Donor Lymphocytes May Reverse Relapsed Leukemia

CHICAGO--Donor lymphocyte infusion is proving to be a potent treatmentfor chronic myelogenous leukemia (CML) patients who relapse afterallogeneic bone marrow transplant (BMT). It also may improve theoverall outcome of CML patients after transplantation, said WilliamDrobyski, MD, at the sixth annual Malnati Symposium in the ClinicalSciences, sponsored by Northwestern University School of Medicine.

"Donor lymphocyte infusion is a powerful form of adoptiveimmunotherapy that is able to eradicate multiple logs of leukemiacells," said Dr. Drobyski, associate professor of medicine,Medical College of Wisconsin, Milwaukee. However, the treatmenthas been most effective in patients with CML. "Response inthese patients has been durable and may be potentially curable,"he added.

Chronic myelogenous leukemia patients who are treated early inthe course of their disease, ie, when they are in cytogenic relapseor in the stable chronic phase, respond much more readily to donorlymphocyte infusion than do individuals with more advanced phasesof CML.

The response also appears to be evolutionary, taking time to develop,Dr. Drobyski said. "In our experience at the Medical Collegeof Wisconsin, the median time to cytogenic remission for CML patientstreated with donor lymphocyte infusion typically is 4 months;the time to molecular remission is 8 months."

Because remission takes time to evolve and an aggressive diseasestate fails to respond to this form of treatment, "it appearsthat the clinical efficacy of donor lymphocyte infusion requiresthat the tumor cell population not be growing so rapidly thatit overwhelms any antileukemia response of the transplant,"he said.

The question for Dr. Drobyski, nevertheless, is not whether donorlymphocyte infusion can salvage a few patients who have relapsed.It is whether the procedure may improve the overall outcome ofpatients undergoing BMT for CML, thus prolonging remission andpotentially eradicating the disease.

Dr. Drobyski began testing this hypothesis by combining donorlymphocyte infusion with a T-cell depleted BMT graft. A totalof 21 patients with CML in primary phase received human leukocyteantigen (HLA) identical bone marrow grafts at the Medical Collegeof Wisconsin between 1988 and 1996.

The patients had total-body irradiation and chemotherapy and thenreceived bone marrow grafts in which approximately 1.6 logs ofT cells were removed plus post-transplantation cyclosporine (Sandimmune)to reduce the severity of graft-versus-host disease (GVHD).

Nine patients who relapsed were treated with donor lymphocyteinfusion, and all nine initially went into remission. Althoughtwo of these patients died--one from GVHD and the other from asubsequent relapse--none of the 21 patients died within the firstyear of follow-up due to a transplantation-related event. A thirdpatient died 6 years after transplantation due to pneumococcalsepsis. Median survival for the group at 4 to 5 years thereforewas approximately 87%.

Dr. Drobyski speculated that better results could have been achievedby treating patients even earlier in the course of their relapseddisease. Most of the patients in this study who received donorlymphocytes had been in hematologic relapse for some time. Ifthe patients had been diagnosed and treated while in cytogenicrelapse, it might have been possible to give fewer T cells andthus reinduce remission without risking GVHD.

He also suggested other possible ways of increasing the therapeuticindex of donor lymphocyte infusion in the future, such as theselective removal of specific T-cell subsets that cause rapidGVHD but spare the antileukemia response of transplantation.

Such strategies may involve depletion of CD8 or CD4+ cells; useof T cell clones with restricted tissue specificity that is targetedto the leukemia cell population rather than to host tissue; earlytreatment of residual disease with reduced T-cell doses; or activationof T-cell suicide genes with antiviral agents.