Stem Cells Allow Autotransplants in CML

SAN DIEGO, Calif--Researchers have demonstrated that in at leastsome patients with chronic myelogenous leukemia (CML), benignhematopoietic stem cell progenitors coexist in the marrow withmalignant cells, creating the possibility that autologous bonemarrow transplantation can be used to treat the disease, PhillipMcGlave, MD, said at a conference sponsored by the Universityof California, San Diego Cancer Center and UCSD School of Medicine.

Bone marrow transplant provides the only curative therapeuticapproach for CML. However, finding a matched donor is often difficult,and patients must be physically able to withstand the complicationsassociated with donor transplants, including graft-versus-hostdisease, said Dr. McGlave, director, Adult Marrow Transplant Program,University of Minnesota Health System.

To eliminate some of the problems of allogeneic transplants, investigatorshave attempted to isolate the patient's own benign hematopoieticstem cells for autologous transplantation. If a sufficient numberof these cells can be obtained from the patient's peripheral bloodor marrow, they can be used to "rescue" the patientfollowing the intensive chemoradiotherapy that kills their malignantcounterparts in the body.

To date, 200 "first generation" autologous transplantsfor the treatment of CML have been performed at eight centersin Europe and North America. In this group of patients, the survivalrate (at a median of 4 years post-transplant) for those with chronicphase CML was 59%, Dr. McGlave reported.

Improved survival was seen in those patients transplanted within12 months of diagnosis and in those less than 40 years of age.No survival advantage could be attributed to any specific methodof pretransplant marrow preparation or to the use of peripheralblood rather than bone marrow as a source of stem cells.

Dr. McGlave stressed that the patients with successful engraftmentwere not disease-free; in fact, "virtually all had some evidenceof CML when they were assessed--either the Philadelphia chromosome(Ph positive metaphases) or, in some cases, clinical evidenceof CML," he noted.

Dr. McGlave added that in some patients, the response to treatmentwas not complete, resulting in early relapse. He cited malignant-cellcontamination of the transplanted bone marrow and the possibleabsence of a graft-versus-leukemia effect as possible causes ofrelapse.

In the next generation of autologous transplants, he said, investigatorswill focus on obtaining a sample that is completely free of malignantcells, by means of stem cell selection; providing greater numbersof benign progenitors for infusion; and promoting a graft-versus-leukemiaeffect to prevent relapse.

Priming the Pump

In a treatment regimen used to stimulate greater numbers of benignprogenitor cells, called "priming," the patient is givenhigh-dose chemoradiotherapy, followed by growth factors. The benignprogenitors are then harvested for autologous transplantation.In most cases, patients are also given antileukemia therapy aftertransplantation.

This approach is being used at the University of Minnesota, butwith modifications to avoid "high-dose, intensive, combinationchemotherapy," he said. Instead, they use cyclophosphamide(Cytoxan, Neosar) as a single-dose priming agent, followed byGM-CSF.

To test the efficacy of these procedures, the Minnesota researchersexamined CML patients' peripheral blood and bone marrow samplesfor the presence of Ph negative metaphases. Before priming, theysaw no Ph negative cells, but after priming, a wide range of Phnegative cells was present in the samples (0% to 100%), with thehighest percentages found in the peripheral blood samples.

Dr. McGlave's group also quantified the CD34+DR- cell populationin the samples. In previously published studies, they have shownthis population to be enriched for benign progenitors. The proportionof CD34+DR- cells did not change in the blood or bone marrow followingpriming. "So this approach is certainly not going to provideus routinely with 100% Ph negative metaphases," he said.

The next step Dr. McGlave's group is investigating is the useof interleukin-2 (IL-2) to stimulate the growth and enhance thecytolytic function of natural killer (NK) cells, which are thoughtto be effector cells in anti-tumor immunity.

Recently, they began infusing low-dose IL-2 into patients withdiseases other than CML, and observed a rise in the number andrelative proportion of NK cells in the peripheral blood lymphocytes.This suggests that they may not need to expand NK cells ex vivo,but may simply give transplant patients low-dose subcutaneousIL-2, he said.

"We now feel it is possible to perform a large-scale selectionof benign progenitor cells that will be acceptable to the FDA,and that the means are at hand to expand this population,"Dr. McGlave said. "We hope to combine these techniques withthe use of subcutaneous IL-2 and begin clinical trials in selectedpatients with early chronic phase CML."