NEWS

Bone Marrow Experts Are Still Debating the Value of Purging

Steve Benowitz

High-dose chemotherapy and autologous bone marrow transplantation can be associated with patients living disease-free with some cancers for long periods of time. However, all too often the cancer returns. In patients with acute myeloid leukemia, for example, there is more than a 50% chance that the disease will return despite such treatment.

An alternative—"purging"—would clean the marrow of all cancer cells and, it is hoped, leave only hematopoietic stem cells and progenitor cells. These "rescued" hematopoietic stem cells—the mother of all types of blood cells—and progenitor cells—stem cells that are committed to differentiating into a particular type of blood cell—would be put back into the body, giving birth to a new, cancer-free blood supply and immune system.

The strategy seems straightforward—in theory. Yet for many bone marrow transplant specialists, purging remains a controversial procedure. "It’s an appealing concept, but no one has proven that purging makes a difference in patient survival," said Morie Gertz, M.D., chairman of hematology at the Mayo Clinic Cancer Center, Rochester, Minn.

Many institutions have been stymied by a variety of technical problems, in addition to a glaring lack of clinical trial data showing the survival benefit of purging marrow versus not purging. As a result, many oncologists remain undecided about purging’s value.

"The virtue of purging is not entirely clear," said Carol Richman, M.D., director of the bone marrow transplant program at the University of California at Davis Medical Center, Sacramento.

Many oncologists blame the post-transplant relapse on cancer cells left in the body after chemotherapy rather than cells missed by purging.

"Purging stem cells or bone marrow is predicated on the notion that if you can really clean up the stem cells, then you are one step closer to achieving a cure with whatever high-dose therapy you’re using to effect a rescue," noted Brian Durie, M.D., director of research and myeloma programs at Cedars-Sinai Comprehensive Cancer Center in Los Angeles. "The question is, how close are we getting to accomplishing this for cancer? The purging techniques are improving, but our ability to cure these cancers with high-dose therapy remains an open question."

Many contend that the technology still may not be good enough. "The issue is, how effective is the purge?" said Stephen Nimer, M.D., head of the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center, New York. "Most of the time, the polymerase chain reaction technology to assess the purge isn’t sensitive enough to tell. It could be PCR negative and you could still have hundreds of thousands of cancer cells in the marrow."



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Dr. Stephen Nimer

 
Beyond the technology, Nimer added that the effectiveness of purging will also largely depend on the effectiveness of the chemotherapy.

"If a patient has a lot of disease and we’re not ridding the patient’s body of cancer with high-dose chemotherapy to begin with, then our ability to purge bone marrow or stem cells may not even matter," he said.

Waiting for Proof

James Vredenburgh, M.D., co-director of the Stem Cell Laboratory at Duke University Medical Center, Durham, N.C., said that more transplant centers do not purge bone marrow than do, which he attributes to both a lack of long-term clinical data and to managed care. "Without trials to prove the benefit, insurance companies won’t reimburse the procedure," Vredenburgh said.

And that proof is what many are waiting for. James Armitage, M.D., chairman of internal medicine at the University of Nebraska Medical Center, Omaha, said his center does not do the procedure because of the lack of proven benefit. "If you could decrease the amount of cancer cells [infused] from an amount that mattered to an amount that didn’t matter . . . no studies have been done to prove that. We see it as a giant risk in manipulating cells at great expense for little gain."

Armitage suggests that while some patients relapse from reinfused cancer cells, "it may also be a reflection of the proliferative nature of tumor cells."

In nearly 90% of stem cell transplant cases, it is not bone marrow, but rather peripheral blood stem cells that are transplanted, Nimer said, a technique that entails collecting stem cells from the blood. Armitage believes that the use of blood-derived hematopoietic stem cells has changed the equation. "It may be that collecting stem cells from blood rather than bone marrow may alter things also. Tumor cells in the blood may not be the same as those in the marrow."

In any case, while several marrow and stem cell purging techniques involve using drugs or immunologic agents such as monoclonal antibodies, another major strategy involves physically separating tumor cells from stem cells through either positive or negative selection.

Positive Selection

Positive selection involves filtering out stem cells with CD34 protein antigen on their surface, though some B and T cells may be lost. In negative selection, tumor cells are pulled out and stem cells and cells involved in immune recovery—such as B, T, and natural killer cells—are frozen for later use. CD34 selection is the only technology currently commercially available.

"Theoretically, you could take all of the stem cells from a patient, pass them through a column that plucks out CD34+ cells and lets all the other cells flow through, and get a product purged of tumor cells," explained Edward Stadtmauer, M.D., director of the Bone Marrow and Stem Cell Transplant Program at the University of Pennsylvania Cancer Center, Philadelphia.



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Dr. Edward Stadtmauer

 
But purging bone marrow certainly is not easy. Richman points out that any purging technique, including CD34 selection, "wastes" cells—as many as half of the engrafting stem cells may be lost.

In addition, antibody purging techniques, which are now being considered as if they were drugs, face tough Food and Drug Administration standards. Because they have been limited to a few academic institutions, they are unlikely to be reproducible on a broad scale. Stadtmauer and others contend that large, randomized clinical trials of at least 1,000 patients each, with one group undergoing purging and one group not, would be required to have some definitive proof of purging’s benefit.

But studies to date have not provided clear answers. At the 1999 American Society of Hematology meeting in New Orleans, a multi-institutional group of researchers described the results of a 3-year study in autologous transplant in multiple myeloma patients. They found that while CD4 selection to purge stem cells worked well to cut the tumor cells’ contamination, it didn’t translate to better patient survival.

At the same time, while oncologists and scientists continue to try to perfect the art and science of purging, they have been buoyed by some recent successes:

• In March, doctors at Rush-Presbyterian St. Luke’s Medical Center in Chicago reported preliminary success in several patients who were treated with a monoclonal antibody, rituximab, as part of a new purging process to rid blood stem cells of chronic lymphocytic leukemia for autologous transplant. Similarly, Memorial Sloan-Kettering Cancer Center researchers in New York have used rituximab (Rituxan®) to eliminate B-cell lymphoma cells from the blood.

"Rituxan clears B cells from the bloodstream just before collecting stem cells, which increases the likelihood of having them cancer-free," Nimer explained. He and his colleagues are participating in an ongoing trial of Rituxan and a chemotherapy regimen of fosamide, carboplatin, and etoposide for lymphoma.

• Scientists at Princess Margaret Hospital’s Ontario Cancer Institute in Toronto reported in October in Blood using an E. coli bacteria toxin called SLT-1 to effectively cleanse lymphoma, breast cancer, and multiple myeloma cells from bone marrow.

• At December’s American Society of Hematology meeting, researchers from Dana-Farber Cancer Institute in Boston reported favorable early results from a nine-patient pilot study treating relapsed non-Hodgkin’s lymphoma patients with microscopic particles coated with anti-CD19 and anti-CD20 antibodies, which specifically targeted tumor cells contaminating the blood stem cells. The tumor cells are removed by gravity sedimentation before the stem cells are infused back into the patient.

Still, the field has a long way to go. Many centers are just beginning to purge stem cells for transplant. Duke University’s purging studies are in their early stages, as are Memorial Sloan-Kettering’s. They will be identifying patients with moderate amounts of disease who are likely to be cured with autologous transplant, Nimer said.

"Those patients would probably be cured anyway, with or without purging," he said. "So how do we know purging really matters?"



             
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