Elderly patients with certain blood cancers generally do not undergo strong high-dose therapy due to perceived age-related risks. However, innovative therapies that combine cancer-fighting antibodies and radiation may provide hope for this patient population, according to two new studies by Center scientists Drs. Ajay Gopal and John Pagel. They presented their findings earlier this week at the 47th annual meeting of the American Society of Hematology in Atlanta.
The majority of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma are over 60 years of age. Many can't tolerate potentially curative high-dose therapies due to concerns about the excessive toxicity associated with stem-cell transplantation. Gopal, an assistant professor at the University of Washington School of Medicine and an assistant member in the Center's Clinical Research Division, conducted a Phase II clinical trial using a monoclonal antibody called myeloablative I-131-anti CD-20, also known as tositumomab, that contains iodine-131, a radioactive substance. Tositumomab belongs to a class of drugs called radioimmunotherapy agents and is directed to the CD-20 receptor located on B lymphocyte cells. Tositumomab attaches to the receptor and kills the cells by exposing them to a radioactive agent. Although the drug targets both normal and cancerous cells, one can live without normal B-cells because the stem-cell transplant eventually repopulates them.
The study found that tositumomab can deliver beneficial radiation doses to tumors while limiting exposure to normal organs, which is ideal for older adults requiring high-dose therapy, as well as other highly compromised patients.
Twenty-four patients were treated with tositumomab followed by an autologous hematopoietic stem cell transplant. Patients were followed for a median of 2.2 years, ranging from one month to 4.9 years. The estimated four-year survival rate was 55 percent, while the estimated four-year progression-free survival rate was 37 percent.
"When used with autologous hematopoietic stem-cell transplantation, it is a well-tolerated and effective transplant option for older adults requiring high-dose therapy for B-cell non-Hodgkin's lymphoma," Gopal said. "Further follow-up and additional patients will help confirm the durability of these findings."
Elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome experience a poor survival rate following chemotherapy and have a poor tolerance for high-dose regimens employed in conventional stem-cell transplants. However, hematologists have reported some success following infusion of allogeneic peripheral blood stem cells in these patients. The reduced intensity transplant for older, high-risk patients may lead to a safely induced graft-vs-leukemia (GVL) effect — the immunological rejection of leukemia cells following bone marrow transplantation — with minimal transplant related deaths. However, GVL effects appear to be most potent in high-risk patients who have a small amount of cancer cells present in the body at the time of transplant.
Pagel, an assistant member in the Clinical Research Division and an assistant professor at the UW School of Medicine, led a Phase I clinical trial to determine the feasibility and safety of targeted radiation therapy to reduce the burden of disease before an established, reduced-intensity chemoradiotherapy transplant was used to allow for a GVL effect. The study was designed to estimate the maximum tolerated dose of I-131-anti-CD45 antibody when combined with fludarabine and low-dose, total-body irradiation.
Thirty-three patients older than 50 years of age with advanced AML (24 patients) or high-risk MDS (nine patients) participated in the study. The irradiation treatment produced remission in every patient, all of whom had complete donor-cell engraftment after four weeks. Fifty-five percent of patients survived disease-free for two to 16 months after transplant. Twenty-seven percent of patients experienced disease relapse by month 38 following the transplant.
"The low survival rate of elderly patients following standard chemotherapy regimens, coupled with poor tolerance to high-dose transplant regimens, creates a significant need for an innovative therapeutic approach for this patient population," Pagel said. "Our study findings suggest that this targeted radiotherapy, combined with a standard reduced intensity transplant regimen, may result in improved outcomes of survival for older, high-risk AML and MDS patients."