Original study
Pilot Study of Denileukin Diftitox Alternate Dosing Regimen in Patients With Cutaneous Peripheral T-Cell Lymphomas

The work was presented in part at the First World Congress of Cutaneous Lymphomas in Chicago, Illinois, September 22-25, 2010.
https://doi.org/10.1016/j.clml.2012.01.011Get rights and content

Abstract

Purpose

To evaluate the safety and efficacy of an alternate dosing regimen in rare primary cutaneous peripheral T-cell lymphoma variants.

Methods

This is a prospective, single center, pilot study of denileukin diftitox (Dd) in patients with persistent or recurrent cutaneous peripheral T-cell lymphomas and mycosis fungoides (MF) variants, excluding Sézary syndrome (SS). Dd was administered at 18 μg/kg per day for 5 days and once weekly for 24 weeks, with response by modified skin weighed assessment tool.

Results

Eight patients, with a median age of 76 years (range, 44-88 years), were treated between December 2003 and July 2008. Five (62.5%) of 8 patients responded, including 3 patients with CD30+ anaplastic large-cell lymphoma (ALCL) with 2 complete responses, one ongoing at 8 years. One patient with CD8+ and 1 patient with natural killer T cell lymphoma (NK-T) had partial responses. Progressive disease occurred in 1 patient positive for human T-cell lymphotropic virus and 1 patient with ALCL. Vascular leak syndrome (VLS) occurred in 6 (75%) of 8 patients during or just after cycle 1. Three were grade 3, and 2 of these resulted in study withdrawal. Other adverse effects included nausea or vomiting (n = 3), fatigue (n = 1), back pain (n = 1), transaminase elevations (n = 3), and elevated creatinine (n = 1).

Conclusions

Dd with an alternate dosing schedule was active in this small study of primary cutaneous T-cell lymphomas.

Introduction

T-cell non-Hodgkin lymphomas (NHL) are classified by the 2008 World Health Organization into immature and/or thymic or mature and/or postthymic peripheral T-cell lymphomas (PTCL) and by site of initial presentation in nodes or extranodal sites.1 T-cell NHLs are a heterogeneous group of lymphomas that account for approximately 10% of aggressive NHLs in the United States and Europe. The 2008 World Health Organization classification2 recognizes >20 histologic subtypes of systemic PTCLs: PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, and anaplastic large-cell lymphoma (ALCL). Systemic ALCLs are divided based on expression of the anaplastic lymphoma kinase (Alk) protein.3 According to the International PTCL study, Alk plus ALCL account for 6.6% and Alk-ALCL for 5.5% PTCL cases.3 Patients with T-cell NHLs are more likely to present with aggressive clinical features, extranodal disease, high lactate dehydrogenase (LDH) levels, and B symptoms when compared with patients with B-cell immunophenotype.4

Cutaneous T-cell lymphomas (CTCL) have a separate classification scheme. The CD30+ proliferative disorders: lymphomatoid papulosis and cutaneous anaplastic large cell lymphoma (pc-ALCL), as well as systemic+ (anaplastic lymphoma receptor tyrosine kinase [Alk+] ALCL, have good outcomes, whereas the Alk-not otherwise specified and systemic peripheral T-cell lymphoma not otherwise specified, NK-T cell lymphoma, and hepatosplenic T-cell lymphoma have poor prognoses.3, 5 cutaneous ALCL is considered as a separate disease entity because treatment and prognosis are distinct from the systemic ALCL.3

According to the National Comprehensive Cancer Network (NCCN) guidelines, first-line therapy for systemic PTCLs is an experimental trial because many subtypes do not respond well to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) based therapies reported a 5-year overall survival (OS) of 37%.6 Other chemotherapies include ACVBP (dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) plus autologous stem cell transplantation for younger patients.6 Anthracycline containing regimen demonstrated higher toxicity but superior event-free survival and OS compared with CHOP.6 Anthracycline-containing regimens have been associated with median 5-year OS rates <40%.6 Patients with ALCL have better outcomes than patients without ALCL, with an overall response rate (ORR) >75% and 5-year OS rates >60%.5 Patients with Alk+ ALCL have higher OS and failure-free survival compared with patients with Alk ALCL, due to differences in age, because patients with Alk+ tend to be younger than patients with Alk.5

There are new therapeutic approaches currently approved or being used in the clinical trials. Pralatrexate, a novel folate antagonist recently approved for relapsed PTCLs, demonstrated an ORR of 27%.7 Other therapies include conjugates (LMB-2, anti-Tac, anti-CD25 fused to Pseudomonas toxin); HDAC-I (histone deacetylase inhibitors; belinostat, panobinostat, romidepsin, and vorinostat); immunomodulators (lenalimide); and immunosuppressive agents (cyclosporine). Multiple monoclonal antibodies being used included alemtuzumab, bevacizumab, iratumumab, KW-0761, SGN-30, siplizumab, and zanolimumab. Nucleoside analogues cladribine, clofarabine, fludarabine, forodesine, gemcitabine, nelarabine, and pentostatin are also active in T-cell lymphomas, but the complete response (CR) rates are low.8

Denileukin diftitox (Dd) is a genetically engineered recombinant fusion protein composed of full-length interleukin (IL) 2 and the catalytic domain of diphtheria toxin.9 When T cells interact with antigen-presenting cells, they are activated and proliferate through synthesis of IL-2 and upregulation of IL-2 surface receptors. The high affinity T-cell receptor is a trimer of 3 distinct protein chains: CD25, the 55-kD alpha subunit; CD122, the 75-kDa beta subunit; and CD132, the 64-kDa gamma subunit.10 Although Dd will bind to low-, intermediate-, or high-affinity receptors, only engagement with intermediate (CD122 and CD132) or high-affinity receptors results in internalization and endocytosis of Dd, required for its cytotoxicity. Unfortunately, only the antibody receptor as recognizing the alpha CD25 chain is available to determine expression of the IL-2 shown in Figure 1 in large-cell transformation of mycosis fungoides (MF).11 After internalization, the active fragment of diphtheria toxin is released into the cytosol after cleavage and inhibits protein synthesis through adenosine diphosphate (ADP)-ribosylation and causes cell death.12 Dd was approved in 1999 for treatment of CTCL based on a 2-dose arm phase III clinical trial.13, 14 Patients enrolled were limited to MF or Sézary syndrome (SS) and were randomized to doses of 9 or 18 μg/kg per day for 5 days, administered once every 3 weeks. The ORR for the pivotal trial was 30%, with a 10% CR rate. There was not a significant difference in response between the 2-dose arms.13, 14 Our study was conducted to explore the response of rare primary cutaneous T-cell lymphoma variants treated with an alternate dosing schedule that consisted of one 5-day standard course followed by weekly infusions of Dd for 6 months.

Section snippets

Study Design and Treatment Plan

This was a prospective, open label, single center investigator-initiated pilot study to assess the response to Dd in patients with persistent or recurrent cutaneous peripheral T-cell lymphomas or rare variants of MF excluding SS. It was conducted between December 2003 and July 2008, and was approved by the institutional review board–ethics committee. Written informed consent was obtained from all of the patients. The study was conducted in accordance with the guidelines for good clinical

Demographics and Response

Eight eligible patients were enrolled between December 2003 and July 2008. The demographics, tumor types, and responses are shown in Table 1. The inclusive study population included 4 women and 4 men, with a median age of 67 years (range, 37-88 years). Enrollment was low due to the rarity of peripheral lymphomas limited to skin only and due to competing protocols at our institution. Five patients with traditional MF and/or SS who were ineligible or who were seropositive for hepatitis C were

Discussion

Although Dd is an approved therapy for patients with persistent or recurrent CTCL whose tumor cells express the alpha chain or CD25 component of the IL-2 receptor, there have been few opportunities to explore alternate dosing schedules or to evaluate clinical responses in uncommon primary cutaneous T-cell lymphoma variants. We reported the first case of a patient with refractory PTCL, which involved skin, mucosa, nodes, and lungs, was successfully treated with Dd.19 Wong et al20 also reported a

Disclosure

The study was funded in part by Ligand Pharmaceuticals. M. Duvic has been a consultant or advisory board member for Eisai pharmaceuticals. R. Talpur has received fees as a consultant for Eisai Pharmaceuticals.

Acknowledgments

Our single center trial was supported in part by a clinical grant from Ligand Pharmaceuticals, by the NCI MDACC Core grant CA16672-22, NCI (R21-CA74117), NIAMS K24 CA 86,815 and by the CTCL patient education and research fund, and the Sherry L Anderson fund for CTCL Research. The authors thank the clinical research fellows, Jenny Vu Pozadzides, MD, Cindy Berthelot, MD, Kelly Vidulich, MD, Katherine Cox, MD, and Lotika Singh, MD, Carol L Wilson, research nurse, and Linda Cook, research assistant.

References (25)

  • K.J. Savage

    Prognosis and primary therapy in peripheral T-cell lymphomas

    Hematology Am Soc Hematol Educ Program

    (2008)
  • A.N. Abouyabis et al.

    Response and survival rates in patients with peripheral T-cell lymphoma treated with anthracycline-based regimens: a comprehensive meta-analysis

    Blood

    (2007)
  • Cited by (13)

    • Tagraxofusp for Blastic Plasmacytoid Dendritic Cell Neoplasm

      2020, Hematology/Oncology Clinics of North America
      Citation Excerpt :

      Whether tagraxofusp can penetrate the blood-brain barrier and is active in BPDCN and other CD123-expressing malignancies in the CNS compartment is unknown: this will be of interest for future investigation. Dose-limiting CLS has been reported with other immunotoxins, including a DT and interleukin-2 fusion protein evaluated in the treatment of cutaneous T-cell lymphomas.46,47 The purported mechanism is direct endothelial toxicity and drug-protein aggregates that interact with the endothelium, disrupting the tight junctions.48

    • Primary cutaneous anaplastic large-cell lymphoma: Complete remission for 13 years after denileukin diftitox

      2017, JAAD Case Reports
      Citation Excerpt :

      Because our patient followed an alternate dosing schedule for DD, our case illustrates that a single standard cycle followed by weekly dosing may be as effective as and less toxic than 5-day courses every 3 weeks. In many cases, patients are unable to tolerate 5 days of infusions, and disease progression or relapse may occur in the extended period between cycles.3 This potentially more cost-effective regimen remains a topic of future investigation.

    • Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

      2014, Blood
      Citation Excerpt :

      The most consistent and early manifestation of VLS appeared to be hypoalbuminemia, and the severity of VLS-related AEs was reduced by administration of parenteral albumin and diuretics (eg, furosemide). Clinical VLS has been reported with other fusion proteins incorporating DT or Pseudomonas exotoxin fragments.29,30 The results of studies conducted in both tissue culture and animals implicated nonspecific update of these protein drugs by vascular endothelium as a putative mechanism for VLS.31

    • Interventions for mycosis fungoides

      2020, Cochrane Database of Systematic Reviews
    View all citing articles on Scopus
    View full text