation of stem cells into infection-fighting white blood cells and platelets which are needed for blood clotting. Finally, the day after the conventionally preserved stem cells are returned to the patient, the cultured cells are collected, washed, analyzed and given to the patient by direct infusion into a vein.

While the long-range purpose of this trial is to help improve bone marrow transplantation, the immediate objectives are to evaluate the performance of the system designed to multiply and mature transplanted cells, to determine the safety and potential side effects of giving those cells to a patient, and to assess how quickly patients regain immune function. Immunity will be measured by the number of different types of immune cells in the circulation and by the frequency and severity of infections and fevers patients experience.

The first U.S. patient to be treated with this investigational technique is Sherri Pearce, 39, of Muskegon, Michigan, who suffers from advanced breast cancer that has spread to her lungs. First diagnosed with breast cancer in April 1992, she had a lumpectomy followed by radiation and chemotherapy, but an annual follow-up chest X-ray in April 1994, found that her cancer had spread to her lungs. She immediately began more chemotherapy which brought a partial remission.

"It feels kind of special to be the first," reports Pearce, "especially for something that is supposed to make the process safer. In fact, I'd rather be first than, say, 7,000th, because I know they're going to pay super-close attention to all my stem cells."

Pearce had her peripheral stem cells harvested on September 23-26 and began four days of high-dose chemotherapy on September 29. She received her frozen cells back on Wednesday, October 5, and the cultured white cells on the following day, Thursday, October 6.

Phase-I trials such as this one are primarily designed to determine the safety of a new treatment. The expanded stem cells did not cause any side effects at this dose. Subsequent groups of patients will receive gradually increasing doses of expanded cells as the researchers continue to look for unexpected toxicities. It will not be possible to measure the clinical effects of expanded cell treatment until this initial trial is completed and analyzed, but Pearce has recovered well from the transplant procedure. Her white blood cell count has rebounded, she is off antibiotics and she will be discharged from the hospital today (October 18).

Although it is being tested first in patients with metastatic breast cancer, this approach could prove useful in all autologous transplants and possibly in "allogeneic" transplants, in which the transplanted marrow comes from a separate donor who is genetically similar to the patient.

Baxter Healthcare Corporation is the primary domestic operating subsidiary of Baxter International Inc. Through its subsidiaries, Baxter is the leading manufacturer and marketer of health-care products and services in nearly 100 countries worldwide. The company concentrates research-and-development programs in biotechnology, cardiovascular medicine, renal therapy and other medical fields. Baxter reported sales of .9 billion in 1993.

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