William I. Bensinger

Autologous Program
The Autologous Stem Cell Transplant Program at the FHCRC is focused on combining improved high dose therapy regimens, peripheral blood stem cells (PBSC) and post transplant immunotherapies designed to increase the fraction of patientswith malignant disease who can be cured. Some of the more innovative treatment strategies developed in the Autologous program have been used to pilot new safer treatment programs developed at the FHCRC are validated through a cooperative, high dose therapy group comprised of smaller, transplant centers in the northwest. In addition, as noted below, some of the treatment strategies developed in the Autologous Program are sufficiently promising to foster new conditioning regimens for patients who can undergo allogeneic transplantation. Due to the success of PBSC in autograft patients, studies of allogeneic PBSC have been underway and have demonstrated significant benefit of PBSC over marrow.

Targeted Radiotherapy Studies
This project involves the use of a radiometal 166-Holmium, which is a high energy beta particle emitting isotope with a relatively short half-life (26 hours). The isotope is coupled to a bone-seeking chelate DOTMP. When given intravenously, 166-Ho-DOTMP is taken up almost exclusively into bone, with negligible uptake in liver, lung, kidneys or gastrointestinal tract. This irradiates all of the marrow bearing areas where the overwhelming bulk of myeloma cells reside. At the FHCRC, a total of 38 patients have received 20-40 Gy of 166-Ho-DOTMP with melphalan of melphalan + TBI. The major toxicities as expected were marrow ablation with minor extramedullary toxicities. No treatment related deaths have occurred at the FHCRC. Approximately 45% of the evaluable patients (25 patients evaluable so far) have achieved complete remissions of their myeloma. Based on these encouraging data a phase III randomized study comparing 166-Ho-DOTMP + melphalan versus melphalan as a preparative regimen for patients with myeloma is planned to begin this summer. This unique approach should allow the delivery of higher doses of radiation to sites of disease while avoiding the dose limiting toxicities of high dose therapy.

If successful, this strategy could be extended to other diseases such as prostate cancer and is currently being studied in Ewing’s sarcoma and breast cancer. The treatment may also serve as a platform for the so named mini-transplants which use less intensive conditioning prior to allogeneic stem cell transplantation in order to avoid the relatively high transplant related mortality occuring after standard allografting. A protocol designed to provided targeted radiotherapy with 166-Ho-DOTMP in combination with allogeneic transplants is underway.

Immunotherapy Studies
Promising studies utilizing interleukin-2 (IL-2) and GM-CSF are being investigated by Dr. Leona Holmberg. In an ongoing trial, autologous peripheral blood stem cells are thawed and incubated for 24 hours with IL-2 prior to transplant into recipients with breast canceror lymphoma. Lymphokine activated killer cell (LAK) cell and natural killer (NK) cell activity is greatly enhanced by this approach. Patients receive low dose IL-2 subcutaneously for up to 4 weeks following stem cell infusion. The treatment has been well tolerated and engraftment has been rapid in all patients. This approach appears to have significant activity in patients with chemotherapy-resistant breast cancer.

In a similar trial, 10 patients with multiple myeloma have received high-dose chemotherapy followed by IL-2 incubated PBSC and low dose IL-2 for 4 weeks. The treatment was well tolerated and all patients are surviving 1 to 4 years from transplant. Only 2 relapses have occurred. Additional studies are underway in patients with lymphomaand CML.