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A Phase II Study of DT Fusion Protein Denileukin Diftitox in Patients with Fludarabine-refractory Chronic Lymphocytic Leukemia¹

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157 [A. E. F., B. L. P., J. H. B., C. L.]; Medical Center of Vincennes, Vincennes, Indiana [D. R. F.]; Medical University of South Carolina, Charleston, South Carolina [P. D. H.]; and Northwestern University Medical School, Chicago, Illinois [R. G.]

Purpose: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB₃₈₉IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells.

Experimental Design: DAB₃₈₉IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 µg/kg/day for up to eight cycles.

Results: Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1–11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB₃₈₉IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing 95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including 98% reduction in 3 patients. DAB₃₈₉IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 µg/ml (n = 5).

Conclusions: DAB₃₈₉IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB₃₈₉IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB₃₈₉IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.

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