Journal of Clinical Oncology, Vol 19, Issue 19
(October), 2001: 3918-3928
© 2001 American Society for Clinical Oncology
Pivotal Study of Iodine I 131 Tositumomab for Chemotherapy-Refractory Low-Grade or Transformed Low-Grade B-Cell Non-Hodgkin’s Lymphomas
By Mark S. Kaminski,
Andrew D. Zelenetz,
Oliver W. Press,
Mansoor Saleh,
John Leonard,
Louis Fehrenbacher,
T. Andrew Lister,
Robert J. Stagg,
George F. Tidmarsh,
Stew Kroll,
Richard L. Wahl,
Susan J. Knox,
Julie M. Vose
From the University of Michigan Medical Center, Ann Arbor, MI; Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY; University of Washington Medical Center and Corixa Corporation, Seattle, WA; University of Alabama, Birmingham, AL; Kaiser Northern California, Vallejo; Stanford University Medical Center, Stanford, CA; University of Nebraska Medical Center, Omaha, NE; and St Bartholomew’s Hospital, London, United Kingdom.
Address reprint requests to Mark S. Kaminski, MD, University of Michigan Cancer Center, 1500 E Medical Center Dr, Rm CCGC 4-316, Ann Arbor, MI 48109-0936; email: mkaminsk{at}umich.edu
 |
ABSTRACT
|
|---|
PURPOSE: To evaluate the efficacy and safety of tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA) in patients with chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL) and to compare its efficacy to the patients’ last qualifying chemotherapy (LQC) regimens.
PATIENTS AND METHODS: Sixty patients who had been treated with at least two protocol-specified qualifying chemotherapy regimens and had not responded or progressed within 6 months after their LQC were treated with a single course of iodine I 131 tositumomab.
RESULTS: Patients had received a median of four prior chemotherapy regimens. A partial or complete response (CR) was observed in 39 patients (65%) after iodine I 131 tositumomab, compared with 17 patients (28%) after their LQC (P < .001). The median duration of response (MDR) was 6.5 months after iodine I 131 tositumomab, compared with 3.4 months after the LQC (P < .001). Two patients (3%) had a CR after their LQC, compared with 12 (20%) after iodine I 131 tositumomab (P < .001). The MDR for CR was 6.1 months after the LQC and had not been reached with follow-up of more than 47 months after iodine I 131 tositumomab. An independent review panel verified that 32 (74%) of the 43 patients with nonequivalent durations of response (> 30 days difference) had a longer duration of response after iodine I 131 tositumomab (P < .001). Only one patient was hospitalized for neutropenic fever. Five patients (8%) developed human antimurine antibodies, and one (2%) developed an elevated TSH level after treatment. Myelodysplasia was diagnosed in four patients in follow-up.
CONCLUSION: A single course of iodine I 131 tositumomab was significantly more efficacious than the LQC received by extensively pretreated patients with chemotherapy-refractory, low-grade, or transformed low-grade NHL and had an acceptable safety profile.
|
INTRODUCTION
|
|---|
ALMOST ALL patients with low-grade non-Hodgkin’s lymphoma (NHL) present with advanced-stage disease and are not considered to be curable by current treatments, including intensive chemotherapy regimens. Although advanced-stage patients have a median survival time of 7 to 10 years, this period of time is generally characterized by multiple episodes of treatment and relapse.1,2 The majority of patients with advanced-stage disease initially respond to a large array of treatment options ranging from involved-field radiotherapy to single-agent chemotherapy to multiagent chemotherapy, but relapse ultimately occurs. Attempts at retreatment with the same or different drug combinations can lead to patient responses, but, as resistance to drug or drug combinations develops, the response rate and response duration decline with subsequent therapy.3,4 In addition, up to 60% of patients may show evidence of transformation to a higher-grade histology. This event usually predicts a short survival time of 6 to 12 months.5-9 Ultimately, nearly all patients will die as a result of progressive disease and/or complications of treatment. Clearly, new treatment approaches are needed for low-grade and transformed low-grade NHL, especially in the chemotherapy-refractory setting.
Recently, new therapeutic strategies, such as those incorporating the use of monoclonal antibodies reactive with lymphoid-associated antigens, are increasingly being evaluated for this disease. Antibodies against the CD20 antigen, an antigen expressed by nearly all B-cell lymphomas, have shown promise. However, unlabeled anti-CD20 antibodies, such as the Food and Drug Administration-approved chimeric antibody rituximab, have demonstrated low complete response (CR) rates and limited durations of response.10 Therefore, a variety of conjugated antibody therapies are under investigation. Higher overall and CR rates have been observed when anti-CD20 antibodies labeled with radionuclides have been used.11 This is presumably a result of the cytotoxic effects of radiation combined with those of the unlabeled antibody, which include complement-mediated cytolysis, antibody-dependent cellular cytotoxicity, and apoptosis. Also, radioisotope emissions are capable of killing not only the cells bound by the radiolabeled antibody but also adjacent cells that may not have been bound by antibody or do not express the target antigen.
The preponderance of experience with radiolabeled anti-CD20 antibodies has been with Iodine-131 Anti-B1 Antibody or iodine I 131 tositumomab (Bexxar; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA), a murine IgG2a antibody radiolabeled with I-131.12-15 Iodine-131 has a long history of safe medical use, has rapid renal clearance, does not accumulate in bone, and can be effectively blocked from the thyroid by potassium iodide. Iodine-131 decay produces not only a short-range beta particle component but also a gamma ray component that enables total-body gamma counts to be obtained over time. These gamma counts enable the calculation of patient-specific pharmacokinetics and the determination of the millicurie activity required for the delivery of an optimal therapeutic dose of total-body radiation. In this way, high tumor radiation doses can be delivered to tumors while controlling the radiation-induced hematologic toxicity.
A phase I/II single center study of iodine I 131 tositumomab established the dosing methodology and the maximum tolerated dose (MTD) of radiation to the whole body (75 cGy for patients who had not undergone a prior stem-cell transplant).12-14 In this study, 42 patients with chemotherapy-relapsed or chemotherapy-refractory low-grade or transformed low-grade NHL with a median of four prior chemotherapy treatments had a response rate of 83% and CR rate of 48%. The median progression-free survival (PFS) was 14 months for responders and 20 months for patients experiencing CR. Seven of 20 complete responders continued in CR for 3 to 5.7 years.
A phase II, multicenter study confirmed the efficacy and safety of iodine I 131 tositumomab.15 In this trial, patients with relapsed or refractory low-grade or transformed low-grade NHL were required to have previously received at least one anthracycline- or anthracenedione-containing regimen and to have not responded to treatment or to have experienced disease progression within 1 year after completing their last chemotherapy regimen. Patients had received a median of four prior chemotherapy treatments. An overall response rate of 57% and a CR rate of 32% were observed in 47 patients. The median PFS was 12 months for all responders and 22 months for complete responders.
The encouraging results from these two trials led to the design of the current study, in which patients with an even poorer prognosis who had failed multiple chemotherapy regimens and had either not responded to or responded and experienced disease progression within 6 months of completion of their last qualifying chemotherapy regimen (LQC) were treated with iodine I 131 tositumomab. The primary goals of this study were to establish the efficacy and safety of a single course of iodine I 131 tositumomab in patients meeting a strict chemotherapy-refractory definition and to compare the efficacy outcomes of a patient’s last chemotherapy regimen with the efficacy outcomes after iodine I 131 tositumomab using a patient-as-own-control paired analysis.
|
PATIENTS AND METHODS
|
|---|
This multicenter, nonrandomized, phase III study evaluated a single dosimetric and therapeutic dose of iodine I 131 tositumomab in patients with chemotherapy-refractory low-grade or transformed low-grade B-cell NHL. The study was conducted at seven clinical sites in the United States and one in the United Kingdom. One patient withdrew consent before receiving the study drug and was excluded from all analyses. The protocol was approved by the institutional review board or ethics committee at each site, and all patients gave written informed consent before study entry.
Patient Eligibility
Adult patients with histologically confirmed low-grade (International Working Formulation for Clinical Usage A, B, or C) or transformed low-grade CD20-positive B-cell lymphomas were eligible. Patients were required to have received at least two prior protocol-specified chemotherapy regimens, and to have experienced relapse within 6 months of completion of or to have not responded to the LQC regimen. All patients were required to have at least one lesion  2 cm2 at baseline. Patients could have no more than 25% of the intertrabecular bone marrow space involved with lymphoma as determined by bone marrow biopsy. There were no restrictions based on bone marrow cellularity. In addition, all patients were required to have adequate performance status, hepatic function, and renal function, and an absolute neutrophil count (ANC) of more than 1,500 cells/mm3, platelets of more than 100,000 cells/mm3, and to have received no prior therapy within the preceding 4 weeks. Patients were excluded for known CNS lymphoma, human immunodeficiency virus infection, the presence of serum human antimurine antibodies (HAMA) as determined from the individual clinical site’s HAMA assay, other malignancies diagnosed within 5 years, prior exposure to monoclonal antibodies (unlabeled or radiolabeled), and prior bone marrow or peripheral stem-cell transplantation.
Qualifying Chemotherapy Regimens
Qualifying chemotherapy regimens were identified prospectively and included single drugs and multidrug combination chemotherapy regimens with known activity in NHL. Patients were required to have received at least two cycles or at least 6 weeks of a single agent of the qualifying regimen unless the disease had clearly progressed during the first cycle of therapy. Patients who were categorized as having transformed low-grade NHL must have received a chemotherapy regimen for intermediate or high-grade NHL. Patients who received a nonqualifying regimen after the LQC were eligible, provided they experienced no response or relapse within 6 months of completion of each of the LQC and the subsequent nonqualifying regimen.
Study Design and Objectives
This was a phase III, multicenter study comparing efficacy outcomes achieved on the patient’s LQC regimen with their efficacy outcomes achieved after iodine I 131 tositumomab. The primary end point of the study was the comparison, assessed by a Masked Independent Randomized Radiology and Oncology Review (MIRROR) Panel, of the number of patients who had a longer duration of response (> 30 days difference) after a LQC regimen with the number of patients who had a longer duration of response after iodine I 131 tositumomab. To provide an adequate control for this trial, an internal control (termed patient-as-own-control) was incorporated into the design. This approach used the duration of response after the LQC regimen as a paired control.
MIRROR Panel
A review of the efficacy outcomes of the LQC regimen and iodine I 131 tositumomab was performed by the MIRROR Panel, which consisted of two independent teams, each comprised of one radiologist and one medical oncologist not otherwise participating in the study. For each patient, one team was randomly assigned to review masked radiographs and medical notes pertaining to the LQC regimen, and the other team was assigned to review similar information for the iodine I 131 tositumomab therapy. Randomization was performed by an independent contract research organization, with each team having an equal chance of being assigned to the LQC or iodine I 131 tositumomab team. The oncologists and radiologists were masked to patient identification, date, sites of disease, treatment, and investigator-assessed outcome. Any discordance between a radiologist’s assessment and an oncologist’s assessment was resolved by a joint review between the radiologist and oncologist.
To ensure all sites of disease were evaluated for response after the LQC regimen, the submission of copies of original medical notes and radiographic reports before and after the LQC was required before study entry. Documentation was considered adequate if it included full documentation of the LQC, including the agents administered, the number of courses, the start and end dates, and an evaluation of patient response to the LQC, including the best response achieved, the date of first response, and the date of nonresponse or disease progression. The same written documentation was required if a patient had received a nonqualifying regimen after the LQC. In addition, computed tomography scans at baseline before the LQC and at subsequent evaluations through nonresponse or disease progression were collected, and copies of these radiographs were required. After the radiographs had been masked, they were used for the independent review.
Baseline evaluation before iodine I 131 tositumomab included physical examination, bone marrow biopsy (bilateral if involvement exceeded 10% in a unilateral biopsy), and radiographic studies, which included computed tomography imaging of chest, abdomen, pelvis, and head and neck for patients with NHL in this region. Tumor burden was estimated based on radiographic tumor measurements. Laboratory tests included a complete blood cell count with differential, platelet counts, serum chemistries, thyroid-stimulating hormone (TSH), and HAMA. Physical examination and radiographic and laboratory monitoring were performed every 6 weeks for 6 months and then every 3 months for up to 2 years until NHL progression or patient death. A repeat bone marrow biopsy was required to confirm CR if the patient had NHL involvement in the baseline bone marrow. All patients were followed-up until death or the last day of analysis.
Drug Preparation
For the first 22 patients, each site radiolabeled tositumomab (the unlabeled antibody) with iodine-131 using the Iodogen method16 and performed quality control testing for immunoreactivity and purity.17 Central radiolabeling was introduced to control product uniformity, allow greater convenience, improve safety, and increase the scale of production. For the remaining patients, iodine I 131 tositumomab was manufactured in a central facility (MDS Nordion, Kanata, Canada) using the same Iodogen method.16
Drug Administration and Dosimetry
The administration of iodine I 131 tositumomab followed procedures previously described in which a dosimetric dose preceded a subsequent therapeutic dose.15 The dosimetric dose given on day 0 consisted of a 1-hour infusion of 450 mg of unlabeled tositumomab followed by a 20-minute infusion of 5 mCi (35 mg) of iodine I 131 tositumomab. Total-body gamma counts using a gamma camera were then obtained on three occasions over the next week (day 0; day 2, 3, or 4; and on day 6 or 7). Using these counts, calculations based on standard internal radiation dosimetry methods18,19 were performed to determine the patient-specific activity (in millicuries) of radiolabeled tositumomab required to deliver a maximum tolerated therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy for patients with platelet counts < 150,000 cells/mm3). Obese patients (patients weighing more than 137% of their lean body weight) had their dose adjusted in the dosimetry calculations based on 137% of their lean body weight. The therapeutic dose was administered between day 7 and day 15. A 450-mg unlabeled tositumomab dose was administered, followed by the patient-specific (in millicuries) activity labeled to 35 mg of tositumomab. Before the dosimetric and therapeutic doses, patients were premedicated orally with 650 mg of acetaminophen and 50 mg of diphenhydramine. In addition, to prevent uptake of iodine-131 by the thyroid, patients received a saturated solution of potassium iodide (two drops orally three times daily) beginning at least 24 hours before the dosimetric dose and continuing for 14 days after the therapeutic dose.
Response Criteria
All measurable and assessable disease was considered in the assessments of response. For the MIRROR Panel assessments of the LQC and iodine I 131 tositumomab, a measurable lesion was defined as any baseline lesion more than 1 cm in both perpendicular diameters. A measurable lesion was defined for the investigator assessment of iodine I 131 tositumomab as any baseline lesion more than 2 cm in both perpendicular diameters. CR was defined as the complete disappearance of all disease-related radiologic abnormalities and other assessable disease. A CR required a negative bone marrow biopsy for patients with a positive baseline biopsy. Partial response was defined as a 50% or greater reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions developing. Stable disease was defined as a less than 50% reduction and less than 25% increase from the nadir in the sum of the products of the longest perpendicular diameters of measurable lesions, with no new lesions developing. Progressive disease was defined as a greater than 25% increase from the nadir value in the sum of the products of the longest perpendicular diameters of the measurable lesions or the appearance of a new lesion. Duration of response was defined as the time from the first documented response to the first documented progression. PFS was defined as the time from the start of treatment (ie, the dosimetric dose) to the first documented progression or death.
Safety Evaluation
All adverse experiences occurring from study entry through 12 weeks after the therapeutic dose or the administration of alternative therapy, whichever occurred first, were recorded and graded using the National Cancer Institute Common Toxicity Criteria (Version 1.0). Only those experiences occurring after that time period that were considered possibly or probably related to the study drug were recorded. All hematologic laboratory abnormalities were considered possibly or probably related to the study drug. Safety was assessed by physical examination and laboratory evaluations that were performed at baseline and at regular intervals throughout the study. Vital signs were recorded every 15 minutes during antibody infusions. Complete blood counts, including differential and platelet counts, were obtained at baseline, 2 days before the therapeutic dose, and weekly beginning 2 weeks after the therapeutic dose for 7 weeks or until consistent grade 0 hematologic toxicity was recorded. Subsequent evaluations were done at week 13, 19, and 25, then every 3 months for 2 years, and every 6 months thereafter until disease progression, death, or date of last data analysis. Long-term follow-up data, including vital status, diagnosis of myelodysplasia and secondary malignancies, TSH laboratory data, use of thyroid medications, HAMA laboratory data, and subsequent therapies for NHL, were collected from all patients.
Serum was collected for HAMA analysis before the administration of the dosimetric dose; 2 days before the therapeutic dose; at weeks 7, 13, and 25; and as part of long-term follow-up. After collection, the sample was aliquoted. The individual clinical site assayed one aliquot, and a second sample was maintained frozen at -20 °C or colder and then analyzed by an independent central laboratory using the ImmuSTRIP HAMA IgG ELISA test kit (Immunomedics, Inc, Morris Plain, NJ). Thyroid function tests were performed at baseline; 6, 9, and 12 months; every 6 months thereafter until disease progression or patient death; and as part of long-term follow-up. The use of thyroid supplementation was collected through the data cutoff date.
Statistical Analysis
Analyses were performed using data through January 31, 2001, from all patients who received the study drug. The level of significance for all comparative analyses was set at 0.05, with exact confidence limits calculated from binomial distributions. No interim analyses for early stoppage were performed. Analyses were performed using SAS (Version 6.12; SAS Institute, Cary, NC). Data for duration of response and PFS were analyzed by Kaplan-Meier techniques.20
Because a standard control chemotherapy salvage regimen was not possible to prescribe for the heavily pretreated refractory patients fulfilling study entry criteria, this study incorporated an internal control that consisted of the response and duration of response of a patient to their LQC. This response was used as a paired comparator to the response to iodine I 131 tositumomab. The patient-specific self-matching on known (age, grade, treatment history, and so on) and unknown prognostic factors enabled a more specific control than that obtainable using an independent historical control arm. Efficacy comparisons were performed using either McNemar’s test21 or a generalization of McNemar’s test. Although McNemar’s test compares the response rates between two groups, the generalization of McNemar’s test also incorporated the duration of response data. Patients with durations of response to the LQC and iodine I 131 tositumomab that differed by more than 30 days were considered nonequivalent responders. Response rates and durations of response from previous phase II studies of iodine I 131 tositumomab were used to determine the sample size.
Univariate analyses to determine prognostic factors of response rate and duration of response were performed using the  2 test22 and logrank test,23 respectively. Multivariate analyses of response rate were performed using a logistic regression model, and multivariate analyses of duration of response were performed using the Cox proportional hazards model.24 The probability of experiencing response as a function of time from the initiation of therapy was estimated nonparametrically using a three-state (not experiencing response, experiencing response, and experiencing disease progression after response) model.25
|
RESULTS
|
|---|
Patient Characteristics
Sixty patients were treated at eight institutions between November 1996 and March 1998. Baseline patient characteristics are listed in Table 1. Virtually all patients (98%) had stage III or IV disease at enrollment, and the majority (56%) had bone marrow involvement. Sixty-five percent of patients had at least one tumor 5 cm in size, and 88% had two risk factors as defined by the International Prognostic Index,26 including 44% who had an elevated lactate dehydrogenase level. Fifteen patients had B symptoms. Of the 36 patients with low-grade NHL, four patients had small lymphocytic NHL; 21 patients had follicular, small, cleaved NHL; and 11 patients had follicular-mixed, small, cleaved, and large-cell NHL. Twenty-three patients had biopsy confirmation of transformed low-grade NHL a median of 10 months before receiving iodine I 131 tositumomab (range, 0.4 to 51 months). The transformed histologies were diffuse large-cell NHL in nine patients, diffuse mixed-cell in six patients, follicular large-cell in four patients, diffuse small-cleaved cell in two patients, and prolymphocytic transformation in two patients. One patient was determined to have de novo mantle-cell lymphoma after subsequent pathology review.
LQC
Patients received a median of four chemotherapy regimens (range, two to 13 regimens) before study entry, and the majority (78%) had received doxorubicin (Adriamycin; Pharmacia & Upjohn Co, Bridgewater, NJ)-containing regimens. Sixteen patients (27%) had also received radiation therapy. The LQC regimens received by the 60 patients before enrollment are listed in Table 2. Cyclophosphamide combination regimens (47%) were the most common. Other combination regimens that did not include cyclophosphamide were the control regimens for 35% of patients. Single-agent fludarabine (15%) and chlorambucil (3%) were the other LQC. The median time from completion of the LQC to the administration of a dosimetric dose of iodine I 131 tositumomab was 4.4 months. Forty-two patients had a final chemotherapy treatment-free interval of less than 6 months from the completion of the LQC to the initiation of iodine I 131 tositumomab, and 54 patients had treatment-free intervals of less than 12 months.
Iodine I 131 Tositumomab Administration
Fifty-eight of the 60 patients received the therapeutic dose 7 to 15 days after the dosimetric dose. Of the two patients who did not, one patient expired from progressive disease before receiving the therapeutic dose, and the other patient experienced infusion-related adverse experiences (chills, fever, urticaria, hypotension, and tachycardia) during administration of the tositumomab (unlabeled antibody) portion of the therapeutic dose, from which the patient recovered. However, it resulted in termination of treatment. To deliver the prescribed 65 or 75 cGy total-body dose, the administered millicurie varied substantially. The median administered therapeutic dose of iodine I 131 tositumomab activity was 91.3 mCi, and the range was from 47.2 to 212.0 mCi.
Response
On an intent-to-treat basis (Table 3), an investigator-assessed response was observed in 17 (28%) of 60 patients after their LQC regimen, compared with 39 (65%) of 60 patients after iodine I 131 tositumomab (P < .001; McNemar’s test). The median duration of response for iodine I 131 tositumomab was 6.5 months (95% confidence interval [CI], 3.1 to 11.3 months), compared with a median duration of response on the LQC regimen of 3.4 months (95% CI, 2.5 to 4.7 months). Two (3%) of 60 patients achieved a CR on the LQC regimen, compared with twelve (20%) of 60 patients who achieved a CR on iodine I 131 tositumomab (P < .001; McNemar’s test). All but one of the 12 patients who experienced CRs after iodine I 131 tositumomab achieved tumor reduction of all measurable disease to less than 1 cm2. One patient had a 1.5 x 1-cm mesenteric lesion believed to represent scar tissue. The median duration of response for the patients who experienced CRs on iodine I 131 tositumomab has not been reached with more than 47 months of follow-up. Nine of the twelve patients with CRs have ongoing responses ranging from 32.3 to 47.4 months at the time of the last data analysis. The median PFS time for the 17 responders to the LQC was 6.3 months (95% CI, 5.4 to 8.1 month), compared with 8.4 months (95% CI, 5.1 to 12.9 months) for the 39 patients who responded to iodine I 131 tositumomab. Figure 1 displays the probability of experiencing response from the start of therapy for all patients on the LQC and iodine I 131 tositumomab.
View larger version (19K):
[in this window]
[in a new window]
|
Fig 1. Probability of experiencing response after iodine I 131 tositumomab and the LQC. The paired data are presented for all 60 patients. (||), patients with censored (ie, ongoing) investigator-assessed responses.
|
|
There was a high concordance between the investigator’s assessment and the MIRROR Panel assessment: 93% agreement for the iodine I 131 tositumomab assessments and 82% agreement for the LQC assessments. On an intent-to-treat basis, the MIRROR Panel–assessed response was observed in 20 (33%) of 60 patients after their LQC regimen, compared with 39 (65%) of 60 patients after iodine I 131 tositumomab (P < .001; McNemar’s test). Two (3%) of 60 patients achieved a CR on the LQC, compared with eleven (18%) of 60 patients who achieved a CR to iodine I 131 tositumomab (P = .011; McNemar’s test).
The primary efficacy end point of the study was the comparison of the number of patients who had a longer duration of response (> 30 days difference) on iodine I 131 tositumomab with the number of patients who had a longer duration of response (> 30 days difference) on their LQC as determined by the MIRROR Panel (Fig 2). Seventeen (28%) of 60 patients had equivalent durations of response ( 30 days difference) after their LQC and iodine I 131 tositumomab. Eleven (26%) of the remaining 43 patients had a longer duration of response (ie, > 30 days longer) on their LQC, whereas 32 of the remaining 41 patients (74%) had a longer duration of response after iodine I 131 tositumomab (P < .001; McNemar’s test).
View larger version (29K):
[in this window]
[in a new window]
|
Fig 2. MIRROR Panel assessment of duration of response. A paired comparison was made of response durations after the LQC and after iodine I 131 tositumomab. An equivalent duration of response was defined as a response lasting 30 days.
* McNemar’s test.
|
|
Of the 15 patients who had one or more B symptoms (night sweats, intermittent fevers, and/or weight loss) at baseline, 13 underwent at least one subsequent assessment of B symptoms. All B symptoms resolved in eight (62%) of the 13 patients after treatment with iodine I 131 tositumomab.
As listed in Table 4, statistically significantly higher response rates were observed in univariate analyses in patients with smaller tumor burdens (response rate, 81%), patients who had not received prior radiotherapy (77%), patients with low-grade NHL (81%), patients with bone marrow involvement (82%), and patients who had received less than four prior chemotherapy regimens (90%). The response rate for the 23 patients with transformed low-grade NHL was 39%. The patients with transformed low-grade NHL included 48% with bulky disease and a median of four prior chemotherapies, with approximately half of the therapies administered after transformation. A higher response rate of 75% was observed in the four patients who transformed to follicular large-cell NHL. Patients with smaller tumor burdens had more durable response durations than those with more extensive disease (median, 9.1 v 3.1 months; P = .03). Response rates were not significantly different for the subgroup analyses of age, sex, race, stage at entry, baseline lactate dehydrogenase level, baseline serum beta-2-microglobulin level, baseline International Prognostic Index status, response to LQC regimen, HAMA status, total-body dose (.65 v .75 Gy), or treating institution. Similar prognostic factors were observed on the basis of investigator and MIRROR Panel assessments of response.
In multivariate analyses, tumor burden of less than 500 g (odds ratio, 9.9; P = .021) and low-grade NHL (odds ratio, 8.3; P = .032) were the only variables significantly associated with a higher rate of response. Smaller tumor burden (relative risk, 0.4; P = .027) was the only variable associated with a longer duration of response.
Adverse Events
Infusions of tositumomab and iodine I 131 tositumomab were well-tolerated. Adverse experiences were reported more frequently with the dosimetric administrations (25 [42%] of 60 patients) than with the therapeutic administrations (14 [24%] of 59 patients). The infusion-related adverse experiences were generally mild (grade 1/2, 98%; grade 3, 2%; and grade 4, 0%) with fever or chills as the most common. Infusion-rate adjustments were required in only five (8%) of 60 patients who received the dosimetric and in three (5%) of 59 patients who received the therapeutic doses. Reasons for rate adjustment included hypotension, rigors, fever, wheezing/coughing, and nasal congestion/edema.
Fifty-nine (98%) of 60 patients experienced at least one adverse event, with 55 (92%) of 60 patients experiencing an event considered by the investigators to be possibly related to therapy. The most common nonhematologic adverse experiences thought to be related to the study drug were fatigue (43%), fever (30%), nausea (25%), chills (15%), vomiting (13%), pruritus (13%), anorexia (10%), and hypotension (10%) (Table 5). Typically, these events were transient and mild to moderate in severity (grade 1 or 2). A total of seven grade 3 or 4 nonhematologic adverse experiences were reported in five patients. The adverse experiences were chills, fever, arthralgia, myalgia, subdural hematoma, lung hemorrhage, and dyspnea.
The principal toxicity was hematologic (Table 6). The median times to nadir from the therapeutic dose for ANC, hemoglobin, and platelet counts were 43, 46, and 34 days from the therapeutic dose, respectively. The median nadir values after the therapeutic dose for ANC, hemoglobin, and platelet counts were 800 cells/mm3, 10.2 g/dL, and 50,000 cells/mm3, respectively. Thirteen patients (22%) had a nadir platelet count of less than 25,000 cells/mm3, including one patient with a platelet count of less than 10,000 cells/mm3, and 12 patients (20%) had a nadir absolute neutrophil count below 500 cells/mm3, including one patient with an absolute neutrophil count below 100 cells/mm3. The median times from the therapeutic dose to recovery of ANC, hemoglobin, and platelet counts to the patient’s baseline hematologic toxicity grade were 74, 78, and 73 days, respectively. The median times from nadir to recovery of ANC, hemoglobin, and platelet counts to grade 2 toxicity were 9, 7, and 8 days, respectively. Nineteen (32%) of 60 patients received hematologic supportive therapy at the discretion of the investigator: nine patients (15%) received a median of one platelet transfusion (range, one to three transfusions), eight patients (13%) received a median of two RBC transfusions (range, one to five transfusions), 10 patients (17%) received granulocyte colony-stimulating factor, and three patients (5%) received erythropoietin.
Fifteen (25%) of 60 patients experienced a total of 31 infections. Twelve of the 15 patients were placed on anti-infective agents, and all 15 patients recovered from their infections. One patient was hospitalized with febrile neutropenia (ANC < 1,000 cells/mm3). No infection was identified, and the patient recovered and was discharged.
Five (8%) of 60 patients developed a positive HAMA titer based on the individual clinical site’s assay at a median of 9.2 months (range, 1.6 to 14.0 months) after the dosimetric dose. Serum was also assessed for HAMA by a centralized assay for 57 of the 60 patients. Two (4%) of 57 patients were positive at baseline (but were not excluded from the study because the clinical site’s assay was negative) and five (9%) of 55 patients developed a positive HAMA titer at a median of 9.2 months (range, 0.7 to 14.0 months) after the dosimetric dose. Conversion to HAMA positivity was not associated with altered efficacy (eg, 80% of the patients converting to HAMA positivity responded) or safety.
Four (7%) of 60 patients had an elevated TSH level at baseline before iodine I 131 tositumomab. One of the four patients began thyroid hormone supplementation at study entry, and one of the four began thyroid supplementation 37 months after iodine I 131 tositumomab. One of the remaining 56 patients developed an elevated TSH level 8.3 months after iodine I 131 tositumomab and began oral thyroid hormone supplementation.
Four patients were diagnosed with myelodysplasia at a median of 35.5 months (range, 20.6 to 40.9 months) after iodine I 131 tositumomab and a median of 5.1 years (range, 4.6 to 5.8 years) after first exposure to chemotherapy that contained alkylating agents. All four patients responded to iodine I 131 tositumomab, including one patient with an ongoing CR more than 43 months after iodine I 131 tositumomab. None of the patients had developed acute leukemia at last follow-up, and three are alive. One died of progressive NHL.
Thirty-five patients had died as of the data cutoff date. There were no deaths that the investigator considered to be possibly related to the iodine I 131 tositumomab. The median survival time from the dosimetric dose was 22.8 months (95% CI, 17.1 to 30.9 months).
|
DISCUSSION
|
|---|
This multicenter study was designed to establish the efficacy and safety of iodine I 131 tositumomab for patients with low-grade or transformed low-grade B-cell NHL with an especially poor prognosis. The patients included in this trial had not responded to at least two different qualifying chemotherapy regimens (median, four regimens) and had disease that had become refractory to chemotherapy. Such patients have few to no reasonable alternative treatment options. Of note, clinical studies of patients meeting these criteria have not been previously reported. Because a matched historical control population was not possible to obtain and a standard comparative chemotherapy regimen was not possible to prescribe for all such patients, this study incorporated an internal control, the efficacy outcome on the LQC regimen. The outcome was used as a paired control to the efficacy outcome after iodine I 131 tositumomab. As a further control, all response assessments were performed by a masked, randomized, independent panel that reviewed radiographs and medical notes.
Despite the unfavorable prognostic nature of the study group, 65% of the patients responded to iodine I 131 tositumomab, and 20% achieved a CR. This is in contrast to a response rate of 28% and a CR rate of 3% for the LQC regimen. The investigator assessment and the MIRROR Panel assessment were nearly identical. In addition, the median duration of response was almost twice as long after iodine I 131tositumomab than was achieved by the LQC regimen (6.5 v 3.4 months). The CRs after iodine I 131 tositumomab were also durable (median response duration had not been reached at more than 47 months). Moreover, nearly three times as many patients had longer durations of response after iodine I 131 tositumomab than after the LQC. This suggests a reversal of the progressively increasing resistance to therapy generally observed in low-grade NHL, as overall lower response rates and shorter durations of response are observed with each successive treatment.3,4 No other agent for low-grade or transformed low-grade NHL has demonstrated a consistent ability to produce higher response rates and longer durations of response than that observed with previous therapy. In addition, even aggressive therapies, such as autologous bone marrow or stem-cell transplantation, have produced disappointing results in extensively pretreated patients and are thus not generally recommended for this patient population.27
Subset analyses revealed that patients with low-grade NHL, no prior radiotherapy, less extensive tumor burdens, presence of bone marrow involvement (an unanticipated finding), and fewer prior therapies had response rates between 77% and 90%. However, those patients with less favorable features still had quite respectable response rates. For instance, although the response rate for transformed low-grade NHL was 39% (CR rate, 13%), most published series have reported a poor prognosis for such patients, with these patients typically experiencing rapidly progressive disease and a median survival of only 6 to 12 months from transformation.5-9 Thus, the results obtained in transformed low-grade NHL patients with iodine I 131 tositumomab suggest this is an effective therapeutic option for patients with this aggressive form of the disease.
Although the patient-as-own-control design of the trial allowed the control of prognostic factors, such as tumor grade, histology, age, number of prior therapies, and so on, it has potential biases. Unlike studies designed with a concurrent randomized control arm, selection biases are possible. The study design does not control for the possible selection of patients more likely to have durable response on iodine I 131 tositumomab. Another possible bias is related to the observation for both the response rate and duration of response to decrease on average with each successive treatment. As patients had to have a limited duration of response to their last chemotherapy regimen, the direction and magnitude of this bias is difficult to determine. Another possible bias is related to the sequential nature of the therapies. Patients not responding to chemotherapy may be expected to have a higher disease burden before receiving iodine I 131 tositumomab. In fact, the median sum of perpendicular products of all baseline measurable disease was 35.0 cm2 before the LQC, compared with 42.8 cm2 before iodine I 131 tositumomab. As the potential biases may act in different directions, the net effect of all biases is difficult to determine.
The efficacy demonstrated in this study was achieved with acceptable safety results. The unlabeled antibody infusions were well-tolerated, with the median duration of the tositumomab infusion of 1 hour and with less than 7% of the infusions requiring a rate adjustment. No deaths were considered related to the study drug. The most prevalent nonhematologic adverse experiences considered by the investigator to be possibly or probably related to the study drug were asthenia, fever, and nausea. These experiences were typically transient and mild to moderate in nature. No significant abnormalities were noted in the nonhematologic laboratory parameters. The hematologic toxicity was acceptable. In addition, iodine I 131 tositumomab produces a single episode of mild bone marrow suppression. This is in contrast to combination chemotherapy regimens, for which patients typically receive cycles of therapy during an up-to-6-month period and are thus exposed to repeated episodes of bone marrow suppression.
A patient-specific dosing methodology was used to minimize radiation-induced hematologic toxicity along with maximizing the radiation dose delivered to tumors. All patients were dosed based on their total-body clearance of iodine I 131 tositumomab as determined from three total-body gamma camera counts obtained during the week after the dosimetric dose.18 With this dosing method, patients with a slower clearance of iodine I 131 tositumomab received a smaller millicurie amount during the therapeutic dose to deliver the same radiation dose. The administered activity to deliver each patient the prescribed 65 or 75 cGy total-body dose ranged from 47.2 to 212.0 mCi. The variability in pharmacokinetics is related to patient-specific factors, such as tumor burden, spleen size, and bone marrow involvement. The dosing method for iodine I 131 tositumomab controls for the variable clearance, unlike dosing methods based on a fixed mCi, mCi/kg, or mCi/m2. This dosing method seemed to limit severe hematologic toxicity in the heavily pretreated chemotherapy-refractory patient population.
In long-term follow-up, four patients were diagnosed as having myelodysplasia. Because all of these patients had been heavily pretreated with chemotherapy (two to four prior regimens) and all had been exposed to alkylating agents that are known to be associated with the development of myelodysplasia and/or acute leukemia,28 it is not currently possible to determine with any certainty to what extent radioimmunotherapy contributed to this problem. However, continued surveillance and study of this development after radioimmunotherapy is needed.
The National Research Council amended its regulations regarding the criteria for the release of patients administered radioactive material in 1997.29 The regulations or modifications of the regulations have been approved by the majority of states. These allow outpatient therapy for iodine I 131 tositumomab.30 With outpatient therapy, patients may need to restrict their contact with other individuals for a short period of time after therapy. With appropriate, simple instructions before patients’ release, recent studies have shown that radiation exposures to others have been less than those specified in the National Research Council guidelines.31
The promising results obtained in this study demonstrate that iodine I 131 tositumomab can be safely and effectively administered using a simple treatment procedure. The majority of patients responded, and durable CRs occurred in this poor-prognostic, heavily pretreated group of patients with low-grade or transformed low-grade NHL, adding a new approach to the therapeutic armamentarium for management of these patients.
|
REFERENCES
|
|---|
1.
Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin’s lymphoma. N Engl J Med 311: 1471-1475, 1984[Abstract]
2.
Young RC, Longo DL, Glatstein E, et al: The treatment of indolent lymphomas: Watchful waiting vs. aggressive combined modality treatment. Semin Hematol 25: 11-16, 1988 (suppl 2)[Medline]
3.
Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4: 1470-80, 1986[Abstract/Free Full Text]
4.
Johnson PWM, Rohatiner AZS, Whelan JS, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13: 140-147, 1995[Abstract/Free Full Text]
5.
Acker B, Hoppe RT, Colby TV, et al: Histologic conversion in the non-Hodgkin’s lymphomas. J Clin Oncol 1: 11-16, 1983[Abstract]
6.
Cullen MH, Lister A, Breakley RL, et al: Histological transformation of non-Hodgkin’s lymphoma: A prospective study. Cancer 44: 645-651, 1979[Medline]
7.
Hubbard SM, Chabner BA, DeVita VT, et al: Histologic progression in non-Hodgkin’s lymphoma. Blood 59: 258-264, 1982[Free Full Text]
8.
Ersboll J, Schultz HB, Perdersen-Bjergaard J, et al: Follicular low-grade non-Hodgkin’s lymphoma: Long-term outcome with or without tumor progression. Eur J Haematol 42: 155-163, 1989[Medline]
9.
Bastion Y, Sebban C, Berger F, et al: Incidence, predictive factors and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15: 1587-1594, 1997[Abstract]
10.
McLaughlin P, Grillo-Lopez A, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16: 2825-2833, 1998[Abstract]
11.
Moskowitz CH: Conventional treatments for non-Hodgkin’s lymphoma: The need for new therapies. J Nuc Med 39: 2S-10S, 1998 (suppl)
12.
Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with 131I anti-B1 (anti-CD20) antibody. N Engl J Med 329: 459-465, 1993[Abstract/Free Full Text]
13.
Kaminski MS, Zasadny KR, Francis IR, et al: Iodine I 131 tositumomab radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14: 1974-1981, 1996[Abstract/Free Full Text]
14.
Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with Iodine I 131 tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96: 1259-1266, 2000[Abstract/Free Full Text]
15.
Vose JM, Wahl RL, Saleh M, et al: Multicenter Phase II Study of Iodine I 131 tositumomab for chemotherapy-relapsed/refractory low-grade B-cell non-hodgkin’s lymphomas. J Clin Oncol 18: 1316-1323, 2000[Abstract/Free Full Text]
16.
Salacinski RP, McLean C, Sykes JEF, et al: Iodination of proteins, glycoproteins, and peptides using a solid-phase oxidizing agent 1,3,4,6-tetrachloro-3a-6a-diphenylglycouril (Iodogen). Anal Biochem 117: 136-146, 1981[Medline]
17.
Colcher D: Centralized radiolabeling of antibodies for radioimmunotherapy. J Nucl Med 39: 11S-13S, 1998 (suppl)
18.
Wahl RL, Kroll S, Zasadny KR: Patient-specific whole body dosimetry: Principles and a simplified method for clinical implementation. J Nucl Med 39: 14S-20S, 1998 (suppl)
19.
Loevinger R, Budinger TF, Watson EE: MIRD Primer for Absorbed Dose Calculations. Reston, VA, The Society of Nuclear Medicine, Inc, 1988
20.
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
21.
McNemar Q: Note on the sampling error of the difference between correlated proportions or percentages. Psychometrika 12: 153-157, 1947
22.
Yates F: Contingency tables involving small numbers and the 2 test. J R Stat Soc 1: 217-235, 1934 (suppl)
23.
Mantel N: Evaluation of survival data and two new rank order statistics arising in first consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline]
24.
Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-220, 1972
25.
Andersen PK, Borgan O, Gill RD, et al: Statistical models based on counting processes. New York, NY, Springer-Verlag, 1992, pp 287-317
26.
Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive NHL: The international non-Hodgkin’s lymphoma prognostic factors project. N Engl J Med 329: 987-994, 1993[Abstract/Free Full Text]
27.
Bierman PJ, Vose JM, Anderson JR, et al: High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 15: 445-451, 1997[Abstract/Free Full Text]
28.
Leone G, Teresa Voso M, Sica S, et al: Therapy-related leukemias: Susceptibility, prevention and treatment. Leuk Lymphoma 41: 255-276, 2001[Medline]
29.
U.S. Nuclear Regulatory Commission: Release of patients administered radioactive materials: Regulatory Guide 8:39. Washington, DC, U.S. Nuclear Regulatory Commission, 1997
30.
Gates VL, Carey JE, Siegel JA, et al: Nonmyeloablative iodine-131 radioimmunotherapy as outpatient therapy. J Nucl Med 39: 1230-1236, 1998[Abstract/Free Full Text]
31.
Rutar FJ, Augustine SC, Jacobson DA, et al: Radiation doses received by non-occupational caregivers exposed to NHL patients receiving radioimmunotherapy. Blood 94: 90a, 1999 (abstr 395)
Submitted December 15, 2000;
accepted May 27, 2001.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
R. M. Sharkey, O. W. Press, and D. M. Goldenberg
A re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma: prospects for dual-targeted antibody/radioantibody therapy
Blood,
April 23, 2009;
113(17):
3891 - 3895.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Winter, D. J. Inwards, S. Spies, G. Wiseman, D. Patton, W. Erwin, A. W. Rademaker, B. B. Weitner, S. F. Williams, M. S. Tallman, et al.
Yttrium-90 Ibritumomab Tiuxetan Doses Calculated to Deliver up to 15 Gy to Critical Organs May Be Safely Combined With High-Dose BEAM and Autologous Transplantation in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
April 1, 2009;
27(10):
1653 - 1659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Illidge, M. Bayne, N. S. Brown, S. Chilton, M. S. Cragg, M. J. Glennie, Y. Du, V. Lewington, J. Smart, J. Thom, et al.
Phase 1/2 study of fractionated 131I-rituximab in low-grade B-cell lymphoma: the effect of prior rituximab dosing and tumor burden on subsequent radioimmunotherapy
Blood,
February 12, 2009;
113(7):
1412 - 1421.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. A. Jacene, R. Filice, W. Kasecamp, and R. L. Wahl
18F-FDG PET/CT for Monitoring the Response of Lymphoma to Radioimmunotherapy
J. Nucl. Med.,
January 1, 2009;
50(1):
8 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Iagaru, S. S. Gambhir, and M. L. Goris
90Y-Ibritumomab Therapy in Refractory Non-Hodgkin's Lymphoma: Observations from 111In-Ibritumomab Pretreatment Imaging
J. Nucl. Med.,
November 1, 2008;
49(11):
1809 - 1812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Bishton, M. F. Leahy, R. J. Hicks, J. H. Turner, A. D. McQuillan, and J. F. Seymour
Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab
Ann. Onc.,
September 1, 2008;
19(9):
1629 - 1633.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. D. Cheson and J. P. Leonard
Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma
N. Engl. J. Med.,
August 7, 2008;
359(6):
613 - 626.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ychou, D. Azria, C. Menkarios, P. Faurous, F. Quenet, B. Saint-Aubert, P. Rouanet, M. Pelegrin, C. Bascoul-Mollevi, D. Guerreau, et al.
Adjuvant Radioimmunotherapy Trial with Iodine-131-Labeled Anti-Carcinoembryonic Antigen Monoclonal Antibody F6 F(ab')2 after Resection of Liver Metastases from Colorectal Cancer
Clin. Cancer Res.,
June 1, 2008;
14(11):
3487 - 3493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Bishton, R. J. Hicks, D. A. Westerman, M. H. Prince, M. Wolf, and J. F. Seymour
A prospective study of the separate predictive capabilities of 18[F]-FDG-PET and molecular response in patients with relapsed indolent non-Hodgkin's lymphoma following treatment with iodine-131-rituximab radio-immunotherapy
Haematologica,
May 1, 2008;
93(5):
789 - 790.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Toma and P. J. Medina
Update on Targeted Therapy--Focus on Monoclonal Antibodies
Journal of Pharmacy Practice,
February 1, 2008;
21(1):
4 - 16.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Khaibullina, B.-S. Jang, H. Sun, N. Le, S. Yu, V. Frenkel, J. A. Carrasquillo, I. Pastan, K. C.P. Li, and C. H. Paik
Pulsed High-Intensity Focused Ultrasound Enhances Uptake of Radiolabeled Monoclonal Antibody to Human Epidermoid Tumor in Nude Mice
J. Nucl. Med.,
February 1, 2008;
49(2):
295 - 302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. G. Oyen, L. Bodei, F. Giammarile, H. R. Maecke, J. Tennvall, M. Luster, and B. Brans
Targeted therapy in nuclear medicine current status and future prospects
Ann. Onc.,
November 1, 2007;
18(11):
1782 - 1792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. A. Jacene, R. Filice, W. Kasecamp, and R. L. Wahl
Comparison of 90Y-Ibritumomab Tiuxetan and 131I-Tositumomab in Clinical Practice
J. Nucl. Med.,
November 1, 2007;
48(11):
1767 - 1776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pantelias, J. M. Pagel, N. Hedin, L. Saganic, S. Wilbur, D. K. Hamlin, D. S. Wilbur, Y. Lin, D. Stone, D. Axworthy, et al.
Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas
Blood,
June 1, 2007;
109(11):
4980 - 4987.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Venugopal and S. A. Gregory
Lymphoproliferative disorders
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
265 - 297.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. K. Tan, R. W. Wassenaar, and W. Zeng
Collimator Selection, Acquisition Speed, and Visual Assessment of 131I-Tositumomab Biodistribution in a Phantom Model
J. Nucl. Med. Technol.,
December 1, 2006;
34(4):
224 - 227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. Leahy, J. F. Seymour, R. J. Hicks, and J. H. Turner
Multicenter Phase II Clinical Study of Iodine-131-Rituximab Radioimmunotherapy in Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
September 20, 2006;
24(27):
4418 - 4425.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. W. Press, J. M. Unger, R. M. Braziel, D. G. Maloney, T. P. Miller, M. LeBlanc, and R. I. Fisher
Phase II Trial of CHOP Chemotherapy Followed by Tositumomab/Iodine I-131 Tositumomab for Previously Untreated Follicular Non-Hodgkin's Lymphoma: Five-Year Follow-Up of Southwest Oncology Group Protocol S9911
J. Clin. Oncol.,
September 1, 2006;
24(25):
4143 - 4149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Pagel, Y. Lin, N. Hedin, A. Pantelias, D. Axworthy, D. Stone, D. K. Hamlin, D. S. Wilbur, and O. W. Press
Comparison of a tetravalent single-chain antibody-streptavidin fusion protein and an antibody-streptavidin chemical conjugate for pretargeted anti-CD20 radioimmunotherapy of B-cell lymphomas
Blood,
July 1, 2006;
108(1):
328 - 336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Goldenberg, R. M. Sharkey, G. Paganelli, J. Barbet, and J.-F. Chatal
Antibody Pretargeting Advances Cancer Radioimmunodetection and Radioimmunotherapy
J. Clin. Oncol.,
February 10, 2006;
24(5):
823 - 834.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Czuczman
Controversies in Follicular Lymphoma: "Who, What, When, Where, and Why?" (Not Necessarily in That Order!)
Hematology,
January 1, 2006;
2006(1):
303 - 310.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Kaminski, J. A. Radford, S. A. Gregory, J. P. Leonard, S. J. Knox, S. Kroll, and R. L. Wahl
Re-Treatment With I-131 Tositumomab in Patients With Non-Hodgkin's Lymphoma Who Had Previously Responded to I-131 Tositumomab
J. Clin. Oncol.,
November 1, 2005;
23(31):
7985 - 7993.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. I. Fisher, M. S. Kaminski, R. L. Wahl, S. J. Knox, A. D. Zelenetz, J. M. Vose, J. P. Leonard, S. Kroll, S. J. Goldsmith, and M. Coleman
Tositumomab and Iodine-131 Tositumomab Produces Durable Complete Remissions in a Subset of Heavily Pretreated Patients With Low-Grade and Transformed Non-Hodgkin's Lymphomas
J. Clin. Oncol.,
October 20, 2005;
23(30):
7565 - 7573.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. L. DeNardo, E. Tobin, K. Chan, B. M. Bradt, and S. J. DeNardo
Direct Antilymphoma Effects on Human Lymphoma Cells of Monotherapy and Combination Therapy with CD20 and HLA-DR Antibodies and 90Y-Labeled HLA-DR Antibodies
Clin. Cancer Res.,
October 1, 2005;
11(19):
7075s - 7079s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Baranowska-Kortylewicz, M. Abe, K. Pietras, Z. P. Kortylewicz, T. Kurizaki, J. Nearman, J. Paulsson, R. L. Mosley, C. A. Enke, and A. Ostman
Effect of Platelet-Derived Growth Factor Receptor-{beta} Inhibition with STI571 on Radioimmunotherapy
Cancer Res.,
September 1, 2005;
65(17):
7824 - 7831.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Leonard, M. Coleman, L. Kostakoglu, A. Chadburn, E. Cesarman, R. R. Furman, M. W. Schuster, R. Niesvizky, D. Muss, J. Fiore, et al.
Abbreviated Chemotherapy With Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab for Untreated Follicular Lymphoma
J. Clin. Oncol.,
August 20, 2005;
23(24):
5696 - 5704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Richman, S. J. DeNardo, R. T. O'Donnell, A. Yuan, S. Shen, D. S. Goldstein, J. M. Tuscano, T. Wun, H. K. Chew, P. N. Lara, et al.
High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, m170, Linked to Indium-111/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human Anti-mouse Antibody
Clin. Cancer Res.,
August 15, 2005;
11(16):
5920 - 5927.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Rao, G. Akabani, and D. A. Rizzieri
Radioimmunotherapy for Non-Hodgkin's Lymphoma
Clin. Med. Res.,
August 1, 2005;
3(3):
157 - 165.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Linden, C. Hindorf, E. Cavallin-Stahl, W. A. Wegener, D. M. Goldenberg, H. Horne, T. Ohlsson, L. Stenberg, S.-E. Strand, and J. Tennvall
Dose-Fractionated Radioimmunotherapy in Non-Hodgkin's Lymphoma Using DOTA-Conjugated, 90Y-Radiolabeled, Humanized Anti-CD22 Monoclonal Antibody, Epratuzumab
Clin. Cancer Res.,
July 15, 2005;
11(14):
5215 - 5222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Bennett, M. S. Kaminski, J. P. Leonard, J. M. Vose, A. D. Zelenetz, S. J. Knox, S. Horning, O. W. Press, J. A. Radford, S. M. Kroll, et al.
Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab
Blood,
June 15, 2005;
105(12):
4576 - 4582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P Levene, G. Singh, and C. Palmieri
Therapeutic monoclonal antibodies in oncology
J R Soc Med,
April 1, 2005;
98(4):
146 - 152.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Kaminski, M. Tuck, J. Estes, A. Kolstad, C. W. Ross, K. Zasadny, D. Regan, P. Kison, S. Fisher, S. Kroll, et al.
131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma
N. Engl. J. Med.,
February 3, 2005;
352(5):
441 - 449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Horning, A. Younes, V. Jain, S. Kroll, J. Lucas, D. Podoloff, and M. Goris
Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab
J. Clin. Oncol.,
February 1, 2005;
23(4):
712 - 719.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Hagemeister, F. Cabanillas, M. Coleman, S. A. Gregory, and P. L. Zinzani
The Role of Mitoxantrone in the Treatment of Indolent Lymphomas
Oncologist,
February 1, 2005;
10(2):
150 - 159.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Vose, P. J. Bierman, C. Enke, J. Hankins, G. Bociek, J. C. Lynch, and J. O. Armitage
Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
January 20, 2005;
23(3):
461 - 467.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Michel, A. V. Rosario, P. M. Andrews, D. M. Goldenberg, and M. J. Mattes
Therapy of Small Subcutaneous B-Lymphoma Xenografts with Antibodies Conjugated to Radionuclides Emitting Low-Energy Electrons
Clin. Cancer Res.,
January 15, 2005;
11(2):
777 - 786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Z. Lin, M. A. Teitell, and G. J. Schiller
The Evolution of Antibodies into Versatile Tumor-Targeting Agents
Clin. Cancer Res.,
January 1, 2005;
11(1):
129 - 138.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Leonard
Targeting CD20 in Follicular NHL: Novel Anti-CD20 Therapies, Antibody Engineering, and the Use of Radioimmunoconjugates
Hematology,
January 1, 2005;
2005(1):
335 - 339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Larson and E. P. Krenning
A Pragmatic Perspective on Molecular Targeted Radionuclide Therapy
J. Nucl. Med.,
January 1, 2005;
46(1_suppl):
1S - 3S.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Sharkey and D. M. Goldenberg
Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies
J. Nucl. Med.,
January 1, 2005;
46(1_suppl):
115S - 127S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. S. Jhanwar and C. Divgi
Current Status of Therapy of Solid Tumors
J. Nucl. Med.,
January 1, 2005;
46(1_suppl):
141S - 150S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kazama, S. C. Faria, V. Varavithya, S. Phongkitkarun, H. Ito, and H. A. Macapinlac
FDG PET in the Evaluation of Treatment for Lymphoma: Clinical Usefulness and Pitfalls
RadioGraphics,
January 1, 2005;
25(1):
191 - 207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. DiJoseph, M. E. Goad, M. M. Dougher, E. R. Boghaert, A. Kunz, P. R. Hamann, and N. K. Damle
Potent and Specific Antitumor Efficacy of CMC-544, a CD22-Targeted Immunoconjugate of Calicheamicin, against Systemically Disseminated B-Cell Lymphoma
Clin. Cancer Res.,
December 15, 2004;
10(24):
8620 - 8629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Davis, M. S. Kaminski, J. P. Leonard, F. J. Hsu, M. Wilkinson, A. Zelenetz, R. L. Wahl, S. Kroll, M. Coleman, M. Goris, et al.
The Radioisotope Contributes Significantly to the Activity of Radioimmunotherapy
Clin. Cancer Res.,
December 1, 2004;
10(23):
7792 - 7798.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-L. Law, C. G. Cerveny, K. A. Gordon, K. Klussman, B. J. Mixan, D. F. Chace, D. L. Meyer, S. O. Doronina, C. B. Siegall, J. A. Francisco, et al.
Efficient Elimination of B-Lineage Lymphomas by Anti-CD20-Auristatin Conjugates
Clin. Cancer Res.,
December 1, 2004;
10(23):
7842 - 7851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Kaminski, A. D. Zelenetz, O. W. Press, M. N. Saleh, J. P. Leonard, L. Fehrenbacher, T. A. Lister, S. Kroll, R. L. Wahl, S. J. Knox, et al.
Tositumomab and Iodine I 131 Tositumomab (The BEXXAR(R) Therapeutic Regimen) Produced Ongoing, Durable Remissions of More Than 5 Years in 9 Patients with Non-Hodgkin's Lymphoma (NHL) in a Pivotal Study of Patients Refractory to Their Last Chemotherapy.
Blood (ASH Annual Meeting Abstracts),
November 16, 2004;
104(11):
2631 - 2631.
[Abstract]
|
|
|
|
|
|
|
J. P. Leonard, M. Coleman, J. C. Ketas, A. Chadburn, R. Furman, M. W. Schuster, E. J. Feldman, M. Ashe, S. J. Schuster, W. A. Wegener, et al.
Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin's Lymphoma: Phase I/II Clinical Trial Results
Clin. Cancer Res.,
August 15, 2004;
10(16):
5327 - 5334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Forero, P. L. Weiden, J. M. Vose, S. J. Knox, A. F. LoBuglio, J. Hankins, M. L. Goris, V. J. Picozzi, D. B. Axworthy, H. B. Breitz, et al.
Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma
Blood,
July 1, 2004;
104(1):
227 - 236.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bendandi, S. A. Pileri, and P. L. Zinzani
Challenging paradigms in lymphoma treatment
Ann. Onc.,
May 1, 2004;
15(5):
703 - 711.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Advani, S. A. Rosenberg, and S. J. Horning
Stage I and II Follicular Non-Hodgkin's Lymphoma: Long-Term Follow-Up of No Initial Therapy
J. Clin. Oncol.,
April 15, 2004;
22(8):
1454 - 1459.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.J. Davies, A.Z.S. Rohatiner, S. Howell, K.E. Britton, S.E. Owens, I.N. Micallef, D.P. Deakin, B.M. Carrington, J.A. Lawrance, S. Vinnicombe, et al.
Tositumomab and Iodine I 131 Tositumomab for Recurrent Indolent and Transformed B-Cell Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
April 15, 2004;
22(8):
1469 - 1479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Vose
Bexxar(R): Novel Radioimmunotherapy for the Treatment of Low-Grade and Transformed Low-Grade Non-Hodgkin's Lymphoma
Oncologist,
April 1, 2004;
9(2):
160 - 172.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Winter, R. D. Gascoyne, and K. Van Besien
Low-Grade Lymphoma
Hematology,
January 1, 2004;
2004(1):
203 - 220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Sharkey, A. Brenner, J. Burton, G. Hajjar, S. P. Toder, A. Alavi, A. Matthies, D. E. Tsai, S. J. Schuster, E. A. Stadtmauer, et al.
Radioimmunotherapy of Non-Hodgkin's Lymphoma with 90Y-DOTA Humanized Anti-CD22 IgG (90Y-Epratuzumab): Do Tumor Targeting and Dosimetry Predict Therapeutic Response?
J. Nucl. Med.,
December 1, 2003;
44(12):
2000 - 2018.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Lister
High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When?
J. Clin. Oncol.,
November 1, 2003;
21(21):
3894 - 3896.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Gopal, T. A. Gooley, D. G. Maloney, S. H. Petersdorf, J. F. Eary, J. G. Rajendran, S. A. Bush, L. D. Durack, J. Golden, P. J. Martin, et al.
High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis
Blood,
October 1, 2003;
102(7):
2351 - 2357.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Rossi, R. M. Sharkey, W. McBride, H. Karacay, L. Zeng, H. J. Hansen, D. M. Goldenberg, and C.-H. Chang
Development of New Multivalent-bispecific Agents for Pretargeting Tumor Localization and Therapy
Clin. Cancer Res.,
September 1, 2003;
9(10):
3886S - 3896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Sharkey, H. Karacay, H. Richel, W. J. McBride, E. A. Rossi, K. Chang, D. Yeldell, G. L. Griffiths, H. J. Hansen, and D. M. Goldenberg
Optimizing Bispecific Antibody Pretargeting for Use in Radioimmunotherapy
Clin. Cancer Res.,
September 1, 2003;
9(10):
3897S - 3913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. DeNardo, G. L. DeNardo, A. Yuan, C. M. Richman, R. T. O'Donnell, P. N. Lara, D. L. Kukis, A. Natarajan, K. R. Lamborn, F. Jacobs, et al.
Enhanced Therapeutic Index of Radioimmunotherapy (RIT) in Prostate Cancer Patients: Comparison of Radiation Dosimetry for 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-Tetraacetic Acid (DOTA)-Peptide versus 2IT-DOTA Monoclonal Antibody Linkage for RIT
Clin. Cancer Res.,
September 1, 2003;
9(10):
3938S - 3944.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. L. DeNardo, G. R. Mirick, L. A. Kroger, B. M. Bradt, K. R. Lamborn, and S. J. DeNardo
Characterization of Human IgG Antimouse Antibody in Patients with B-Cell Malignancies
Clin. Cancer Res.,
September 1, 2003;
9(10):
4013S - 4021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. W. Press, J. M. Unger, R. M. Braziel, D. G. Maloney, T. P. Miller, M. LeBlanc, E. R. Gaynor, S. E. Rivkin, and R. I. Fisher
A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911
Blood,
September 1, 2003;
102(5):
1606 - 1612.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. Witzig, C. A. White, L. I. Gordon, G. A. Wiseman, C. Emmanouilides, J. L. Murray, J. Lister, and P. S. Multani
Safety of Yttrium-90 Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed Low-Grade, Follicular, or Transformed Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
April 1, 2003;
21(7):
1263 - 1270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Buchsbaum and A. F. LoBuglio
Targeting of 125I-Labeled B Lymphocyte Stimulator
J. Nucl. Med.,
March 1, 2003;
44(3):
434 - 436.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Kostakoglu and S. J. Goldsmith
18F-FDG PET Evaluation of the Response to Therapy for Lymphoma and for Breast, Lung, and Colorectal Carcinoma
J. Nucl. Med.,
February 1, 2003;
44(2):
224 - 239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Sgouros, S. Squeri, A. M. Ballangrud, K. S. Kolbert, J. B. Teitcher, K. S. Panageas, R. D. Finn, C. R. Divgi, S. M. Larson, and A. D. Zelenetz
Patient-Specific, 3-Dimensional Dosimetry in Non-Hodgkin's Lymphoma Patients Treated with 131I-anti-B1 Antibody: Assessment of Tumor Dose-Response
J. Nucl. Med.,
February 1, 2003;
44(2):
260 - 268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Ansell, K. M. Ristow, T. M. Habermann, G. A. Wiseman, and T. E. Witzig
Subsequent Chemotherapy Regimens Are Well Tolerated After Radioimmunotherapy With Yttrium-90 Ibritumomab Tiuxetan for Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
September 15, 2002;
20(18):
3885 - 3890.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Seldin
Techniques for Using Bexxar for the Treatment of Non-Hodgkin's Lymphoma*
J. Nucl. Med. Technol.,
September 1, 2002;
30(3):
109 - 114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. O. Dillman
Radiolabeled Anti-CD20 Monoclonal Antibodies for the Treatment of B-Cell Lymphoma
J. Clin. Oncol.,
August 15, 2002;
20(16):
3545 - 3557.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Michel and M. J. Mattes
Intracellular Accumulation of the Anti-CD20 Antibody 1F5 in B-Lymphoma Cells
Clin. Cancer Res.,
August 1, 2002;
8(8):
2701 - 2713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. Witzig, L. I. Gordon, F. Cabanillas, M. S. Czuczman, C. Emmanouilides, R. Joyce, B. L. Pohlman, N. L. Bartlett, G. A. Wiseman, N. Padre, et al.
Randomized Controlled Trial of Yttrium-90-Labeled Ibritumomab Tiuxetan Radioimmunotherapy Versus Rituximab Immunotherapy for Patients With Relapsed or Refractory Low-Grade, Follicular, or Transformed B-Cell Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
May 15, 2002;
20(10):
2453 - 2463.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. D. Cheson
CHOP plus Rituximab -- Balancing Facts and Opinion
N. Engl. J. Med.,
January 24, 2002;
346(4):
280 - 282.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Vose, B. C.-H. Chiu, B. D. Cheson, J. Dancey, and J. Wright
Update on Epidemiology and Therapeutics for Non-Hodgkin's Lymphoma
Hematology,
January 1, 2002;
2002(1):
241 - 262.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. D. Cheson
Some Like It Hot!
J. Clin. Oncol.,
October 1, 2001;
19(19):
3908 - 3911.
[Full Text]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
