Histone deacetylase inhibitors induce changes in gene expression that lead to cellular differentiation and reversal of the transformed phenotype. Interest in clinical development of these agents has been spurred by the responses observed in patients with T-cell lymphoma to romidepsin, previously FK228 and depsipeptide. To date, 61 patients with CTCL and 34 with PTCL have been accrued to our ongoing multiinstitutional trial of romidepsin for patients with recurrent or refractory cutaneous or peripheral T-cell lymphoma. Romidepsin is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m2. Complete and partial responses have been observed in patients with CTCL, with a complete response in a patient with Sézary syndrome ongoing for over 45 months and a partial response ongoing for over 60 months. Both complete and partial responses were observed in patients with various subtypes of PTCL, including PTCL, unspecified, ALK-/CD30+ anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma, with a complete response ongoing for over 34 months. Responses will be updated for presentation. Molecular endpoint analysis was performed in normal and malignant circulating peripheral mononuclear cells, PBMCs, and in tumor samples. Immunoblot analysis demonstrated increased histone acetylation in PBMCs of 2-fold or greater from 19 of 33 patients at 4 or 24 hrs. RT-PCR of RNA demonstrated a 2-fold or greater increased expression of MDR-1 in PBMCs from 27 of 45 patients, 11 of which were greater than 4-fold. Microarray performed on CTCL patient samples detected significant changes with treatment. In addition, changes in the 5 gene signature for CTCL previously published (

Nebozhyn et al. Blood 2006; 107:3189
) were also detected when analyzed by QPCR. MDR1 expression was evaluated by RT-PCR in 30 patient’s tumors. MDR1 expression level was not significantly increased at the time of progression, mean 3.2 and 4.9 (s.d. 3.1 and 5.5, respectively) in MDR1 units as defined in Zhan et al. Blood 1997 89:3795. Since differentiating agents have been shown to induce expression of fetal hemoglobin in the laboratory, fetal hemoglobin levels were assayed in patients on this clinical trial. Increased circulating fetal hemoglobin of 2, 5, and 10 fold was observed in 34, 24, and 15 patients, respectively, from 44 patients evaluated. SNP analysis is being performed on the MDR1 gene for comparison with pharmacokinetics and induction of fetal hemoglobin and MDR1 itself. In conclusion, romidepsin has significant single agent activity in patients with CTCL or PTCL. Molecular effects can be assayed in patients treated with romidepsin and related agents. Further clinical development of these agents should include combination trials and the identification of molecular markers of response.

Topics:
biological markers, lymphoma, t-cell, peripheral, phase 2 clinical trials, romidepsin, lymphoma, t-cell, cutaneous, fetal hemoglobin, partial response, complete remission, neoplasms, reverse transcriptase polymerase chain reaction

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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