T cell lymphoma, cutaneous

Combinations of drugs displaying distinct effects on cell proliferation/ differentiation and immunomodula-tion (e.g., retinoids and chemotherapy in advanced cutaneous T cell lymphoma). 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Denileukin -for use in refractory CD25 positive cutaneous T-cell lymphomas diftitox (Ontak) Ontak 9-18pg/kg IV(oveM5min) days 1-5... 

In the oxygen-independent Type III reactions the excited/sensi-tized psoralen donates its excitation energy directly to, or reacts with, the target compound. This occurs if the substrate and the target compound (e.g., DNA) are already in close proximity or intercalated. The reactions will proceed very rapidly via the excited singlet state, and are, typically, cyclization reactions or electron-transfer between the sensitizer and the target. In addition, the psoralen can be ionized, either directly or via the excited state, and react with the target compound in the form of a radical cation. Furocoumarins are also employed in treatment of cutaneous T-cell lymphoma and some infections connected with AIDS, by so-called photopheresis processes [71, 74-76]. In this case, peripheral blood is exposed to, e.g., photoactivated (sensitized) 8-methoxypsoralen (8-MOP) in an extracorporeal flow system. This... 

Chemotherapy-induced neutropenia Neutropenia during bone marrow transplant Severe chronic neutropenia Autologous or allogeneic bone marrow transplantation Mobilization of autologous PBPCs after chemotherapy Persistent or recurrent cutaneous T cell lymphoma Feb. 1991 June 1994 Dec. 1994 Dec. 1995 April 1998 Feb. 1994... 

UV and/or laser activation of oxsoralen for psoriasis or cutaneous T-Cell lymphoma. 

Piekarz RL, Robey R, Sandor V, Bakke S, Wilson WH, Dahmoush L, Kingma DM, Turner ML, Altemus R, Bates SE (2001) Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma a case report. Blood 98 2865-2868 Pierson T, McArthur J, Siliciano RF (2000) Reservoirs for HlV-1 mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 18 665-708... 

Woo S, Gardner ER, Chen X, Ockers SB, Baum CE, Sissung TM, Price DK, Erye R, Piekarz RL, Bates SE, Figg WD. (2009) Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res 15 1496-1503. 

HDAC inhibitors have received tremendous attention with the recent FDA approval of Vorinostat (Zolinza) or suberoylanilide hydroxamic acid (SAHA) for the treatment of cutaneous T-cell lymphoma (CTCL). Multiple compounds have thus entered into clinical trials for a wide variety of diseases. Many of these compounds were inspired in some part from HDAC natural product inhibitors. In addition, one natural product Romidepsin has also gained FDA approval for treating cutaneous T-cell lymphoma. 

After 5 years in the FDA s fast track development program, Romidepsin (Fig. 18) was approved by the FDA for refractory cutaneous T-cell lymphoma on November 6,2009. In the literature, romidepsin has also been called depsipeptide, FK228, FR901228, and NSC-630176. It was isolated from bacterial fermentation extracts from Chromobacterium violaceum and is a potent inhibitor of HDAC. In some human cancer cell lines, romidepsin inhibits HDACs at levels ten times that of TSA. 

Riley K. (2009) FDA Approves Drug treatment for rare cancer Cutaneous T-cell Lymphoma affects about 1,500 Americans annually. FDA News Release (Webpage last assessed on 6/2/2010). http //www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/2009/ucml89629.htm. 

Duvic, M. and Zhang, C. (2006) Clinical and laboratory e5q>erience of vorinostat (suberoylanilide hydroxamic acid) in die treatment of cutaneous T-cell lymphoma. British Journal of Cancer, 95, S13—S19. 

In the same year, m-carboxycinnamic acid bishydroxamide (CBHA) and suberoylanihde hydroxamic acid (SAHA) were identified as inducers of terminal differentiation of murine erythroleukemia (MEL) cells (Fig. 4) [45]. It was not until two years later, however, that the HDACl and HDAC3 inhibiting capacities of these compoimds were recognized [46]. SAHA is currently the leading compoimd in the clinic, and is undergoing phase III chnical trials for the treatment of cutaneous T cell lymphoma (CTCL). 

Vorinostat (Zolinza) [Histone Deacetylase Inhibitor] Uses Rx cutaneous manifestations in cutaneous T-cell lymphoma Action Histone deacetylase inhibitor Dose 400 mg PO daily w/ food if intolerant X 300 mg PO d for X 5 d each wk Caution [D /-] w/ warfarin (t INR) Disp Caps SE NA /D, dehydration, fatigue, anorexia, dysgeusia, DVT, PE, Xplt, anemia, hypoglycemia, QT prolongation Interactions t Risk of thrombocytopenia GI bleed W/HDAC inhibitors (valproic acid) EMS May t QT interval, monitor ECG may t glucose T risk of DVT has been r orted OD Sxs unknown... 

Bexarotene is a member of a subclass of retinoids that selectively activate rehnoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of rehnoic acid receptors (RARs). After oral administration bexarotene is rapidly absorbed. Bexarotene is thought to be eliminated primarily through the hepatobiliary system. It is approved for the treatment of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Adverse events possibly related to treatment are lipid abnormalities, hypothyroidism, rash, and blood dyscrasias. 

Topical and oral bexarotene are approved for early-stage (patch and plaque) cutaneous T-cell lymphoma that is refractory to at least one other therapy. Oral bexarotene is also approved for refractory cases of advanced disease however, the best response has been noted in early disease. 

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