Phase II study of denileukin diftitox for previously treated low grade non-Hodgkin’s lymphoma: E1497 final report

Purpose Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. Patients and Methods Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 μg/kg once daily for 5 days every 3 weeks, up to eight cycles. Results Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25− histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. Conclusion Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25− B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.

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Interim Analysis of a Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v104.11.2641.2641 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2641-2641 ◽

Cited By ~ 5

Author(s):

Nam H. Dang ◽

Barbara Pro ◽

Fredrick B. Hagemeister ◽

Dan Jones ◽

Barry Samuels ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Phase Ii ◽

Hodgkin’S Lymphoma ◽

Phase Ii Study ◽

Single Agent ◽

Hodgkin's Lymphoma ◽

Denileukin Diftitox ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract Denileukin diftitox (Ontak) is a fusion protein combining the enzymatically active domain of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor (IL-2R). The drug has established efficacy in cutaneous T-cell lymphoma (CTCL), and we have recently demonstrated its single-agent activity in B-cell non Hodgkin’s lymphoma (NHL) (Dang et al. Journal of Clinical Oncology. In Press). We initiated a phase II study to evaluate its efficacy in relapsed/refractory T-cell NHL, excluding CTCL. Denileukin diftitox was administered at a dose schedule of 18 μg/kg/day by IV infusion once daily for 5 days every three weeks, for up to 8 cycles. Premedications in the form of corticosteroids, antihistamines and fluids were given prior to each drug infusion to reduce the incidence and severity of acute hypersensitivity. 14 patients are currently evaluable for response. Median age was 57 (range 26–80), and mean number of previous treatments was 2.2 (range 1–4). Tumor CD25 status was determined by immunohistochemistry and/or flow cytometry, with CD25-positivity being defined as 10% or more of tumor cells expressing detectable CD25. Of the 7 patients with CD25+ T-NHL, there were 2 CR (1 case of Alk-1 negative ALCL and 1 case of PTCL), 3 PR (1 case of PTCL and 2 cases of angioimmunoblastic lymphoma), 1 SD (1 case of PTCL) and 1 PD (1 case of PTCL). Of the 7 patients with CD25− T-NHL, there were 2 PR (1 case of PTCL and 1 case of T/NK-lymphoma), 4 SD (3 cases of PTCL and 1 case of Sezary syndrome), and 1 PD (1 case of angioimmunoblastic lymphoma). Overall response rate (CR+ PR) was 50%, with 2 of 14 patients having CR (14%) and 5 of 14 patients having PR (36%). One patient with Alk-1negative ALCL still has an ongoing CR at 15+ months. Treatment was well-tolerated, with the majority of toxicity being grade 1 or 2 and transient. Denileukin diftitox appears to have activity in relapsed/refractory T-cell NHL, and is well-tolerated at the dosing schedule tested. Additional patients are being studied to further evaluate the relationship between detectable CD25 expression and tumor response to denileukin diftitox.

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Primary treatment of low-grade non-Hodgkin's lymphoma using an all oral anthracycline-containing regimen, chlorambucil, idarubicin, dexamethasone (CID) - a phase II study

Cancer Chemotherapy and Pharmacology ◽

10.1007/s002800000124 ◽

2000 ◽

Vol 46 (1) ◽

pp. 63-68 ◽

Cited By ~ 3

Author(s):

Penelope Taylor ◽

Graham Jackson ◽

Michael Galloway ◽

Michael Soukop ◽

Hazel Tinegate ◽

...

Keyword(s):

Phase Ii ◽

Hodgkin’S Lymphoma ◽

Phase Ii Study ◽

Primary Treatment ◽

Hodgkin's Lymphoma ◽

Low Grade ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

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Randomized Phase II Study of Interleukin-12 in Combination with Rituximab in Previously Treated Non-Hodgkin's Lymphoma Patients

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-06-1245 ◽

2006 ◽

Vol 12 (20) ◽

pp. 6056-6063 ◽

Cited By ~ 40

Author(s):

Stephen M. Ansell ◽

Susan M. Geyer ◽

Matthew J. Maurer ◽

Paul J. Kurtin ◽

Ivana N.M. Micallef ◽

...

Keyword(s):

Phase Ii ◽

Hodgkin’S Lymphoma ◽

Phase Ii Study ◽

Hodgkin's Lymphoma ◽

Interleukin 12 ◽

Non Hodgkin’S Lymphoma ◽

Randomized Phase Ii ◽

Non Hodgkin's Lymphoma ◽

Previously Treated

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Phase II study of cladribine with rituximab (R-2-CdA) therapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e19501 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e19501-e19501

Author(s):

H. Nagai ◽

S. Kusumoto ◽

K. Sawada ◽

M. Yamaguchi ◽

N. Takayama ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Hodgkin’S Lymphoma ◽

Phase Ii Study ◽

B Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

Severe Neutropenia ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Previously Treated

e19501 Background: Although cladribine has been reported to be one of active purine analogs against indolent B-cell non-Hodgkin's lymphoma (B-NHL), there are few reports of combination usage of cladribine and rituximab. We conducted a multicenter phase II study to investigate efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy for relapsed indolent B-NHL. Methods: Eligibility criteria were as follows: relapsed pts with indolent B-NHL from systemic chemotherapy, ages less than 75 years; PS 0–2 by ECOG's scale. Patients received 0.09mg/kg of cladribine intravenously (2 hrs infusion) on days 1 to 5 and 375mg/m2 of rituximab intravenously on days 1 and 15, every 4 weeks, for a total of 4 cycles. Primary endpoint was overall response rate (ORR). Secondary endpoints were % complete response (%CR), 2 years progression free survival (2-y PFS), and 2 years overall survival (2-y OS). Results: A total of 20 out of 45 planned patients were enrolled and received R-2-CdA therapy from Apr 2005 to Jul 2007. Their median age was 58.5 (42–72), and the median number of prior regimens was 2 (1–3). Histologies included 16 follicular lymphomas, 2 MALT lymphomas, 1 nodal marginal B cell lymphoma, and 1 lymphoplasmacytic lymphoma. Fifteen pts (75%) were previously treated with rituximab. The ORR was 90% with 70% of % CR. Median PFS was 20.1 months (5.6–32.9 months) at a median follow-up time of 27 months. 2-y PFS and 2-y OS were 63.2% (95%CI, 28.1–67.8%), and 89.5% (95%CI, 69.8–97.2%), respectively. Severe neutropenia and thrombocytopenia of grade 3 or 4 were observed in 15% and 10% respectively. Conclusions: R-2CdA therapy was demonstrated to have high activity with durable PFS and acceptable toxicity in relapsed indolent B-NHL, even if patients were previously treated with rituximab. Although a large-scaled further trial remains to be needed, R-2-CdA therapy could be a good option of salvage therapy in relapsed indolent B-NHL. No significant financial relationships to disclose.

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