Denileukin Diftitox (Ontak™) Therapy for Patients with Systemic Mastocytosis.

Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells in various tissues. Patients (pts) with SM are empirically treated with recombinant interferon-alpha (IFN-α) or cladribine when cytoreduction is required. However, treatment with these agents has been associated with poor response rates, poor tolerance, and/or short response duration, and the prognosis of pts with SM is unchanged. This underscores the urgent need of new therapeutic approaches. Atypical expression of CD25 (the alpha-subunit of the interleukin-2 [IL-2] receptor), on the membrane of neoplastic mast cells represents an attractive therapeutic target. Denileukin diftitox (Ontak™) is an engineered fusion protein containing the active domain of the diphtheria toxin and the full-length sequence of IL-2, thus targeting IL-2 receptor-expressing cells. Upon internalization, protein synthesis is inhibited and cytotoxicity ensues. We designed a pilot trial for SM pts that either had aggressive form, or indolent form with uncontrolled symptoms despite supportive care measures, in which Ontak™ was initially administered at 9 ∝g/kg/day intravenously on days 1 through 5 every 21 days. This dose was increased after 3 cycles to 18 ∝g/kg/day in pts with no response and no significant toxicity. Therapy was discontinued in pts who showed no response after 6 cycles. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). Thus far, a total of 7 symptomatic pts have been treated, 5 with aggressive and 2 with indolent SM. Median age was 58 years (range, 41 to 65), time from diagnosis to Ontak™ therapy 64 mo (range, 1 to 158), Hb 11.8 gr/dL (range, 9.2 to 13), WBC 7.9 ×10⁹/L, (range, 2.5 to 16.9), platelet count 275 ×10⁹/L (range, 54 to 759), eosinophil 2.3% (range, 0% to 6.1%). Five patients were previously treated with imatinib mesylate and one with cladribine; one pt had not received any prior therapies. One pt, who had undergone splenectomy, had hepatomegaly and 1 other had splenomegaly prior to start of Ontak™ therapy. In all patients malignant mast cells expressed CD25. A total of 33 cycles were administered. The median number of cycles was 5.5 (range 3 to 6). No significant responses have been observed among 7 pts treated. No significant difference was found between pre- and post- Ontak™ therapy in the percentage of bone marrow mast cells, and only one patient had decreased serum tryptase level at the end of the therapy (by 33%). No responses in C-findings were noted in patients with aggressive disease. However, symptoms related to SM improved in 3 patients and were eliminated in one. Therapy with Ontak™ was well tolerated with all toxicities being grade 1–2, without any grade 3–4. In summary, therapy with Ontak™ is very well tolerated but has no appreciable activity in pts with SM at the dose and schedule used in this study.