- © 2004 by American Society of Clinical Oncology
Phase II Study of Denileukin Diftitox for Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
- Nam H. Dang,
- Fredrick B. Hagemeister,
- Barbara Pro,
- Peter McLaughlin,
- Jorge E. Romaguera,
- Dan Jones,
- Barry Samuels,
- Felipe Samaniego,
- Anas Younes,
- Michael Wang,
- Andre Goy,
- Maria A. Rodriguez,
- Pamela L. Walker,
- Yolanda Arredondo,
- Ann T. Tong and
- Luis Fayad
- From the Departments of Lymphoma/Myeloma, Hematopathology, Diagnostic Radiology, and Cardiology, University of Texas M.D. Anderson Cancer Center, Houston, TX
- Address reprint requests to Nam H. Dang, MD, PhD, The University of Texas M.D. Anderson Cancer Center, Department of Lymphoma/Myeloma, 1515 Holcombe Blvd, Box 429, Houston, TX 77030; e-mail: nhdang{at}mail.mdanderson.org
Abstract
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.
INTRODUCTION
Denileukin diftitox (ONTAK; Ligand Pharmaceuticals Inc, San Diego, CA) is a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin (DT) and the full-length sequence of interleukin-2 (IL-2) that targets lymphoma and leukemia cells expressing the IL-2 receptor (IL-2R).1,2 When the fusion gene is expressed in Escherichia coli, it results in the production of a single polypeptide chain with the capacity to bind to cells expressing IL-2R. Following internalization, protein synthesis is inhibited, resulting in cytotoxicity.1
The IL-2R consists of three different membrane proteins: an α-subunit (CD25), a β-subunit (CD122), and a γ-subunit (CD132).3 The IL-2R exists in complexes of these subunits that exhibit low (α-γ), intermediate (β-γ), and high affinity (α-β-γ) for IL-2. Only the intermediate- and high-affinity complexes permit endocytosis of denileukin diftitox.4,5 High-affinity IL-2R is expressed on activated T cells, B cells, and monocytes, but not on other normal human tissues.6 Constitutive expression of IL-2R is observed on lymphoma or leukemia cells of T- and B-cell origin, including chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), Hodgkin's disease, and non-Hodgkin's lymphoma (NHL).7-10 Cells exhibiting the high-affinity IL-2R seem to be approximately 1 log more sensitive to the cytotoxic effects of denileukin diftitox than cells expressing the intermediate-affinity IL-2R.4
Denileukin diftitox was shown to have substantial antitumor activity in patients with persistent or recurrent CTCL whose malignant cells exhibit CD25 expression.11-14 In heavily pretreated patients with advanced and/or recurrent CTCL who respond to denileukin diftitox, treatment is associated with significant improvements in self-rated quality of life, skin appearance, and pruritus severity.15 Because denileukin diftitox infrequently causes myelosuppression, it can be particularly useful in patients with cancer who have limited bone marrow reserves because of previous irradiation or chemotherapy. Responses to the drug have also been reported in patients with panniculitic lymphoma16 and CD25-expressing refractory peripheral T-cell lymphoma.17 The efficacy of denileukin diftitox has been established in CTCL but not in B-cell NHL. In a phase I trial in patients with lymphomas expressing CD25, two partial responses (PR) in patients with follicular lymphoma and one complete response (CR) in a patient with diffuse large-cell lymphoma were observed.18 Responses to denileukin diftitox have recently been reported in CD25-expressing refractory or relapsed CLL.19 Whether the CD25 expression threshold used in the phase III trial in CTCL (≥ 20% of cells) is required for benefit from denileukin diftitox is not known. In the phase III CTCL trial, 11 patients who responded to denileukin diftitox and who subsequently relapsed received additional therapy with the drug. At the time of re-treatment, skin biopsy specimens were CD25− in eight of these patients; however, five of the 11 patients, all of whom had low or undetectable CD25 expression, achieved a PR after re-treatment, suggesting that patients with CD25− tumors may benefit from therapy.
Despite recent advances in the treatment of NHL, limited treatment options are available for patients who have failed or relapsed following standard chemotherapy, immunotherapy, radioimmunotherapy, or transplantation. In addition, patients frequently have reduced bone marrow function from prior therapy or progressive disease. Because of its specific targeted mechanism of action and lack of significant myelosuppression, denileukin diftitox may provide an additional therapeutic option in these settings. The purpose of this phase II study was to evaluate the efficacy and toxicity of denileukin diftitox in patients with relapsed or refractory, CD25+ or CD25− B-cell NHL.
PATIENTS AND METHODS
Patients
Patients with relapsed or refractory, low- or intermediate-grade, B-cell NHL and whose tumor tissue assay was either CD25+ (≥ 10% of cells) or CD25− (< 10% of cells) by immunohistochemistry or flow cytometry before treatment with denileukin diftitox were eligible for the study. All patients with B-cell histologies, including mantle-cell lymphomas and those with transformed or divergent histologies, were eligible. Patients must have had one or more prior therapeutic regimen. Patients eligible for autologous bone marrow transplantation (BMT) could receive denileukin diftitox treatment to maximum reduction of tumor bulk (a minimum of two cycles before crossing over to BMT). Other inclusion criteria included the following: a negative test result for HIV, minimum life expectancy ≥ 12 weeks, Zubrod performance status ≤ 2, absolute neutrophil count (ANC) ≥ 1,000/μL, and platelet count ≥ 40,000/μL (unless secondary to marrow involvement by lymphoma), serum bilirubin level ≤ 1.5 mg/dL, aminotransferase level less than 4× the upper limit of normal, serum creatinine level ≤ 1.5 mg/dL, and serum albumin level ≥ 3.0 g/dL. CD25 expression was determined by immunohistochemistry on formalin-fixed, paraffin-embedded, biopsy material (4C9 antibody; Novocastra, Newcastle-on-Tyne, UK). The level of CD25 expression was determined by a manual count of 100 to 200 tumor cells, identified with the aid of parallel CD20 and CD3 immunostains. The level of CD25 in activated T cells within a section of non-neoplastic lymph node was used as a staining control. In a subset of cases, CD25 expression of tumor cell populations was also determined by flow cytometry using a phycoerythrin-labeled anti-CD25 antibody (BC Biosciences, San Jose, CA) and correlated with levels detected by immunostaining. For both assays, tumors were considered positive if ≥ 10% tumor cells had detectable CD25.
Patients with another malignancy were ineligible, with the exception of those with basal cell carcinoma of the skin or in situ cervical carcinoma, who had been treated with curative intent. Patients must not have had any anticancer treatment (including radiotherapy) within the past 4 weeks (any irradiated area was not assessable for response). Patients were not permitted to have had a prior allogeneic BMT, though a prior autologous BMT was acceptable. Patients were ineligible if they had any serious intercurrent illness and active infection; had congestive heart failure, significant arrhythmia, or a history of myocardial infarction during the 12 months before study entry; were receiving concomitant corticosteroids (though treatment for adverse events such as hypersensitivity-type reactions was permitted); or had active CNS disease or a history of seizure. Patients with a history of known hypersensitivity to denileukin diftitox or any of its components, including diphtheria toxin, IL-2, or specific excipients, were also excluded, as were patients who were pregnant or nursing. For women of childbearing potential (ie, exclusion of postmenopausal women, women who have been surgically sterilized), adequate birth control methods were mandatory.
All patients provided signed informed consent according to institutional guidelines before study entry. Human investigations were performed after approval by The University of Texas M.D. Anderson Cancer Center institutional review board, and in accord 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 for 5 consecutive days as an intravenous (IV) infusion over 45 to 60 minutes. Cycles were repeated every 3 weeks. This dose level was maintained throughout the study as long as it was tolerated. Treatment was interrupted in patients experiencing grade 2 or 3 toxicity until toxicities resolved to grade 1 or less before continuing, with a maximum delay of 14 days. If toxicities did not improve to grade 1or less in the 14-day period, the patient was removed from the study. On resumption of treatment, a reduced dose of 9 μg/kg once daily for 5 days could be administered at the determination of the attending physician. To reduce the frequency and severity of acute hypersensitivity-type reactions,20 premedication consisting of dexamethasone 8 mg IV, diphenhydramine 25 to 50 mg IV or orally, and acetaminophen 650 mg orally was administered 30 minutes before each infusion of denileukin diftitox, unless patients had a prior allergic reaction to any of these drugs.
After every two cycles, restaging was performed. A CR was defined as the absence of clinical and histologic disease. A PR was defined as ≥ 50% reduction in measurable disease. Stable disease (SD) was defined as less than 50% reduction in measurable disease and no evidence of progression. Progressive disease was defined as an increase in the size of existing tumor lesions or the appearance of new lesions not previously identified. Treatment was continued in responding patients (CR and PR) to a maximum of eight cycles. For patients with SD, denileukin diftitox was continued for as long as therapeutic benefit was evident.
Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria. All adverse events, regardless of severity or presumed relationship to the study drug, were recorded. For serious life-threatening grade 4 toxicities, the attending physician was given the option to remove the patient from the study. Denileukin diftitox treatment courses were suspended pending recovery to ANC greater than 1,000/μL, platelets greater than 40,000/μL (unless secondary to marrow involvement by lymphoma), and serum albumin ≥ 3 g/dL. The primary criterion for treatment discontinuation was unacceptable toxicity despite dose modification. In addition, patients were permitted to discontinue participation at their will or by investigator decision at any time.
Statistics
Patient characteristics, the safety profile, treatment administration, and response rate by baseline patient characteristics were characterized with descriptive methods. Patient probabilities of overall survival, time to treatment failure, and progression-free survival (PFS) were calculated from time of entry into the protocol using the Kaplan-Meier method.21
RESULTS
Patient Population
A total of 50 patients from The University of Texas M.D. Anderson Cancer Center were entered into the study. Five patients were not assessable—three did not return after receiving one cycle of treatment, and two refused to start treatment following study registration. These patients were excluded from the evaluation. Baseline characteristics of the 45 assessable patients are shown in Table 1. The predominant histologies were diffuse large-cell lymphoma, mantle-cell lymphoma, and small lymphocytic lymphoma. Tumor CD25 status was positive in 23 patients, negative in 17 patients, and not determined in five patients. Most patients had undergone multiple prior treatments, including autologous stem-cell transplantation (n = 7). All other patients were not candidates for BMT at the time of registration because of the disease being refractory or some other comorbidity. Thrombocytopenia was common, with 17 patients (38%) having less than 100,000 platelets/μL and 10 (22%) having less than 75,000/μL. On study entry, 32 patients (71%) had disease that was refractory to the most recent chemotherapy treatment.
Assessable Patient Characteristics at Baseline (N = 45)
Treatment Summary
A total of 162 cycles of denileukin diftitox was administered (18 μg/kg/d [150 cycles] and 9 μg/kg/d [12 cycles]). In patients assessable for response, the median number of treatment cycles was two (range, one to eight). In patients with responsive or stable disease, the median number of treatment cycles was four (range, two to eight). Six patients had toxicity-related treatment delays, four patients discontinued treatment because of toxicity (two due to hypoalbuminemia, two due to pulmonary toxicity), and one patient who also received vancomycin died of complications from toxic epidermal necrolysis. This patient had failed eight prior therapies, including autologous stem-cell transplantation, before enrollment onto this study.
Response
Forty-five patients were assessable for response. Response by histology and tumor CD25 status are shown in Table 2. Three CRs (6.7%; one patient each with diffuse large-cell lymphoma, follicular mixed lymphoma, and mantle-cell lymphoma) and eight PRs (17.8%; four patients with diffuse large-cell lymphoma, one with follicular center cell lymphoma grade 3, two with mantle cell lymphomas, and one with small lymphocytic lymphoma) were observed, for an overall response rate of 24.5%. Nine patients (20%) had SD. All patients had prior treatment with rituximab. Additional details on patients with responsive disease are shown in Table 3.
Response by Histology and Tumor CD25 Status
Characteristics of Patients With Responsive Disease
No obvious correlation was seen between response and CD25 expression. The overall response rate was 22% (one CR, four PRs) in CD25+ histologies, 29% (two CRs, three PRs) in CD25- histologies, and 20% (one PR) in the patient with unknown CD25 status. Stable disease occurred in five patients (22%) with CD25+ histologies and three patients (18%) with CD25- histologies. One patient (20%) had SD in the group with undetermined CD25 status. The best objective response in patients who responded was obtained after a median of four cycles (range, two to eight). The median PFS for these 45 patients was 2 months, with a PFS at 20 months of 5% (95% CI, 0% to 14%; Fig 1A). In patients who responded to treatment the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range 9 to 28 months); the 20-month PFS is 24% (95% CI, 0% to 60%; Fig 1B). In the responder group, seven patients are still alive (64%), for a projected 20-month survival of 65%. In comparison, 14 of 34 patients (41%) in the group of nonresponders are alive, for a 20-month survival of 22% (95% CI, 4% to 40%; Fig 2; log-rank P = .03). Of the four patients in the responder group who died, causes of death were disease in two patients, potential toxicity in one (toxic epidermal necrolysis while the patient was in PR), and one unrelated cause (myocardial infarction while the patient was in CR). Seven patients in the responder group had a relapse, and two patients remain in continuous remission at 540 and 630 days after treatment initiation (Table 3).
Progression-free survival for all evaluable patients (A) and for patients responding to denileukin diftitox (B), based on Kaplan-Meier estimates.
Overall survival comparison between patients responding and not responding to denileukin diftitox, based on Kaplan-Meier estimates.
Toxicity
Overall, treatment was well tolerated, with the majority of toxicities being grade 1 or 2 in severity and transient. Grade 3 and 4 toxicities are summarized in Table 4. The most frequent toxicities included hypoalbuminemia, fatigue, and transient elevations in serum transaminase levels. Hematologic toxicity was observed more commonly in patients with bone marrow involvement. One patient who also received vancomycin developed toxic epidermal necrolysis.
Toxicity (N = 45)
CD4, CD8, and IL-2R Levels
The median number of CD4+ and CD8+ lymphocytes did not change significantly during the course of treatment (Fig 3). Pretreatment serum IL-2R levels were also measured in 20 patients. No statistically significant difference in the median serum IL-2R levels was found between responders (n = 7; median, 7.8 pmol/L; range, 1.8 to 29.7 pmol/L) and nonresponders (n = 13; median, 9.4 pmol/L; range, 2.3 to 59.7 pmol/L; P = .55, Mann-Whitney).
Median CD4+ and CD8+ levels pretreatment and after each denileukin diftitox treatment cycle.
DISCUSSION
Even with recent advances in immunotherapy and radioimmunotherapy, many patients with NHL relapse or fail all available treatment options. Some of these patients may be effectively treated with allogeneic or autologous stem-cell transplantation; however, others may not be eligible for transplant because of age, comorbidity, or lack of a suitable donor. Some patients relapse after transplantation. Patients who relapse or whose disease is refractory to treatment typically have limited bone marrow reserve because of prior treatment or advanced disease. Thus, additional therapies that are not myelosuppressive and can kill multidrug-resistant malignant stem cells can play an important therapeutic role in the treatment of NHL. Immunotoxins, such as denileukin diftitox, are one class of agents that display these characteristics and are under investigation in the treatment of chemoresistant hematologic malignancies.22 In an earlier phase I trial of denileukin diftitox in lymphomas expressing IL-2R, objective responses were observed in three patients with relapsed NHL—two with follicular lymphoma, and one with diffuse large-cell lymphoma that was refractory to primary chemotherapy and who relapsed less than 100 days after autologous BMT.18 To date, our study was the first phase II study to evaluate denileukin diftitox in the treatment of refractory or relapsed B-cell NHL. In addition, we sought to determine whether the drug would be active in this patient population regardless of whether CD25 expression was low or undetectable.
The results of our study are notable because an objective response rate of 24.5% (including three CRs) was observed in a very heavily pretreated and myelosuppressed NHL patient population. The median number of prior treatments for patients in this study was four (range, one to nine), with seven patients having undergone previous autologous stem cell transplantation. Other indicators that patients were heavily pretreated in general were that thrombocytopenia was common and that most patients had disease refractory to the most recent chemotherapy treatment. Three patients with diffuse large-cell lymphoma and one patient with follicular center cell lymphoma grade 3 achieved PR with denileukin diftitox following relapse after autologous BMT. A durable remission was also reported following denileukin diftitox therapy in a patient with stage IV NHL mixed follicular type who relapsed after autologous transplant and who failed multiple therapies, including rituximab, CHOP, and fludarabine.23 In our study, SD was also observed in 20% of patients. In this patient population, achieving SD can be clinically meaningful. The ability to induce tumor response or stabilize disease in such heavily treated patients suggests that denileukin diftitox may be a useful option in refractory or relapsed B-cell NHL. We are also currently evaluating denileukin diftitox in the treatment of relapsed or refractory T-cell NHL.
In theory, response of malignant cells to denileukin diftitox (or other receptor-targeted IL-2 toxin therapy) is defined by the ability of the IL-2R on the cell surface to bind the toxin with sufficient affinity and to transport that toxin to an intracellular compartment where it exerts cytotoxicity.5 In turn, these properties are thought to depend on the relative composition of the IL-2R in terms of its subunits α (CD25), β (CD122), and γ (CD132), with the β subunit demonstrating the greatest direct correlation with the inhibition of cell protein synthesis.5 In our study, responsive disease or SD did not correlate with CD25 expression. Similarly, no clear correlation has been observed between CD25 expression and responsiveness of patients with CTCL treated with denileukin diftitox.11,13,24 In a retrospective analysis of IL-2R isoform and clinical response in patients with NHL screened for a phase I/II denileukin diftitox study, 14 of 31 patients with low-grade B-cell NHL expressed the α subunit (one patient had an objective response) and none expressed the β subunit, while 10 of 35 patients with intermediate-grade NHL expressed the α subunit (one patient had an objective response) and five patients expressed α-β (one patient had an objective response).24 In the intermediate-grade NHL group, no difference was seen in response by the isoform. These findings corroborate in vitro data, which suggest that expression of the β subunit in conjunction with the α subunit (rather than the α subunit alone) may provide more direct correlation with inhibition of cell protein synthesis in patients receiving denileukin diftitox.5 Thus, based on the apparent affinity of denileukin diftitox for the CD122 subunit of the IL2R,5 CD25 expression alone may not be the most accurate gauge of drug affinity for the receptor or clinical efficacy.
Several potential reasons may therefore exist for the finding that tumor cell CD25 expression did not correlate with response to denileukin diftitox in the present study. As mentioned previously, CD25 is part of the IL-2 receptor complex, which also can consist of CD122 and CD132, and expression of CD25 alone does not reflect relative levels of other chains and thus may not predict relative drug affinity or clinical efficacy. In addition, the threshold for CD25 detection may be higher than that for efficacy, possibly because the number of cells or the number of receptors per cell necessary for response is below the level of detection. Another issue relating to IL-2R expression and tumor sensitivity to denileukin diftitox is that receptor expression is partially dependent on the biopsy specimen. Significant variability has been observed from lesion to lesion in individual patients with CTCL, as well as interindividual variability, and we observed both in our study. Although the exact explanation behind our observation that denileukin diftitox activity is not correlated with detectable CD25 expression remains to be elucidated, our findings have significant clinical implications. By demonstrating that denileukin diftitox can be an effective drug for the treatment of relapsed/refractory B-cell NHL, regardless of tumor CD25 expression, we have shown that current methods of evaluating CD25 expression in the clinical setting (by either immunohistochemistry or flow cytometry) are not adequate to predict potential responses. Importantly, our work thus suggests that CD25 expression should not be a prerequisite for denileukin diftitox treatment in relapsed/refractory B-cell NHL and that patients with B-cell NHL may potentially benefit from denileukin diftitox treatment, regardless of tumor CD25 status.
Denileukin diftitox treatment was well tolerated. The toxicity profile was similar to that observed in patients with CTCL,13 with the most common toxicities being hypoalbuminemia and elevated serum hepatic transaminase levels. Most toxicities were low grade and transient. Little hematologic toxicity was observed; the incidence of grade 3 or 4 toxicities, other than elevated transaminase levels, was relatively low. Of note was the fact that a marked decrease in grade 3 and 4 capillary-leak syndrome was seen compared with previous studies involving denileukin diftitox. This decrease most likely was due to both our premedication regimen and an increased awareness of and vigilance for early detection and management of this condition in patients being given this drug. The use of a premedication regimen in our study appeared to decrease the incidence and severity of acute hypersensitivity-type reactions.24 The mean number of denileukin diftitox cycles administered increased for cohorts of patients accrued to our study over time, probably because of increasing familiarity with the drug and its administration and because patients became more compliant as they were better able to understand and manage treatment toxicities. Furthermore, as noted in previous reports, the severity and frequency of toxicities decreased with increasing cycles of denileukin diftitox treatment. Our data demonstrating that denileukin diftitox has single-agent activity with a favorable toxicity profile in a group of heavily pretreated patients with relapsed/refractory B-cell NHL would therefore suggest that this drug has clinical utility in a number of settings. Among possible future uses for denileukin diftitox may be as part of a combination regimen for the treatment of B-cell NHL, in view of its unique mechanism of action and, particularly, its lack of myelosuppression.
As part of the premedication regimen to reduce the frequency and severity of potential adverse events, corticosteroids were given to patients with each administration of denileukin diftitox. Consistent with previous findings,20 corticosteroid premedication in patients with CTCL improved the tolerability and potentially decreased the rate of discontinuation of denileukin diftitox because of adverse events. Allowing patients to remain on therapy by minimizing the frequency and severity of side effects through corticosteroid administration is potentially important for maximizing drug effectiveness, in view of the fact that the best objective response was obtained after a median of four treatment cycles. A consideration regarding the use of corticosteroid premedication is the potential role of steroids in the antitumor effect of denileukin diftitox. Corticosteroids may potentially be synergistic with their lymphotoxic effect; conversely, corticosteroids may potentially interfere with the activity of denileukin diftitox through several possible mechanisms.20 Corticosteroids may hypothetically decrease IL-2 receptor expression on the surface of the tumor cell. In addition, besides the direct cytotoxic effect of denileukin diftitox on tumors, it has been speculated that this drug enhances bystander effects by influencing the immune system, which can be abrogated by corticosteroids.
As in patients with CTCL18 or NHL,18,25 in our study, median CD4+ and CD8+ levels did not change with denileukin diftitox treatment. Further, sIL-2R levels did not appear to correlate with response in our study. In a previous report,18 patients with CTCL who did not respond to denileukin diftitox had significantly higher sIL-2R levels than those who did respond. Whereas in patients with NHL who responded, no significant change in mean sIL-2R levels was seen but mean levels increased significantly in nonresponders.
In summary, denileukin diftitox appears to be effective in CD25+ B-cell NHL, as well as in tumors with low or undetectable CD25 expression. The drug was well tolerated at the dosage schedule evaluated. Because of its activity and tolerability in a heavily pretreated population, evaluation of denileukin diftitox in combination with other agents in B-cell NHL may be warranted.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Nam H. Dang, Ligand Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: Nam H. Dang, Ligand Pharmaceuticals.
Footnotes
-
Supported in part by the Medical Affairs Department of Ligand Pharmaceuticals Inc. The work of N.H. Dang is supported in part by a grant from The M.D. Anderson Physician-Scientist Program and the Gillson Longenbaugh Foundation.
The work reported is original, and interim results were presented previously at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Published in the Proceedings of the American Society of Clinical Oncology, 39th Annual Meeting, 2003, volume 2, page 570, abstract 2292; and at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003. Published in the Journal of the American Society of Hematology, 2003, volume 102 (part 2), page 303b, abstract 4935.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
- Received March 9, 2004.
- Accepted August 4, 2004.
