Agents In Cutaneous T-cell Lymphoma Research Articles

A Phase I Trial Assessing the Feasibility of Romidepsin Combined with Brentuximab Vedotin for Patients Requiring Systemic Therapy for Cutaneous T-Cell Lymphoma

Introduction: Although most patients (pts) with cutaneous T-cell lymphoma (CTCL) have an indolent course, outcomes for advanced stages (≥IIB) are suboptimal (Dummer R, et al. Nat Rev Dis Primers, 2021). A more aggressive approach of combination cytotoxic therapies in CTCL in the past has been shown to result in higher response rates, but sequential therapies have similar disease-free and overall survival and less toxicities (Kaye FS et al, NEJM, 1989). With the advent of several biological agents in CTCL with favorable toxicity profiles compared to cytotoxics, including the CD30-directed antibody-drug conjugate brentuximab vedotin (BV), and HDAC inhibitors (HDACi), rational novel combinatorial approaches may be beneficial as response rates for single agents remain modest. Evidence suggests that HDAC inhibition may upregulate CD30 expression (Hasanali ZS et al, Sci Transl Med, 2015), supporting the combination of the HDACi romidepsin (R) with BV in pts with CTCL. Methods: In this multicenter phase I trial of R+BV, pts age ≥18 with stage ≥IB CTCL, good organ function, ECOG PS≤2, <Grade (G) 2 neuropathy, who required systemic treatment were enrolled irrespective of CD30 expression. A traditional "3+3" design with 4 dose levels (DL -2, -1, 0, & 1) was used to define the maximum tolerated dose (MTD). Prior HDACi or BV use was allowed. Enrollment started at DL 0, with R given at 10mg/m2 on days (D) 1, 8 & 15, and BV at 1.2mg/kg (max. 120mg) on D1 & 15 of a 28 day cycle for ≤16 cycles. At DL 1, the R dose was 14mg/m2, with BV 1.2mg/kg, both on D1 & 15. Dosing in the de-escalation cohorts -1 and -2 was as follows: R 10mg/m2 & BV 1.2mg/kg D1 & 15 (DL-1) or R 10mg/m2 D1, 8 & 15 with BV 0.9mg/kg D1 &15 (DL-2). Once the MTD was established, 9 additional pts were enrolled in an expansion cohort. Response was measured using the Global Response Score (GRS; Olsen EA et al. JCO, 2011) using the mSWAT for skin assessment, and flow cytometry and CT imaging every 3 cycles for assessment of extracutaneous sites. There was a "run-in" phase of treatment with R alone given 14 days prior to D1 (D-14) with skin biopsies taken at baseline and prior to C1D1 to assess changes in CD30 expression. The trial was registered in clinicaltrials.gov (NCT02616965). Results: A total of 15 pts were enrolled (DL0: n=3; DL1: n=3; expansion cohort: n=9). No pts were enrolled in the de-escalation cohorts. No pt in the dose finding cohorts experienced a DLT, and DL1 was determined as the MTD. In the expansion cohort at DL1, 9 pts were enrolled, 1 of which experienced a DLT (G3 fatigue >72h) during cycle 1. Median age was 65 years (range 51-79); 83% (n=12) were male; median ECOG PS 1 (0-2); median prior lines of systemic therapy 2 (0-4), including 2 pts with prior HDACi, and 3 pts with prior BV exposure. All pts had Mycosis fungoides (MF) or Sezary syndrome (SS). Stage at enrollment was stage IB in 2 (13%), IIB in 7 (47%), IVA1 and IVB in 1 each (7% each) and IVA2 in 4 (27%). The most common treatment-related adverse events (AE) were nausea (67%), vomiting, constipation, diarrhea, fatigue, leukopenia, peripheral sensory neuropathy (33% each), gastro-esophageal reflux, dizziness, dysgeusia, transaminitis, headaches, and neutropenia (20% each; see Table 1). No pts experienced ≥G4 AE. The only G3 AEs observed were transaminitis, fatigue and fever (n=1 each), all resolved spontaneously. Response assessment at data cut off on 7/1/22 was available for 11 of 15 pts. The overall response rate (ORR) by GRS was 64% (7/11; 95%CI 35-92%; n=1 CR). Both pts with prior HDACi exposure, and 2 of 3 with prior BV exposure responded. The median change in mSWAT was a decrease of 57% from baseline (range -25 to -100%, Fig 1). At data-cut off, 1 pt remained on treatment, while 7 pts (47%) came off treatment due to progression, 2 (13%) each due to non-adherence related to COVID-19 concerns and toxicities (recurrent thrombophlebitis; fatigue), and 1 (7%) each due to patient preference, provider preference and completion of study treatment after 16 cycles. With a median follow up of 8 months (0.2-38), median progression-free survival was 5.5m, and median OS not reached (1y OS 81%). Conclusion: In this phase I study exploring the combination of R+BV, the regimen was well tolerated and efficacious in MF/SS including heavily pretreated pts with advanced disease and prior exposure to HDACi and BV. Correlative studies, including analysis of changes in CD30 expression after 1 dose of R, and association of response with CD30 expression, are pending. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cutaneous T-Cell Lymphoma Skin Microbiome Is Characterized by Shifts in Certain Commensal Bacteria but not Viruses when Compared with Healthy Controls

Cutaneous T-Cell Lymphoma Skin Microbiome Is Characterized by Shifts in Certain Commensal Bacteria but not Viruses when Compared with Healthy Controls

Romidepsin Plus Liposomal Doxorubicin Is Safe and Effective in Patients with Relapsed or Refractory T-Cell Lymphoma: Results of a Phase I Dose-Escalation Study

The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL. Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days. Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response. Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.

Development of a Pathway-Directed Drug Screen Platform for Cutaneous T Cell Lymphoma Using Patient-Derived Xenograft Models

Cutaneous T cell lymphoma (CTCL) is an orphan disease and represents 3% of non-Hodgkin lymphomas. Mycosis fungoides and Sézary syndrome (MF/SS) are the most common subtypes of CTCL. The development of targeted therapies for orphan diseases is challenging, but particularly so in the case of MF/SS due to the lack of reliable preclinical models for this malignancy, which is limited to the skin at the early stage, but disseminated to lymph nodes and other organs as disease progresses. Here we report a novel patient-derived xenograft (PDX) mouse model of MF/SS that recapitulates the multi-compartmental nature of CTCL and a blood-based genetic biomarker assay for quantitative monitoring of systemic tumor burden in PDX mice. The PDX models were extensively characterized and exhibit cardinal clinical and histologic features of CTCL, including erythematous scaly skin lesions and eventual lymphomatous dissemination to the spleen and other organs, and maintain the molecular characteristics of their clinical counterparts. The malignant T cells harvested from spleen of PDX mice shared identical TCR sequences and immunophenotypes with corresponding MF/SS patient donor, which featured as losing CD7 and CD26 expression in CD4+ T cells. We also developed a quantitative assay of tumor burden in PDX mice by determining the amount of human β-actin cell-free DNA (cfDNA) in the plasma. The cfDNA levels in the plasma were increased in a linear fashion and correlated with the tumor growth post-implantation. To explore the utility of this PDX model for drug testing, we searched for novel agents for CTCL by performing a high-throughput screen of selected available targeted agents and identified phosphatidylinositol 3-kinase (PI3K) as a high value target. A PI3K inhibitor was advanced to our PDX model with favorable results including disease attenuation and survival prolongation. Further experiments using isoform-specific siRNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as the tumor-driving isoform. Additional studies showed synergistic combination of PI3K-δ inhibitors with histone deacetylase (HDAC) inhibitors. The particularly potent combination of copanlisib and panobinostat is proposed for further clinical development. Disclosures McCormick: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aduro BioTech,Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; BridgeBio Pharma,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Caris Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NeuroTrials,LLC: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences,Inc.: Research Funding; Leidos Biomedical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Navire: Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Riptide Bioscience: Membership on an entity's Board of Directors or advisory committees; Quadriga Biosciences: Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PMV Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ai:Nurix Inc: Research Funding; ADC Therapeutics: Honoraria; Bayer: Honoraria; BMS: Honoraria; Kirin: Honoraria; Immune Design: Honoraria; Seattle Genetics: Honoraria.

&lt;p&gt;Mogamulizumab: a new tool for management of cutaneous T-cell lymphoma&lt;/p&gt;

Cutaneous T-cell lymphoma (CTCL) poses unique treatment challenges, given its range of presentations and numerous systemic therapy options. These options often lack comparative evidence or are characterized by low response rates and short remission duration in relapsed/refractory disease. The approval of mogamulizumab, a humanized, glycoengineered IgG1κ monoclonal antibody targeting the chemokine receptor type 4 (CCR4) chemokine receptor, brings a novel tool into the spectrum of treatment options for advanced CTCL and adult T-cell leukemia/lymphoma (ATLL). CCR4 is expressed in almost all cases of ATLL, and in a majority of CTCLs, particularly when blood involvement is present. In a Phase III randomized trial, mogamulizumab was associated with 28% overall response rate among patients with relapsed CTCL, median progression-free survival of 7.7 months, and median duration of remission of 14.1 months. Responses are more frequent among patients with Sézary syndrome and within the blood compartment. Common adverse effects include rash and infusion reactions, which are usually low grade. Sentinel reports indicate that exposure to mogamulizumab may result in severe or refractory graft vs host disease after allogeneic bone marrow transplantation, highlighting the need for vigilance and expert management. Further research may establish incremental efficacy of combining mogamulizumab with cytotoxic or immunomodulatory agents in CTCL, ATLL, and possibly other lymphomas and even solid tumors.

Targeting BRD4 Disables IL-15 Oncogenic Signaling in Cutaneous T-Cell Lymphoma Via Down Regulation of IL-15 Receptor Complex

Targeting the epigenome is a promising strategy in the treatment of advanced stage cutaneous T-cell lymphoma (CTCL). CTCL is a malignancy of mature CD4+ T-cells which initially involves the skin but may progress to involve blood and visceral organs. There is no curative treatment, and drug resistance is a common problem. A hallmark feature in the development and progression of CTCL is global dysregulation of the epigenome resulting in aberrant gene expression, increased expression of oncogenes, and silencing of tumor suppressors.Bromodomain 4 (BRD4) is a master epigenetic regulator of gene expression recently identified as a survival factor in many hematologic and solid malignancies. A member of the bromodomain and extra terminal (BET) protein family, BRD4 binds chromatin in super-enhancer regions to direct downstream gene expression through interaction with co-factors such as Mediator and p-TEFb. Recently, a small molecule specific inhibitor of BRD4, JQ1, has been investigated as an anti-tumor agent. The role of BRD4, and therefore the efficacy and mechanism of JQ1 in CTCL is not known.Our group recently reported the critical role of IL-15 signaling in the development and progression of CTCL (Mishra et al, Cancer Discovery, 2016). Utilizing CTCL-derived cell lines, patient samples, and the newly characterized IL-15 transgenic mouse model of CTCL, we describe the effects of IL-15 signaling on BRD4 expression, and demonstrate for the first time regulation of IL-15 receptor expression by BRD4. We also describe the efficacy of JQ1 as an anti-tumor agent in CTCL which acts by inducing cell cycle arrest in cell lines and preventing disease progression in IL-15 transgenic mice.IL-15 signaling through its heterotrimeric receptor is a driver of oncogenesis in CTCL. Treatment of primary CD4+ T-cells from healthy donors with IL-15 (100ng/ml) for 48 hours increases protein expression of BRD4 (Figure 1A). To evaluate the occupancy of BRD4 in regulatory regions of IL-15 receptor genes, we performed ChIP-sequencing for BRD4 binding in CD4+ T-cells from a healthy donor, fresh CTCL cells, and JQ1-treated CTCL cells. At the gene locus for IL-15Rα (Chromosome 10p14-p15), we observed increased BRD4 binding at the transcription start site. This occupancy is reversed upon treatment with JQ1, to a level comparable to that of healthy donor CD4+ T-cells. This pattern is recapitulated in regulatory regions for IL-15Rβ and IL-15Rγ loci. To determine if decreased BRD4 occupancy following JQ1 treatment results in decreased IL-15 receptors gene expression, immunoblotting was performed for each receptor subunit. Treatment of the CTCL cell line HuT78 cells, with JQ1 results in significant reduction in the expression of all three IL-15 receptor subunits compared to vehicle. IL-15Rα expression decreased 2.3-fold, IL-15Rβ by 17-fold, and IL-15Rγ by 122-fold (Figure 1A).To determine the efficacy of JQ1 as an anti-tumor agent, CTCL-derived cell lines were treated with increasing doses of JQ1 for 72 hours. Cell viability and cell cycle analysis was performed and IC50 values were calculated for each cell line. At 10µM dose, there were significant decreases in % cell viability for all 5 cell lines (MyLa 66±2.56; HuT102 37±1.39; HuT78 30±1.86; HH 19±2.15; SeAx 36±0.79; p<0.0001 for all of the above). IC50 for MyLa is 21µM, HuT102 0.445µM, SeAx 4.45µM, HuT78 0.167µM, and HH 0.461µM. Treatment of these cell lines with JQ1 also resulted in a dose-dependent increase of cells in sub-G0 phase of the cell cycle, corresponding with increased Annexin V staining.IL-15 transgenic mice universally develop CTCL by 3-4 weeks of age. We treated these mice with 50mg/kg JQ1 (n=8) or a vehicle control (n=5) beginning at 4 weeks of age for 4 weeks. Scoring of the morphology, and severity of skin lesions histologically (Figure 1B) demonstrated a significant difference between JQ1 treated animals and controls (Figure 1C,p=0.0041), with JQ1-treated animals having milder disease.We conclude that BRD4 binding at regulatory regions enhances IL-15 receptor expression in CTCL. Increased receptor expression may augment IL-15 signaling, a known oncogenic mechanism in this malignancy. Furthermore, JQ1 reverses the effects of BRD4 on IL-15 receptor expression, results in significant cytotoxicity in cell lines, and prevents development of severe disease in a mouse model of CTCL. BRD4 therefore represents a promising therapeutic target in CTCL. [Display omitted] DisclosuresPorcu:Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial.

Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma.

Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease.

Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma

High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

Role of infectious agents in cutaneous T-cell lymphoma: Facts and controversies

The etiology of cutaneous T-cell lymphoma (CTCL) remains unknown, with potential infectious causes having been explored. This contribution evaluates the evidence suggesting an infectious etiology and pathogenesis of the disease, characterizes the relationships between various specific pathogens and CTCL, and discusses some of the difficulties in establishing a causal link between infectious agents and CTCL carcinogenesis. Researchers have evaluated CTCL specimens for evidence of infection with a variety of agents, including human T-lymphotropic virus, Epstein-Barr virus, human herpesvirus-8, and Staphylococcus aureus, although other pathogens also have been detected in CTCL. Although there is significant evidence implicating one or more infectious agents in CTCL, studies to date have not linked definitively any pathogen to disease development, and various studies have yielded conflicting results.

Novel therapeutic agents for cutaneous T-Cell lymphoma.

Mycosis fungoides (MF) and Sezary Syndrome (SS) represent the most common subtypes of primary Cutaneous T-cell lymphoma (CTCL). Patients with advanced MF and SS have a poor prognosis leading to an interest in the development of new therapies with targeted mechanisms of action and acceptable safety profiles. In this review we focus on such novel strategies that have changed the treatment paradigm of this rare malignancy.

Final Results of Phase II Trial of Pegylated Liposomal Doxorubicin (PLD) Followed by Bexarotene (Bex) in Advanced Cutaneous T-Cell Lymphoma (CTCL)

Abstract 882 Background:PLD is approved for treatment of Kaposi’s sarcoma and concentrates highly in the skin. Overall response (ORR: complete response [CR] + partial response [PR] rates) ranging from 56% to 88%, and CRs from 20% to 44% have been reported with PLD in CTCL patients (pts) without strictly defined response criteria (Cancer 2003; 98: 993–1001; Arch Dermatol 2008; 144: 727–33) Bex is a synthetic retinoid with an ORR of approximately 50% in relapsed/refractory CTCL (J Clin Oncol 2001; 19: 2456–71; Arch Dermatol 2001; 137: 581–93). To clarify the true ORR for PLD and to assess whether the ORR and remission durations can be improved by sequential Bex following PLD, a multi-institutional phase II trial was undertaken for pts with advanced stage/refractory CTCL. Methods:Pts were treated with PLD 20mg/m2 IV every 2 weeks for 8 doses (16 weeks) followed by 16 weeks with Bex 300mg/m2 orally. Response assessments were performed after 8 (PLD) and 16 weeks (Bex). The Severity-Weighted Assessment Tool (SWAT) (Arch Dermatol 2002; 138: 42–8) was the primary measure of skin response with the Composite Assessment of Index Lesion Severity (J Clin Oncol 2001; 19: 2456–71) and a self-reported pruritus scale as secondary measures. For stage IV pts with baseline lymphadenopathy, CT of chest, abdomen and pelvis was repeated. Sézary cell count and/or flow cytometry were repeated for patients with Sézary syndrome. Pts with complete disappearance of skin lesions on examination were deemed to have a clinical CR (CCR) in skin. A repeat skin biopsy without evidence of disease changed CCR to full CR. Results:All of the planned 37 pts with stages IV (21 including 7 Sézary syndrome), IIB (10) or refractory earlier stage (6) CTCL have been enrolled and have completed 32 weeks of treatment. Median age was 56 years (27–81). There were 20 males and 17 females. All pts had prior topical treatment with or without irradiation. Fourteen pts had no prior systemic therapy; while23 pts had prior systemic therapies (median 2, range 1–11). Median follow-up for surviving pts is 7.54 months (0.7–41.9). Thirty-four pts were assessable for response (2 withdrew consent, 1 died of disease progression 5 days after initiation of 1st cycle). For 34 assessable pts: ORR 14/34 (41%: PR 12, CCR 2). Maximum responses were all seen after 16 weeks PLD. Median progression free survival (PFS) is 4.82 months. To date, 18 pts have died of disease progression and 1 patient died of CHF which occurred 3 months after last study intervention. That patient had a pretreatment left ventricular ejection fraction of 60%. Treatment-related grade 3/4 serious adverse events occurred in 9 pts: 4 tumor pain, 2 (grade 3) hand-foot syndrome, 1 infection- unknown ANC- skin (cellulitis), 1 infection- normal ANC- skin (cellulitis), 1 neutropenia. Conclusions:With strict criteria, PLD ORR is among the highest reported for single agents in CTCL but lower than previously reported. The population contained a high proportion of patients with advanced disease as reflected in the initial stage and the poor survival. Sequential bexarotene did not increase the response rate or duration. Disclosures:Horwitz:Celgene: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Merck: Honoraria; Millennium: Consultancy; Genzyme: Research Funding.

Novel Systemic Drugs for Cutaneous T-Cell Lymphoma

For the last few years new therapeutic options for primary cutaneous T-cell lymphoma (CTCL) have been recently introduced into clinical trials, particularly for patients with advanced stage and refractory disease. Systemic treatment uses biological response modifiers, such as fusion molecules, rexinoids, interferons as well as monoclonal antiobodies, and new antiproliferative drugs, such as histone deacetylase inhibitors, proteasome inhibitors or forodesine. This review focuses on recent advances in the development of systemic agents for CTCL including both novel patented compounds and novel therapeutic protocol of intervention.

Immune Modulators as Therapeutic Agents for Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma at all stages appears to be responsive to immune modulatory therapeutic approaches. We describe here the mechanistic rationale for the use of interferons, interleukin-12, retinoids, Toll-like receptor agonists, photopheresis and combinations of immune preserving, immune stimulatory therapies for CTCL.

Effect of dose on denileukin diftitox (Dd) response in treatment-naïve cutaneous T-cell lymphoma (CTCL) subjects: A retrospective analysis of three phase III studies

e19509 Background: Three phase III studies (10, 11, 14) have been conducted with Dd, a novel IL-2 receptor-targeted recombinant fusion protein, in subjects with CTCL. Dd is approved for the treatment of persistent/recurrent CD25(+) CTCL and is the most extensively studied agent in CTCL. We retrospectively analyzed the efficacy of two Dd doses in treatment-naïve CD25(+) CTCL subjects to understand the relationship between dose and response to therapy. Methods: Studies 10 and 11 included early or advanced stage CD25(+) subjects (CD25 immunostaining in &gt;20% of malignant cells) while 14 included CD25(-). Subjects received 9 or 18 mcg/kg/day IV for 5 days, repeating every 21 days for up to 8 courses; subjects in study 14 only received the higher dose. Study 11 included a placebo arm. Subject demographics were similar among the three studies and between the 2 dose groups in each. Response confirmation required ≥2 consecutive courses (3 observations) and was adjudicated by an independent Data Endpoint Review Committee in each study, using a weighted severity skin, blood and lymph node count. The primary endpoint was ORR (CR, CCR, PR) and the key secondary endpoint was progression-free survival (PFS). Results: Integrated efficacy results for ORR and PFS are shown in the table for treatment-naïve CD25(+) subjects. In general, the nature and incidence of the adverse events reported in the 3 studies were similar, with studies 11 and 14 proving to be broadly consistent with study 10 in terms of safety. Tolerability of 9 and 18 mcg/kg/d was similar in study 10. In study 11, the only AEs that were more frequent in the high-dose group were vomiting (13.3% vs 34.5%) and dysgeusia (0% vs 10.9%). Conclusions: Overall, there was a trend towards higher efficacy favoring 18 mcg/kg/day in treatment-naïve CD25(+) subjects. The ORR was statistically significant for the higher dose group. [Table: see text]

Effect of dosing cycles on safety of denileukin diftitox (Dd) in cutaneous T-cell lymphoma (CTCL) patients: Integrated analysis of three phase III studies

e19557 Background: Dd is a novel IL-2 receptor-targeted recombinant fusion protein that is approved for treatment of persistent/recurrent CTCL expressing CD25. To date, Dd is the most extensively studied agent in CTCL. The safety of Dd was assessed with respect to dosing cycle in CTCL subjects in 3 large phase III studies: 93–04–10 (study 10), L4389–11 (study 11) and L4389–14 (study 14). Methods: Subjects received Dd doses of 9 or 18 mcg/kg IV daily for 5 days, repeating every 21 days for up to 8 cycles; study 11 also included a placebo arm. Subjects in studies 10 and 11 were CD25(+); study 14 also included CD25(-) subjects. Safety data from these studies were integrated and are presented by dosing cycle. Results: Table 1 shows a summary of all reported adverse events (AEs) by cycle for the 3 studies. For subjects completing at least 4 cycles of Dd treatment the incidence of any AEs was lower in the 3rd and 4th cycles as compared to the 1st and 2nd cycles and the incidence of AEs continued to decrease after cycle 4. Conclusions: In the studies analyzed, the incidence of AEs decreased with each subsequent treatment cycle for subjects receiving Dd. [Table: see text] [Table: see text]

Failure to Detect Human T-Lymphotropic Virus Type-I Proviral DNA in Cell Lines and Tissues from Patients with Cutaneous T-Cell Lymphoma

Previous molecular studies investigating the presence of HTLV-I proviral DNA in cell lines and tissue samples of patients with cutaneous T-cell lymphoma (CTCL) have reported a detection rate ranging from 0-92%. Despite the lack of epidemiologic data linking HTLV-I infection with CTCL, the molecular data still invite speculation regarding the precise role of HTLV-I in the pathogenesis of CTCL. To determine the detection rate of HTLV-I proviral DNA among CTCL patients referred to our medical center, we analyzed Epstein-Barr virus-transformed cell lines established from peripheral blood of seven CTCL patients and 43 tissue samples from 22 patients with different stages of disease. Genomic DNA was polymerase chain reaction-amplified with primers within the HTLV-I tax gene region. Amplification products were probed with nested oligonucleotide probes by Southern blot analysis. No HTLV-I proviral sequences were detected in the samples (0/50). Using HTLV-I/II pol primers, no HTLV-I pol gene sequences were detected. In tissues from one patient, HTLV-II pol and tax gene sequences were detected; however, HTLV-II proviral integration was not detected by Southern blot analysis of the genomic DNA. Our data suggest: (i) HTLV-I does not appear to be a primary etiologic agent in CTCL; and (ii) HTLV-II pol and tax gene sequences can be detected in a minority of CTCL patients, but this does not necessarily imply an etiologic role.

Retroviruses and Cutaneous T-Cell Lymphoma

Since the discovery of the first human retrovirus, HTLV-I, and its etiologic role in ATL, the search for a retrovirus and its role in the development and progression of CTCL has been vigorously pursued and debated. Current studies in CTCL have evaluated serum antibodies to retroviral proteins, electron microscopy to identify viruslike particles, and Southern blot analysis and PCR amplification to detect proviral DNA sequences. There have been inconsistent findings within and between a variety of studies, emphasizing the need for critical evaluation of experimental methods and their potential shortcomings. Several interesting observations have included (1) serologic evidence of HTLV-I infection in a small subset of CTCL patients, (2) cloning of a deleted HTLV-I proviral genome from a B-cell line established from the peripheral blood of a CTCL patient, (3) detection of retrovirus in Langerhans cells and B cells, and (4) molecular evidence for the presence of an HTLV-I-like retrovirus. By viewing CTCL as a model of tumor progression, mechanisms by which retroviruses play a role in the development and progression of CTCL are facilitated. Future studies will need to correlate the detection of proviral sequences and the nature of a retroviral infection with specific cell types and stage of disease and determine if these findings demonstrate a causal role in CTCL or a secondary phenomenon due to CTCL-associated immunosuppression. It is likely that new data will be reported between the writing of this article and the time of publication; however, the currently available data reviewed in this article do not provide conclusive evidence that retroviruses play a primary etiologic role in CTCL.