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Phase I/II Trial of IDEC-Y2B8 Radioimmunotherapy for Treatment of Relapsed or Refractory CD20⁺ B-Cell Non-Hodgkin's Lymphoma

From the Divisions of Hematology and Nuclear Medicine, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN; IDEC Pharmaceuticals Corporation, San Diego, CA; Division of Hematology/Oncology, Department of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; University of California—Los Angeles, Los Angeles, CA; City of Hope, Duarte, CA; Henry Ford Hospital, Detroit, MI; Sidney Kimmel Cancer Center, San Diego, CA; and Fox Chase Cancer Center, Philadelphia, PA.

Address reprint requests to Thomas E. Witzig, MD, 920 E Hilton Building, Mayo Clinic, Rochester, MN 55905; email witzig{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy.

PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20⁺ B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass 5 cm.

RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/µL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease ( 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody).

CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ATTEMPTS TO TREAT B-cell malignancies with immunotherapy using monoclonal antibodies that are reactive against B-cell antigens began more than a decade ago.^1-3 In early studies using murine monoclonal antibodies, responses were limited by the development of human antimouse antibody (HAMA), by the relative inability of mouse antibodies to recruit human immune effector mechanisms for tumor killing, and by downregulation of the target antigen.⁴ Efficacy with anti-idiotype antibodies could also be limited by circulating free antigen. More recently, genetically modified antibodies containing murine variable-region genes and human constant-region genes have been engineered, and target antigens have been identified that do not shed or modulate. Rituximab (Rituxan and MabThera; IDEC Pharmaceuticals Corp, San Diego, CA, and Genentech, Inc, South San Francisco, CA)⁵ is an example of a chimeric antibody that targets CD20⁺ B cells. It has been shown to produce objective tumor responses in approximately 50% of patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL) with low toxicity and induction of human antichimeric antibody (HACA) in less than 1% of patients.⁵ The median time to disease progression (TTP) was 13.2 months.⁶

Radionuclides have been conjugated to monoclonal antibodies for the purpose of radioimmunotherapy (RIT) in an effort to improve the response rate. The aim of RIT is to use the monoclonal antibody to target radiation to tumor tissue while limiting toxicity to normal cells. Thus, tumor cells are eliminated via the effector mechanisms of antibody targeting and from the radiation emitted by the conjugated radionuclide. The most common radionuclide used for RIT to date has been iodine-131 (¹³¹I). The advantages of ¹³¹I RIT are that ¹³¹I is commercially available, dosimetry can be performed after trace doses of the radioimmunoconjugate, and most nuclear medicine departments are familiar with its use. ¹³¹I RIT^7-12 has been complicated by several factors, including the long 8-day half-life of the radioisotope, dehalogenation of iodinated antibody both in blood and at tumor sites, hypothyroidism, and the gamma emission of ¹³¹I,^13,14 which results in irradiation of distant organs, restrictions on the patient to prevent exposure to family and the public, and hospitalization with shielding in some cases.^9,15,16

The development and improvement of methods for attaching metal chelating groups to proteins have made it possible to study other potentially useful radioisotopes such as yttrium-90 (⁹⁰Y). ⁹⁰Y provides advantages over ¹³¹I because it delivers higher beta energy (2.3 MeV v 0.61 MeV) to the tumor and has a path length of 5 to 10 mm, resulting in the improved ability to kill both targeted and neighboring cells, an advantage particularly in bulky or poorly vascularized tumors. In addition, because ⁹⁰Y is a pure beta-emitting radioisotope, all patients can be treated as outpatients. Although ⁹⁰Y provides some potential therapeutic advantages, it cannot be used for imaging, as ¹³¹I can; however, the gamma emitter indium-111 (¹¹¹In) has been successfully used as an imaging agent and can be conjugated to monoclonal antibodies.^17-20

IDEC-Y2B8 (Zevalin; IDEC Pharmaceuticals Corp) is a unique compound composed of the following: a murine immunoglobulin G1 kappa monoclonal antibody ibritumomab (IDEC-2B8); the linker chelator tiuxetan (isothiocyanatobenzyl MX-DTPA); and the radioisotope ⁹⁰Y that is securely chelated via the linker. Like its unlabeled chimeric counterpart, rituximab, IDEC-Y2B8 targets the CD20 antigen present on 95% of B-cell lymphomas.^{21 111}In ibritumomab tiuxetan (IDEC-In2B8) is the ¹¹¹In-labeled murine monoclonal antibody used for imaging and dosimetry. Rituximab, a chimeric mouse/human antibody, is given initially to clear peripheral B lymphocytes and optimize biodistribution of the radiolabeled antibody.

A previous phase I/II dose-escalation study of IDEC-Y2B8 in patients with relapsed or refractory low- or intermediate-grade B-cell lymphoma demonstrated activity and determined the maximum-tolerated dose.²² Unlike the current study, patients in that study received the unlabeled murine antibody ibritumomab before imaging with IDEC-In2B8 and treatment with IDEC-Y2B8. Fourteen patients were treated at four single-dose levels ranging from 20 to 50 mCi. Marrow ablation occurred in patients who received more than 40 mCi (> 0.6 mCi/kg) of IDEC-Y2B8. Hematologic toxicity was found to correlate best with millicuries of ⁹⁰Y administered per kilogram of body weight rather than with total millicuries or millicuries per meter squared. The overall response rate (ORR; complete plus partial responders) at all doses and for all histologies was 64%.

We designed the current phase I/II trial based on the positive results of that previous trial. The aim was to learn the maximum-tolerated single dose of IDEC-Y2B8 that could be delivered in an outpatient setting without the need for stem-cell collection or routine use of growth factors. A second goal was to compare the two doses of unlabeled rituximab to be used before IDEC-In2B8 and IDEC-Y2B8 to choose the dose for imaging and dosimetry.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Patients with histologically confirmed relapsed or refractory low-grade or follicular B-cell NHL (International Working Formulation [IWF] A to D; Revised European-American Lymphoma classification: small lymphocytic lymphoma, lymphoplasmacytoid, and follicular center grades 1, 2, and 3, respectively) who had experienced treatment failure with two prior regimens or an anthracycline, and those with intermediate-grade and mantle-cell NHL in first or subsequent relapse were included in the study provided they met the following criteria: bidimensionally measurable disease, a demonstrable monoclonal CD20⁺ B-cell population in lymph nodes or bone marrow, a bone marrow biopsy specimen or aspirate demonstrating less than 25% involvement with NHL, and a prestudy performance status of 0, 1, or 2 according to the World Health Organization scale. In addition, patients had to be at least 18 years of age, not pregnant or lactating, using accepted birth control methods, and had to have a life expectancy of 3 months. Within 2 weeks before initial treatment, patients were required to have acceptable hematologic status (hemoglobin level 8 g/dL, absolute neutrophil count 1,500 x 10⁶/L, platelet count 100,000 x 10⁶/L), hepatic function (total bilirubin level 2.0 mg/dL, alkaline phosphatase level four times normal, AST four times normal), and renal function (serum creatinine concentration 2.0 mg/dL). Patients with a bone marrow biopsy specimen or aspirate that demonstrated 25% involvement with NHL, prior external-beam radiation therapy to 25% of the patient's bone marrow, a history of HAMA/HACA, or prior anti-CD20 therapy were excluded. There was no limitation on number of prior therapies/relapses. All prior chemotherapy (including corticosteroids) had to have been completed 4 weeks before study treatment. The study was approved by the institutional review board at each study site, and written informed consent was obtained from all patients.

Study Design
We conducted an open-label, multicenter, phase I/II study comprised of three groups of patients. The phase I, group 1 segment was designed to determine the dose of rituximab (100 mg/m² or 250 mg/m²) to be infused as unlabeled antibody before IDEC-In2B8 and IDEC-Y2B8 administration; these patients then received four weekly doses of standard rituximab (375 mg/m²/wk) without IDEC-Y2B8. The phase I, group 2 segment was designed to determine the maximum-tolerated dose of IDEC-Y2B8 (0.2, 0.3, or 0.4 mCi/kg ⁹⁰Y, approximately 2 mg ibritumomab), and the phase II, group 3 segment was designed to evaluate further safety and efficacy of the chosen doses of rituximab/IDEC-Y2B8. Dosimetry calculations to determine the safety of treatment were performed before treatment at the individual study sites. Central dosimetry was performed by the Mayo Clinic and Oak Ridge Institute for Science and Education.

The IDEC-Y2B8 regimen consists of the following components: rituximab, IDEC-In2B8 (5 mCi ¹¹¹In, 1.6 mg ibritumomab), and IDEC-Y2B8. The production of rituximab has been described previously.²³ The chimeric antibody was supplied in pharmaceutical glass vials containing 10 mL (100 mg) or 50 mL (500 mg) of antibody solution diluted into a final volume of normal saline for a maximal concentration of 1 mg/mL. The product was to be stored in a secure refrigerator at 2°C to 8°C. The antibody was administered as an intravenous infusion at an initial dose rate of 50 mg/hr for the first hour and escalated gradually to a maximum of 300 mg/hr for the first infusion and 400 mg/hr for the following infusion. Patients were typically pretreated with 25 to 50 mg of intravenous or oral diphenhydramine and 650 mg of oral acetaminophen. Corticosteroids were not used.

IDEC-Y2B8 and IDEC-In2B8 consist of the ibritumomab anti-CD20 monoclonal antibody covalently bound to the isothiocyanatobenzyl derivative of DTPA (tiuxetan) that chelates either ⁹⁰Y or ¹¹¹In. Ibritumomab is an immunoglobulin G1 kappa isotype monoclonal antibody produced in Chinese hamster ovary cells. The Chinese hamster ovary master cell bank has been fully characterized and found to be negative for Mycoplasma, infectious viruses, or replicating viruses. The ibritumomab antibody was purified by a protein A, ion exchange, and hydrophobic interaction chromatography process that has been validated. The purified antibody was subsequently reacted with the isothiocyanatobenzyl derivative of DTPA to form ibritumomab tiuxetan. Ibritumomab tiuxetan is prepared by IDEC Pharmaceuticals (San Diego, CA) and retains more than 90% immunoreactivity with the CD20 antigen compared with the native ibritumomab antibody. The formulated conjugate (ibritumomab tiuxetan) and other components of the radiolabeling kit were provided to each clinical site. The ibritumomab tiuxetan antibody was radiolabeled at the clinical sites with either ¹¹¹In or with ⁹⁰Y. ¹¹¹In (5.5 mCi) and ⁹⁰Y (45 mCi) were mixed by inversion with sodium acetate (for ¹¹¹In, 1.2 times the volume of ¹¹¹In; for ⁹⁰Y, equivalent volume of ⁹⁰Y). Ibritumomab tiuxetan (1 mL for IDEC-In2B8 and 1.5 mL for IDEC-Y2B8 at a concentration of 1.6 mg/mL) was transferred to the radiolabel, mixed by inversion, and incubated for 5 minutes. Formulation buffer was added to 10 mL (Chinn et al, manuscript submitted for publication).

Both a radioincorporation assay and a binding assay were performed to verify that an acceptable percentage of antibody conjugate chelated the radiolabel and that CD20 binding was not compromised through radiolabeling. The release specification for radioincorporation was 95%. The release specification for binding was 70% for SB cells (CD20⁺) and 10% for HSB cells (CD20^-).

Patients received rituximab and IDEC-In2B8 on day 0 followed by gamma camera imaging on days 0 through 6. If the predicted delivered dose of radiation to any nontumor organ was more than 20 Gy or if the dose to the bone marrow was more than 3 Gy, no treatment with IDEC-Y2B8 was to be administered. On day 7, the patient received a second dose of rituximab followed by IDEC-Y2B8 at a dose of 0.2, 0.3, or 0.4 mCi/kg. Patients more than 80 kg were to receive a maximum dose of 32 mCi. Both the imaging dose of IDEC-In2B8 and the therapeutic dose of IDEC-Y2B8 were to be administered by a slow (10-minute) intravenous push injection immediately after infusion of rituximab. Weekly complete blood counts were performed for 12 weeks, and the patients were evaluated every 3 months for the first 2 years and every 6 months through 4 years. Scans of measurable lesions were repeated on all patients approximately 28 days after treatment; if a response (complete response [CR] or partial response [PR]) was observed, it was confirmed with repeat imaging 28 days later.

Toxicity was evaluated using the 1988 version of the National Cancer Institute's Adult Toxicity Criteria, which varies from the 1998 version in that grade 4 thrombocytopenia is defined as less than 25,000/µL instead of less than 10,000/µL. Laboratory testing included hematology and serum chemistry assays, immunoglobulin concentrations, HACA/HAMA^24,25 assays, rituximab levels, and bcl-2 analysis on DNA from blood and marrow cells. Hematology, serum chemistry, and immunoglobulin studies were all conducted at the individual study sites. The remaining assays were performed at IDEC Pharmaceuticals Clinical Immunology Laboratory.

Detection of human bcl-2 translocation was performed using a modification of the Gribben method.²⁶ Genomic DNA was extracted from patients' baseline bone marrow or blood. It was tested in duplicate in a nested polymerase chain reaction, along with various positive and negative controls for a breakpoint in either the major breakpoint region or the minor cluster region. Samples were also collected after treatment and run along with the baseline samples to confirm remission or to detect residual disease.

Statistical Methods
Response categories consisted of CR, PR, stable disease, and progressive disease.^27-29 CR required regression of all lymph nodes on computed tomography scans of the neck, chest, abdomen, and pelvis to 1 cm x 1 cm in size; that any node that was palpable on physical examination after therapy be negative on biopsy or fine-needle aspirate; that bone marrow be histologically negative for lymphoma; and that the liver and spleen (if abnormal at baseline) be returned to normal. PR was defined as 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of all the measured lesions and no simultaneous increase in size of any other lesion or no new lesions. Stable disease referred to patients who did not show at least a 50% decrease or increase in SPD, and progressive disease was considered as any single observation of a 50% increase in SPD from nadir or the appearance of a new lesion. Response classifications of PR and CR required confirmation by reassessment 28 days after the original determination of response.

The primary efficacy end point was ORR (CR plus PR); secondary end points were TTP for responders and response duration. ORR data were analyzed based on the confidence limits method. TTP was measured from the date of rituximab IDEC-In2B8 administration until disease progression; duration of response was measured from the date of first observation of response to disease progression. The Kaplan-Meier product-limits method was used to analyze the TTP in responders; curves were generated using PROC LIFETEST (SAS/STAT Users Guide, Version 6, SAS Institute, Cary, NC).

The safety variables to be analyzed included all adverse events within the first 12 weeks regardless of attribution to study drug, disease, or other causes, and laboratory data for blood chemistry, hematology, immunoglobulins, flow cytometry, and HACA/HAMA. Clinical adverse-event data were assigned preferred terms using a modified Coding Symbols for Thesaurus of Adverse Reaction Terms dictionary (U.S. Food and Drug Administration, Rockville, MD) and were analyzed by calculating the number and percent of patients and events for each dosing group. If the same adverse event was reported on consecutive days, it was recorded as a single event, and the most severe grade among the individual events was used to characterize this combined event.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Rituximab Before IDEC-In2B8
Six patients in group 1 received rituximab followed by IDEC-In2B8 on days 0 and 7. In three patients, 100 mg/m² was administered; the other three patients received 250 mg/m². The 250-mg/m² rituximab dose was chosen as the dose to be given before IDEC-In2B8 and IDEC-Y2B8 for subsequent patients in groups 2 and 3 because no difference in imaging nor dosimetry was observed between the first and second week in both dosing groups, and there was potential for enhanced clinical response from the higher dose of rituximab. After treatment with rituximab/IDEC-In2B8, group 1 patients received four weekly doses of 375 mg/m² rituximab. Two patients achieved a PR, and four experienced disease progression.

Phase I/II Trial of IDEC-Y2B8
Fifty-one patients were enrolled onto the study of IDEC-Y2B8 RIT; 15 were in group 2 (phase I) and 36 in group 3 (phase II). Five patients received 0.2 mCi/kg, 15 received 0.3 mCi/kg, and 30 received 0.4 mCi/kg. One patient was not treated. Seventy-one percent of the patients were men, 96% were white, and the median age was 60 years (mean, 59.9 years; range, 24 to 82 years). Twelve patients (24%) were 70 years of age. The tumor histology was low grade in 66% of patients (6% IWF A, 27% B, and 33% C); intermediate grade in 28% (4% D, 6% F, and 18% G); and mantle-cell NHL in 6%. Two of the 14 patients with intermediate-grade disease had transformed lymphoma. The median time from diagnosis to IDEC-Y2B8 treatment was 3.8 years (range, 0.7 to 33.1 years). All 51 patients had received prior chemotherapy with a median of two prior regimens (range, one to seven), and 47 (92%) had received an anthracycline. Ten patients (20%) were resistant to prior chemotherapy (ie, they had no response), and nine (18%) were resistant to the last chemotherapy regimen. Seventeen patients (37%) had received prior conventional external-beam radiation therapy. Fourteen patients (27%) had two extranodal sites at diagnosis, 19 (37%) had bulky disease at study entry (masses 7 cm), 30 (59%) had at least one mass 5 cm, and 22 (43%) had bone marrow involvement with lymphoma at study entry.

Phase I Results of IDEC-Y2B8
Fifteen patients were treated with IDEC-Y2B8 in phase I, with five patients treated in each dose group (0.2, 0.3, and 0.4 mCi/kg). It was recognized early in phase I that the pretreatment platelet count (a surrogate for prior bone marrow damage from chemotherapy or external-beam radiation therapy and/or lymphomatous involvement of the marrow) was predictive for hematologic toxicity. Two of two patients with baseline platelet counts of 100,000 to 120,000/µL developed nadir platelet counts of less than 25,000/µL at the 0.2- or 0.3-mCi/kg dose levels, whereas none of eight patients with baseline platelet counts 150,000/µL developed thrombocytopenia at these dose levels.

For this reason, the study was modified so that patients with baseline platelet counts 150,000/µL were escalated to 0.4 mCi/kg, and additional patients with baseline platelet counts of 100,000 to 149,000/µL were treated with 0.3 mCi/kg. The maximum-tolerated dose was 0.4 mCi/kg (0.3 mCi/kg for the mildly thrombocytopenic patients).

Phase II Results of IDEC-Y2B8
For phase II, 250 mg/m² of rituximab and 0.4 mCi/kg of IDEC-Y2B8 (0.3 mCi/kg for patients with baseline thrombocytopenia) were administered. Thirty-six patients were enrolled onto the phase II portion: 10 at the 0.3-mCi/kg dose level and 25 at the 0.4-mCi/kg dose level. One patient did not receive IDEC-Y2B8 therapy (see Safety). The patients in groups 2 and 3 were combined for the analysis of safety and efficacy. There were 51 patients in the intent-to-treat analysis, including the one patient who did not receive IDEC-Y2B8 and another patient who was not assessable because she had residual disease after chemotherapy (measurable lesions < 2 cm) rather than the required progressive disease.

The ORR for intent-to-treat patients (Table 1) was 67% (26% CR; 41% PR; 95% confidence interval, 54 to 80). The response rate was 82% (26% CR; 56% PR) for 34 patients with low-grade NHL and 43% (29% CR; 14% PR) for 14 patients with intermediate-grade disease. None of the three patients with mantle-cell disease responded. The mean change in lymph node lesion size was as follows: -97% in patients who achieved a CR; -86% in patients who achieved a PR; and -37% in patients with stable disease. Estimated median TTP determined by Kaplan-Meier analysis was 12.9+ months (95% confidence interval, 12.4 to –) for the intent-to-treat responders (Figs 1, 2, and 3). The median duration of response estimated by Kaplan-Meier analysis was 11.7+ months (95% confidence interval, 10.5 to –). The upper limit of the confidence interval could not be estimated because currently there are a significant number of ongoing responders. At the time of this report, eight patients had died from disease progression 1 to 10 months after treatment. There were no treatment-related deaths.

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier graph of TTP in 34 responders (DR, duration of response). The asterisk indicates that the upper limit of the confidence interval could not be estimated because currently there are a significant number of ongoing responders.

View larger version (79K): [in this window] [in a new window]   Fig 2. Abdominal computed tomography (CT), single-photon emission computed tomography (SPECT), and corresponding IDEC-In2B8 imaging at 24, 96, and 144 hours in a patient with NHL with bulky periaortic lymphadenopathy.

View larger version (88K): [in this window] [in a new window]   Fig 3. Abdominal computed tomography scan of a 78-year-old woman with follicular NHL. Hydronephrosis secondary to mass visible on gamma camera scan resolved after treatment. (A and C) Pretreatment computed tomography scans; (B) corresponding IDEC-In2B8 gamma camera imaging; (D) posttreatment computed tomography scan.

The relationship between the response to treatment and baseline prognostic variables was analyzed for patients in the 0.3- and 0.4-mCi/kg dose groups (n = 46; Table 2). Histologic grade (low or intermediate) and IWF histologic classification correlated with response to therapy. Eighty-four percent of patients with low-grade NHL (IWF A, B, C; Revised European-American Lymphoma classification: small lymphocytic lymphoma, lymphoplasmacytoid, and follicular center grades 1, 2) responded compared with 40% of patients with intermediate-grade and mantle-cell disease (P = .005). Of patients with zero to one extranodal disease sites at diagnosis, 82% (22 of 27) responded, compared with 33% (four of 12) of those with two sites (P = .008). Although responses were observed in patients with bulky disease, the response rate in patients with lesions 7 cm was 41% (seven of 17 patients) versus 86% (25 of 29 patients) in those with lesions less than 7 cm (P = .002). Of 32 responders, the mean largest single lesion dimension was 5.0 cm versus 7.9 cm in the 14 nonresponders (P = .001). In the univariate analysis, age, sex, lactate dehydrogenase levels, splenomegaly, prior anthracycline treatment, resistance to any prior or most recent chemotherapy, bone marrow involvement, baseline natural killer cells, and number of prior relapses did not correlate significantly with outcome of treatment (.106 P .99).

In a stepwise logistic regression analysis (Table 3) that included only patients with all data available (n = 43), three factors–low-grade/follicular histologic types, absence of bone marrow involvement, and nonbulky disease–were independent predictors of response. The discrepancy in the significance of bone marrow involvement between the univariate and logistic regression analysis is a result of the small patient numbers and slightly different sample size.

bcl-2 baseline data were collected for peripheral blood in 32 of 36 patients with low-grade or follicular NHL. In addition, data were also available for eight patients with intermediate-grade and mantle-cell disease, although it was not required in the protocol. At baseline, 13 of 40 patients (33%) had a positive bcl-2 status in peripheral blood. Of these 13 patients, 10 (77%) were responders. Of the 10 responders who were positive at baseline, follow-up data at the time of response confirmation are available for seven. All seven patients converted to a bcl-2—negative status at follow-up evaluation.

Baseline samples for bcl-2 in bone marrow were available for 31 of 36 patients with low-grade or follicular disease and six additional patients with intermediate-grade and mantle-cell disease. At baseline, 12 of 37 patients (32%) had a positive bcl-2 status in bone marrow. Of these 12 patients, nine (75%) were responders. Of the nine responders who were positive at baseline, three converted to negative status at the time of response confirmation, one remained positive, and no follow-up data are available for the remaining five patients.

Safety
All patients were eligible for IDEC-Y2B8 treatment on day 7 based on MIRDOSE3 software (Oak Ridge Associated Universities, Oak Ridge, TN) dosimetry estimates from the IDEC-In2B8 scans and IDEC-In2B8 blood activity. The upper limit of acceptable radiation dose was defined as 20 Gy for normal organs and 3 Gy for bone marrow. One patient was not treated based on site-specific (non-MIRDOSE), image-based, bone marrow dosimetry, although the estimated marrow radiation dose was acceptable on blood-derived and sacral image—derived MIRDOSE3 dosimetry performed by the central dosimetrist (Oak Ridge Institute for Science and Education).

Adverse events were primarily hematologic, with thrombocytopenia being the most common (Table 4). Hematologic toxicity was transient and reversible. Median nadir values for the 0.4-mCi/kg dose group were 50,000/µL for platelets, 1,100/µL for absolute granulocytes, and 9.9 g/dL for hemoglobin (Table 5). For patients in the 0.4-mCi/kg group whose nadir values were less than 50,000/µL for platelets, 1,000/µL for granulocytes, or 10 g/dL for hemoglobin, the median time to recovery to these levels was 14 days. Five patients (10%) developed nadir platelet counts less than 10,000/µL. Fourteen patients (27%) developed nadir granulocyte counts less than 500/µL. Six patients received RBC transfusions, three received granulocyte colony-stimulating factor, and 10 received platelet transfusions. A significant correlation was noted between percent bone marrow involvement with NHL at baseline and hematologic toxicity (Table 6). During the 1-year observation period, only three patients required hospitalization for infection: one patient developed pneumonia on day 52 while neutropenic (absolute granulocyte count, 645/µL); another developed Pseudomonas pneumonia 7 months after therapy; and the third had progressive NHL with secondary lymphomatous gastrosplenic fistula and resultant clostridial sepsis 8 weeks posttreatment after granulocyte recovery. All three patients recovered with appropriate therapy.

No clinical hepatic toxicity was noted; however, total bilirubin level was elevated after treatment in two patients. One patient with massive hepatosplenomegaly caused by disease progression had an elevated total bilirubin level (2.1 mg/dL) 6 months after treatment concurrent with a low total albumin level and a high alkaline phosphatase level. A second patient with known hypertension, diabetes, hypercholesterolemia, and coronary artery disease who was receiving multiple medications experienced transient hyperbilirubinemia of uncertain origin (maximum bilirubin level, 2.5 mg/dL) 1 month after treatment. Direct bilirubin was not obtained, but subsequent determination was normal. Mean serum immunoglobulin levels remained within the normal range throughout a 1-year period. Two patients had decreases in immunoglobulin levels of at least 50% from baseline. One patient (2%) developed a HAMA and HACA 2 months after treatment. This patient was also hospitalized for 1 day 3 months after treatment for nonhemodynamically significant pericarditis that resolved with a short course of nonsteroidal anti-inflammatory medication. Although temporally associated, the investigator did not think there was a relationship between these two events.

Dosimetry
Median half-life for blood and plasma ⁹⁰Y was 28 hours (range, 14 to 36 hours). Median area under the curve for blood and plasma ⁹⁰Y was 24 and 22 µg-hr/mL, respectively (range, 4 to 48 µg-hr/mL). Median radiation dose to major organs was 3.41 Gy to liver, 2.55 Gy to lungs, 0.38 Gy to kidney, and 0.53 Gy to bone marrow. Detailed dosimetry data were collected and are reported separately.³⁰

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Although initial therapy for patients with NHL is often successful, the treatment for patients who relapse remains problematic. Patients in relapse may respond again to chemotherapy, but the TTP becomes shorter, and eventually the disease becomes resistant. Lymphoma cells are usually radiosensitive, but the disease is typically widespread, making it difficult to provide conventional radiation therapy. Immunotherapy with rituximab, an antibody directed against the CD20 antigen present on nearly all B-cell NHLs, has been shown to produce responses in approximately 50% of patients with relapsed or refractory low-grade or follicular NHL with an excellent safety and toxicity profile. Most of the responses were PRs, and the TTP was 13.2 months in responders.⁶

The mechanisms of action for rituximab include binding of complement with subsequent induction of complementdependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis.^23,31 It is our hypothesis that combining the radioisotope ⁹⁰Y with the ibritumomab monoclonal antibody may produce even higher response rates than those found with unlabeled antibodies alone because of the added antitumor effect of the high-energy beta emission and path length (X₉₀ = 5 mm) of ⁹⁰Y. The first step in testing this hypothesis was to investigate the safety and efficacy of IDEC-Y2B8 RIT in combination with rituximab in a phase I/II trial as treatment for relapsed B-cell NHL.

A previous dose-escalating trial of IDEC-Y2B8 was conducted that used the murine ibritumomab as the unlabeled pretreatment antibody and required stem-cell collection. It is difficult to compare these two trials directly because the dose levels varied (20 to 50 mCi v 12 to 42 mCi) between the trials. However, one apparent difference between the two studies is the greater HAMA rate observed in the earlier trial (12.5% v 2% in the present trial). We hypothesize that the lower HAMA/HACA rate could be related to use of the less antigenic, chimeric antibody as pretreatment.

In the present trial, we demonstrated that IDEC-Y2B8 could be safely delivered as a single 0.4-mCi/kg dose in an outpatient setting without the need for stem-cell collections. Dosimetry was performed in this study to ensure that the radiation delivered by IDEC-Y2B8 to normal organs did not exceed an acceptable level, and, indeed, these criteria were not exceeded in any patient. IDEC-Y2B8 was well tolerated, and the main side effect was reversible hematologic toxicity (primarily thrombocytopenia).

IDEC-Y2B8 produced an ORR of 67% with a projected TTP of 12.9+ months. In patients with low-grade NHL, an 82% response rate was achieved. We believe that these results are generalizeable to the overall population of patients with relapsed NHL because 43% of patients had marrow involvement with lymphoma, 37% had bulky disease ( 7 cm), 59% had bulky masses 5 cm, nearly all had undergone a prior anthracycline-based chemotherapy regimen, and 28% had 2 extranodal sites of disease. It should be emphasized that patients with more than 25% tumor involvement in the marrow and those with platelet counts less than 100,000/µL were not eligible for this trial. These patients were excluded because of anticipated more severe myelosuppression. Additional trials of RIT are needed for this group using either smaller doses or after full courses of rituximab or chemotherapy to clear marrow of lymphomatous involvement. Our trial included only three patients with mantle-cell lymphoma, and their lack of response should not discourage further study of this important subset of patients with B-cell NHL, especially in light of the 33% response rate found in patients with mantle-cell lymphoma treated with rituximab.³²

Because patients in this trial received two doses of 250 mg/m² rituximab before IDEC-Y2B8, it could be argued that the responses were simply a result of rituximab. This seems unlikely because this is a much smaller total dose of rituximab than that used in the pivotal rituximab trial⁵ (500 mg/m² v 1,500 mg/m²), and the ORR of 82% of patients with low-grade or follicular NHL achieved with IDEC-Y2B8 is substantially higher than the 48% ORR achieved with rituximab.

The pivotal rituximab trial included 20% patients with disease classified as IWF A as compared with 10% of the low-grade population in this trial. This is significant because the response rate to rituximab in this subgroup was 12% in the pivotal rituximab trial compared with 58% in the follicular subgroup. In this trial, the IWF-A patient population was too small (three patients with one response) to determine a meaningful response rate. It is therefore important to demonstrate definitively in a prospective, randomized clinical trial that the RIT approach with IDEC-Y2B8 produces a superior rate of response and TTP compared with rituximab in this patient population. This study is ongoing.

Other investigators have used different monoclonal antibodies with and without radionuclides for treatment of NHL. Lundin et al³³ used CAMPATH-1H, a humanized, anti-CD52 monoclonal antibody that binds most T and B lymphocytes, as therapy for 50 patients with relapsed NHL and found a 14% PR in all patients and a 50% (four of eight patients) response in patients with mycoses fungoides. Although the antibody was unlabeled, ie, no radionuclides were chelated, 28% of patients developed grade 4 neutropenia, opportunistic infections occurred in seven patients, and bacterial sepsis occurred in nine. Lym-1 is a murine monoclonal antibody that targets an epitope on the HLA-DR10 antigen found on malignant B cells. This antibody was conjugated to ¹³¹I and used to treat 20 patients with relapsed NHL in a phase I trial by DeNardo et al.³⁴ The goal was to administer multiple doses (up to four) of ¹³¹I—Lym-1 without the use of stem cells. The investigators reported that 29% of patients were able to receive all four planned doses. The ORR was 52% with mean duration of response of 10.4 months. Similar to the results in this article, the primary toxicity was hematologic. ¹³¹I—anti-CD20 (anti-B1) radioimmunoconjugates have been used in several trials of patients with relapsed NHL.^9,35 More recently, Kaminski et al³⁶ reported on ¹³¹I—anti-CD20 as primary therapy of newly diagnosed, low-grade B-cell NHL and found a 100% response rate but a 33% HAMA rate. Myeloablative doses of ¹³¹I—anti-CD20 followed by stem-cell rescue has been used in selected patients with relapsed B-cell NHL. Liu et al³⁷ recently reported their long-term results using this strategy in 29 patients, achieving an 86% ORR, with 79% of patients achieving a CR. Nearly half (14 of 29) of the patients remain in unmaintained CR 27 to 87+ months after high-dose RIT. Some of the nonhematologic toxicities in the study by Liu et al included cardiopulmonary insufficiency in 7% of patients (two of 29), hypothyroidism in 60%, serious infections in 10%, and second malignancies in 7% of assessable patients (two of 27). This same group has also reported preliminary results of an ongoing trial to combine RIT with high-dose chemotherapy followed by autologous stem cells.³⁸

The two radioisotopes most commonly used in RIT today are ⁹⁰Y and ¹³¹I. There have been no prospective randomized trials to compare ⁹⁰Y—anti-CD20 with ¹³¹I—anti-CD20; however, the studies to date indicate that both radioisotopes can be provided with acceptable toxicity and have efficacy in treating NHL. Ibritumomab has the advantage of directly inducing apoptosis.³¹ We chose the radioisotope ⁹⁰Y because the significantly higher beta energy and longer path length may result in greater efficacy than the mixed gamma/betaemitting isotope ¹³¹I. Because ⁹⁰Y dose not emit gamma radiation, hospitalization is never required, and patients are not restricted in their daily activities and exposure to others. This trial of IDEC-Y2B8 has established a safe and efficacious nonmyeloablative dose that can be used for future studies. These studies will further define the role this agent will play in the overall approach to the treatment of B-cell NHL.

	ACKNOWLEDGMENTS

 
Supported by IDEC Pharmaceuticals Corporation, San Diego, CA.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Miller R, Maloney D, Warnke R, et al: Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med306:517-522, 1982[Medline]

2. Nadler L, Stashenko P, Hardy R, et al: Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res40:3147-3154, 1980[Abstract/Free Full Text]

3. Nadler LM, Takvorian T, Botnick L, et al: Anti-B1 monoclonal antibody and complement treatment in autologous bone marrow transplantation for relapsed B-cell non-Hodgkin's lymphoma. Lancet2:427-431, 1984[Medline]

4. Ritz J, Pesando J, Notis-McConarty J, et al: Modulation of human acute lymphoblastic leukemia antigen induced by monoclonal antibody in vitro. J Immunol125:1506-1514, 1980[Medline]

5. McLaughlin P, Grillo-López A, Link B, 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 Oncol16:2825-2833, 1998[Abstract]

6. McLaughlin P, Grillo-López A, Maloney D, et al: Efficacy controls in long-term follow-up of patients treated with rituximab for relapsed or refractory, low-grade or follicular NHL. Blood 92:414a-415a, 1998 (suppl 1)

7. Eary J, Badger C, Press O, et al: Treatment of B-cell lymphoma with I-131 labeled murine monoclonal antibodies. J Nucl Med29:757-758, 1988 (abstr)

8. Press O, Farr A, Borroz K, et al: Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res49:4906-4912, 1989[Abstract/Free Full Text]

9. Kaminski M, Zasadny K, Francis I, et al: Radioimmunotherapy of B-cell lymphoma with [¹³¹I] anti-B1 (anti-CD20) antibody. N Engl J Med329:459-465, 1993[Abstract/Free Full Text]

10. Kaminski M, Zasadny K, Milik A, et al: Updated results of a phase I trial of ¹³¹-I-anti-B1 (anti-CD20) radioimmunotherapy (RIT) for refractory B-cell lymphoma. Blood 82:332a, 1993 (suppl 1; abstr)

11. Wahl R, Zasadny K, Milik A, et al: 131 I anti-B1 radioimmunotherapy of non-Hodgkin's lymphoma without marrow transplantation: Expanded phase I study results. J Nucl Med 35:101P, 1994 (abstr)

12. Press O, Eary J, Appelbaum F, et al: Phase II trial of ¹³¹I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B-cell lymphomas. Lancet346:336-340, 1995[Medline]

13. Scheinberg D, Strand M: Kinetic and catabolic considerations of monoclonal antibody targeting in erythroleukemic mice. Cancer Res43:265-272, 1983[Abstract/Free Full Text]

14. Anderson W, Strand M: Radiolabeled antibody: Iodine versus radiometal chelates. Natl Cancer Inst Monogr3:149-151, 1987

15. Ward J: Biotechnology and nuclear medicine: Radiology brings biotechnology into the picture to combat cancer. Adv Radiol Sci Professionals 11:24-25, 108, 1998

16. Gates VL, Carey JE, Siegel JA, et al: Nonmyeloablative iodine-131 anti-B1 radioimmunotherapy as outpatient therapy. J Nucl Med39:1230-1236, 1998[Abstract/Free Full Text]

17. Murray J, Rosenblum M, Sobol R, et al: Radioimmunoimaging in malignant melanoma with ¹¹¹In-labeled monoclonal antibody 96.5. Cancer Res45:2376-2381, 1985[Abstract/Free Full Text]

18. Dillman R, Beauregard J, Ryan K, et al: Radioimmunodetection of cancer with the use of indium-111-labeled monoclonal antibodies. NCI Monogr3:33-36, 1987

19. Lamki LM, Babaian R, Murray JL, et al: The effect of increasing "cold" antibody dose on prostatic cancer metastases detection and on body distribution of PAY-276 monoclonal antibody. J Nucl Med27:1021, 1986 (abstr)

20. Rosenblum M, Murray J, Haynie T, et al: Pharmacokinetics of 111-In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma. Cancer Res45:2382-2386, 1986[Abstract/Free Full Text]

21. Stashenko P, Nadler L, Hardy R, et al: Characterization of a human B lymphocyte-specific antigen. J Immunol125:1678-1685, 1980[Abstract]

22. Knox S, Goris M, Trisler K, et al: Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res2:457-470, 1996[Abstract]

23. Reff M, Carner K, Chambers K, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood83:435-445, 1994[Abstract/Free Full Text]

24. Maloney D, Grillo-López A, Bodkin D, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol15:3266-3274, 1997[Abstract]

25. Maloney D, Grillo-López A, White C, et al: IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood90:2188-2195, 1997[Abstract/Free Full Text]

26. Gribben J, Freedman A, Woo S, et al: All advanced stage non-Hodgkin's lymphomas with a polymerase chain reaction amplifiable breakpoint of bcl-2 have residual cells containing the bcl-2 rearrangement at evaluation and after treatment. Blood78:3275-3280, 1991[Abstract/Free Full Text]

27. Horning S, Cheson B, Peterson B, et al: Response criteria and quality assurance of responses in the evaluation of new therapies for patients with low-grade lymphoma. Proc Am Soc Clin Oncol 16:18a, 1997 (abstr)

28. Grillo-López A, Horning S, Cheson B, et al: Development of response criteria for low-grade or follicular lymphomas and application in a 166 patient study. Exp Hematol25:732, 1997 (abstr)

29. Grillo-López A, Cheson B, Horning S, et al: Response criteria for NHL: Importance of "normal" lymph node size and correlations response. Blood 92:412a, 1998 (suppl 1) (abstr)

30. Wiseman GA, White CA, Witzig TE, et al: Final dosimetry results of IDEC-Y2B8 phase I/II yttrium-90 radioimmunotherapy trial in non-Hodgkin's lymphoma. J Nucl Med 40:64p, 1999 (abstr)

31. Maloney D, Smith B, Appelbaum F: The anti-tumor effect of monoclonal anti-CD20 antibody (MAB) therapy includes direct anti-proliferative activity and induction of apoptosis in CD20 positive non-Hodgkin's lymphoma (NHL) cell lines. Blood 88:637a, 1996 (abstr)

32. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood92:1927-1932, 1998[Abstract/Free Full Text]

33. Lundin J, Osterborg A, Brittinger G, et al: CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: A phase II multicenter study–European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol16:3257-3263, 1998[Abstract]

34. DeNardo GL, DeNardo SJ, Goldstein DS, et al: Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma. J Clin Oncol16:3246-3256, 1998[Abstract]

35. Kaminski M, Zasadny K, Francis I, et al: Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol14:1974-1981, 1996[Abstract/Free Full Text]

36. Kaminski M, Gribbin T, Estes J, et al: I-131 anti-B1 antibody for previously untreated follicular lymphoma (fl): Clinical and molecular remissions. Proc Am Soc Clin Oncol 17:2a, 1998 (abstr 6)

37. Liu S, Early J, Petersdorf S, et al: Follow-up of relapsed B-cell lymphoma patients treated with iodine-131—labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol16:3270-3278, 1998[Abstract]

38. Press O, Eary J, Liu S, et al: A phase I/II trial of high dose iodine 131-anti-B1 (anti-CD20) monoclonal antibody, etoposide, cyclophosphamide, and autologous stem cell transplantation for patients with relapsed B cell lymphomas. Proc Am Soc Clin Oncol 17:3a, 1998 (abstr)

Submitted December 21, 1998; accepted July 22, 1999.

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