Complete Responses with Denileukin Diftitox in Cutaneous T-Cell Lymphoma Studies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3745-3745
Author(s):  
Francine Foss ◽  
Madeleine Duvic ◽  
Elise A. Olsen ◽  
Anna Kozlovski
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Lymphoma ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Stage I ◽  
Advanced Stage ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox ◽  
Significant Difference

Abstract Abstract 3745 Poster Board III-681 Cutaneous T-cell lymphoma (CTCL) is a disorder of CD4+ helper T-cells with manifestations in the skin, nodes, and, in advanced stages, blood and visceral sites. For many patients, the clinical course of the disease is chronic and progressive, despite multiple therapeutic interventions. To date, are few controlled clinical trials which demonstrate durable complete responses (CR) in advanced stage patients. Denileukin diftitox (DD) is a recombinant fusion protein targeting interleukin-2 receptor which has demonstrated efficacy in early and advanced stage CTCL with response rates of 30% and 44% in two clinical trials of CTCL pts with Stage Ib-IVA relapsed and refractory CTCL or Stage I-III disease, ≤3 prior therapies respectively. In these trials, patients (pts) were randomized to receive DD at a dose of either 9 or 18 ug/kg/d daily x 5 every 21 days. Another rollover trial enrolled pts who had progressed after prior response with DD (N=29) or were CD25- (N=36); all pts in the rollover trial were treated with DD at 18ug/kg dose. Of 263 intent-to-treat pts in these trials, 227 had CD25+ skin infiltrates by immunohistochemistry (IHC) confirmed by a reference pathologist and 36 were CD25-. Overall, 24 (9.1%) pts attained durable complete response (CR). The median age of the responders was 59, and 12 CR pts were over age 60. Of the CR group, 15 pts had early stage (I-IIa) disease and 9 had advanced stage (IIb-IV) CTCL. The mean prior therapies was 3.6 with 37% of patients having received >3 therapies. Of the 24 CR pts, 21 were CD25+ and 3 were CD25-. Two CR were pts who had previously responded to DD in an earlier clinical trial. Of all pts receiving 9 ug/kg dose (N=80), there were 6 (7.5%) CR; for all pts receiving 18 ug/kg dose (N=183), there were 18 (9.8%) CR. There was no significant difference frequency of CR between the 9 and 18 ug/kg groups (P=0.56) or between the CD25+ (N=118) and CD25- (N=36) pts treated at 18 ug/kg dose (P=0.64). CR rate was similar between the early and advanced stage patients (10.7% vs 8.9% respectively). The median time to response was 53.5 vs 41days for CD25+ pts treated in the 9 and 18 ug/kg groups respectively, and 43 days for the CD25- group. The response durations ranged from 57 days to >1325 days in the CD25+ and 190-400 days in the CD25- groups. Of the 24 CR, 7 have progressed as of the time of the analysis and 17 remain in CR. The overall median PFS at the time of analysis has not been reached (range 169-1388+ days). Of the 24 CR, 3 pts had hypersensitivity reactions and 3 had capillary leak syndrome associated with DD treatment. In summary, these studies demonstrate clinical benefit of DD with CR in both early and advanced CTCL at both 9 and 18 ug/kg doses and with durable responses in a small number of pts whose malignant lymphocytes were CD25- by ICH. Disclosures: Foss: Eisai : Speakers Bureau. Olsen:Eisai: Research Funding. Kozlovski:Eisai Pharm: Employment.

A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 454-457 ◽  
Author(s):  
Francine Foss ◽  
Marie France Demierre ◽  
Gina DiVenuti
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Leukemia Cells ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 1 Trial ◽  
Denileukin Diftitox

Abstract Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the α/p55/CD25, β/p75/CD122, and γ/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10–6M to 10–8 M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day × 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.

scholarly journals Advanced-Stage Primary Cutaneous T-Cell Lymphoma Treated with Bexarotene and Denileukin Diftitox

2011 ◽  
Vol 3 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Iván Cervigón-González ◽  
Luis Miguel Torres-Iglesias ◽  
Ángel Palomo-Arellano ◽  
Braulio Gil-Pascual
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Advanced Stage ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox

Phase III Placebo-Controlled Trial of Denileukin Diftitox for Patients With Cutaneous T-Cell Lymphoma

2010 ◽  
Vol 28 (11) ◽  
pp. 1870-1877 ◽  
Author(s):  
H. Miles Prince ◽  
Madeleine Duvic ◽  
Ann Martin ◽  
Wolfram Sterry ◽  
Chalid Assaf ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Targeting ◽  
Cell Lymphoma ◽  
Controlled Trial ◽  
Interleukin 2 ◽  
Group Versus ◽  
T Cell Lymphoma ◽  
Phase Iii ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox

Purpose This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD; DAB389–interleukin-2 [IL-2]), a recombinant fusion protein targeting IL-2 receptor–expressing malignant T lymphocytes, in patients with stage IA to III, CD25 assay–positive cutaneous T-cell lymphoma (CTCL), including the mycosis fungoides and Sézary syndrome forms of the disease, who had received up to three prior therapies. The primary end point was overall response rate (ORR). Patients and Methods Patients (N = 144) with biopsy-confirmed, CD25 assay–positive CTCL were randomly assigned to DD 9 μg/kg/d (n = 45), DD 18 μg/kg/d (n = 55), or placebo infusions (n = 44), administered for 5 consecutive days every 3 weeks for up to eight cycles. Patients were monitored for drug efficacy, clinical benefit, and safety of DD. Results ORR was 44% for all participants treated with DD (n = 100; 10% complete response [CR] and 34% partial response [PR]) compared with 15.9% for placebo-treated patients (2% CR and 13.6% PR). ORR was higher in the 18 μg/kg/d group versus the 9 μg/kg/d group (49.1% v 37.8%, respectively), and both doses were significantly superior to placebo. Progression-free survival (PFS) was significantly longer (median, > 2 years) for both DD doses compared with placebo (median, 124 days; P < .001). Rates of moderately severe and severe adverse events (AEs) were slightly higher in the DD groups, whereas moderate and mild AEs were similar to placebo. No statistical differences were observed for drug-related serious AEs. Conclusion DD had a significant and durable effect on ORR and PFS with an acceptable safety profile in patients with early- and late-stage CTCL.

Use of serum soluble interleukin-2 receptor levels to monitor the progression of cutaneous T-cell lymphoma

1998 ◽  
Vol 38 (2) ◽  
pp. 207-220 ◽  
Author(s):  
Eric C. Vonderheid ◽  
Qian Zhang ◽  
Stuart R. Lessin ◽  
Marcia Polansky ◽  
J.Todd Abrams ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Interleukin 2 Receptor ◽  
Soluble Interleukin 2 Receptor

Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

2001 ◽  
Vol 19 (2) ◽  
pp. 376-388 ◽  
Author(s):  
Elise Olsen ◽  
Madeleine Duvic ◽  
Arthur Frankel ◽  
Youn Kim ◽  
Ann Martin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Therapeutic Interventions ◽  
Phase Iii ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox ◽  
Grade 3 ◽  
Dose Levels

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Phar-maceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on ≥ 20% of lymphocytes were assigned to one of two dose levels (9 or 18 μg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti–interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 μg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

NK/T Cell Versus Peripheral T Cell Lymphoma: Significant Differences in Clinical Characteristics and Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4600-4600
Author(s):  
Soon-Thye Lim ◽  
Fei Gao ◽  
Lay-Cheng Lim ◽  
Richard Quek ◽  
Daryl Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Who Classification ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
T Cell Lymphoma ◽  
Stage I ◽  
Advanced Stage ◽  
Peripheral T Cell Lymphoma ◽  
Nk T Cell

Abstract Background: To compare the clinico-pathologic characteristics and prognosis of Natural Killer/T cell lymphoma (NK/TL) with peripheral T cell lymphoma (PTCL). Methods: A total of 556 resident patients (pts) with lymphoma were treated in the departments of medical oncology and hematology in an Asian institution from 2000 to 2005. Of these pts, 71 (12.8%) had NK/TL or PTCL and were included in this analysis. Pathology was centrally reviewed and classified according to the WHO classification. Results: NK/TL and PTCL comprised of 4.7% (26/556) and 7.9% (45/556) of all cases. Of the PTCL cases, histology was PTCL-NOS in 21, anaplastic large cell in 12 (5 were ALK-1 positive) and angioimmunoblastic T cell in 8 pts. Subcutaneous panniculitis T cell and γ/δ T cell lymphoma accounted for one case each. There were no significant differences between the two groups of pts in terms of sex, performance status, extranodal involvement and LDH level at presentation. However, more patients with NK/TL presented with stage I/II disease (65% vs. 31%, p=0.003). Among pts with NK/TL, 17 (65%) received CHOP-based chemotherapy, 4 received radiation alone and 5 received palliative chemotherapy. In the PTCL group, 39 (87%) received CHOP-based chemotherapy, 2 received radiation alone and 3 received palliative treatment only. Compared to PTCL, NK/TL was associated with a significantly inferior rate of complete remission (27% vs. 58%, p=0.01) and inferior overall survival (5 vs. 28.4 mos, p=0.001). Although age &gt; 60, ECOG ≥ 2, elevated LDH, advanced stage, IPI ≥ 2 and NK/T cell histology were each associated with decreased survival on univariate analysis, only NK/T cell histology and advanced stage were independently associated with decreased survival (see table 1). Conclusions: Contrary to expectation, the incidence of PTCL based on WHO classification in this Asian series is not higher than that reported in Western series. Compared to PTCL, the NK/T subtype is associated with a paricularly inferior prognosis and overrides the prognostic significance of IPI. These data suggest that NK/TL should be considered as a seperate entity and should not be considered together with other subtypes of T cell lymphoma in clinical trials. Table 1. NK/TL vs. PTCL: Univariate and Multivariate Analyses Univariate Analysis Multivariate Analysis Median (yr) P Hazard Ratio 95% CI P Male vs. Female 1.03 vs. Not reached 0.06 0.62 0.28 to 1.40 0.25 Age&lt;60 vs. ≥ 60 2.37 vs. 0.51 0.01 1.41 0.70 to 2.83 0.33 ECOG 0/1 vs. ≥ 2 1.99 vs. 0.36 0.002 1.52 0.63 to 3.65 0.354 LDH normal vs. High Not reached vs. 0.75 0.03 1.29 0.53 to 3.13 0.57 Stage I/II vs. III/IV 1.99 vs. 1.41 0.16 2.91 1.17 to 7.2 0.02 IPI 0/1 vs. ≥ 2 Not Reached vs. 0.42 0.002 2.22 0.82 to 5.99 0.12 PTCL vs. NK/TL 2.37 vs. 0.42 0.001 5.8 2.36 to 14.24 &lt;0.001

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