Abstract
Interleukin-2 (IL-2) has demonstrated activity as an antineoplastic and biomodulatory agent, but its activity in hematologic malignancies has not been fully defined. Cutaneous T-cell lymphoma (CTCL) has been characterized as a disorder of mature clonal CD4+CD7− cells with a predominantly Th2 cytokine profile and a blunted response to Th1 and Fas-associated apoptosis. Durable responses have been reported in several advanced CTCL patients in prior studies using high dose IL-2, but the capacity of IL-2 as an immune modulator to upregulate Th1 cytokine secretion and to facilitate a cytotoxic T-cell response in CTCL has not been studied. To further explore the activity of IL-2 to restore a Th1 phenotype and to induce an antitumor response in CTCL, we treated 11 patients with advanced or refractory CTCL with intermediate dose IL-2 (11 MIU subcutaneously daily x 4 days for 6 weeks with 2 weeks rest). The median age was 60 (range 55–72) among 6 females and 5 males. Disease was stage IB-IIA in 4, IIB in 2, III-IVB in 5, and 7 had circulating Sezary cells. Four had evidence of significant lymphadenopathy on CT scans. The mean prior therapies was 3, with 4 patients having received 3 or more systemic cytotoxic therapies. Five patients had prior electron beam irradiation, and 5 had prior biological therapies, including IFN in 3, bexarotene in 4, and interleukin-12 in one. The median cycles administered was 2 (range 1–8). Two patients were discontinued for toxicity, one with grade 3 constitutional symptoms and one who had severe underlying cardiovascular disease and developed bilateral lower extremity deep venous thromboses. Overall, therapy was well tolerated with grade 3 fatigue in 3 patients and grade 2 eosinophilia in one. Response data includes: 4 patients with partial response, including 3 with Sezary syndrome and one with diffuse plaque stage disease; 3 patients with stable disease; 2 patients with progressive disease; 2 patients discontinued before completing one cycle and were inevaluable for response. One patient with diffuse pruritis, erythroderma and circulating Sezary cells completed 8 cycles of therapy and had a complete response in the skin but persistence of a low number of Sezary cells in the blood. Immunophenotypic analysis of circulating lymphocytes revealed an overall increase in CD4+CD25+ cells during therapy, suggesting a direct immunomodulatory effect of IL-2. In summary, our experience with intermediate dose IL-2 demonstrates that the therapy was well tolerated and was associated with biological activity in patients with extensive and refractory CTCL, with responses noted in 3 of 7 patients with Sezary syndrome. Based on our results, we intent to explore the biomodulatory effects of IL-2 on both normal T-cells and Sezary cells to attempt to define the role of IL-2 as a single agent or in combination with other biological agents in patients with CTCL.
Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.
