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, 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,
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 (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."