Photo by Clay Eals
People older than 50 years with leukemia or other potentially fatal blood disorders may now be treated successfully by stem- cell transplantation, according to a study by investigators in the Hutch Clinical Research Division.
While stem-cell transplantation is an effective therapy for patients with blood malignancies, the high levels of radiation and chemotherapy that conventionally have been administered to destroy malignant cells can cause significant toxicity in older patients or those otherwise medically unfit.
Using a procedure known as a nonmyeloablative stem-cell transplant, also called a mini-transplant, doctors found that a combination of low-level radiation and potent immunosuppressive drugs allows more than half of patients with successful transplants to achieve complete remissions more than a year after treatment.
The results of the study, led by Dr. Rainer Storb, head of the Hutch's Transplantation Biology program, and Dr. Peter McSweeney, a former Center investigator who is associate professor of medicine at the University of Colorado, were published in the June 1 Blood.
Conventional stem-cell transplants use massive doses of total body irradiation and potent chemotherapy to eliminate leukemic cells. The intense treatment destroys the blood and immune system and is fatal unless the patient is rescued by infusion of donor bone marrow or stem cells isolated from peripheral blood.
In contrast, the mini-transplant's success relies on the ability of donor immune cells to target and destroy the cancer in the patient, Storb said.
"The revolutionary part of this concept is that the cancer is eliminated through the donor T cells rather than with high-dose chemotherapy and radiation," he said.
The technique promises to extend the benefits of transplantation to a much broader population of patients than ever before, including leukemia patients like Scott Kyle of Homer, Alaska, whose fungal infection following a bout with pneumonia made him ineligible for a conventional transplant.
"My heart, kidneys and lungs had suffered, and my doctor said I would not be able to withstand a standard stem-cell transplant," Kyle said.
Referred to Storb by his physician, Kyle underwent low-dose radiation before he was infused with his brother Gary's tissue-matched stem cells. Following the transplant, he was treated with immunosupressive drugs to help minimize graft rejection and graft-vs-host disease, a potentially severe side effect of transplantation.
Two and a half years post-transplant, Kyle remains cancer-free.
Kyle and other patients treated with the mini-transplant procedure have not suffered any of the severe side effects - including extreme nausea, mucositis, diarrhea, hair loss and heart, liver, and lung complications - that can plague patients treated with harsher preparative regimens.
The radiation dose in the mini-transplant is about six times lower than that given in conventional transplants, and no high-dose chemotherapy is used, Storb said.
"We are deliberately reducing the total-body irradiation from the typical pre-bone-marrow transplantation regimen doses of 1,200 to 1,500 centigray, which is equivalent to being close to the epicenter of a nuclear bomb blast, to 200 centrigray," he said.
Because the minimal radiation dose is ineffective at eliminating the patient's leukemic cells, the result of the transplant is a coexistence of donor and host immune cells, a condition called "mixed chimerism."
This allows donor T cells to recognize the patient's malignant cells as foreign and destroy them, a phenomenon known as the graft-vs.-leukemia effect.
A significant benefit of the milder treatment is that few patients require hospitalization, with most undergoing the procedure in an outpatient setting followed by clinic visits two to three times a week the first month and once or twice a week for the duration of their recovery period.
"We are transplanting into the patient a new immune system that hopefully won't tolerate the cancer cells," McSweeney said.
"The ability to perform low-toxicity donor-cell transplants in an outpatient setting may open the door to a new era of tumor immunotherapy in which donor immunity can be exploited, eventually for a wide range of cancers."
In addition, the researchers speculate that the lower doses of radiation may prove to minimize the occurrence of secondary cancers later in life.
The study involved 45 patients of with a median age of 56 years treated between 1997 and 1999 who were ineligible for a conventional bone-marrow or stem-cell transplant. The patients had been diagnosed with acute and chronic leukemias, multiple myeloma, non-Hodgkin's and Hodgkin's lymphomas, myelodysplastic and myeloproliferative syndromes and other diseases often treated with bone-marrow transplantation.
Eight patients with chronic leukemia entered complete molecular remissions, which is a state of no detectable cancer cells, and this suggests strongly that donor immune cells might eradicate these diseases. The patients were followed through their treatment and recovery period, an average of 417 days, and survival among the patients was approximately 66 percent.
Patients in the study were treated at the Hutchinson Center, UW Medical Center, Veterans Affairs Medical Center in Seattle, the University of Leipzig in Germany, or Stanford University.
To date, more than 300 patients have been treated with this procedure, including more than 100 grafts from unrelated donors, and the number of collaborating institutions has increased to 12.