inhibiting angiogenesis and inducing antitumor immune responses. A phase I trial of an Phlorizin oral mTOR inhibitor everolimus showed promising activity in PTCL and Hodgkin lymphoma . The ORR was 56% in patients with PTCL . Other agents in this class include temsirolimus and are currently being tested in clinical trials alone and in combination with other biologic agents . 6 Nucleoside analogs Purine analogs such as fludarabine, cladrabine and pentostatin are active in T cell lymphomas. The newer agents in this class include gemcitabine, nelarabine and forodesine with specific activity in T cell lymphomas as described below. 6.1 Gemcitabine An analog of deoxycitadine that is deaminated and inactivated by deaoxycytidine deaminase and then incorporated into DNA results in chain termination and inhibition of DNA synthesis.
In addition, it also inhibits ribonucleoside reductase, an enzyme that is required for DNA synthesis. This nucleoside analog has been studied as a single agent in patients with PTCL with relapsed disease and has shown an ORR of high throughput chemical screening 59% with 12% CRs and a DOR lasting 15 months. Marchi et al. have studied single agent gemcitabine in patients with CTCL and reported a response rate of 75% with 22% CRs and a median DOR lasting 10 months. These data support the activity of gemcitabine in T cell malignancies, which has led to trials in combination with other agents in T cell lymphomas. Major toxicity of gemcitabine is myelosuppression. 6.2 Forodesine Another promising agent in this class called forodesine is a transition state travoprost price purine nucleoside phosphorylase inhibitor .
Inhibition of this enzyme leads to apoptosis and proliferation blockage of lymphocytes. Fordesine has shown in vitro activity against CLL, NHL, T cell acute lymphocytic leukemia and B cell ALL as well as synergy with other antilymphoma agents. Furman et al. treated 34 patients LY-231514 ic50 with T cell ALL using oral forodesine and demonstrated a 32.4% response rate including a 20% CR. In CTCL, Duvic et al. have reported an ORR of 39% in heavily pretreated patients in a small 36 patient study. 6.3 Clofarabine This is a deoxyadenosine analog that has been approved for the treatment of relapsed pediatric ALL. Horowitz et al. have been conducting a phase II trial of this agent in patients with PTCL and have reported a preliminary result of one PR and one CR in 11 evaluable patients. The trial is ongoing.
Lenalidomide , a second generation analog nursing model of thalidomide, is an immunomodulatory agent with potent anticancer properties that is currently approved for the treatment of multiple myeloma. IMiDS are found to possess common biological effects that include activation of NK cells and T cells, modulation of various cytokines such as tumor necrosis factor alpha, interleukin 12 and interferon gamma in a tumor microenvironment and inhibition of angiogenesis. They have also been shown to have direct antitumor activity . Lenalidomide has encouraging activity in T cell malignancies although the studies are small. Querfeld et al. reported the first 10 patients enrolled in a phase II trial of lenalidomide for CTCL in 2005. Three out of 8 evaluable patients showed objective responses and 4 patients achieved a minor response, including skin improvement and regression of lymphadenopathy.