Abstract

PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment.

Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months.

PTCL subtypeNo. of PatientsNo. evaluableResponsesORR
PTCL-nos 20 15 3 CR, 5 CRu, 4 PR, 2 SD, 1 PD 80% 
Angioimmunoblastic 10 3 CR, 5 CRu, 1 PR 100% 
Anaplastic large cell 2 CR, 2 CRu 100% 
Enteric T-cell 1 CRu 100% 
Hepatosplenic n/a n/a 
Nasal/nasal type T/NK cell 1 CRu 100% 
Subcutaneous panniculitic T-cell 1 PR 100% 
PTCL subtypeNo. of PatientsNo. evaluableResponsesORR
PTCL-nos 20 15 3 CR, 5 CRu, 4 PR, 2 SD, 1 PD 80% 
Angioimmunoblastic 10 3 CR, 5 CRu, 1 PR 100% 
Anaplastic large cell 2 CR, 2 CRu 100% 
Enteric T-cell 1 CRu 100% 
Hepatosplenic n/a n/a 
Nasal/nasal type T/NK cell 1 CRu 100% 
Subcutaneous panniculitic T-cell 1 PR 100% 

Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis.

Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.

Author notes

Disclosure:Consultancy: Therakos, Gloucester. Research Funding: Eisai Inc, Hospira. Honoraria Information: Gloucester, Therakos, Merck. Membership Information: Merck, Genentech, Speakers Bureau. Off Label Use: We will be presenting safety, tolerability, and efficacy information using denileukin diftitox (Dd) with CHOP chemotherapy in patients with peripheral T-cell lymphoma. Dd is currently FDA-approved in another T-cell lymphoma, CTCL.