Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma.

We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with > 1 prior therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS). The MTD identified was bortezomib 1.3 mg/m(2) (days 1, 4, 8, and 11), dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12), and romidepsin 10 mg/m(2) (days 1, 8, and 15) every 28 days. Thrombocytopenia (64%) was the most common ≥ grade 3 hematologic toxicity. Peripheral neuropathy occurred in 76% of patients (n = 19) (≥ grade 3, 8%; 95% confidence interval [CI] 1%-26%). Maintenance romidepsin 10 mg/m(2) (on days 1 and 8 of a 28-day cycle) proved feasible, with 12 patients receiving a median of 7.5 cycles (range: 1-29). An OR (M-protein) of > minor response (MR) was seen in 18 of 25 patients (72%); 2 (8%) had complete remissions (CRs) and 13 (52%) had partial responses (PRs), including 7 (28%) with very good PRs (VGPRs). The median TTP was 7.2 (95% CI: 5.5-19.6) months, and the median OS was > 36 months. This regimen shows activity with manageable toxicity and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as NCT00431990.

Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin.

Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m(2) romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8-12 mg/m(2) romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m(2) over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT-prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate.

Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with denileukin diftitox (ONTAK).

Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with heavily pretreated advanced and/or recurrent CTCL, the effects of an interleukin-2 receptor-targeted fusion protein, denileukin diftitox (DAB389IL-2, ONTAK), on patient-rated overall quality of life (QOL), skin appearance, and pruritus severity were evaluated. A total of 71 patients with stage IB-IVA CTCL received intravenous denileukin diftitox 9 microg/kg/day or 18 microg/kg/day over 15-60 minutes for 5 consecutive days on an outpatient basis; cycles were planned for every 21 days for a total of 8 cycles over 6 months. Prior to each treatment cycle, patients were evaluated for disease response and were asked to self-rate their overall QOL via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, skin appearance (7-point scale), and pruritus severity (10-cm visual analogue scale). Composite FACT-G and most individual subscale scores (physical, social/family, emotional, and functional well being) in documented responders (n = 21) gradually increased during the study period, generally reaching statistical significance (P < 0.05) by cycle 3, and were significantly (P < or = 0.041) higher than the scores of nonresponders at endpoint. Additionally for responders, assessments of skin severity and pruritus severity showed significant (P < or = 0.05) improvements at study endpoint compared with baseline. Adverse transfusion-related events (eg, hypersensitivity reactions, flu-like syndrome) were common during cycles 1 and 2, and vascular-leak syndrome occurred in 25% of patients. Denileukin diftitox was not associated with any clinically significant myelosuppression. Heavily pretreated patients with advanced and/or recurrent CTCL who responded to denileukin diftitox therapy showed significant improvements in self-rated overall QOL, skin appearance, and pruritus severity.

Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma.

BACKGROUND: Histone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations. METHODS: Patients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received ≥ 1 dose of romidepsin were included in the AE analyses. RESULTS: Overall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade ≥ 3 infections. In both patient populations, the greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during cycles 1-2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for ≥ 6 cycles. CONCLUSIONS: This study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade ≥ 3 infections. The greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1-2. Extended dosing of romidepsin can be tolerated in responding patients. TRIAL REGISTRATION: NCT00426764,NCT00106431.

Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses.

BACKGROUND: Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received ≥ 1 prior therapy. Approval for PTCL was based on results (n = 130; median follow-up, 13.4 months) from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL. The objective is to present updated data (median follow-up, 22.3 months) and to characterize patients who achieved long-term responses (≥ 12 months) to romidepsin. METHODS: Patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; patients with response or stable disease could continue romidepsin beyond 6 cycles. The primary endpoint was rate of confirmed/unconfirmed complete response (CR/CRu) determined by an Independent Review Committee. Secondary endpoints included objective response rate (ORR) and duration of response (DOR). For patients who achieved CR/CRu, baseline characteristics by DOR (≥ 12 vs < 12 months) were examined. RESULTS: The ORR to romidepsin was 25%, including 15% with CR/CRu. The median DOR for all responders was 28 months (range, < 1-48+) and was not reached for those who achieved CR/CRu. Patients with lack of response or transient response to prior therapy achieved durable responses with romidepsin. Of the 19 patients who achieved CR/CRu, 10 had long-term (≥ 12 months) responses; none of the baseline characteristics examined-including heavy pretreatment, response to prior therapy, or advanced disease-precluded long-term responses to romidepsin. With a median progression-free survival of 29 months, patients who achieved CR/CRu for ≥ 12 months had significantly longer survival vs those with CR/CRu for < 12 months or < CR/CRu. Extended treatment and longer follow-up did not affect the reported safety profile of romidepsin. CONCLUSIONS: Treatment with romidepsin leads to highly durable responses in a subset of patients with relapsed/refractory PTCL, with responses ongoing as long as 48 months.

Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin.

Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient-assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses.

Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy.

PURPOSE: Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. RESULTS: Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). CONCLUSION: Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

Romidepsin inhibits Ras-dependent growth transformation of NIH 3T3 fibroblasts and RIE-1 epithelial cells independently of Ras signaling inhibition.

BACKGROUND: Despite intensive effort, currently no effective anti-Ras therapies have successfully reached clinical application. Previous studies suggest that the histone deacetylatse (HDAC) inhibitor romidepsin, which is currently in clinical trials for the treatment of multiple malignancies, can block Ras-dependent signaling and growth transformation. These studies suggest that mutational activation of Ras may be a useful biomarker for sensitivity to romidepsin and that the anti-tumor activity of this HDAC inhibitor may involve inhibition of Ras effector-mediated signaling. RESULTS: To rigorously assess romidepsin as an antagonist of Ras, we utilized two well-characterized cell models for Ras transformation. We found that romidepsin blocked the anchorage-dependent and -independent growth of NIH 3T3 fibroblasts and RIE-1 epithelial cells transformed by all three Ras isoforms. However, romidepsin treatment also blocked growth transformation caused by other oncoproteins (B-Raf and ErbB2/Neu), suggesting that romidepsin is not selective for Ras. We also observed striking differences in romidepsin-mediated growth inhibition between transformed NIH 3T3 fibroblasts compared to RIE-1 epithelial cells, suggesting that the mechanism by which romidepsin blocks transformation is dependent on cellular context. Finally, we found that romidepsin did not inhibit Ras activation of the ERK and AKT effector pathways in NIH 3T3 and RIE-1 cells, suggesting that romidepsin does not directly antagonize Ras. CONCLUSION: Taken together, our results suggest that romidepsin is not selective for Ras-transformed cells and that the anti-tumor activity of romidepsin is not due to direct inhibition of Ras function.

The Friday night bunch: a lesbian community in West Texas.

Life in the rural United States, isolated and surrounded by fundamentalists, drives one farmwoman to affirm her lesbianism and fulfill her desires, while writing a dissertation about West Texas farmwomen, her friends and neighbors. By recognizing their anger and its causes, she must recognize her own and come to terms with it. In the midst of emotional turmoil about who she has been and who she might become, she accidentally gathers around her a small group of lesbians who are equally isolated, with similar radical ideas.