Efforts to improve the rate of remission and reduce the risk of relapse in patients with advanced hematologic malignancies are focusing on interleukin-2 (IL-2, aldesleukin(Drug information on aldesleukin), Proleukin), said Alexander Fefer, MD, of the University of Washington Medical School and Fred Hutchinson Cancer Research Center, Seattle.
Administered after autologous bone marrow or peripheral blood stem cell transplantation (which Dr. Fefer collectively refers to as autologous stem cell transplantation or ASCT), IL-2 may induce a therapeutic graft-versus-tumor reaction and prevent relapses, he said at the Chemotherapy Foundation's 13th annual symposium.
Although ASCT is widely used in acute myelogenous leukemia (AML) and non-Hodgkin's lymphoma (NHL), these treatments are limited by their high and early relapse rate. Such relapses may be due to residual host tumor cells that survived chemotherapy and radiotherapy or the progeny of clonogenic tumor cells transferred with contaminated marrow or stem cells, Dr. Fefer said.
In phase I/II trials, IL-2 induced a variety of immunomodulatory effects. It appears to stimulate lymphokine-activated killer (LAK) cells and induce secretion of secondary cytokines. It has been shown to be effective against minimal residual disease, which is common after ASCT, and it is hoped that it will also be effective against clonogenic tumor cells, he said. Toxicity in these trials was significant, though reversible.
Phase III Trials
An intergroup phase III trial has been initiated by the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) in post-ASCT patients with AML and high risk for relapse.
Patients will be conditioned with busulfan (Myleran) and cyclophosphamide(Drug information on cyclophosphamide), and will receive bone marrow or peripheral blood stem cells. Once they have exhibited engraftment and recovered from toxicity, they will be randomized to receive one course of IL-2 or to be observed.
Because high-dose IL-2 has induced toxicity serious enough to require hospitalization, a high induction dose (9 million IU/m²/day as a continuous IV infusion) will be administered on an inpatient basis on days 1 to 4. A lower maintenance dose (1.6 × 106 IU/m²/day as a continuous IV infusion) will be given on days 9 to 18 on an outpatient basis.
A second phase III trial initiated by SWOG is studying post-transplant IL-2 in NHL, Dr. Fefer said. Patients with low, intermediate-, or high-grade NHL at high risk for post-transplant relapse will be conditioned with total body irradiation, etoposide(Drug information on etoposide) (VePesid), and cyclophosphamide, and then receive peripheral blood stem cells.
After engraftment and recovery from toxicity, they will be randomized to IL-2 therapy or observation. The IL-2 regimen will be given according to the same schedule as in the AML trial.
Dr. Fefer said that although this investigational approach is in its earliest stages, "the results of the trials may have important implications for ASCT and, possibly, for the treatment of hematologic malignancies in clinical settings other than ASCT."
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