Therapeutic options for chronic lymphocytic leukemia (CLL) at relapse are limited because of myelosuppressive toxicity. Denileukin diftitox (ONTAK®, Ligand Pharmaceuticals) is a genetically engineered fusion protein comprising the enzymatically active domain of diphtheria toxin and the full length sequence of interleukin-2 (IL-2) targeting malignancies expressing the medium and high affinity IL-2 receptors. We designed a phase II study to evaluate the efficacy of ONTAK® in patients with fludarabine-refractory CLL, which is a follow-up to the previously published study (

Frankel, et al, Clin. Cancer Res. 2003; 9:3555
). Denileukin diftitox was administered at a dose of 18μg/kg IV daily for 5 days every 3 weeks, for a maximum of 8 cycles. Thirteen patients have been treated so far, with 10 patients being evaluable for response (completed ≥ 3 cycles). Median age was 59 years (range 44–84), and 62% (8/13) were Rai stage III-IV, with a median of 3 prior therapies (range 1–6). The overall response was 40%, with 1 CR (10%, duration of response 5+ months) and 3 PR (30%, duration of response 3+, 3+ and 4+ months). Two responding patients (both PR) are still on study, while two (1 CR, 1 PR) were removed from study because of toxicities after 7 and 5 cycles, respectively. Four patients (40%) had progressive disease after cycles 3, 4, 4, and 7, respectively. One patient has completed four cycles and restaging studies are pending. Of the 3 patients not evaluable for response, two are still on study (having not completed 3 cycles), while one refused further treatment after 4 doses of cycle one. The grade 3/4 toxicities encountered were: neutropenia 4/13, thrombocytopenia 4/13, vascular leak syndrome 3/13, left ventricular cardiac dysfunction 1/13, hypotension 2/13, tachyarrhythmia 3/13, elevated PT 1/13, fatigue 1/13, rash 1/13, SIADH 1/13, constipation 1/13, vomiting 2/13, petechiae 1/13, transient elevation of GGT 1/13, transient elevation of AST/ALT 7/13, hyperglycemia 4/13, electrolyte imbalance 8/13, infection and/or febrile neutropenia 4/13, insomnia 1/13, visual disturbance 1/13, dyspnea 2/13, hypoxia 2/13. We conclude that denileukin diftitox has activity in CLL, with toxicities that can be managed with adequate premedication and close monitoring.

Topics:
chronic b-cell leukemias, chronic lymphocytic leukemia, denileukin diftitox, fludarabine, phase 2 clinical trials, toxic effect, aldesleukin, cancer, cardiac function, impaired, constipation

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2005, The American Society of Hematology
2004
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