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Single-Agent Monoclonal Antibody Efficacy in Bulky Non-Hodgkin's Lymphoma: Results of a Phase II Trial of Rituximab

From the Stanford University Medical Center, Stanford; IDEC Pharmaceuticals Corp, San Diego; Hoag Cancer Center, Newport Beach; Kenneth Norris Cancer Center, Los Angeles, CA; St. Louis University Medical Center, St. Louis, MO; University of Iowa General Hospital, Iowa City, IA; Fred Hutchinson Cancer Research Center, Seattle, WA; and University of Virginia Health Science Center, Charlottesville, VA.

Address reprint requests to Thomas A. Davis, MD, EPN 715, 6130 Executive Blvd, Rockville, MD 20852; email davist{at}ctep.nci.nih.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS: Thirty-one patients received intravenous infusions of rituximab 375 mg/m² weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis.

RESULTS: No patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline.

CONCLUSION: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
RITUXIMAB (RITUXAN; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc., South San Francisco, CA) is a highly specific mouse/human chimeric antibody engineered by grafting the variable regions targeting the CD20 antigen from murine antibody genes onto the constant regions of human immunoglobulin (Ig) G genes. Rituximab binds complement and induces antibody-dependent cellular cytotoxicity.^1,2 Binding inhibits proliferation and directly induces apoptosis.³ Relative to murine antibodies, mouse/human chimeric antibodies have the clinical advantages of reduced immunogenicity,^4-6 extended half-lives in humans, and enhanced interaction with human effector cells.^1,2,7

The CD20 antigen is a 35,000 da phosphoprotein present exclusively on B cells, including those in most B-cell lymphomas.⁸ The CD20 antigen is a suitable target for treatment of B-cell hematologic malignancies because the antigen does not circulate in the plasma as free protein that could competitively inhibit antibody binding to lymphoma cells,^8,9 does not shed from the surface of CD20⁺ cells after antibody binding,⁷ and does not seem to be internalized, and subsequently downregulated, upon antibody binding.⁷ The absence of CD20 expression on plasma cells allows for continued production of Igs. After depletion, a normal B-cell population can be reconstituted from the stem cells and pre-pre (or pro-) B cells.

To date, results of four single-agent rituximab trials in adult patients with low-grade or follicular non-Hodgkin's lymphoma (NHL) have been reported: two phase I/II studies,^10,11 a pivotal 166-patient trial,¹² and a phase II study that investigated an expanded dosing regimen.^13,14 Treatment with the combination of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone^15,16 and rituximab and interferon¹⁷ has also been investigated. Trials of rituximab as a single agent or in combination with chemotherapy are ongoing in patients with intermediate- and high-grade lymphoma.^16,18

Two phase I/II dose-escalation studies^10,11 showed that intravenous (IV) infusion of rituximab was safe and well tolerated, with significant clinical activity. Assessment of the dose regimens used in these studies led to the selection of a 375-mg/m² dose administered once weekly for four doses for a pivotal open-label, single-arm efficacy and safety study in 166 patients. In the pivotal study,¹² adverse events associated with treatment were primarily grade 1 or 2 and infusion related and included transient fever, chills, nausea, and headache. Only one patient (<1%) developed human antichimeric antibody (HACA). The overall response rate (ORR) was 48% for the intent-to-treat population and 50% for the assessable population. The median time to progression (TTP) in assessable responders was 13.2 months, and the median duration of response was 11.6 months. Responses were observed in patients whose disease had progressed despite prior anthracycline treatment and/or autologous bone marrow transplantation, in those older than 60 years, and in those with bulky and extranodal disease. Half of all patients had bcl-2 rearrangements detectable by polymerase chain reaction (PCR) at baseline, and half of these became PCR negative after therapy. In a study of eight weekly rituximab infusions in 37 patients,¹³ the ORR was 57% in the intent-to-treat population and 60% in the assessable population, with median TTP in responders and duration of response not yet reached after a median of 15.4+ and 11.6+ months of observation, respectively.

Although many investigators have assumed that antibody therapy would be ineffective in bulky disease,⁵ an exploratory analysis of the pivotal trial data (unpublished) showed a 48% ORR in patients with lesions between 5 and 7 cm and a 35% ORR in patients with lesions 7 cm; however, patients with lesions 10 cm were excluded from this trial. Tumor-related pain at the site of disease was reported, and tumor lysis syndrome has been reported in isolated nonstudy patients with high numbers of circulating malignant cells. For this reason, the present study was conducted to evaluate the safety and efficacy of the same dosing regimen in patients with bulky (> 10 cm) low-grade or follicular B-cell NHL and, as such, to add to our knowledge of the biology of antibody-based therapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Patients with histologically confirmed low-grade or follicular B-cell NHL (International Working Formulation [IWF] types A through D; Table 1) with either relapsed disease or primary therapy failure and progressive disease that required further treatment were enrolled onto the study provided they met the following requirements: bidimensionally measurable disease, at least one lesion greater than 10 cm in its greatest diameter, a demonstrable monoclonal CD20-positive B-cell population in a pathologic lymph node or bone marrow specimen, and a prestudy World Health Organization performance status of 0, 1, or 2. In addition, patients had to be at least 18 years of age, not pregnant or lactating, using accepted birth control methods, and have a life expectancy 4 months. Within 2 weeks before administration of the first infusion, patients were required to have a hemoglobin level 8.0 g/dL, absolute granulocyte count 1,500/µL, platelet count 75,000/µL, serum creatinine concentration 2.0 mg/dL, total bilirubin level 2.0 mg/dL, and alkaline phosphatase and AST two times normal. For patients with IWF type A lymphoma, lymphocyte counts had to be 5,000/µL. Concurrent corticosteroid use was not allowed. The study was approved by the institutional review board at each study site, and written informed consent was obtained from all patients.

Antibody
The production of the antibody has been described previously.^2,19,20 The vialed product was formulated as 10 mg/mL rituximab, 25 mmol/L sodium citrate, pH 6.5, with 0.07% polysorbate 80 in 0.15 mol/L saline. The product was administered as an IV infusion at an initial dose rate of 50 mg/h for the first hour and was escalated gradually to a maximum of 400 mg/h (300 mg/h for the first infusion only).

Monitoring
Toxicity was evaluated using the National Cancer Institute's Adult Toxicity Criteria (February 1988 Guidelines). Laboratory testing included hematology and serum chemistry assays, HACA assays,^19,20 Ig levels, and urinalysis. Evaluations for disease assessment included physical examination (baseline, end of therapy, 1 and 3 months after treatment, every 3 months for 2 years, and every 6 months thereafter), chest radiograph (baseline); computed tomography (CT) or magnetic resonance imaging (MRI) (baseline, 1 and 3 months after treatment, every 3 months for 2 years, and then every 6 months thereafter); and bone marrow biopsy (baseline and at confirmation of complete response [CR], if positive at baseline). An evaluation, including CT or MRI, was performed 28 days after the onset of response to confirm that response.

For pharmacokinetic analysis, serum samples were obtained from all patients before and immediately after each infusion; at weeks 5, 6, 7, and 8; and at 3 months after the last dose of rituximab. A smaller group of patients had additional serum samples collected at 24, 48, 72, and 96 hours after the first and fourth infusions for extended pharmacokinetic analysis. The serum was diluted serially and added to microtiter plates coated with polyclonal goat antirituximab antibody. Bound rituximab was detected using labeled goat antihuman IgG and compared with a standard curve.

End Points and Response Criteria
To investigate the safety and efficacy of rituximab in NHL patients with bulky (> 10 cm) disease, ORR (complete response + partial response), TTP, and response duration were determined. Patients were assessable for efficacy if they completed four full infusions of rituximab, satisfied all prestudy entry criteria, and met criteria for evaluation of response. Response categories consisted of CR, partial response (PR), stable disease, and progressive disease.^21,22 CR required that all lymph nodes visible on CT scans of neck, chest, abdomen, and pelvis be less than 1 cm x 1 cm; any node that was palpable on physical examination (and considered to be involved in lymphoma) be no longer palpable or negative on biopsy or fine-needle aspirate; bone marrow must have been histologically negative for lymphoma; and the liver and spleen (if abnormal at baseline) must have returned to normal size. PR was defined as 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of all the measured lesions (SPD) 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 were confirmed by reassessment 28 days after the original determination of response.

Statistical Methods
TTP and response duration in responders were measured from the first infusion and the first observation of response, respectively, until progression. The Kaplan-Meier product-limit method was used to analyze the TTP in responders; curves were generated using PROC LIFETEST (SAS Institute, Inc, Cary, NC). The Wilcoxon rank sum test was used to compare serum concentration data with clinical response. Clinical adverse event data were assigned preferred terms using COSTART²³ and were analyzed by calculating the number and percentage of patients and events, whether the event was considered related to the study treatment, and by severity of event. Any adverse event reported as probably or possibly related or of unknown relationship to the study treatment was considered a related adverse event. If the same adverse event was reported on consecutive days, then the specific number of times that the event occurred was recorded as a single event. The most severe grading among the individual events was used to characterize this unified event. Adverse events were further classified as having occurred during the treatment period (time interval between first rituximab infusion and 30 days after the fourth infusion) or follow-up (time interval between 31 days after the fourth infusion and 1 year after the first infusion).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Characteristics of the 31 patients included 97% white, 87% low-grade and 13% follicular intermediate-grade histologies, and 68% stage III/IV at initial diagnosis. All patients (52% male; aged 33 to 79 years; median age, 55 years) had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Median time from diagnosis was 4 years. No patients had been diagnosed with transformation of their disease to a higher grade of NHL. These data are listed in Tables 1 and 2. All 31 patients received all four rituximab doses.

Clinical Adverse Events
Most clinical adverse events (93%) were mild to moderate (grade 1 or 2). No patient had treatment discontinued because of an adverse event. The majority of patients experienced adverse events during the first infusion, and incidence declined with subsequent infusions. The most common related events observed during the treatment period (22 days of treatment plus 30 days of follow-up) included transient fever (61% of patients), chills (36%), leukopenia (23%), nausea (19%), dizziness (19%), and throat irritation (19%). Tumor lysis syndrome was not reported; four patients received allopurinol prophylactically.

Related grade 3 or 4 nonhematologic clinical events occurred in four patients and consisted of pulmonary disorders in two patients, chills in one patient, and infusion-related hypotension (90/70 mmHg) and pain in one patient. Events resolved in three of these four patients. No patients died during the treatment period, although one patient died approximately 10 months after treatment from bronchiolitis obliterans. In the latter patient, extensive cultures and stains were negative. Serum was negative for rheumatoid factors and DNA antibodies, and C3 and C4 were normal. Electron microscopy showed no evidence of immune complex deposits and no evidence of viral inclusions or particles. Specifically, IgG, IgM, IgA, and C1Q deposits were not present by immunofluorescence. This patient had no known pulmonary involvement with lymphoma at baseline but had a history of asthma and a 40 pack/year history of smoking. Although histologic, immunofluorescent, and electron microscopic studies did not provide evidence to suggest that this patient's bronchiolitis obliterans was related to treatment with rituximab, because of the temporal relationship to antibody treatment, that possibility could not be ruled out.

No grade 3 or 4 infections were reported, and no patients were hospitalized for infection. Six infections reported in five patients consisted of pneumonia, rhinitis, sinusitis, herpes zoster, and uncategorized infection.

Hematology and Chemistry Laboratory Effects
Seven patients had transient grade 3 or 4 levels of one or more hematologic parameters. Hemoglobin concentration declined to less than 8 g/dL in two patients during the treatment period (8.5 and 10.0 g/dL at baseline) and in one patient during follow-up (8.5 g/dL at baseline); all concentrations returned to more than 8 g/dL within 1 week with or without transfusion. In one patient with extensive lymphomatous involvement in the bone marrow and a history of pancytopenia, baseline platelet count and absolute neutrophil count (ANC) (76,000/µL and 2,700/µL, respectively) decreased to grade 4 levels (platelet count, < 25,000/µL; ANC < 500/µL). Hematologic recovery did not occur before disease progression and subsequent chemotherapy in this patient. ANC declined to less than 1,000/µL in four other patients during the treatment period (baseline levels between 1,400 and 5,500/µL) and in one patient during the 1-year follow-up (4,300/µL at baseline).

No hepatic or renal toxicity was noted. No patient developed HACA. Quantitative data on serum Ig levels were collected for 1 year, and mean serum Ig levels did not decrease to less than the normal range. Individual Ig levels were less than the normal range and reduced by 50% of baseline in five patients (16%) at single time points.

Response to Treatment
Three patients were unassessable for efficacy as follows: one because of treatment with cytoxan and corticosteroids before response evaluation, one because of an incomplete response evaluation, and the third because of no response evaluation. In assessable patients, the ORR was 43% (12 of 28) with one CR and 11 PRs, as summarized in Table 3. The ORR was 39% in the 31 intent-to-treat patients, with one CR and 11 PRs. No site-specific clustering of responses was apparent. The median time to response was 50 days (the first time point for response assessment) with continued improvement in response for up to 3 months. This time to response is similar to that observed in patients without bulky disease treated with rituximab on other protocols.

The median TTP for the 12 responders was 8.1 months (range, 4.5 to 18.6+ months), with a median duration of response of 5.9 months (range, 2.8 to 12.1+ months). These data are listed in Table 4. Responses are ongoing in four of the 12 responders, with durations of 11.0+, 11.0+, 11.8+, and 12.1+ months.

The average decrease in lesion size in patients who achieved a PR was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Tumor size was reduced by at least 20% in 65% of patients (20 of 31). Of 10 patients with "B" symptoms or other disease-related signs and symptoms at baseline, eight experienced complete resolution or transient relief. Two patients with continuing symptoms did not respond to rituximab therapy.

Subgroup Analysis
An exploratory analysis of prognostic factors defined in the medical literature (IWF histologic subtype, age, sex, B symptoms, performance status, stage of disease, extranodal disease, splenomegaly, bone marrow infiltration, elevated lactate dehydrogenase [LDH] level, and response to prior therapy)^24-27 and response was performed.

An increased likelihood of response to rituximab therapy was shown for IWF types B, C, or D versus type A lymphoma (P = .0050; histology types defined in Table 1). Twelve (55%) of 22 patients with histologic types B, C, or D responded, and none of nine patients with histologic type A responded. Patients with type A histology were predominantly male (78%) with a median age of 62 years and a median time from diagnosis to study entry of 4.4 years. A statistically significant correlation was noted between response to rituximab and sex (P = .029), with nine (60%) of 15 women responding to rituximab treatment and three (19%) of 16 men responding. However, this was believed to be caused by a confounding variable because most males in this study had type A histology.

Age, lymphoma grade, years since diagnosis, LDH or IgM levels, bone marrow involvement, and presence of extranodal disease or splenomegaly were not correlated with response to rituximab treatment (.128 P .99). Number of prior chemotherapy courses, number of relapses, resistance to any or all courses of chemotherapy, prior aggressive chemotherapy, and prior anthracycline therapy were not correlated significantly with response to rituximab therapy (.060 P .99).

Rituximab Serum Levels
Median antibody concentration was higher in responders compared with nonresponders. Although no correlation was noted between serum antibody concentration and the number of circulating B cells at baseline (as observed previously in the pivotal trial), a negative correlation was shown between antibody concentration and tumor bulk at baseline. Median serum antibody levels were lower in patients with histologic type A lymphoma than in those with histologic types B, C, and D at all time points, and levels were significantly different before and after the third infusion and at 2 weeks after treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Oncologic literature has documented the relationship between the presence of bulky disease, defined as lesions greater than 5 cm,²⁸ 7 cm,^29-32 or 10 cm,^29,30,32-34 and both shortened survival^{28,29,31,34-38} and poor response to chemotherapy and/or autotransplantation.^29,35,38 Additional studies have shown that treatment-induced mortality is more frequent in patients with bulky disease.³⁷ Given the poor prognosis of these high-risk patients, it has been argued that more aggressive therapy, even with its increased toxicity, is warranted.^{28,31,34,36,39,40}

An exploratory subgroup analysis of data from the prior rituximab pivotal trial¹² evaluated the relationship between response and several prognostic factors, including the presence of bulky disease. In that trial, patients with bulky disease with at least one lesion between 5 and 7 cm showed an ORR of 48% (42 assessable patients), and patients with at least one lesion greater than 7 cm showed an ORR of 35% (20 assessable patients). A single patient with a 13-cm lesion was enrolled and achieved a PR. No treatment-induced mortality occurred, and the safety profile was not apparently different in this subgroup. Although based on a small patient subset, these data suggested that single-agent rituximab therapy may be effective for NHL patients with bulky disease and may be less toxic than aggressive chemotherapy treatment.

In the current study of rituximab treatment in patients with bulky disease, the ORR was 39% for intent-to-treat patients and 43% for assessable patients. No significant differences in ORR (.54 P .80) were noted between the current bulky study population (43%) and pivotal trial patients with 5- to 7-cm lesions (48%), pivotal trial patients with greater than 7-cm lesions (35%), or the general pivotal trial population (50%). Response rate comparisons with other single-agent therapies are difficult because, although the literature describes poor prognosis in patients with bulky disease, response rates in a homogeneous bulky disease populations are not usually reported. A 43% ORR with antibody therapy in this relapsed bulky disease population is extremely encouraging.

The median TTP in responders was 8.1 months, and median duration of response was 5.9 months; response is ongoing in one third of responders, with observation time exceeding 11 months. Based on Kaplan-Meier estimates, the median TTP and duration of response in the current trial were not statistically different (.19 P .46) from that of pivotal trial patients with 5- to 7-cm lesions (9.1 and 5.5 months, respectively), pivotal trial patients with greater than 7-cm lesions (13 and 11.5 months, respectively), or the general pivotal trial population (13.2 and 11.6 months, respectively) (unpublished data).¹²

The median serum antibody concentration in the current rituximab trial was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline. An analysis of rituximab levels in the pivotal trial population showed a similar negative correlation between serum levels and tumor bulk and between serum levels and levels of peripheral-blood B cells.⁴¹ Further investigation into higher or extended dosing regimens, or the use of baseline tumor burden, rather than body surface area to determine rituximab dose is therefore warranted.

Although a comparison across trials is difficult, more adverse events and more grades 3 and 4 adverse events were reported in this bulky disease trial than were reported in the pivotal trial¹²; however, types of events deserved in both studies were similar. Almost twice as many patients reported pain and B symptoms at baseline, and more than three times as many had splenomegaly and restricted motion when compared with the patient population in the pivotal trial. LDH levels were more commonly elevated, and pain was more frequent and more severe in the current trial. Patients with lesions 10 cm were excluded from the pivotal study, with the exception of one patient with a 13-cm lesion; thus, the overall differences in frequency and severity of adverse experiences may be a result of the difference in tumor bulk and metabolic activity between the two study populations. Differences specific to bulky disease populations may include treatment-related symptoms attributable to tumor size and the likelihood of more frequent and more severe symptoms and complications from disease and prior therapy. For this reason, patients with bulky disease should be monitored closely during treatment.

Despite the bulk of disease in the patients in the present study, no patient was reported to have developed tumor lysis syndrome, although none had 5,000/µL circulating lymphocytes at baseline. An atypical tumor lysis syndrome was reported in four patients (three patients with chronic lymphocytic leukemia/prolymphocytic leukemia) with high numbers of circulating tumor cells (baseline lymphocyte counts from 73,000 to 132,000/µL).⁴²

In conclusion, rituximab given once weekly for four 375-mg/m² IV infusions is safe and well tolerated and resulted in an excellent single-agent ORR of 43% in assessable patients with bulky relapsed or refractory low-grade or follicular B-cell NHL. When comparing across studies, baseline signs and symptoms as well as grade 3 and 4 adverse events, although similar in type, were more frequent in this bulky disease population. Therapy was administered on an outpatient basis and was completed in 22 days. Future trials to examine extended dosing schedules in this bulky disease population may elucidate better the relationship between cumulative dose, serum levels, and response.

	ACKNOWLEDGMENTS

 
Supported by clinical grants from IDEC Pharmaceuticals Corporation, San Diego, CA. C.A.W., A.J.G.L., R.W., and S.D. are employees of IDEC Pharmaceuticals

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. 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)

2. Reff M, Carner K, Chambers K, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445, 1994[Abstract/Free Full Text]

3. Demidem A, Lam T, Alas S, et al: Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 12:177-186, 1997[Medline]

4. LoBuglio A, Wheeler R, Trang J, et al: Mouse/human chimeric monoclonal antibody in man: Kinetics and immune response. Proc Natl Acad Sci USA 86:4220-4224, 1989[Abstract/Free Full Text]

5. Grossbard M, Press O, Appelbaum F, et al: Monoclonal antibody-based therapies of leukemia and lymphoma. Blood 80:863-878, 1992[Free Full Text]

6. Colnaghi M: Generation of monoclonal antibodies for in vivo approaches. Nucl Med Biol 18:15-18, 1991

7. Press O, Appelbaum F, Ledbetter J, et al: Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 69:584-591, 1987[Abstract/Free Full Text]

8. Stashenko P, Nadler L, Hardy R, et al: Characterization of a human B lymphocyte-specific antigen. J Immunol 125:1678-1685, 1980[Abstract]

9. Einfeld D, Brown J, Valentine M, et al: Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 7:711-717, 1988[Medline]

10. Maloney D, Liles T, Czerwinski D, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994[Abstract/Free Full Text]

11. Maloney D, Grillo-López A, Bodkin D, et al: IDEC-C2B8 anti-CD20 antibody: Results of long-term followup of relapsed NHL phase II trial patients. Blood 86:54a, 1995 (abstr)

12. 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 4-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract]

13. Piro L, White C, Grillo-López A, et al: Rituxan (rituximab, IDEC-C2B8): Interim analysis of a phase II study of once weekly times 8 dosing in patients with relapsed low-grade or follicular non-Hodgkin's lymphoma. Blood 90:510(a), 1997 (abstr)

14. Piro L, White C, Grillo-López A, et al: Extended Rituxan (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol (in press)

15. Czuczman M, Grillo-López A, Jonas C, et al: IDEC-C2B8 and CHOP chemotherapy of low-grade lymphoma. Blood 86:54a, 1995 (abstr)

16. Link B, Grossbard M, Fisher R, et al: Phase II pilot study of the safety and efficacy of rituximab in combination with CHOP chemotherapy in patients with previously untreated- or high- grade NHL. Proc Am Soc Clin Oncol 17:3a, 1998 (abstr)

17. Davis T, Maloney D, White C, et al: Combination immunotherapy of low grade or follicular (LG/F) non-Hodgkins lymphoma (NHL) with rituximab and alpha interferon: Interim analysis. Proc Am Soc Clin Oncol 17:11a, 1998 (abstr 39)

18. Coiffier B, Ketterer N, Haioun C, et al: A multicenter, randomized phase II study of rituximab (chimeric anti-CD20 mAb) at two dosages in patients with relapsed or refractory intermediate or high grade NHL or in elderly patients in first-line therapy. Am Soc Hematol 90:510a, 1997 (abstr)

19. 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. Blood 90:2188-2195, 1997[Abstract/Free Full Text]

20. 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 Oncol 15:3266-3274, 1997[Abstract]

21. 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)

22. 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 Hematol 25:732, 1997 (abstr)

23. Food and Drug Administration: Coding Symbols for Thesaurus of Adverse Reaction Terms (ed 5). Rockville, MD, United States Food and Drug Administration, 1995

24. Weisdorf D, Andersen J, Glick J, et al: Survival after relapse of low-grade non-Hodgkin's lymphoma: Implications for marrow transplantation. J Clin Oncol 10:942-947, 1992[Abstract]

25. Shipp M, Harrington D: A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993[Abstract/Free Full Text]

26. López-Guillermo A Montserrat E, Bosch F, et al: Applicability of the International Index for Aggressive Lymphomas to patients with low-grade lymphoma. J Clin Oncol 12:1343-1348, 1994[Abstract]

27. Hermans J, Krol A, van Groningen K, et al: International prognostic index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades. Blood 86:1460-1463, 1995[Abstract/Free Full Text]

28. Jeffery G, Mead G, Whitehouse J, et al: Involved field radiotherapy or chemotherapy in the management of stage I nodal intermediate grade non-Hodgkin's lymphoma. Br J Cancer 64:933-937, 1991[Medline]

29. Coiffier B, Gisselbrecht C, Vose J, et al: Prognostic factors in aggressive malignant lymphomas: Description and validation of a prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol 9:211-219, 1991[Abstract]

30. Coiffier B, Gisselbrecht C, Herbrecht R, et al: LNH-84 regimen: A multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 7:1018-1026, 1989[Abstract]

31. Velásquez W, Jagannath S, Tucker S, et al: Risk classification as the basis for clinical staging of diffuse large-cell lymphoma derived from 10-year survival data. Blood 74:551-557, 1989[Abstract/Free Full Text]

32. Zuckerman K, LoBuglio A, Reeves J: Chemotherapy of intermediate- and high-grade non-Hodgkin's lymphomas with a high-dose doxorubicin-containing regimen. J Clin Oncol 8:248-256, 1990[Abstract]

33. Shipp M: Aggressive Non-Hodgkin's Lymphoma: Identification and Treatment of High-Risk Patients. Thousand Oaks, CA, Amgen, Inc.

34. Shipp M, Neuberg D, Janicek M, et al: High-dose CHOP as initial therapy for patients with poor-prognosis aggressive non-Hodgkin's lymphoma: A dose-finding pilot study. J Clin Oncol 13:2916-2923, 1995[Abstract]

35. Shipp M, Harrington D, Klatt M, et al: Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 104:757-765, 1986

36. Jagannath S, Velásquez W, Tucker S, et al: Tumor burden assessment and its implication for a prognostic model in advanced diffuse large-cell lymphoma. J Clin Oncol 4:859-865, 1986[Abstract/Free Full Text]

37. Rapoport A, Rowe J, Kouides P, et al: One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: Value of pretransplant disease status for predicting outcome. J Clin Oncol 11:2351-2361, 1993[Abstract/Free Full Text]

38. Velásquez W, McLaughlin P, Tucker S, et al: ESHAP—An effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Oncol 12:1169-1176, 1994[Abstract/Free Full Text]

39. Coiffier B, Lepage E: Prognosis of aggressive lymphomas: A study of five prognostic models with patients included in the LNH-84 regimen. Blood 74:558-564, 1989[Abstract/Free Full Text]

40. Shipp M: Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has "high-risk" disease? Blood 83:1165-1173, 1994[Abstract/Free Full Text]

41. Berinstein N, Grillo-López A, White C, et al: Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 9:1-7, 1998[Free Full Text]

42. Byrd J, Waselenko J, Maneatis T, et al: Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: Association with increased infusion-related side effects and rapid tumor lysis. Blood 92:106a, 1998 (abstr) (suppl 1)

Submitted October 15, 1998; accepted February 2, 1999.

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