Journal of Clinical Oncology, Vol 19, Issue 2
(January), 2001: 376-388
© 2001 American Society for Clinical Oncology
Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma
By Elise Olsen,
Madeleine Duvic,
Arthur Frankel,
Youn Kim,
Ann Martin,
Eric Vonderheid,
Brian Jegasothy,
Gary Wood,
Michael Gordon,
Peter Heald,
Allan Oseroff,
Lauren Pinter-Brown,
Glen Bowen,
Timothy Kuzel,
David Fivenson,
Francine Foss,
Michael Glode,
Arturo Molina,
Elizabeth Knobler,
Stanford Stewart,
Kevin Cooper,
Seth Stevens,
Fiona Craig,
James Reuben,
Patricia Bacha,
Jean Nichols
From the Duke University Medical Center, Durham, NC; University of Texas Anderson Cancer Center, Houston, and University of Texas Health Sciences Center at San Antonio, San Antonio, TX; Hollings Cancer Center, Charleston, SC; Stanford University, Stanford, University of California Los Angeles, Los Angeles, and City of Hope, Duarte, CA; Washington University, St Louis, MO; Allegheny University, Philadelphia, and University of Pittsburgh, Pittsburgh, PA; University Hospital of Cleveland, Cleveland, OH; Indiana University, Indianapolis, IN; Yale University, New Haven, CT; Roswell Park Cancer Institute, Buffalo, and Columbia Presbyterian, New York, NY; University of Michigan, Ann Arbor, and Henry Ford Health System, Detroit, MI; Northwestern University Medical School, Chicago, IL; Boston University Medical Center, Boston, and Seragen, Inc, Hopkinton, MA; University of Colorado, Denver, CO; and Vanderbilt University, Nashville, TN.
Address reprint requests to Elise A. Olsen, MD, Duke University Medical Center, Box 3294, Durham, NC 27710; email olsen001{at}mc.duke.edu
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ABSTRACT
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PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Phar-maceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.
PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on  20% of lymphocytes were assigned to one of two dose levels (9 or 18 µg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti–interleukin-2 and serum concentrations of denileukin diftitox were also measured.
RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 µg/kg/d was similar, and there was no evidence of cumulative toxicity.
CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
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INTRODUCTION
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CUTANEOUS T-CELL lymphoma (CTCL) is a malignant lymphoma characterized by a phenotypically diverse but categorizable clinical presentation and a typical histopathologic picture of malignant CD4+ or CD8+ T-lymphocytes in the skin.1-3 Treatments are generally tailored to the stage of CTCL with many patients progressing inexorably through a panoply of immunomodulatory or cytotoxic therapies usually utilized, but not Food and Drug Administration-approved, for this particular indication. Treatment is indicated to modulate symptoms, improve clinical appearance, prevent secondary complications, and prevent progression of disease which, in turn, has an impact on survival.4 As many patients become refractory to the currently available treatments, new therapies are needed to manage this malignancy.
Denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin and human interleukin (IL)-2.5 This gene, as expressed in Escherichia coli, results in the production of a single polypeptide chain that, at picomolar concentrations, is capable of inhibiting protein synthesis in cells that express the IL-2 receptor (IL-2R), resulting in cell death.6 The human IL-2R is present in three forms: low, intermediate, and high affinity.7 The high affinity IL-2R is a complex of 3 distinct proteins of 55kD (CD25, p55, TAC,  chain), 75 kD (CD122, p75, ß chain), and 64 kD (CD132, p64,  chain). The CD25 protein alone defines a low affinity IL-2R. The CD122 and CD132 proteins together define an intermediate affinity IL-2R, and all three proteins together define a high affinity IL-2R.8 The low affinity receptor is incapable of mediating endocytosis of bound ligand whereas the intermediate or high affinity-complex rapidly internalizes bound IL-2. The high affinity receptor may be the biologically relevant form of the IL-2R on mature activated T-cells while the intermediate affinity receptor may mediate proliferation in cell types such as natural killer cells. Expression of a high affinity form of IL-2R is normally restricted to activated T-lymphocytes, B-lymphocytes, and macrophages9, but constitutive expression of one or more of the IL-2R subunits may be seen on certain leukemic or lymphomatous cells of T- and B-cell origin including CTCL.10 While denileukin diftitox binds to all three forms of the IL-2R, only cells with intermediate or high affinity receptors will internalize it.11
Denileukin diftitox has been shown in a phase I/II trial to be well tolerated and to have antitumor effects in patients with CTCL and non-Hodgkin’s lymphoma whose malignant cells express the IL-2R.12,13 The purpose of this multicenter, randomized, blinded, parallel-group study was to evaluate the efficacy, safety, and pharmacokinetics of two dose levels of denileukin diftitox in patients with CTCL whose malignant cells express IL-2R.
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PATIENTS AND METHODS
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Male patients and nonpregnant, nonlactating female patients 18 years old were eligible to participate. Women of child-bearing potential had to agree to practice contraception. All patients had to have either 1) a biopsy diagnostic of or consistent with CTCL within 6 months of study entry or 2) a biopsy suggestive of CTCL within that time frame in conjunction with a diagnostic biopsy of skin in the past or concurrent diagnostic material from blood or lymph node. To be eligible to participate, patients had to have 20% of lymphocytes within the skin biopsy stain positively for CD25 by immunohistochemistry. Patients who had high-grade large-cell and/or poorly differentiated tumors were excluded. All histologic and immunohistochemical interpretations were made by a central pathologist (FC).
Patients with stage Ib-III CTCL (CTCL Cooperative Group staging, Table 13), either mycosis fungoides or Sézary’s syndrome, which had recurred or persisted after 4 previous treatments for CTCL (excluding topical or systemic corticosteroids) or patients with stage IVa CTCL who had failed at least one previous therapy were eligible for study consideration. Patients must not have previously received IL-2 fusion proteins and must have been off all previous treatment for CTCL for more than 14 days.
Screening/staging evaluation consisted of physical examination, blood work, chest x-ray, computed tomography (CT) scan of the axilla, abdomen, and pelvis, and lymph node biopsy if there was palpable adenopathy of 1 cm2. Laboratory testing included routine hematology, serum chemistries, and urinalysis. All patients were screened for potential blood involvement with CTCL by fluorescence-activated cell sorting (FACS) analysis at a central lab (JR); blood samples were analyzed by using three-color flow cytometry, which permitted the identification of surface antigens. The whole blood lysis method for the analysis of lymphocytic subsets in peripheral blood was used. Positive blood involvement as part of the tumor burden calculation was considered in patients who had 20% of all lymphocytes with CD3+, CD4+, CD45RO+, CD7- phenotype. Those patients with nodal (defined as LN3 or LN414) or blood involvement had to have a bone marrow biopsy as well; if the latter was positive, patients were excluded from study participation.
Patients had to test negative for human immunodeficiency virus, human T-cell lymphotrophic virus type I, hepatitis B (surface antigen), and hepatitis C (surface antibody). Patients had to have normal organ function and serum albumin more than 3.0 g/dL, hepatic AST  75 U/L and ALT 100 U/L; hematocrit greater than 27%, hemoglobin 9 g/mL and platelets 100,000 cells/µL without transfusion support; creatinine 1.8 mg/dL or creatinine clearance 50 mL/min with urine protein less than 2+ mg/dL or less than 1 gram per 24 hours. Patients had to be free of any signs of active systemic infection and had to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Cardiac status had to be at least a New York Heart Association class I or II and hypertension, if present, had to be well controlled.
Dosing
The drug was supplied as a frozen (-10°C) sterile solution formulated in citrate buffer in 2-mL single-use vials at a concentration of 150 µg/mL. Patients were randomly assigned to one of two dose levels of denileukin diftitox 9 or 18 µg/kg/d. Randomization was stratified by stage of CTCL, ie, IIa or IIb. The study drug was diluted with sterile nonpreserved saline to a minimum concentration of 15 µg/mL and delivered by a pump device into a running infusion line in a 15- to 60-minute period. This outpatient procedure was repeated for 5 consecutive days approximately every 21 days. Patients were to receive a maximum of eight courses or 6 months of therapy; however, up to three additional courses could be given to patients who had a documented ongoing response.
Patients were permitted to receive 650 mg of acetaminophen and routine doses of antihistamine 30 to 60 minutes before infusion of the study drug and either 25 mg of promethazine or 10 mg of prochlorperazine for nausea. Systemic corticosteroids as premedication or concomitant medication during infusion of denileukin diftitox were prohibited, although exceptions were granted based on individual infusion-related adverse events. Oral hydroxyzine and topical emollients (Aquaphor, Eucerin; Beiersdorf Inc, Norwalk, CT) and bath additives (Aveeno Bath; Rydelle Laboratories, Racine, WI) were permitted as "rescue" medications throughout the study.
Assessment of Efficacy
A rigorous and multifactorial approach to define response was used in this study. Separate safety and efficacy assessors were used. The assessor used the following tools to quantify tumor burden: (1) in the skin by either the severity weighted assessment tool (SWAT)15,16 in those patients with more than 10% involved body-surface area (BSA) or, in patients with 10% BSA involved, by summation of bidimensional measurements of up to five selected target lesions; (2) in the lymph nodes by bidimensional measurements of up to five target nodes, and (3) in the blood by FACS analysis. The SWAT required investigators to map patch, plaque, and tumor lesions on a two-dimensional ventral and dorsal drawing of a human figure. A standardized grid was then placed over the figures and used to calculate the BSA involved. The final values were weighted dependent on the type of lesion (1 = patch, 2 = plaque, 4 = tumor) and the values added to produce the SWAT score. The same weighting scores were applied to target lesions in those patients with limited (10% BSA) disease.
At baseline, the summation of the number and size of all 1 cm2 lymph nodes, noted by palpation and/or CT scan, that were histologically either LN3 or LN4 was performed. A change from baseline for lymph nodes was determined at each course and by CT scan at the time of objective response and during follow-up at 6 and 12 months. The percentage of abnormal circulating lymphocytes by FACS analysis was noted at baseline and repeated at each course for those patients with 20% abnormal lymphocytes.
Tumor burden (the average of the skin, lymph node, and blood changes) was assessed at baseline and at 3-week intervals of time. Overall response was determined by taking into account changes in tumor burden defined as follows: complete response (CR), clinically and histologically clear of disease; clinical complete response (CCR), no evidence of disease clinically but histologic clearing not verified; partial remission (PR), 50% reduction measured tumor burden; stable disease (SD), less than 50% improvement in tumor burden and less than 50% increase in tumor burden; and progressive disease (PD), 50% increase in tumor burden, appearance of new nodes histopathologically documented to be LN3, development of visceral disease or more than two new CTCL sites in those with 10% BSA at baseline.
A documented response was defined as lasting at least 6 weeks. All responses were verified by an independent panel of physicians (the Data End Point Review Committee). Duration of response for those who responded to therapy was measured from the date of first dose until relapse.
Global CTCL severity was assessed by the investigator with a 10-cm visual analog scale (VAS) with 0 = no involvement and 10 = extremely severe involvement. The investigator rated the erythroderma severity score from 1 to 5, where 1 = no erythema; 2 = mild: diffuse erythema without edema, scaling or fissuring/exudation; 3 = mild/moderate: diffuse erythema with either edema, nonconfluent scaling or fissuring/exudation; 4 = moderate/severe: diffuse erythema with two or three of the following: edema, nonconfluent scaling, and/or fissuring/exudation; or 5 = severe: diffuse erythema with edema, confluent scaling (generalized exfoliation) and fissuring/exudation.
Patients were also asked to independently assess response by giving a global assessment of their skin on a Lickert-type scale where -2 = definitely worse, -1 = possibly worse, 0 = no change, +1 = possibly improved, +2 = definitely improved, +3 = almost normal, and +4 = normal. At the beginning of each course, patients were also asked to measure severity of pruritus on a 10-cm VAS of 0 = no itch to 10 cm = worst imaginable itch.
The use of rescue medications was also tabulated at the beginning of each course as an indirect means of assessing improvement. A quality-of-life questionnaire (FACT-G), validated for use in cancer patients, addressed changes in functional status.
Assessment of Safety
Physical examination was done on day 1 before each successive treatment course and on days 10 and 18 between treatment courses. The following labs were also done at each of these visits: electrolytes, glucose, liver function tests, lactate dehydrogenase, creatinine, blood urea nitrogen, total protein, albumin, calcium, phosphorus, complete blood count with differential, and a quantitative urinalysis.
Antibody Measurements
Antibodies to denileukin diftitox and IL-2, as determined by enzyme-linked immunoadsorbent assay (ELISA), were measured at day 1 before each course. An in vitro assay was used to assess neutralizing antibodies by measuring the ability of serum antibodies to protect a human IL-2R expressing cell line from the cytotoxic effects of denileukin diftitox. The results are reported in units of neutralizing activity where one unit is the amount of antibody that will neutralize 2.3 µg of denileukin diftitox (lower limit quantitation = 0.02 NU/mL).
Pharmacokinetic Measurements
Blood samples were drawn immediately after dose administration and at specified intervals after dosing with denileukin diftitox on days 1 and 5 of course 1 and days 1 and 5 of course 3. Serum concentrations of immunoreactive denileukin diftitox were determined in a standard asymmetric sandwich ELISA by using two antibodies: one to the diphtheria toxin portion and one to the IL-2 portion of the molecule. A sample processing step that dissociates denileukin diftitox from bound antibodies allows the determination of total circulating levels of denileukin diftitox. The lower limit of quantitation of denileukin diftitox in serum is 0.2 ng/mL. Pharmacokinetic parameters associated with clearance of denileukin diftitox were calculated based on serum concentration versus time profiles. Blood samples for full pharmacokinetic analysis were drawn from a subset of patients. Samples were only drawn at a small number of time points for the other patients in the study. Bayesian analysis, based on population means calculated from the full pharmacokinetic analysis results (Vd and rate constants), was used to generate pharmacokinetic parameters for the patients with partial sampling data.
Statistical Analysis
Intent-to-treat analysis was used for the safety and efficacy data and included all patients who received at least one dose of the study drug. The total number of objective responders (CR, CCR, and PR) determined by the Data End Point Review Committee is the primary efficacy variable; the best response for each patient was used for the analysis where CR > CCR > PR. The two-sided 95% confidence intervals (CIs) are presented for the proportion of the complete and partial responders combined for each dose group and for both dose groups combined. Patient global skin assessment and need for rescue medications between groups were compared by using the Wilcoxon rank sum test. The pruritus VAS and need for rescue medication by patients was compared by use of the Wilcoxon signed-rank test: patients with at least 20% reduction in the number of dosage units from baseline were considered improved in symptoms.
Patients were categorized based on the following baseline demographic parameters: age, sex, race, body mass index, and circulating malignant cells (not present or present at a level of 20% of circulating lymphocytes with an abnormal phenotype of CD3+, CD4+, CD45RO+, CD7-). A linear regression model was run with each of the pharmacokinetic variables to determine the potential significant contribution of each demographic parameter. Separate models were run for the 9- and 18-µg/kg/d dose levels. A P value .05 was required for significance.
Patients were classified based on whether they experienced a particular adverse event or grade shift in laboratory parameter. The Kruskal-Wallis test was used to determine statistical differences in distribution of adverse events or laboratory changes and antidenileukin diftitox or anti-IL-2 antibody titers. A linear regression model was run with each adverse event or laboratory parameter shift to determine the potential significant contribution of each pharmacokinetic variable, irrespective of dose, with a P value .05 required for significance.
Patients were categorized as responders or nonresponders. The relationship between antitumor effects and development of antibodies was demonstrated graphically for the responder and nonresponder groups. Values for pharmacokinetic parameters, irrespective of dose level, were examined in relationship to response.
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RESULTS
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One hundred twenty-five of the 276 screened patients had biopsies histologically compatible with CTCL and containing 20% CD25+ expressing cells. Seventy-one of these patients also met other inclusion criteria and were enrolled in the study. Two of these patients were later determined to be ineligible after treatment was initiated: one patient was found to be human T-cell lymphotrophic virus type I -positive and one had not recovered from toxicity related to previous radiation and chemotherapy.
The demographic and staging characteristics by treatment group are given in Table 2. No statistically significant differences between treatment groups were seen in demographic or baseline characteristics or previous therapies. Overall, 63% of the patients had stage IIb or greater disease. In general, this was a heavily pretreated population with a median of five previous therapies.
Of the 71 randomly assigned and treated patients, 42% (30 of 71) received eight courses of treatment: 43% of those assigned to 9 µg/kg/d and 42% of those assigned to 18 µg/kg/d. Eighteen percent (13 of 71) of patients entered the follow-up phase: 14% of the 9-µg/kg/d patients and 22% of the 18-µg/kg/d patients.
Efficacy
Overall, 30% (21 of 71: CI, 18% to 41%) of the CTCL patients treated with denileukin diftitox had an objective response with 10% of the patients with CR or CCR. Eight of 35 (23%: CI, 10% to 40%) of the patients on the 9-µg/kg/d arm and 13 of 36 (36%: CI, 21% to 54%) of patients on the 18-µg/kg/d arm had an objective response (Table 3). The overall difference in the rates of best response for the two dose groups was not statistically different. There was, however, a trend suggesting a dose-effect for those patients with more advanced disease: an objective response was seen in two of 21 (10%) of those patients with more than or equal to stage IIb disease treated with 9 µg/kg/d versus nine (38%) of 24 of those treated with 18 µg/kg/d (P = .07) (Table 3). Figures 1 and 2 are representative photos of patients who had an objective response to denileukin diftitox. Table 4 gives specifics of all documented responders.
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Fig 1. Forty-four-year-old man with stage Ib cutaneous T-cell lymphoma who completed 17 courses of DAB389IL-2. At the end of treatment, he had a partial remission but went on to a complete response off therapy and remains in remission 18 months off treatment. (A) Baseline, pretreatment; (B) status after 10 cycles of DAB389IL-2.
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Fig 2. Sixty-four-year-old woman with stage Ib cutaneous T-cell lymphoma who completed nine courses of DAB389IL-2 with a partial response at completion of therapy. (A) Baseline, pretreatment; (B) status after three cycles of DAB389IL-2.
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The median time to first response was 6 weeks (three to 27) and 95% (20 of 21) of those who eventually had an objective response had at least a 25% decrease in disease by week 9. Responses continued to evolve with further denileukin diftitox administration: in all seven complete responders, one to seven further courses of treatment after achievement of a PR were necessary to achieve a CR or CCR.
For all patients with an objective response, the median duration of response, calculated from the time of first dose of study drug to the time of loss of maximum response, was 6.9 months with a range of 2.7 to more than 46.1 months. This was similar across the two treatment arms (Table 5).
In those patients with a documented objective response, the decrease in tumor burden, amelioration of symptoms, and improvement as measured by Quality of Life questionnaire were correlated (Table 6). In addition, the 21 responders showed improvement in the other four parameters measured: improvement in Physician Global Severity (64% improvement on a 10-cm VAS), Erythroderma Score (2-point improvement on a 5-point scale), Patient Global Skin Assessment (2-point improvement on a 7-point scale), and Pruritus Score (50% improvement on 10-cm VAS). The use of rescue medications was also decreased in those who responded to denileukin diftitox.
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Table 6. Change in Secondary Parameters for Responders and Nonresponders* to Denileukin Diftitox (median change from baseline to end of treatment period)
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Fifty of the 71 patients were classified as nonresponders; of these, two (3%) of 71 patients met the definition for PD, 23 of 71 (32%) had SD, and 25 of 71 (35%) withdrew early from the study because of adverse events with fewer than the required number of disease evaluations necessary to document a response. Some of these nonresponders experienced substantial improvement in their disease. Twelve of 23 (52%) of the patients classified as having SD had a 50% decrease in tumor burden at some point during the study but for less than the 6 weeks necessary to verify an objective PR. Likewise, nine of 25 (36%) of the nonassessable patients had a 50% decrease in tumor burden at the time they discontinued from the study. All 17 responders and 13 of the 23 SD patients with clinically significant baseline pruritus ( 2 cm on a 10-cm VAS ) showed significant improvement with treatment (decrease of 2 cm).
Safety
Of the 71 randomly assigned and treated patients, 58% (41 of 71) received fewer than eight courses of treatment (57% on 9 µg/kg/d and 58% on 18 µg/kg/d). Reasons for discontinuation from the study included adverse events in 37% (31% of the 9-µg/kg/d patients and 42% of the 18-µg/kg/d patients), treatment failure in 11% (17% of the 9-µg/kg/d and 6% of the 18-µg/kg/d), and other reasons in 10% (consent withdrawal, protocol deviation, intermittent course of treatment).
Two patients died within 90 days of the last dose of study drug with cause of death noted as "remotely related" to denileukin diftitox. Both patients had been on the 18-µg/kg/d dose of denileukin diftitox. One patient, a 51-year-old man with Sézary’s syndrome, was entered inappropriately into the study with pancytopenia from previous radiation and chemotherapy. He developed sepsis, electrolyte imbalance, and hypoalbuminemia. Abdominal ultrasound detected echogenic kidneys consistent with medullary renal disease. He died of sepsis and renal failure 58 days after his last dose of denileukin diftitox. The second patient, a 68-year-old man with stage IIa CTCL, had had previous coronary artery bypass grafts with persistent angina. He developed a rash, fatigue, hypotension and malaise during his first course of denileukin diftitox and 10 days later developed progressive unstable angina with coronary stenosis found on cardiac catheterization. He died of an acute myocardial infarction 26 days after his last dose of denileukin diftitox.
Clinical adverse events grouped by dose and grade of severity are listed in Table 7. The first occurrence of adverse effects in most patients was during the first treatment course (87%). The administration of denileukin diftitox was associated with a group of acute hypersensitivity-type events occurring during or within 24 hours of study drug infusion in 60% of the patients (Table 7). Such immediate effects included dyspnea (20%), back pain (17%), hypotension (17%), and chest pain/tightness (13%). Twenty-two patients had cutaneous infusion-related events including pruritus (13%) and flushing of face and/or upper body (13%). These acute symptoms were treated by temporarily interrupting or decreasing the rate of infusion and/or by the administration of antihistamines or corticosteroids. Investigators were encouraged to medicate these patients with an antihistamine and acetaminophen before administration of subsequent doses of denileukin diftitox. Routine premedication with systemic corticosteroids was prohibited but two patients whose acute infusion-related symptoms (back pain in both cases) responded to corticosteroids were subsequently given 15 to 30 mg of methylprednisolone to modify or prevent repetitive infusion-related symptoms without loss of response to the denileukin diftitox.
Constitutional and gastrointestinal symptoms consisting of chills/fever, asthenia, nausea/vomiting, myalgia, arthralgia, headache, diarrhea, and anorexia were the most frequently reported adverse events with 92% (65 of 71) of the patients experiencing at least one symptom. Most patients (85%, 55 of 65) had flu-like symptoms that were mild to moderate in severity and generally responded well to treatment with antipyretics, antiemetics, and/or antidiarrheal agents. One patient developed dehydration that required intravenous fluid replacement. Anorexia occurred in 44% of the patients.
A vascular leak syndrome (VLS) was defined retrospectively as the simultaneous occurrence, regardless of severity, of at least two of the following: edema, hypoalbuminemia ( 2.8 g/dL), and/or hypotension occurring during days 1 to 14 of the beginning of a cycle. By this definition, 25% (18 of 71) of the patients experienced VLS. The incidence of VLS reported in this retrospective analysis may be inflated because hypotension, as noted above, could also occur as an acute infusion-related event. Most (96%) of the cases of hypotension in association with low albumin and/or edema occurred on a dosing day rather than in the postdosing period. The VLS was usually self-limited and was treated based on the primary clinical problem (judicious use of diuretics for edema and slow hydration for hypotension). Five patients required hospitalization for management of complications including pulmonary edema and renal insufficiency. Nine of the 13 who were retreated with denileukin diftitox did not experience further symptoms. The four patients who experienced a second episode of VLS on rechallenge had albumin levels less than 2.8 g/dL at the start of the course in which the second episode occurred. Serum albumin levels less than 3.0 g/dL seemed to predict and may predispose patients to this syndrome. Preexisting edema was also a risk factor for development of the syndrome.
Thrombosis-related events were reported in 11% (eight of 71) of the patients. One patient, previously described with preexisting cardiopulmonary disease, experienced an acute myocardial infarction 10 days after his last dose of denileukin diftitox. Two patients developed deep venous thromboses, one while hospitalized for management of fluid status related to congestive heart failure and VLS. This latter patient also experienced a pulmonary embolus during her hospital stay. One patient with a history of severe peripheral vascular disease developed an arterial thrombosis of a lower extremity. In addition, four patients had episodes of mild superficial thrombophlebitis that were not considered serious and that resolved without specific therapy.
Infections ranging from upper respiratory infections to sepsis were reported in 56% (40 of 71) of the patients. Most (80%, 32 of 40) of these patients had infections that are typical in patients with advanced stage and/or heavily pretreated CTCL and were considered unrelated to treatment. This is supported by the observation that most cases of sepsis were due to Staphylococci, which is common in patients with a compromised skin barrier, and there was a greater frequency and severity of infection in patients with advanced disease.
A variety of "rashes," classified as maculopapular, petechial, vesicular-bullous, urticarial, and/or eczematous, occurred in 35% (25 of 71) of the patients; 15% of the patients had a "rash" during dosing days. Noninfusion related "rashes" were reported in 25% of the patients. Most occurrences of "rash" tended to be mild to moderate and were treated with antihistamines, oral and/or topical corticosteroids, and/or emollients. Determining causality in relation to drug therapy was often difficult. However, four patients were hospitalized for "rash," and four other patients discontinued treatment because of "rash." Likewise, relationship of drug to pruritus, reported by 21% (15 of 71) of patients, was difficult to assess because 75% of the patients entered the trial with clinically significant pruritus.
Hemoglobin less than 8 mg/dL did not occur in any patient (Table 8). Leukopenia (< 2000 cells/µL) occurred in three patients, neutropenia (< 1,000 cells/µL) in two patients, and thrombocytopenia (< 50,000/µL) in one patient. These were not dose-related and did not limit treatment. In contrast, lymphopenia (< 1,000/µL) occurred in 70% of the patients. However, 24% of the patients had lymphopenia by this definition at baseline. All four patients who developed absolute lymphocyte counts of less than 200/µL were in the 18-µg/kg/d treatment group. No patients discontinued the study secondary to lymphopenia. Lymphopenia was not associated with clinical response to treatment or with adverse clinical sequelae and lymphocyte counts returned to baseline levels within 2 weeks of completion of a course of therapy.
In general, changes in clinical chemistry parameters were transient. Elevations of transaminase levels more than five times upper limits of normal occurred in 17% (12 of 71) of the patients. Hypoalbuminemia 2.3 g/dL occurred in 15% of the patients. Most of the clinical chemistry changes occurred during the first course, resolved within 2 weeks, and were less frequent and/or less severe during subsequent courses.
Proteinuria ( 2+), microscopic hematuria (six to 10 RBCs per high-power field), and casts were observed in 6% of the cases. The proteinuria and hematuria were more common with the higher dose of denileukin diftitox. Seven of 71 (10%) patients had more than 50% increase in serum creatinine over baseline, and 1 patient had a creatinine 4 mg/dL. Serum creatinine elevation was most likely related to dehydration and/or VLS and generally responded quickly to fluids and/or judicial use of diuretics. Most renal changes first occurred during the initial treatment course and normalized off drug. One patient developed thyrotoxicosis deemed probably related to denileukin diftitox.
Immunogenicity
Before receiving the fusion toxin, 19 (32%) of 60 patients had detectable levels of antidiphtheria toxin antibodies ( 1:25) that cross-reacted with denileukin diftitox in an ELISA assay. By the end of two courses, all but one patient had developed antidenileukin diftitox antibodies (Table 9). No apparent qualitative differences were noted between the two dose groups with respect to the timing or magnitude of antidenileukin diftitox antibody titers. After initial exposure to denileukin diftitox, the majority of patients developed moderate titers (1:625 or 1:3125) of antibody that did not change appreciably with additional therapy.
As expected, development of antidenileukin diftitox neutralizing antibodies paralleled the increase in antidenileukin diftitox ELISA titers. At baseline, 45% (27 of 60) of the patients had preexisting antibodies ( 0.05 NU/mL) that cross-reacted with and partially neutralized the activity of denileukin diftitox in an in vitro cell-based assay. By the end of two courses, all but one patient had elevated levels ( 0.8 NU/mL) of antidenileukin diftitox neutralizing antibodies. The timing and magnitude of neutralizing antibody development was similar for both dose groups and did not appear to impair response to treatment.
Anti-IL-2 antibody ELISA titers in these patients were not measurable at baseline and increased only slightly (low titer 1:25 or 1:125) after denileukin diftitox administration in 56% of the patients. As with the antidenileukin diftitox antibody levels, the results were similar for both doses.
A Kruskal-Wallis test was used to determine statistical differences in the distribution of the most common clinical or laboratory adverse events and antidenileukin diftitox or anti-IL-2 antibody levels. Higher antidenileukin diftitox antibody levels were associated with a lower incidence of rash, hypoalbuminemia, and transaminase elevations. No correlation between anti-IL-2 antibody levels and any clinical or laboratory adverse events was observed. Of particular note is the fact that the levels of antibodies to antidenileukin diftitox or anti-IL-2 antibodies did not correlate with the incidence of any other adverse event including either the acute infusion-related events or VLS.
Despite the development of antibodies to denileukin diftitox, some patients experienced significant antitumor effects that evolved over time during the treatment period. The percentage of individuals with detectable baseline levels of antibodies was similar between responders (N = 18) and assessable nonresponders (N = 20): 33% and 40%, respectively, for baseline ELISA titers 1:25. The percentage of patients with significant baseline neutralizing antibody levels was also similar between the responder and nonresponder groups. With the exception of one individual in the responder group, patients in both groups developed high levels of antibodies to denileukin diftitox (Fig 3).
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Fig 3. Median anti-DAB389IL-2 antibody titers at baseline and after each course comparing responders and nonresponders where n = total number of patients for whom antibody samples were available; number at each time point varied. Only patients with baseline and at least one postbaseline assessment were included in the graph. The nonresponder group includes only assessable patients, ie, patients who had at least two efficacy evaluations 6 weeks apart post baseline. C, course; D, day.
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Development of antibodies to IL-2 as measured by ELISA also did not preclude response. In fact, three patients classified as CR had high levels of anti-IL-2 antibodies (titers of 1:125 and 1:1625).
Pharmacokinetics
Pharmacokinetic parameters of denileukin diftitox are summarized in Table 10. As illustrated in Fig 4 and Table 10, serum concentrations of denileukin diftitox after the first dose displayed two-compartment behavior with a short distribution phase (half-life of approximately 2 to 5 minutes) and a longer terminal phase (half-life of approximately 70 to 80 minutes). The systemic exposure to denileukin diftitox was highly variable but proportional across the two doses examined. No accumulation was evident between the first and fifth doses of either course 1 or course 3.
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Fig 4. Mean serum denileukin diftitox concentrations (± SEM) on course 1 day 1 and course 1 day 5 at both dose levels where N = the total number of patients for whom pharmacokinetic samples were available; number at each time point varied.
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Clearance of denileukin diftitox was increased approximately two- to three-fold by course 3 (Fig 5). Denileukin diftitox serum concentrations during course 3 at both dose levels exceeded the threshold level required for antitumor activity based on in vitro data with IL-2R expressing tumor cell lines (1 to 10 ng/mL for > 90 minutes). The more rapid clearance observed by course 3 is presumably the result of the fact that all but one patient had developed significant antidenileukin diftitox antibodies after two courses of treatment. Although results suggest that patients with higher antibody titers have faster clearance rates, there was no apparent linear relationship between absolute antibody titer and clearance rate. Therefore, the impact of antibodies on circulating concentrations of denileukin diftitox may be dependent on the nature of the antibodies induced in each individual, eg, affinity and specificity for a particular epitope.
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Fig 5. Mean serum denileukin diftitox concentrations (± SEM) on course 1 day 1 and course 3 day 1 at both dose levels where n = the total number of patients for whom pharmacokinetic samples were available; number at each time point varied.
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A linear regression analysis showed that neither peak serum concentration (Cmax) nor total exposure (AUC) was related to age, sex, race, body mass index, presence of circulating IL-2R expressing cells, or soluble IL-2R levels. In addition, no consistent relationships were determined between Cmax or AUC values and frequency of the clinical or laboratory adverse events. This result was not unexpected because a minimal dose/toxicity relationship was observed.
In contrast, because there is a suggestion of higher response rate for patients with advanced disease at the higher (18-µg/kg/d) dose level, one might expect that response may be related to Cmax or AUC. However, as described above, mean denileukin diftitox concentrations measured at both the 9-µg/kg/d and 18-µg/kg/d dose levels were within the target therapeutic range. Individual values varied so widely that no definite conclusions can be made with respect to the correlation between response and either Cmax or AUC values.
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DISCUSSION
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This was the first phase III trial of two doses of a fusion toxin directed against the IL-2R in patients with CTCL. Denileukin diftitox (Ontak) has recently been approved by the Food and Drug Administration in the United States for the treatment of patients with recurrent or persistent CTCL whose malignant cells express the CD25 component of the IL-2 receptor. In the current study, by using rigorous standardized measures to assess both tumor burden and symptom status, denileukin diftitox has been shown to induce a 30% objective response (21 of 71) in CTCL patients with mycosis fungoides or Sézary’s syndrome who were heavily pretreated and/or had advanced disease. Documented responses included 10% CR/CCR and 20% PR with a median duration of 6.9 months. These results are similar to those seen in an earlier phase I/II trial in CTCL patients. In addition, there were important symptomatic benefits. Of the 71 patients entered, 53 had significant pruritus at baseline and 36 (68%) of these had clinically significant improvement, an important factor in quality of life for these patients.
Most of the side effects were seen during the first or second courses, and patients who continued on treatment were less likely to have serious adverse effects with subsequent courses. Tolerability of 9 and 18 µg/kg/d was similar although there was an increased incidence of hypotension and/or hypoalbuminemia at the higher dose. These results and the lack of a clear dose-response for overall efficacy leave the choice of dose to the discretion of the patient’s physician on a case-by-case basis. This study did not address whether dose escalation might improve efficacy in those initially given the lower dose of denileukin diftitox.
Regarding specific approaches to modification or prevention of adverse events with denileukin diftitox, it is important to be aware that some patients will develop a VLS, usually within the first 14 days of a given course. The mechanism for the vascular leak syndrome may be a combination of dehydration, hypoalbuminemia, and increased capillary permeability. Special caution should be taken in patients with preexisting cardiovascular disease. Weight, edema, blood pressure (supine and orthostatic), and serum albumin levels should be carefully monitored on an outpatient basis. The type of treatment will depend on whether edema (diuretics) or hypotension (fluids) is the primary clinical problem. Thirteen of the 18 patients retrospectively identified with VLS were retreated with denileukin diftitox; nine (69%) did not have further symptoms. However, the severity of the symptoms experienced by an individual patient may lead the clinician to discontinue further treatment, and indeed, five of the 18 patients with VLS in this study were not rechallenged. Preexisting low serum albumin levels seem to predict and may predispose patients to this syndrome. Patients with low albumin levels should not receive denileukin diftitox until their albumin levels are 3 g/dL. All four patients who experienced a second episode of VLS had low albumin levels at the start of the course in which the second episode occurred.
The second group of side effects that potentially could limit further treatment are those best termed "hypersensitivity" reactions. These include acute back or chest pain, hypotension, dyspnea, angioedema, pruritus, and rash that occur at the time of or within one hour of infusion of denileukin diftitox. Slowing or temporarily stopping the infusion of denileukin diftitox can generally ameliorate these adverse effects that are similar in nature to those seen with many other large protein agents such as monoclonal antibodies. Pretreatment with nonsteroidal anti-inflammatory agents and antihistamines is recommended. Significant improvement in symptoms without compromise of efficacy was noted in those patients who received corticosteroids during infusion following an acute infusion reaction with denileukin diftitox. Further studies are in progress to determine if systemic corticosteroids may ameliorate or prevent various adverse events. These "hypersensitivity" side effects also may lessen in severity with subsequent courses of treatment, and hence, less premedication may be needed as treatment proceeds. Patients with severe hypersensitivity reactions should not receive further denileukin diftitox treatment.
Constitutional symptoms are generally limited to fever/chills, arthralgias, myalgias, headache, and asthenia, generally decrease in frequency and degree with repetitive courses, and can often be moderated with antipyretics. These side effects are similar to those observed with other biologic response modifiers. Premedication with acetaminophen and nonsteroidal anti-inflammatory agents has been shown to decrease the incidence of these reactions. In contrast to the other adverse events, liver enzyme elevation, anemia, leukopenia and thrombocytopenia are generally mild and, in this study, did not require treatment and did not limit further treatment with denileukin diftitox.
The question remains whether CD25 is an adequate screen for likelihood of response to denileukin diftitox. Only 58% of all skin samples of CTCL patients screened for inclusion in this study were positive by the criteria used ( 20% of cells expressed CD25). However, results from multiple biopsies taken from different anatomic sites on different days from the same patient showed variable results. In 44% (14 of 32) of the patients examined, there were conflicting results regarding CD25 expression. Whether this variability is biologic or secondary to the inherent insensitivity of the screening assay is unclear. It is also uncertain whether patients with CD25 expression below this threshold may also benefit from treatment with denileukin diftitox. Three of seven patients enrolled in this study had multiple skin biopsy samples showing variable CD25 expression and responded to treatment, as did five of 11 responders who relapsed and were found to have low to nondetectable CD25 expression on post-treatment biopsies. In an earlier phase I/II trial, response to treatment with denileukin diftitox was seen in 1 of 3 patients with biopsies negative for CD25 expression. Studies are currently underway to evaluate denileukin diftitox in patients with CTCL and other non-Hodgkin’s lymphomas whose biopsies show CD25 expression less than 20%.
In summary, denileukin diftitox is a novel genetically engineered agent that specifically targets the CTCL tumor cell. It has been shown to induce substantial and durable partial and complete responses in patients with persistent or recurrent CTCL who have had extensive previous treatment. Because myelosuppression is an uncommon effect, denileukin diftitox may be particularly useful in patients with compromised marrow reserves as a result of previous x-ray therapy and/or multiagent chemotherapy. In general, clinical benefit is evident after the first or second course of therapy, allowing the informed clinician to rapidly make decisions regarding continued treatment and to adjust the dose and/or frequency of denileukin diftitox or adjuvant medications should side effects occur. Denileukin diftitox is an important new agent for patients with advanced or recurrent CTCL, particularly those in whom there is a high degree of symptomatology and disfigurement and those who have a potentially life-threatening disease.
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NOTES
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None of the authors have equity interests in Seragen with the exception of P.B. and J.N.. Seragen, Inc is a wholly owned subsidiary of Ligand Pharmaceuticals Inc, San Diego, CA. Seragen holds the license for Ontak.
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accepted August 25, 2000.
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O. Murillo, A. Arina, I. Tirapu, C. Alfaro, G. Mazzolini, B. Palencia, A. L.-D. De Cerio, J. Prieto, M. Bendandi, and I. Melero
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Clin. Cancer Res.,
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[Abstract]
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T. Maier, A. Tun-Kyi, A. Tassis, K.-P. Jungius, G. Burg, R. Dummer, and F. O. Nestle
Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells
Blood,
October 1, 2003;
102(7):
2338 - 2344.
[Abstract]
[Full Text]
[PDF]
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A. E. Frankel, D. R. Fleming, P. D. Hall, B. L. Powell, J. H. Black, C. Leftwich, and R. Gartenhaus
A Phase II Study of DT Fusion Protein Denileukin Diftitox in Patients with Fludarabine-refractory Chronic Lymphocytic Leukemia
Clin. Cancer Res.,
September 1, 2003;
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3555 - 3561.
[Abstract]
[Full Text]
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P. W. Heald
Memorials and Mandates for Cutaneous Lymphomas
Arch Dermatol,
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139(7):
926 - 928.
[Full Text]
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J. Lundin, H. Hagberg, R. Repp, E. Cavallin-Stahl, S. Freden, G. Juliusson, E. Rosenblad, G. Tjonnfjord, T. Wiklund, and A. Osterborg
Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome
Blood,
June 1, 2003;
101(11):
4267 - 4272.
[Abstract]
[Full Text]
[PDF]
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A.C. Church
Clinical advances in therapies targeting the interleukin-2 receptor
QJM,
February 1, 2003;
96(2):
91 - 102.
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R. Hassan, M. R. Lerner, D. Benbrook, S. A. Lightfoot, D. J. Brackett, Q.-C. Wang, and I. Pastan
Antitumor Activity of SS(dsFv)PE38 and SS1(dsFv)PE38, Recombinant Antimesothelin Immunotoxins against Human Gynecologic Cancers Grown in Organotypic Culture in Vitro
Clin. Cancer Res.,
November 1, 2002;
8(11):
3520 - 3526.
[Abstract]
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[PDF]
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K. S. McGinnis, M. Shapiro, J. M. Junkins-Hopkins, M. Smith, S. R. Lessin, C. C. Vittorio, and A. H. Rook
Denileukin Diftitox for the Treatment of Panniculitic Lymphoma
Arch Dermatol,
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D. Fan, S. Yano, H. Shinohara, C. Solorzano, M. Van Arsdall, C. D. Bucana, S. Pathak, E. Kruzel, R. S. Herbst, A. Onn, et al.
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Mol. Cancer Ther.,
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[Abstract]
[Full Text]
[PDF]
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A. E. Frankel, B. L. Powell, P. D. Hall, L. D. Case, and R. J. Kreitman
Phase I Trial of a Novel Diphtheria Toxin/Granulocyte Macrophage Colony-stimulating Factor Fusion Protein (DT388GMCSF) for Refractory or Relapsed Acute Myeloid Leukemia
Clin. Cancer Res.,
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[Abstract]
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D. A. Vallera, C. Li, N. Jin, A. Panoskaltsis-Mortari, and W. A. Hall
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[Abstract]
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V. Sandor, S. Bakke, R. W. Robey, M. H. Kang, M. V. Blagosklonny, J. Bender, R. Brooks, R. L. Piekarz, E. Tucker, W. D. Figg, et al.
Phase I Trial of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228, NSC 630176), in Patients with Refractory Neoplasms
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[Abstract]
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J. M. Connors, E. D. Hsi, and F. M. Foss
Lymphoma of the Skin
Hematology,
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[Abstract]
[Full Text]
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D. G. Maloney, B. M. Sandmaier, S. Mackinnon, and J. A. Shizuru
Non-Myeloablative Transplantation
Hematology,
January 1, 2002;
2002(1):
392 - 421.
[Abstract]
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M. Duvic, K. Hymes, P. Heald, D. Breneman, A. G. Martin, P. Myskowski, C. Crowley, and R. C. Yocum
Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial Results
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M. Duvic, A. G. Martin, Y. Kim, E. Olsen, G. S. Wood, C. A. Crowley, R. C. Yocum, and for the Worldwide Bexarotene Study Group
Phase 2 and 3 Clinical Trial of Oral Bexarotene (Targretin Capsules) for the Treatment of Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma
Arch Dermatol,
May 1, 2001;
137(5):
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[Abstract]
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J. P. Greer, M. C. Kinney, and T. P. Loughran Jr.
T Cell and NK Cell Lymphoproliferative Disorders
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TOP
ABSTRACT
INTRODUCTION
