Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma

Authors

  • Nam H. Dang,

    1. Department of Hematologic Malignancies, Nevada Cancer Institute, Las Vegas, NV
    Search for more papers by this author
  • Barbara Pro,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Fredrick B. Hagemeister,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Felipe Samaniego,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Dan Jones,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Barry I. Samuels,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Maria A. Rodriguez,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Andre Goy,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Jorge E. Romaguera,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Peter McLaughlin,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Ann T. Tong,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Francesco Turturro,

    1. Louisiana State University Health Sciences Center, Feist-Weiller Cancer Center, Shreveport, LA, USA
    Search for more papers by this author
  • Pamela L. Walker,

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Luis Fayad

    1. Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author

Dr Nam H. Dang, Department of Hematologic Malignancies, Nevada Cancer Institute, 10441 W. Twain Ave., Las Vegas, NV 89135, USA. E-mail: ndang@nvcancer.org

Summary

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2–diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 μg/kg/d × 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26–80 years), 70·4% male, and mean prior therapies: 2·5 (range 1–6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48·1%), stable disease in eight (29·6%) and six (22·2%) had progressive disease. An objective response was achieved in eight of 13 patients (61·5%) with CD25+ tumours (four CR/four PR) and five of 11 patients (45·5%) with CD25 tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1–38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4–5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25+ and CD25 tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.

The non-Hodgkin lymphoma (NHL) comprise a heterogenous group of haematological malignancies, the majority of which are of B-cell lineage, with 12–30% of NHL in the USA and Europe arising from T-cell lineage (Coiffier et al, 1990; Gisselbrecht et al, 1998; Economopoulos et al, 2005). Although T-cell NHLs (T-NHLs) are less common than B-cell NHLs, they are generally more aggressive and associated with a poorer prognosis (Melnyk et al, 1997; Gisselbrecht et al, 1998; Escalón et al, 2005). The response to conventional chemotherapy in patients with T-NHL is generally poor, although response rates of 25–60% have been observed in relapsed/refractory patients treated with purine analogues (Dearden & Foss, 2003). While more intensive regimens, such as high-dose chemotherapy followed by autologous stem cell transplant (SCT), appear promising, this treatment paradigm requires further study in larger, prospective, randomised trials (Vose et al, 1990; Rodriguez et al, 2001; Jantunen & D'Amore, 2004). High-dose therapy with stem cell transplantation can result in relatively long-lasting remission in a subset of patients with relapsed/refractory disease, but a major drawback with this approach is that many patients are not candidates because they cannot be effectively debulked with salvage therapy.

The limited efficacy of conventional treatment regimens, combined with advances in the understanding of T-cell biology, has enabled the development of biologically targeted therapies. Denileukin diftitox (ONTAK®; Ligand Pharmaceuticals Incorporated, San Diego, CA, USA), a recombinant cytotoxic protein comprised of the interleukin-2 (IL-2) ligand genetically fused to the enzymatically active and membrane translocation domains of the diphtheria toxin, is an example of a biologically directed therapy (Foss, 2000). The IL-2 component of this toxin selectively targets the medium and high affinity IL-2 receptor (IL-2R)-expressing cells, whereas the diphtheria toxin component inhibits protein synthesis leading to apoptosis of target-specific cells.

The IL-2R comprises three distinct subunits, designated α (CD25 or Tac), β (CD122) and γ (CD132) that can be expressed in several permutations leading to an IL-2R complex that exhibits low (α), intermediate (βγ) or high affinity (αβγ) for IL-2 (Nakase et al, 1994; Re et al, 1996; Nichols et al, 1997). The high-affinity subunit of IL-2R is expressed on activated T- and B lymphocytes, natural killer (NK) cells, and macrophages, but not on normal cells or resting T and B cells (LeMaistre et al, 1992; Taniguchi & Minami, 1993; Nakase et al, 1994). The expression of IL-2R has also been detected on a number of malignant cells of T- and B-cell origin, including low- and intermediate-grade NHL, Hodgkin disease, chronic lymphocytic leukaemia (CLL), and cutaneous T-cell lymphoma (CTCL) (Rosolen et al, 1989; LeMaistre et al, 1992; Nakase et al, 1994; Foss, 2000; Foss, 2001).

Denileukin diftitox is currently indicated for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2R. A number of clinical studies with denileukin diftitox have demonstrated substantial antitumour activity in CTCL (Foss et al, 1994; Duvic et al, 1998; Saleh et al, 1998; Olsen et al, 2001; Carretero-Margolis & Fivenson, 2003) and activity in other haematological malignancies has also been described, including refractory Hodgkin disease (LeMaistre et al, 1992) and fludarabine-resistant CLL (Frankel et al, 2003). In addition, we demonstrated in a recent phase II study that denileukin diftitox has single-agent activity and is well tolerated in patients with CD25+ or CD25 relapsed/refractory B-cell NHL (Dang et al, 2004). Anecdotal reports have also suggested that denileukin diftitox is active in relapsed CD25+ peripheral T-cell lymphoma (Talpur et al, 2002). The objectives of this phase II study conducted at The University of Texas M.D. Anderson Cancer Center were to evaluate the response rate, progression-free survival (PFS), and toxicities of denileukin diftitox in patients with CD25+ or CD25 relapsed/refractory T-NHL.

Methods

Patient eligibility

Patients from the University of Texas M.D. Anderson Cancer Center with relapsed or refractory, low- or intermediate-grade T-NHL and whose tumour tissue assay was either CD25+ (≥10% of tumour cells) or CD25 (<10% of cells) by immunohistochemistry or flow cytometry before treatment with denileukin diftitox were eligible for study participation. Patients with all T-cell histologies, with the exception of CD25+ CTCL, were eligible. Additional inclusion criteria were treatment with at least one prior regimen, negativity for human immunodeficiency virus, a life expectancy of ≥12 weeks, and a Zubrod performance status ≤2. Patients were also required to have an absolute neutrophil count (ANC) ≥1 × 109/l, platelet count ≥40 × 109/l (unless secondary to marrow involvement by lymphoma), serum bilirubin ≤25·7 μmol/l, aminotransferase less than four times the upper limit of normal, serum creatinine ≤132·6 μmol/l, and serum albumin ≥30 g/l. All patients were required to have tumour staging workup to determine the extent of disease within 2 weeks before treatment and bidimensionally measurable disease. Patients eligible for autologous SCT were eligible to receive denileukin diftitox treatment to maximum reduction of tumour bulk, and were required to receive a minimum of two cycles of therapy before crossing over to SCT.

Patients were excluded if they had another malignancy, with the exception of basal cell carcinoma of the skin or in situ cervical carcinoma treated with curative intent therapy, had received any anticancer treatment (including radiotherapy) within 4 weeks prior to study initiation (any irradiated area was not assessable for response), had received any experimental therapy within 30 d of study initiation, or had a prior allogeneic SCT, although prior autologous SCT was acceptable. Patients were also ineligible if they had active central nervous system disease; history of seizure; any serious intercurrent illness or active infection; congestive heart failure, significant arrhythmia or a history of myocardial infarction within 12 months before study entry; or were using concurrent corticosteroids (permitted only for the treatment of adverse events, such as hypersensitivity-type reactions). Pregnant or nursing females, as well as patients with a known history of hypersensitivity to denileukin diftitox or any of its components, including diphtheria toxin, IL-2 or specific excipients, were excluded. Women of childbearing potential were required to use adequate birth control methods.

Immunostaining for CD25 detection was performed on paraffin-embedded formalin-fixed biopsy material using anti-CD25 (4C9; Novocastra, Newcastle-Upon-Tyne, UK) and avidin–biotin conjugated reagents (LSAB+; Dakocytomation, Carpinteria, CA, USA) with the antigen–antibody reaction visualised using 3-amino-9-ethylcarbazole. Heat-induced epitope retrieval was conducted using citrate pH 6·0 buffer. The proportion of morphologically identifiable CD25 was counted at 400× magnification by eye and scored as positive if >10% of tumour cells. In some cases, CD25 was also assessed in tumour cells by four-colour flow cytometry (FCM) using antibodies directed against CD25, CD3 and CD20 with CD45 antibodies employed for gating purposes (all antibodies from BD Biosciences, San Diego, CA, USA). Positive level for CD25 expression by FCM was set by comparison with isotype control levels. All cases studied by immunostaining and FCM showed concordance in qualitative CD25 expression.

All patients provided signed informed consent according to institutional guidelines before study entry. The protocol was approved by the University of Texas M.D. Anderson Cancer Center institutional review board and the study was conducted in accordance with an assurance filed with and approved by the US Department of Health and Human Services.

Treatment

Patients were administered denileukin diftitox at a dose of 18 μg/kg once daily as an intravenous (i.v.) infusion over 45–60 min for five consecutive days, repeated every 3 weeks, for up to eight cycles. This dose was maintained throughout the study providing it was tolerated. In patients experiencing grade 2 or 3 toxicity, denileukin diftitox treatment was withheld until the toxicity resolved to grade 1 or less, with a maximum delay of 14 d. If the toxicity did not improve to grade 1 or less within 14 d, the patient was removed from the study. When the treatment was resumed, a reduced dose of 9 μg/kg once daily for five consecutive days was administered. To reduce the frequency and severity of acute hypersensitivity-type reactions, premedication consisting of dexamethasone 8 mg i.v., diphenhydramine 25–50 mg i.v., and acetaminophen 650 mg orally was administered 30 min before each infusion of denileukin diftitox, unless patients were allergic to any of these drugs. Hydration with 250–500 cm3 saline solution was also typically administered pre- and post-treatment with each dose of denileukin diftitox.

Tumour restaging was performed after every two cycles, or more frequently if clinically indicated. Patients who responded with either a complete response (CR), defined as the absence of clinical and histological disease or partial response (PR), defined as a ≥50% reduction in measurable disease and no evidence of progression, continued treatment for a maximum of eight cycles. Patients with stable disease (SD), defined as a <50% reduction in measurable disease and no evidence of progression, remained on treatment as long as they continued to derive therapeutic benefit, for a maximum of eight cycles. Treatment was discontinued in patients with progressive disease (PD), defined as an increase in the size of existing tumour lesions or the appearance of new lesions not previously identified.

Treatment toxicity was assessed using the National Cancer Institute Common Toxicity Criteria. All adverse events, regardless of severity or relationship to study drug, were recorded. The attending physician was given the option of removing from the study patients who experienced serious grade 4 toxicity. Denileukin diftitox was withheld pending recovery to ANC ≥1 × 109/l, platelets ≥40 × 109/l (unless secondary to marrow involvement by lymphoma) and serum albumin ≥30 g/l. The primary criterion for treatment discontinuation was unacceptable toxicity despite dose modification. Patients were permitted to discontinue participation at their own will or by investigator discretion at any time. Patients who went on to receive transplantation while in remission were censored at the time they received additional therapy as part of transplantation.

Statistics

The primary endpoint of the study was the proportion of patients achieving objective response (CR + PR). PFS was also evaluated, defined as the time period starting with the first dose of denileukin diftitox to the time of documented disease progression, death or initiation of new therapy, including therapy as part of transplantation while in remission. Subgroup analyses were also conducted to evaluate the relationship of response with CD25 status. All patients receiving treatment were evaluable for efficacy and toxicity.

Patient characteristics, safety, treatment administration and response rate by baseline patient characteristics were characterised descriptively.

Results

Patient population

Twenty-seven patients were enrolled between June 2001 and October 2005, treated with denileukin diftitox, and were evaluable for efficacy and safety. The median age of patients was 55 years (range, 26–80 years), 70·4% were male, 13 of 27 (48·1%) were CD25+, 11 of 27 (40·7%) were CD25, and three of 27 (11·1%) had undetermined CD25 status due to insufficient tumour samples (Tables I and II). The predominant histology was peripheral T-cell lymphoma (19 of 27; 70·4% of patients). Other histologies included angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma and NK/T-cell lymphoma. All patients received ≥1 prior therapeutic regimens and the mean number of prior therapies was 2·5 (range, 1–6). One patient received a previous autologous SCT.

Table I.   Patient characteristics at baseline (n = 27).
CharacteristicValue
  1. ANC, absolute neutrophil count; NK, natural killer.

Age (years)
 Median55
 Range26–80
Sex, n (%)
 Male19 (70.4)
 Female8 (29.6)
No. previous treatments
 Mean2.5
 Range1–6
Patients who previously underwent autologous stem-cell transplant, n (%)1 (3.7)
ANC, mean (×109/l)3.81
Haemoglobin, mean (g/l)116
Platelets, mean (×109/l)160
Histology, n
 Peripheral T-cell lymphoma19
 Angioimmunoblastic T-cell lymphoma3
 Alk-1-negative anaplastic large-cell T-cell lymphoma2
 Alk-1-positive anaplastic large-cell T-cell lymphoma1
 NK/T-cell lymphoma1
 Sézary syndrome1
Table II.   Response stratified by histology and tumour CD25 status.
Histology, nCD25+ (n = 13)*CD25 (n = 11)CD25 unknown (n = 3)
CRPRSDPDCRPRSDPDCRPRSDPD
  1. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NK, natural killer.

  2. *CD25 positivity defined as ≥10% of tumour cells expressing detectable CD25 as assessed by immunohistochemistry, flow cytometry or both.

Peripheral T-cell lymphoma331411400011
Angioimmunoblastic T-cell lymphoma010001010000
Alk-1-negative anaplastic large-cell T-cell lymphoma100010000000
Alk-1-positive anaplastic large-cell T-cell lymphoma000000000001
NK/T-cell lymphoma000001000000
Sézary syndrome000000100000

Treatment summary

For all evaluable patients, the mean number of denileukin diftitox treatment cycles was 4·1 (range, 1–8). In patients with responding or SD, the mean number of cycles was 5·0 (range, 1–8). Eighty-seven cycles were administered at the 18-μg/kg dose and 28 cycles at the 9-μg/kg dose.

Response

The objective response rate was 48·1%, consisting of six CRs (22·2%; four patients with peripheral T-cell lymphoma, and two patients with Alk-1-negative anaplastic large-cell lymphoma) and seven PRs (25·9%; four patients with peripheral T-cell lymphoma, two patients with angioimmunoblastic T-cell lymphoma and one patient with NK/T-cell lymphoma) (Table II). In addition, eight (29·6%) patients had SD.

In the overall evaluable population, 13 patients had CD25+ tumours and 11 patients had CD25 tumours. Patients with CD25+ tumours had a higher objective response (8/13; 61·5%) than patients with CD25 tumours (5/11; 45·5%) (Table III). Four of 13 (30·8%) patients with CD25+ tumours had a CR, while two of 11 (18·2%) patients with CD25 tumours achieved a CR. Meanwhile, four of 13 (30·8%) patients with CD25+ tumours and three of 11 (27·3%) patients with CD25 tumours achieved a PR. In contrast, non-response (SD or PD) was observed in five of 13 (38·5%) patients with CD25+ tumours versus six of 11 (54·5%) patients with CD25 tumours. Characteristics of responders are presented in Table IV.

Table III.   Response to denileukin diftitox by CD25 status.
Response typeCD25+ (n = 13)*CD25 (n = 11)
  1. Values given are n (%).

  2. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

  3. *CD25 positivity defined as ≥10% of tumour cells expressing detectable CD25 as assessed by immunohistochemistry, flow cytometry or both.

Objective response8 (61.5)5 (45.5)
 CR4 (30.8)2 (18.2)
 PR4 (30.8)3 (27.3)
Non-response5 (38.5)6 (54.5)
 SD1 (7.7)5 (45.5)
 PD4 (30.8)1 (9.1)
Table IV.   Characteristics of patients who responded to denileukin diftitox.
HistologyCD25 statusPrior treatment, n (type)Response to prior therapyTime to first response to denileukin diftitox (no. cycles)Time to best response to denileukin diftitox (no. cycles)PFS (months)Reason of study
  1. PFS, progression-free survival; CR, complete response; PR, partial response; ALCL, anaplastic large-cell T-cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; ESHAP, etoposide, methylprednisolone, cytarabine and cisplatin; HD, high-dose; PTCL, peripheral T-cell lymphoma; HCVIDD, hyperfractionated cyclophosphamide, dexamethasone, liposomal doxorubicin and vincristine; HCVAD, hyperfractionated cyclophosphamide, dexamethasone, doxorubicin and vincristine; AILD, angioimmunoblastic lymphadenopathy; ICE, ifosfamide, carboplatin and etoposide; ATT, alternating triple therapy; CVP, cyclophosphamide, vincristine and prednisone; TT, taxol/topotecan.

CR
 ALCL Alk-1 negative+4 (CHOP, ESHAP, HD cyclophosphamide, HD ifosfamide/etoposide)Relapse2438+Continues in CR
 PTCL+1 (HCVIDD, equivalent to HCVAD)Refractory2610Disease progression
 ALCL Alk-1 negative1 (HCVIDD, equivalent to HCVAD)Refractory4810Allogeneic stem cell transplant
 PTCL+1 (HCVIDD, equivalent to HCVAD)Relapse223Disease progression
 PTCL+1 (HCVAD)Refractory112Disease progression
 PTCL1 (HCVIDD, equivalent to HCVAD)Refractory2411Disease progression
PR
 AILD1 (CHOP)Relapse229Disease progression
 PTCL+3 (CHOP, ICE, compound 506)Refractory448Disease progression
 PTCL+1 (CHOP)Relapse116Disease progression
 PTCL+6 (ATT, compound 506, HD ifosfamide/etoposide, alemtuzumab, CVP, TT)Refractory225Allogeneic stem cell transplant
 AILD+1 (CHOP)Relapse225Patient decision
NK/T-cell lymphoma, angiocentric1 (HVCIDD, equivalent to HCVAD)Refractory114Disease progression
 PTCL4 (CHOP, ESHAP, etoposide, TT)Relapse111Patient decision

The median PFS for responding patients was 6 months (range, 1–38+ months) (Fig 1), with one noteworthy 80-year-old patient with an ongoing CR at 38+ months. Of note is the fact that one patient who experienced a CR and another who had a PR went on to receive allogeneic stem cell transplantations while in remission induced by denileukin diftitox. One patient with relapsed CD25 negative- angioimmunoblastic lymphadenopathy presented with widespread positron-emission tomography (PET)-positive adenopathy and disease involving 50% of his bone marrow, with platelet count of 30 × 109/l. Following treatment with denileukin diftitox, the patient experienced a complete resolution of his adenopathy, with a negative repeat PET scan. Bone marrow studies revealed only trace involvement of residual disease, as reflected also by the fact that the platelet count recovered to 130 × 109/l.

Figure 1.

 Kaplan–Meier estimate of progression-free survival of patients responding to denileukin diftitox y-axis, cumulative probability.

Toxicity

Overall, denileukin diftitox was well tolerated; most toxicities were grade 1 or 2 and transient (Table V). The most common toxicities were hypoalbuminaemia (74·1%), transaminase elevation (74·1%), oedema (63·0%) and skin reaction (59·3%). The only grade 3 toxicities reported in more than one patient were transaminase elevation (22·2%) and fatigue (7·4%). There were no haematological adverse events observed. No grade 4 adverse events were reported. No opportunistic infections were reported among patients during the time period of the trial.

Table V.   Toxicity (n = 27).
Toxicity (no. patients)Grade 1Grade 2Grade 3Grade 4Total
  1. Values in parentheses are in percentage.

Hypoalbuminaemia0191020 (74.1)
Transaminase elevation3116020 (74.1)
Oedema2141017 (63.0)
Skin reaction691016 (59.3)
Fatigue742013 (48.1)
Fever2101013 (48.1)
Cough54009 (33.3)
Constipation80008 (29.6)
Nausea/vomiting51006 (22.2)
Anorexia22004 (14.8)
Sensory/pain21003 (11.1)
Infection02103 (11.1)
Insomnia30003 (11.1)
Pleural effusion02002 (7.4)
Stomatitis02002 (7.4)
Diarrhoea11002 (7.4)
Pneumonitis10102 (7.4)
Dysphagia01001 (3.7)
Pulmonary embolism00101 (3.7)

Discussion

This is one of the largest trials evaluating single-agent treatment in relapsed T-NHL (excluding CTCL). Although high-dose chemotherapy regimens and SCT are being investigated as treatment options for patients with relapsed/refractory T-NHL, intensive chemotherapy may not be well tolerated, and not all patients meet the criteria for SCT. In addition, previous treatments and the presence of advanced disease contribute to limited bone marrow reserves in these patients. Therefore, effective alternative therapies with reduced toxicities are desirable for previously treated patients.

The response rate observed in this study (48%) compares favourably with that achieved in other single-agent studies. Other novel agents, such as nucleoside analogues, immune therapies, and a histone deacetylase inhibitor have also been studied as monotherapy in the treatment of T-NHL. A phase II study of pentostatin reported a 42% response rate in 14 patients with relapsed T-NHL (excluding patients with CTCL). In this study, pentostatin was also found to reduce CD26+ T lymphocyte levels, which may be associated with immunosuppression and increased risk of infection (Dang et al, 2003). Gemcitabine has shown activity in patients with relapsed/refractory T-NHL with response rates of 60% in smaller, single institution studies (Zinzani et al, 1998; Sallah et al, 2001). In one phase II study of 10 patients with refractory T-NHL treated with gemcitabine, two patients developed neutropenic fever, requiring subsequent dose reductions and the addition of colony stimulating factor (Sallah et al, 2001). In addition, a European pilot study found a 36% response rate with alemtuzumab in heavily pretreated PTCL patients (Enblad et al, 2004); however, significant haematological and infectious complications were observed in those patients, leading to an early closure of the study. Results of these and other trials of novel agents are summarised in Table VI (Waldman et al, 1995; Monfardini et al, 1996; Zinzani et al, 1998; Sallah et al, 2001; Dang et al, 2003; Ansell et al, 2004; Czuczman et al, 2004; Enblad et al, 2004; Forero-Torres et al, 2004; Tsimberidou et al, 2004; Piekarz et al, 2005).

Table VI.   Results of pilot and phase II studies of novel agents in T-cell non-Hodkin lymphoma (NHL).
DrugTotal no. patientsTotal no. T-cell NHL patients*Overall response rate (%)*Duration of response (months)Reference
  1. NR, not reported; PR, partial response, CR, complete response

  2. *Excludes cutaneous T-cell lymphoma patients.

  3. †Includes cutaneous T-cell lymphoma patients.

Investigational
 AraG (506U78)19812.5NRCzuczman et al (2004)
 Anti-CD25, yttrium-90 labelled181656PR, 9.2 (mean)Waldman et al (1995)
 SGN-30 (chimaeric monoclonal antibody)5533NRForero-Torres et al (2004)
 MDX-060 (fully human anti-CD30)48633NRAnsell et al (2004)
 Depsipeptide1919268–14 (range)Piekarz et al (2005)
Marketed
 Gemcitabine10106016.2 (mean)Sallah et al (2001)
 Gemcitabine13863NRZinzani et al (1998)
 Alemtuzumab1414367 (mean)Enblad et al (2004)
 Pentostatin1412426 (median)†Dang et al (2003)
 Pentostatin42105018 (median)†Tsimberidou et al (2004)
 Pentostatin3710103Monfardini et al (1996)

Our current study was the first phase II trial demonstrating the single-agent activity of denileukin diftitox in patients with relapsed/refractory T-NHL. The objective response rate of 48·1% was higher than that observed in patients with B-cell NHL (24·5%) (Dang et al, 2004). These results are promising, given that T-NHLs are more aggressive and generally associated with a poorer prognosis than B-cell NHLs (Melnyk et al, 1997; Gisselbrecht et al, 1998). Denileukin diftitox was also well tolerated, with the majority of toxicities grade 1 or 2 and transient, consistent with prior observations of denileukin diftitox-related adverse events. The proactive approach of managing anticipated hypersensitivity reactions by administering premedications combined with vigilant patient monitoring appeared to improve patient tolerability of denileukin diftitox. No grade 4 toxicities and no haematological adverse events were reported.

Notably, in the current study, two patients who achieved denileukin diftitox-induced remission (one CR in a patient with CD25 Alk-1 negative anaplastic large-cell T-cell lymphoma and one PR in a patient with CD25+ peripheral T-cell lymphoma) also underwent successful allogeneic SCT. These data indicate that denileukin diftitox may be as effective as salvage therapy prior to SCT in patients with relapsed/refractory T-NHL who achieved remission with treatment. Because denileukin diftitox is not associated with haematological toxicity, it may be better tolerated as salvage than conventional chemotherapy in a population already myelosuppressed due to heavy pretreatment with chemotherapy. Based on the success of post-treatment allogeneic SCT observed in the current study, the efficacy of denileukin diftitox in this setting, including outcomes following transplantation, should be evaluated in future clinical trials.

In the current study of treatment of relapsed/refractory T-NHL with denileukin diftitox, patients with CD25+ tumours had a higher response rate (but not statistically significant) than those with CD25 tumours. In particular, within the PTCL subset, there were three CRs (27·3%) and three PRs (27·3%) of 11 CD25+ PTCL patients (overall response rate: 54·6%), while there was one CR (16·7%) and one PR (16·7%) of six CD25 PTCL patients (overall response rate: 33·3%). This is in contrast to prior studies in patients with CTCL (Foss et al, 1994) or relapsed/refractory B-cell NHL (Dang et al, 2004), in which no such association was observed. These results may be due to one of several factors. One possible explanation for this discrepancy may lie in the fact that CD25 expression is required for the formation of high-affinity IL-2R; however, CD25 expression by itself does not indicate the presence of high-affinity receptor complex (Foss et al, 1994). In fact, a previous study evaluating the association between response to an IL-2 toxin and expression levels of the individual IL-2R subunits in cultured haematopoietic cells revealed that the expression of β-subunit (CD122) was more strongly associated with sensitivity to denileukin diftitox compared with the expression of α-subunit (CD25) (Re et al, 1996). A separate study previously demonstrated that high-affinity IL-2Rs facilitated the entry of denileukin diftitox 500–1000 times more efficiently than low- or intermediate-affinity IL-2Rs (Waldman et al, 1995); tumours expressing CD25 only, without the co-expression of CD122 and/or CD132, did not internalise the fusion toxin (Dang et al, 2003). It is possible that the majority of CD25+ tumours in the current study also expressed the CD122 (β) and/or CD132 (γ) IL-2R subunits, resulting in an intermediate- or high-affinity receptor complex and efficient internalisation of the fusion toxin. Likewise, the antitumour activity observed in CD25 patients may be accounted for by the fact that CD25 tumours could still express βγ subunits (CD122 and CD132), resulting in the formation of an intermediate-affinity IL-2R. Although we did not assess the expression of CD122 or CD132 in our study population, determining the co-expression of CD25 with CD122 and CD132 may be a better indication of responsiveness to denileukin diftitox and should be evaluated in future studies. It is also possible that some patients that were assessed as having CD25 tumours may have actually had CD25+ tumours due to a lack of sensitivity of the CD25 detection assay. Thus, the relationship between response and CD25+ status may have actually been stronger if the majority of CD25 responders were of undetectable CD25+ status. Another explanation may be simply due to the fact that the study involved relatively few numbers of patients in each subset, and the small sample size may therefore influence the observed difference in response to denileukin diftitox between CD25+ and CD25 T-NHL. Hence, additional studies with larger numbers of patients are needed to better evaluate the potential association between tumour CD25 expression and response to denileukin diftitox.

The current study demonstrated that denileukin diftitox is an active treatment for relapsed/refractory T-NHL, with response observed in both CD25+ and CD25 tumours. The encouraging antitumour activity and predictable and favourable toxicity profile of denileukin diftitox in this heavily pretreated population is promising and warrants further studies, perhaps at earlier stages in the disease, and in combination with other chemotherapeutic agents.

Acknowledgements

The study was supported in part by Ligand Pharmaceuticals Incorporated. The authors wish to thank the staff of Thomson Scientific Connexions for their work in the preparation of this manuscript.

Ancillary