The overall goal of this proposal is to develop a novel treatment for chronic myeloid leukemia (CML) by enhancing the graft-versus-leukemia effect (GvL). GvL is critical to the therapeutic efficacy of BMT for CML, but serious morbidity and mortality of graft-versus-host disease (GvHD) set limits on our ability to use Gvl effectively. Interleukin-1 receptor antagonist (IL-1ra) set limits on our mortality of acute GvHD in a murine model. In addition, IL-1ra inhibits CML progenitor growth in vitro Based on these data, a two-step approach in the development of Gvl enhancement as a new treatment for CML is proposed. First, a phase II trial will be performed to determine whether interferon-alpha plus donor lymphocytes provide a GvL effect in patients with CML that has relapsed after an allogeneic BMT. Preliminary data indicate that these infusions can induce hematologic, cytogenetic, and molecular genetic remissions. Cells containing brc/abl transcripts cannot be detected using a very sensitive polymerase chain reaction (PCR) technique. The same technique is an effective way to detect relapse at a very early stage, and provides the opportunity to initiate GvL at time when the tumor burden is very low. In order to accomplish this goal a quantitative PCR technique will be developed. The GvL effect is likely to be associated with GvHD. Preliminary data from the preclinical murine model suggest that cytokine dysregulation is important in the pathophysiology of GvHD, as demonstrated by the detection of IL-I and TNF alpha message in the skin and lymphocytes during acute GvHD. IL-1ra is a very effective means of preventing and treating experimental GvHD. Therefore, the second step to this approach is a phase I/II trial of IL- 1ra in patients with acute GvHD that is unresponsive to conventional treatment. IL-1ra is particularly attractive therapy for GvHD in these patients because it inhibits CML progenitor growth in vitro, and thus may enhance GvL, while having no effect on normal hematopoiesis. During these human studies the role of inflammatory cytokines in the induction and maintenance of GvHD and GvL effects will be analyzed. These studies lay the groundwork for the final goal: to use interferon-alpha (to reduce the CML burden), peripheral blood lymphocytes (to induce GvL) and IL-1ra (to control GvHD and limit CML progenitor proliferation) as primary therapy for CML.
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