Phase I/II Study of Galiximab, an Anti-CD80 Antibody, for Relapsed or Refractory Follicular Lymphoma
http://www.100md.com
《临床肿瘤学》
the Roswell Park Cancer Institute, Buffalo, NY
Biogen Idec Inc, San Diego, CA
Mayo Clinic, Rochester, MN
University of Nebraska, Omaha, NE
M.D. Anderson Cancer Center, Houston, TX
University of California Los Angeles, Los Angeles, CA
Arizona Cancer Center, Tucson, AZ
Duke University, Durham, NC
Cornell Medical Center, New York, NY
Northwestern University, Chicago, IL
University of Colorado Health Sciences Center, Aurora, CO
ABSTRACT
PURPOSE: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.
PATIENTS AND METHODS: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.
RESULTS: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).
CONCLUSION: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.
INTRODUCTION
The success of rituximab has changed the way non-Hodgkin's lymphoma (NHL) is managed today. Despite impressive single-agent efficacy in patients with relapsed or refractory indolent lymphoma,1,2 many patients do not respond, and patients who do respond relapse after a median of approximately 1 year and become resistant. Radiolabeled antibodies (ibritumomab tiuxetan and tositumomab and iodine I131 tositumomab), more aggressive combination regimens, and myeloablative therapies offer increased response rates but at the cost of increased toxicity,3-6 which limits their use in a significant number of patients. Less myelosuppressive therapies are needed.
CD80 (B7.1) is a membrane-bound costimulatory molecule that is known for its role in regulating T-cell activity.7,8 Several studies have suggested that CD80 may also play a role in the regulation of normal and malignant B cells.9,10 CD80 is transiently expressed on the surface of activated B cells, antigen-presenting cells (APCs), and T cells but is constitutively expressed on a variety of NHLs, including follicular lymphoma, making it an attractive target for lymphoma therapy.11,12 In vitro, cross linking CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation, to upregulate proapoptotic molecules, and to induce antibody-dependent cell-mediated cytotoxicity (ADCC).9 These observations constitute the rationale for development of an anti-CD80 therapy for B-cell lymphoma.
Galiximab is a chimeric, anti-CD80, immunoglobulin (Ig) G1 lambda monoclonal antibody with human constant regions and primate (cynomologous macaque) variable regions. The antibody is structurally indistinguishable from human antibodies and, therefore, is unlikely to be significantly immunogenic in humans. This makes it more suitable for potential repeated dosing in lymphoma patients. The specificity of galiximab binding to human CD80 has been validated in competitive binding studies with several lymphoma cell lines. Galiximab has also been shown to bind CD80 on T cells and block CD80-CD28 interaction without interfering with the interaction between CD80 and CD152 (CTLA-4; unpublished observations). Preclinical in vitro and in vivo studies evaluated galiximab as a targeted therapy for lymphoma with promising results.13,14 Because of its immunomodulatory properties, galiximab has previously been studied as a treatment for psoriasis. A total of 242 patients with moderate to severe plaque psoriasis received galiximab treatment. Galiximab was well tolerated, with a safety profile similar to placebo. This report presents results from a multicenter, phase I/II clinical study evaluating safety, efficacy, and pharmacokinetics (PK) of single-agent galiximab in patients with relapsed or refractory follicular lymphoma.
PATIENTS AND METHODS
Study Objectives
The primary objective of the study was to characterize the safety profile of escalating doses of galiximab in patients with relapsed or refractory follicular lymphoma. Secondary objectives included the evaluation of PK and efficacy.
Eligibility Criteria
Adult patients ( 18 years) with histologically confirmed follicular lymphoma who had relapsed or failed to respond to primary therapy were eligible for this study. Patients were required to have progressive disease (PD) requiring further treatment. Patients were not permitted to have had cancer radiotherapy, biologic therapy, chemotherapy, or immunosuppressive therapy within 3 weeks before the first scheduled galiximab treatment. Patients with major surgery (other than diagnostic surgery) within 4 weeks or lymphoma antibody therapy or autologous bone marrow transplantation within 6 months were excluded. Inclusion criteria also required patients to have a good WHO performance status (status of 2 or less); bidimensionally measurable disease with at least one lesion 2.0 cm in a single dimension; and adequate hematologic, renal, and hepatic function. Patients were excluded if they had CNS lymphoma, active opportunistic infection, or serious nonmalignant disease or were HIV positive. Because the effects of galiximab on embryogenesis are unknown, additional criteria for eligibility excluded patients who were pregnant or breast feeding. In addition, patients of reproductive potential had to agree to use accepted birth control methods during treatment and for approximately 3 months after the last infusion of galiximab. Concomitant therapy with other lymphoma treatments or other investigational drugs was not permitted during the study.
The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients, and each participating clinical site received approval from its institutional review board.
Study Design
This was an open-label, multicenter, phase I/II study. Patients received intravenous infusions of galiximab at doses of 125, 250, 375, or 500 mg/m2 once weekly for 4 weeks. Galiximab was administered in an outpatient setting over a 1-hour period. Antibody doses were diluted with normal saline for a total final volume of 75 to 150 mL in accordance with the protocol. Doses were individually formulated according to assigned treatment group and the patient's body-surface area. Patients were assigned sequentially to a treatment group. Enrollment onto a higher dose cohort was not permitted until three patients in the previous treatment group were at least 7 days beyond their first infusion with no dose-limiting toxicities (DLTs) reported. DLT was defined as grade 3 toxicity not associated with an infusion, any grade 4 toxicity, or adverse reactions that prevented completion of an infusion within 48 hours.
After the administration of study treatment, patients entered a follow-up period (through month 48). All patients who withdrew from the study early or who were alive at the end of the 48-month study period were observed, at 6-month intervals, for continuation of response (if applicable), initiation of other lymphoma therapy, survival status, and cause of death (if applicable).
Galiximab Antibody
Galiximab is an IgG1 lambda, anti-CD80 monoclonal antibody developed using PRIMATIZED antibody technology (Biogen Idec Inc, San Diego, CA) to decrease immunogenicity. The variable regions are of cynomologous macaque origin, and the constant regions are of human origin. Galiximab is formulated for intravenous injection as a sterile product in 10 mmol/L sodium citrate, containing 150 mmol/L sodium chloride, and 0.02% polysorbate 80 at pH 6.5. Galiximab was supplied by IDEC Pharmaceuticals Corporation (now known as Biogen Idec Inc, San Diego, CA).
Study End Points
Safety. Safety evaluations included medical histories, physical examinations, clinical adverse events (AEs), clinical laboratory evaluations (hematology, serum chemistry, and immunology), vital sign measurements, urinalysis, serious AEs (SAEs), and deaths. Hematology evaluations included nadir data analyses of hemoglobin, platelet counts, WBC counts, absolute lymphocyte counts, and absolute neutrophil counts. Immunology evaluations included Ig concentrations (IgG, IgM, and IgA), lymphocyte subsets, and antigaliximab antibody formation. Serum concentrations of human antibodies to galiximab were evaluated at baseline and at day 50 and months 3, 6, 9, and 12 after treatment using an enzyme-linked immunosorbant assay method. The lower limit of quantitation for this assay is 250 ng/mL. AE data were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0).
PK. Serum samples were obtained before infusion, within 10 minutes of the completion of infusions (days 1, 8, 15, and 22), and on days 29, 36, 43, and 50 and at months 3, 6, 9, and 12. PK analyses included galiximab serum concentrations, the maximum observed concentration (Cmax), the time to maximum observed concentration, serum half-life, and the area under the concentration time curve (AUC).
Data were analyzed using a noncompartmental linear regression method to determine the serum half-life using data from all samples collected after study day 1 that contained galiximab concentrations exceeding the lower limit of quantitation for the assay (250 ng/mL). AUC was calculated using the linear/logarithmic trapezoidal method and determined with time extrapolated out to infinity.
Efficacy. Evaluation of disease was performed by comprehensive scans (computed tomography, magnetic resonance imaging, and x-rays) and physical examination at baseline (study entry), 1 month after completion of galiximab treatment (day 50), every 3 months thereafter for years 1 and 2, and every 6 months for years 3 and 4. Response to treatment was analyzed using standard outcome measures for clinical trials (complete response [CR], unconfirmed complete response, partial response [PR], stable disease [SD], and PD) as defined by the International Workshop Response Criteria (IWRC) for NHL.15 The primary efficacy end point was overall response rate (ORR). Secondary efficacy end points included CR rate, unconfirmed CR rate, PR rate, duration of response, and time to progression.
Immunohistochemistry. In addition, fresh frozen tumor samples were analyzed at baseline for expression levels of cell surface CD80 antigens using immunohistochemical techniques. Tissue sections were stained with commercially available anti-CD80 antibody (BD Pharmingen, San Diego, CA) using the DAKO Envision Plus detection system (DAKO, Copenhagen, Denmark). An independent certified pathologist from IMPATH Predictive Oncology (Los Angeles, CA) reviewed the slides. Slides were evaluated for adequacy of tissue, percent positive staining, and staining intensity (1+, 2+, or 3+) for each antibody, with the lowest intensity reported as 1+ and the highest intensity reported as 3+. Frozen tonsil and known positive cell lines were used as controls with every batch of samples.
Statistical Methods
Patients were considered assessable for safety if they received at least one infusion of galiximab. Patients were considered assessable for PK analyses if they received four infusions of galiximab and had sufficient data available (a complete data set during the treatment period and at least three points after the last infusion) for calculation of PK parameters. Patients were considered assessable for efficacy if they met all prestudy entry criteria (unless granted as an exemption), received four infusions of galiximab, and did not receive additional lymphoma therapy before the first response assessment on day 50.
Summary descriptive statistics were used for all continuous variables (No., mean, standard deviation, median, minimum, and maximum) and categoric variables (No. and %). The 95% CI for ORR was calculated. All CIs for proportions were calculated using the methodology for inference about a single proportion. For Kaplan-Meier median estimates, a 95% CI was calculated using Greenwood's formula for SE.
RESULTS
Patient Characteristics
Between January 30, 2002, and February 19, 2003, 38 patients with relapsed or refractory follicular lymphoma were enrolled at nine clinical sites. Baseline characteristics for all enrolled patients are listed in Table 1. The majority of patients presented with stage III or IV disease (90%). All patients had received at least one prior course of lymphoma therapy (range, one to nine courses). Prior therapies included chemotherapy (53%), single-agent rituximab (45%), rituximab-chemotherapy combination therapy (40%), and other bioimmunotherapy (26%). Nine patients (24%) were rituximab nave. The median time from the most recent relapse was 2.3 months (range, 0.2 to 37.1 months).
Of the 38 patients enrolled, 37 (97%) received galiximab treatment (three patients at 125 mg/m2, three at 250 mg/m2, 21 at 375 mg/m2, and 10 at 500 mg/m2). All 37 patients were evaluated for safety. Of the 37 patients who received galiximab treatment, 35 (95%) were considered assessable for efficacy. Two patients were excluded because they did not complete treatment; both developed PD after two infusions of galiximab.
Nonhematologic Toxicity
Antibody infusions were delivered over 1 hour in an outpatient setting and were safe and well tolerated. No DLTs were reported, and dose escalation was feasible up to 500 mg/m2 weekly for 4 weeks. AEs generally occurred during the treatment period and were typically brief.
Thirty-three patients (87%) withdrew from the study; 27 patients (71%) withdrew because of disease progression requiring treatment with other lymphoma therapy, one patient (3%) withdrew because of the initiation of other lymphoma therapy in the absence of disease progression, one patient (3%) was lost to follow-up, and four patients (11%) withdrew for other reasons. No patient withdrew from the study because of toxicity. Two responders remain on study without progression.
Nonhematologic AEs of possible, probable, or unknown relationship to galiximab treatment (related) were reported for 22 (60%) of 37 patients (Table 2). The most common related AEs were fatigue (32% of patients), nausea (14%), and headache (11%). All events except one were grade 1 or 2. A single episode of grade 3 axillary pain of unknown relationship to galiximab was reported in a patient in the 500 mg/m2 treatment group. The event was considered related to study disease and resolved. Two patients experienced AEs (grade 1 back pain, grade 1 dizziness, and grade 1 infusion site inflammation) on a treatment day that required infusion rate reduction or interruption. Neither patient discontinued study treatment. No related SAEs were reported.
Hematologic Toxicity
Cytopenias were rare. Only one (3%) of 37 patients experienced cytopenias. A patient in the 125 mg/m2 treatment group developed transient grade 2 anemia and grade 3 febrile neutropenia. Both events were considered by the investigator to be unrelated to galiximab and resolved after treatment (RBC transfusion and ceftazidime). The patient had bone marrow involvement, and the events were considered related to study disease.
Serum Chemistry
The majority of patients had unchanged or improved serum chemistry results throughout the study. Only one patient had a shift in toxicity greater than 1 grade. This patient experienced a two-grade shift in creatinine attributed to disease progression that caused bilateral ureteral obstruction.
Infections
Nine infections were reported in seven patients (19%; four urinary tract infections, four upper respiratory tract infections, and one nonspecific infection). Eight of the nine infections were grade 1 or 2. All nine infections were considered not related to galiximab, and all resolved or were controlled. A single episode of grade 3 pneumonia not otherwise specified (not related) was observed and reported as an SAE. The event was considered related to concurrent illness and resolved with treatment (paracetamol, ibuprofen, and propacet).
Immunology
Median serum Ig concentrations and T-cell counts fluctuated throughout the study but remained within the normal range. The median B-cell count remained within the normal range through month 9. No patient developed antigaliximab antibodies.
Immunohistochemistry
Fresh-frozen tumor tissue was obtained from 12 (34%) of 35 patients at baseline and evaluated for CD80 expression by immunohistochemistry. All samples were positive for CD80; the majority had 1+ to 2+ intensity.
PK
Cmax and AUC were proportional to the administered dose of galiximab (Table 3). There was a steady increase in the pre- and postinfusion concentration during the treatment period, with a continued decline after treatment (Fig 1). Serum galiximab concentrations were detectable 6 to 9 months after treatment, and the mean terminal half-life ranged from 13 to 24 days.
Efficacy
The ORR for patients assessable for efficacy was 11% (four of 35 patients), with two CRs and two PRs. Three responders were in the 375 mg/m2 treatment group, and one was in the 500 mg/m2 treatment group. An additional 12 patients (34%) had SD as their best response. The relationship between time to response and serum concentrations was evaluated for the four responders. Of interest, time to response was delayed (months 3, 6, 9, and 12), and the maximum reduction in tumor burden for two of three responders occurred at 9 and 12 months when galiximab serum concentrations were near or below the limit of detection (Fig 2); serum concentrations for the fourth responder were not available past month 3. Several prognostic factors have been defined in the medical literature, but because of the small sample size, statistical correlations could not be made between baseline prognostic variables and clinical response. All responders received prior chemotherapy, and three of the four responders received prior rituximab; none had detectable rituximab serum concentrations at study entry. Three responders had stage IV disease and one had stage III disease at study entry, with the maximum diameter of the largest tumor ranging from 2.7 to 5.0 cm (Table 4). In addition, responders did not seem to have higher expression levels of CD80 than nonresponders.
Tumor burden reductions were observed at all doses. Seventeen (49%) of 35 patients had reductions in tumor burden after galiximab treatment; six patients (17%) had reductions 50% (Fig 3). Two patients had a decrease in indicator lesions greater than 50% but were classified as having PD; one patient developed a new lesion, and the second patient had nonmeasurable disease progression. Lesion measurements were not available for four patients who progressed on or before their first response assessment.
The median time to progression for the 35 assessable patients was 1.7 months. Thirty-three patients (94%) had PD at months 1.2 to 26.5. Two patients remain on study without PD; both are responders at months 22 and 24.4.
Thirty-one of 35 assessable patients remain alive at months 1.6 to 27.6. Four deaths occurred off study (8.1 to 26.1 months after first infusion). None of the deaths were related to study treatment.
DISCUSSION
A clear need for new NHL therapies exists. Results from this study of galiximab therapy for patients with relapsed or refractory follicular NHL are promising (a favorable safety profile and evidence of clinical activity) and provide a framework for future studies.
The favorable safety profile of galiximab is notable, particularly with respect to the lack of myelosuppression typical with standard chemotherapies, radiotherapy, and other antibody therapies.1,3,4,16-18 Galiximab infusions were delivered over 1 hour in an outpatient setting and were well tolerated with no DLTs. The primary AEs (fatigue, nausea, and headache) were typically mild to moderate (grade 1 or 2). Evaluation of vital sign measurements, infection rates, hematology, serum chemistry, urinalysis, WBC phenotypes, and Ig concentrations revealed no safety issues of clinical concern with galiximab infused at doses up to 500 mg/m2 once weekly for 4 weeks. No patient developed antigaliximab antibodies. Because galiximab is a PRIMATIZED antibody, the risk of immunogenicity is low compared with murine and some chimeric antibodies, which can potentially restrict repeated administration.
The maximum-tolerated dose of galiximab is still unknown. With biologic therapies, the optimal dose may be different from the maximum-tolerated dose. The ORR was 11% (four of 35 patients). An additional 12 patients (34%) had SD as their best response, and almost half of all patients (49%) experienced a reduction in tumor burden. Although three (15%) of 20 assessable patients responded in the 375 mg/m2 treatment group (two CRs and one PR) and one (11%) of nine patients responded in the 500 mg/m2 treatment group (one PR), the study's small sample size prevents us from drawing statistical conclusions regarding the optimal dose for efficacy. Of interest, the time to best response for the four responders was delayed (months 3, 6, 9, and 12). The mechanism of action for delayed responses is unclear. Traditionally, monoclonal antibodies against cell-surface antigens were believed to induce antitumor activity through cellular opsonization and ADCC.18-20 Indeed, in vitro studies demonstrated that galiximab binds with high specificity to CD80 on B-cell lymphoma cell lines and induces ADCC.13,21 However, it is unlikely that this is the sole mechanism of action responsible for clinical activity, and there is a growing recognition that alternative and/or additional pathways may be involved in the antitumor activity of monoclonal antibodies.
Tumor growth is a dynamic process; while abnormal cells undergo uncontrolled proliferation, constant cell turnover enables dead tumor cells to be taken up by APCs and processed and tumor-associated antigens (TAA) to be presented to the immune system. Because lymphoma cells develop from normal B cells, such TAAs are perceived as self-antigens. During development, regulatory mechanisms condition the immune system to recognize but not react to self antigens. These mechanisms include the deletion of T cells in the thymus expressing receptors that bind with a strong affinity to self antigens. Tolerance of the T-cell repertoire toward self-antigens is maintained later in life through peripheral tolerance mechanisms.22,23 One of these peripheral tolerance mechanisms is believed to involve CTLA-4 interactions with its ligands CD80 and CD86.23 During costimulation of nave T cells in the periphery through CD80-CD28 and CD86-CD28 interactions, it is thought that CTLA-4 is upregulated on these T cells. To maintain peripheral tolerance toward TAA, CTLA-4 on stimulated nave T cells could bind to CD80 on activated T cells or CD80 and CD86 on APCs presenting TAA. This could result in the inhibition of activation or deletion of stimulated nave anti-TAA T cells. If CTLA-4 induction is diminished by galiximab binding to CD80, it is possible that peripheral tolerance could be broken, allowing the proliferation of anti-TAA T cells by costimulatory molecules (eg, CD86, integrins, and so on) on APCs. Galiximab binding to CD80 on lymphoma cells may induce cell death, thereby increasing the number of TAA presented on APCs and enhancing the stimulation of anti-TAA T cells. Once activated, the expansion of nave anti-TAA T cells might proceed slowly because of limited stimulation through self-antigens and because of the blockade of CD28-CD80 interactions by galiximab. This may explain tumor reductions observed several months after treatment when galiximab concentrations are no longer detectable in the circulation. Although an increase in T-cell counts in this study was not observed, we would expect the majority of autoreactive cells to be found in tumor-associated tissues and not in the circulation.
Cmax and AUC increased proportionally with the administered dose of galiximab, and the mean terminal half-life ranged from 13 to 24 days. This is longer than the mean half-life observed with rituximab (approximately 9 days) administered at the standard dose (375 mg/m2) using the same treatment schedule (weekly for 4 weeks).1 This difference can be attributed to a higher CD20 antigen density on malignant and normal B cells.
Because galiximab's safety profile and mechanism of action differ from chemotherapies and other NHL antibody therapies, galiximab offers the potential for integration with other lymphoma therapies. In vitro and in vivo studies show that administering galiximab in combination with rituximab leads to enhanced antitumor activity in lymphoma models, supporting the rationale for a combination study.13,14 A phase I/II study of galiximab in combination with rituximab therapy in patients with relapsed or refractory patients is ongoing. Preliminary results show promising clinical activity without added toxicity compared with single-agent rituximab alone.24 Ongoing and future studies are warranted to further evaluate the therapeutic role of galiximab in the treatment of follicular lymphoma. Future studies in other CD80-positive hematologic malignancies (eg, diffuse large B-cell NHL, chronic lymphocytic leukemia, Hodgkin's disease, and multiple myeloma) are also under consideration.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Aron Thall, Biogen Idec; Baha Alkuzweny, Biogen Idec; Deborah M. Finucane, Biogen Idec; Bryan R. Leigh, Biogen Idec. Consultant/Advisory Role: Myron S. Czuczman, Biogen Idec; Thomas E. Witzig, Biogen Idec; Joseph O. Moore, Amgen, Biogen Idec; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec; John Sweetenham, Biogen Idec. Stock Ownership: Aron Thall, Biogen Idec; Baha Alkuzweny, Biogen Idec; Deborah M. Finucane, Biogen Idec; Bryan R. Leigh, Biogen Idec. Honoraria: Myron S. Czuczman, Biogen Idec; Anas Younes, Biogen Idec; Christos Emmanouilides, Biogen Idec; Thomas P. Miller, Biogen Idec; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec, Genentech; John Sweetenham, Biogen Idec. Research Funding: Myron S. Czuczman, Biogen Idec; Thomas E. Witzig, Biogen Idec; Christos Emmanouilides, Biogen Idec; Thomas P. Miller, Biogen Idec; Joseph O. Moore, Biogen Idec, Genta, Ligand; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec, Genentech; John Sweetenham, Biogen Idec. Other Remuneration: Leo I. Gordon, Biogen Idec, Genentech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We would like to acknowledge the investigational site coordinators, the Biogen Idec 114 to 20 study management team and preclinical group, and the patients who participated in this study, without whom drug development would not advance.
NOTES
Supported by Biogen Idec Inc, San Diego, CA.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
Presented in part at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002; the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003; and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
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Biogen Idec Inc, San Diego, CA
Mayo Clinic, Rochester, MN
University of Nebraska, Omaha, NE
M.D. Anderson Cancer Center, Houston, TX
University of California Los Angeles, Los Angeles, CA
Arizona Cancer Center, Tucson, AZ
Duke University, Durham, NC
Cornell Medical Center, New York, NY
Northwestern University, Chicago, IL
University of Colorado Health Sciences Center, Aurora, CO
ABSTRACT
PURPOSE: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.
PATIENTS AND METHODS: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.
RESULTS: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).
CONCLUSION: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.
INTRODUCTION
The success of rituximab has changed the way non-Hodgkin's lymphoma (NHL) is managed today. Despite impressive single-agent efficacy in patients with relapsed or refractory indolent lymphoma,1,2 many patients do not respond, and patients who do respond relapse after a median of approximately 1 year and become resistant. Radiolabeled antibodies (ibritumomab tiuxetan and tositumomab and iodine I131 tositumomab), more aggressive combination regimens, and myeloablative therapies offer increased response rates but at the cost of increased toxicity,3-6 which limits their use in a significant number of patients. Less myelosuppressive therapies are needed.
CD80 (B7.1) is a membrane-bound costimulatory molecule that is known for its role in regulating T-cell activity.7,8 Several studies have suggested that CD80 may also play a role in the regulation of normal and malignant B cells.9,10 CD80 is transiently expressed on the surface of activated B cells, antigen-presenting cells (APCs), and T cells but is constitutively expressed on a variety of NHLs, including follicular lymphoma, making it an attractive target for lymphoma therapy.11,12 In vitro, cross linking CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation, to upregulate proapoptotic molecules, and to induce antibody-dependent cell-mediated cytotoxicity (ADCC).9 These observations constitute the rationale for development of an anti-CD80 therapy for B-cell lymphoma.
Galiximab is a chimeric, anti-CD80, immunoglobulin (Ig) G1 lambda monoclonal antibody with human constant regions and primate (cynomologous macaque) variable regions. The antibody is structurally indistinguishable from human antibodies and, therefore, is unlikely to be significantly immunogenic in humans. This makes it more suitable for potential repeated dosing in lymphoma patients. The specificity of galiximab binding to human CD80 has been validated in competitive binding studies with several lymphoma cell lines. Galiximab has also been shown to bind CD80 on T cells and block CD80-CD28 interaction without interfering with the interaction between CD80 and CD152 (CTLA-4; unpublished observations). Preclinical in vitro and in vivo studies evaluated galiximab as a targeted therapy for lymphoma with promising results.13,14 Because of its immunomodulatory properties, galiximab has previously been studied as a treatment for psoriasis. A total of 242 patients with moderate to severe plaque psoriasis received galiximab treatment. Galiximab was well tolerated, with a safety profile similar to placebo. This report presents results from a multicenter, phase I/II clinical study evaluating safety, efficacy, and pharmacokinetics (PK) of single-agent galiximab in patients with relapsed or refractory follicular lymphoma.
PATIENTS AND METHODS
Study Objectives
The primary objective of the study was to characterize the safety profile of escalating doses of galiximab in patients with relapsed or refractory follicular lymphoma. Secondary objectives included the evaluation of PK and efficacy.
Eligibility Criteria
Adult patients ( 18 years) with histologically confirmed follicular lymphoma who had relapsed or failed to respond to primary therapy were eligible for this study. Patients were required to have progressive disease (PD) requiring further treatment. Patients were not permitted to have had cancer radiotherapy, biologic therapy, chemotherapy, or immunosuppressive therapy within 3 weeks before the first scheduled galiximab treatment. Patients with major surgery (other than diagnostic surgery) within 4 weeks or lymphoma antibody therapy or autologous bone marrow transplantation within 6 months were excluded. Inclusion criteria also required patients to have a good WHO performance status (status of 2 or less); bidimensionally measurable disease with at least one lesion 2.0 cm in a single dimension; and adequate hematologic, renal, and hepatic function. Patients were excluded if they had CNS lymphoma, active opportunistic infection, or serious nonmalignant disease or were HIV positive. Because the effects of galiximab on embryogenesis are unknown, additional criteria for eligibility excluded patients who were pregnant or breast feeding. In addition, patients of reproductive potential had to agree to use accepted birth control methods during treatment and for approximately 3 months after the last infusion of galiximab. Concomitant therapy with other lymphoma treatments or other investigational drugs was not permitted during the study.
The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients, and each participating clinical site received approval from its institutional review board.
Study Design
This was an open-label, multicenter, phase I/II study. Patients received intravenous infusions of galiximab at doses of 125, 250, 375, or 500 mg/m2 once weekly for 4 weeks. Galiximab was administered in an outpatient setting over a 1-hour period. Antibody doses were diluted with normal saline for a total final volume of 75 to 150 mL in accordance with the protocol. Doses were individually formulated according to assigned treatment group and the patient's body-surface area. Patients were assigned sequentially to a treatment group. Enrollment onto a higher dose cohort was not permitted until three patients in the previous treatment group were at least 7 days beyond their first infusion with no dose-limiting toxicities (DLTs) reported. DLT was defined as grade 3 toxicity not associated with an infusion, any grade 4 toxicity, or adverse reactions that prevented completion of an infusion within 48 hours.
After the administration of study treatment, patients entered a follow-up period (through month 48). All patients who withdrew from the study early or who were alive at the end of the 48-month study period were observed, at 6-month intervals, for continuation of response (if applicable), initiation of other lymphoma therapy, survival status, and cause of death (if applicable).
Galiximab Antibody
Galiximab is an IgG1 lambda, anti-CD80 monoclonal antibody developed using PRIMATIZED antibody technology (Biogen Idec Inc, San Diego, CA) to decrease immunogenicity. The variable regions are of cynomologous macaque origin, and the constant regions are of human origin. Galiximab is formulated for intravenous injection as a sterile product in 10 mmol/L sodium citrate, containing 150 mmol/L sodium chloride, and 0.02% polysorbate 80 at pH 6.5. Galiximab was supplied by IDEC Pharmaceuticals Corporation (now known as Biogen Idec Inc, San Diego, CA).
Study End Points
Safety. Safety evaluations included medical histories, physical examinations, clinical adverse events (AEs), clinical laboratory evaluations (hematology, serum chemistry, and immunology), vital sign measurements, urinalysis, serious AEs (SAEs), and deaths. Hematology evaluations included nadir data analyses of hemoglobin, platelet counts, WBC counts, absolute lymphocyte counts, and absolute neutrophil counts. Immunology evaluations included Ig concentrations (IgG, IgM, and IgA), lymphocyte subsets, and antigaliximab antibody formation. Serum concentrations of human antibodies to galiximab were evaluated at baseline and at day 50 and months 3, 6, 9, and 12 after treatment using an enzyme-linked immunosorbant assay method. The lower limit of quantitation for this assay is 250 ng/mL. AE data were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0).
PK. Serum samples were obtained before infusion, within 10 minutes of the completion of infusions (days 1, 8, 15, and 22), and on days 29, 36, 43, and 50 and at months 3, 6, 9, and 12. PK analyses included galiximab serum concentrations, the maximum observed concentration (Cmax), the time to maximum observed concentration, serum half-life, and the area under the concentration time curve (AUC).
Data were analyzed using a noncompartmental linear regression method to determine the serum half-life using data from all samples collected after study day 1 that contained galiximab concentrations exceeding the lower limit of quantitation for the assay (250 ng/mL). AUC was calculated using the linear/logarithmic trapezoidal method and determined with time extrapolated out to infinity.
Efficacy. Evaluation of disease was performed by comprehensive scans (computed tomography, magnetic resonance imaging, and x-rays) and physical examination at baseline (study entry), 1 month after completion of galiximab treatment (day 50), every 3 months thereafter for years 1 and 2, and every 6 months for years 3 and 4. Response to treatment was analyzed using standard outcome measures for clinical trials (complete response [CR], unconfirmed complete response, partial response [PR], stable disease [SD], and PD) as defined by the International Workshop Response Criteria (IWRC) for NHL.15 The primary efficacy end point was overall response rate (ORR). Secondary efficacy end points included CR rate, unconfirmed CR rate, PR rate, duration of response, and time to progression.
Immunohistochemistry. In addition, fresh frozen tumor samples were analyzed at baseline for expression levels of cell surface CD80 antigens using immunohistochemical techniques. Tissue sections were stained with commercially available anti-CD80 antibody (BD Pharmingen, San Diego, CA) using the DAKO Envision Plus detection system (DAKO, Copenhagen, Denmark). An independent certified pathologist from IMPATH Predictive Oncology (Los Angeles, CA) reviewed the slides. Slides were evaluated for adequacy of tissue, percent positive staining, and staining intensity (1+, 2+, or 3+) for each antibody, with the lowest intensity reported as 1+ and the highest intensity reported as 3+. Frozen tonsil and known positive cell lines were used as controls with every batch of samples.
Statistical Methods
Patients were considered assessable for safety if they received at least one infusion of galiximab. Patients were considered assessable for PK analyses if they received four infusions of galiximab and had sufficient data available (a complete data set during the treatment period and at least three points after the last infusion) for calculation of PK parameters. Patients were considered assessable for efficacy if they met all prestudy entry criteria (unless granted as an exemption), received four infusions of galiximab, and did not receive additional lymphoma therapy before the first response assessment on day 50.
Summary descriptive statistics were used for all continuous variables (No., mean, standard deviation, median, minimum, and maximum) and categoric variables (No. and %). The 95% CI for ORR was calculated. All CIs for proportions were calculated using the methodology for inference about a single proportion. For Kaplan-Meier median estimates, a 95% CI was calculated using Greenwood's formula for SE.
RESULTS
Patient Characteristics
Between January 30, 2002, and February 19, 2003, 38 patients with relapsed or refractory follicular lymphoma were enrolled at nine clinical sites. Baseline characteristics for all enrolled patients are listed in Table 1. The majority of patients presented with stage III or IV disease (90%). All patients had received at least one prior course of lymphoma therapy (range, one to nine courses). Prior therapies included chemotherapy (53%), single-agent rituximab (45%), rituximab-chemotherapy combination therapy (40%), and other bioimmunotherapy (26%). Nine patients (24%) were rituximab nave. The median time from the most recent relapse was 2.3 months (range, 0.2 to 37.1 months).
Of the 38 patients enrolled, 37 (97%) received galiximab treatment (three patients at 125 mg/m2, three at 250 mg/m2, 21 at 375 mg/m2, and 10 at 500 mg/m2). All 37 patients were evaluated for safety. Of the 37 patients who received galiximab treatment, 35 (95%) were considered assessable for efficacy. Two patients were excluded because they did not complete treatment; both developed PD after two infusions of galiximab.
Nonhematologic Toxicity
Antibody infusions were delivered over 1 hour in an outpatient setting and were safe and well tolerated. No DLTs were reported, and dose escalation was feasible up to 500 mg/m2 weekly for 4 weeks. AEs generally occurred during the treatment period and were typically brief.
Thirty-three patients (87%) withdrew from the study; 27 patients (71%) withdrew because of disease progression requiring treatment with other lymphoma therapy, one patient (3%) withdrew because of the initiation of other lymphoma therapy in the absence of disease progression, one patient (3%) was lost to follow-up, and four patients (11%) withdrew for other reasons. No patient withdrew from the study because of toxicity. Two responders remain on study without progression.
Nonhematologic AEs of possible, probable, or unknown relationship to galiximab treatment (related) were reported for 22 (60%) of 37 patients (Table 2). The most common related AEs were fatigue (32% of patients), nausea (14%), and headache (11%). All events except one were grade 1 or 2. A single episode of grade 3 axillary pain of unknown relationship to galiximab was reported in a patient in the 500 mg/m2 treatment group. The event was considered related to study disease and resolved. Two patients experienced AEs (grade 1 back pain, grade 1 dizziness, and grade 1 infusion site inflammation) on a treatment day that required infusion rate reduction or interruption. Neither patient discontinued study treatment. No related SAEs were reported.
Hematologic Toxicity
Cytopenias were rare. Only one (3%) of 37 patients experienced cytopenias. A patient in the 125 mg/m2 treatment group developed transient grade 2 anemia and grade 3 febrile neutropenia. Both events were considered by the investigator to be unrelated to galiximab and resolved after treatment (RBC transfusion and ceftazidime). The patient had bone marrow involvement, and the events were considered related to study disease.
Serum Chemistry
The majority of patients had unchanged or improved serum chemistry results throughout the study. Only one patient had a shift in toxicity greater than 1 grade. This patient experienced a two-grade shift in creatinine attributed to disease progression that caused bilateral ureteral obstruction.
Infections
Nine infections were reported in seven patients (19%; four urinary tract infections, four upper respiratory tract infections, and one nonspecific infection). Eight of the nine infections were grade 1 or 2. All nine infections were considered not related to galiximab, and all resolved or were controlled. A single episode of grade 3 pneumonia not otherwise specified (not related) was observed and reported as an SAE. The event was considered related to concurrent illness and resolved with treatment (paracetamol, ibuprofen, and propacet).
Immunology
Median serum Ig concentrations and T-cell counts fluctuated throughout the study but remained within the normal range. The median B-cell count remained within the normal range through month 9. No patient developed antigaliximab antibodies.
Immunohistochemistry
Fresh-frozen tumor tissue was obtained from 12 (34%) of 35 patients at baseline and evaluated for CD80 expression by immunohistochemistry. All samples were positive for CD80; the majority had 1+ to 2+ intensity.
PK
Cmax and AUC were proportional to the administered dose of galiximab (Table 3). There was a steady increase in the pre- and postinfusion concentration during the treatment period, with a continued decline after treatment (Fig 1). Serum galiximab concentrations were detectable 6 to 9 months after treatment, and the mean terminal half-life ranged from 13 to 24 days.
Efficacy
The ORR for patients assessable for efficacy was 11% (four of 35 patients), with two CRs and two PRs. Three responders were in the 375 mg/m2 treatment group, and one was in the 500 mg/m2 treatment group. An additional 12 patients (34%) had SD as their best response. The relationship between time to response and serum concentrations was evaluated for the four responders. Of interest, time to response was delayed (months 3, 6, 9, and 12), and the maximum reduction in tumor burden for two of three responders occurred at 9 and 12 months when galiximab serum concentrations were near or below the limit of detection (Fig 2); serum concentrations for the fourth responder were not available past month 3. Several prognostic factors have been defined in the medical literature, but because of the small sample size, statistical correlations could not be made between baseline prognostic variables and clinical response. All responders received prior chemotherapy, and three of the four responders received prior rituximab; none had detectable rituximab serum concentrations at study entry. Three responders had stage IV disease and one had stage III disease at study entry, with the maximum diameter of the largest tumor ranging from 2.7 to 5.0 cm (Table 4). In addition, responders did not seem to have higher expression levels of CD80 than nonresponders.
Tumor burden reductions were observed at all doses. Seventeen (49%) of 35 patients had reductions in tumor burden after galiximab treatment; six patients (17%) had reductions 50% (Fig 3). Two patients had a decrease in indicator lesions greater than 50% but were classified as having PD; one patient developed a new lesion, and the second patient had nonmeasurable disease progression. Lesion measurements were not available for four patients who progressed on or before their first response assessment.
The median time to progression for the 35 assessable patients was 1.7 months. Thirty-three patients (94%) had PD at months 1.2 to 26.5. Two patients remain on study without PD; both are responders at months 22 and 24.4.
Thirty-one of 35 assessable patients remain alive at months 1.6 to 27.6. Four deaths occurred off study (8.1 to 26.1 months after first infusion). None of the deaths were related to study treatment.
DISCUSSION
A clear need for new NHL therapies exists. Results from this study of galiximab therapy for patients with relapsed or refractory follicular NHL are promising (a favorable safety profile and evidence of clinical activity) and provide a framework for future studies.
The favorable safety profile of galiximab is notable, particularly with respect to the lack of myelosuppression typical with standard chemotherapies, radiotherapy, and other antibody therapies.1,3,4,16-18 Galiximab infusions were delivered over 1 hour in an outpatient setting and were well tolerated with no DLTs. The primary AEs (fatigue, nausea, and headache) were typically mild to moderate (grade 1 or 2). Evaluation of vital sign measurements, infection rates, hematology, serum chemistry, urinalysis, WBC phenotypes, and Ig concentrations revealed no safety issues of clinical concern with galiximab infused at doses up to 500 mg/m2 once weekly for 4 weeks. No patient developed antigaliximab antibodies. Because galiximab is a PRIMATIZED antibody, the risk of immunogenicity is low compared with murine and some chimeric antibodies, which can potentially restrict repeated administration.
The maximum-tolerated dose of galiximab is still unknown. With biologic therapies, the optimal dose may be different from the maximum-tolerated dose. The ORR was 11% (four of 35 patients). An additional 12 patients (34%) had SD as their best response, and almost half of all patients (49%) experienced a reduction in tumor burden. Although three (15%) of 20 assessable patients responded in the 375 mg/m2 treatment group (two CRs and one PR) and one (11%) of nine patients responded in the 500 mg/m2 treatment group (one PR), the study's small sample size prevents us from drawing statistical conclusions regarding the optimal dose for efficacy. Of interest, the time to best response for the four responders was delayed (months 3, 6, 9, and 12). The mechanism of action for delayed responses is unclear. Traditionally, monoclonal antibodies against cell-surface antigens were believed to induce antitumor activity through cellular opsonization and ADCC.18-20 Indeed, in vitro studies demonstrated that galiximab binds with high specificity to CD80 on B-cell lymphoma cell lines and induces ADCC.13,21 However, it is unlikely that this is the sole mechanism of action responsible for clinical activity, and there is a growing recognition that alternative and/or additional pathways may be involved in the antitumor activity of monoclonal antibodies.
Tumor growth is a dynamic process; while abnormal cells undergo uncontrolled proliferation, constant cell turnover enables dead tumor cells to be taken up by APCs and processed and tumor-associated antigens (TAA) to be presented to the immune system. Because lymphoma cells develop from normal B cells, such TAAs are perceived as self-antigens. During development, regulatory mechanisms condition the immune system to recognize but not react to self antigens. These mechanisms include the deletion of T cells in the thymus expressing receptors that bind with a strong affinity to self antigens. Tolerance of the T-cell repertoire toward self-antigens is maintained later in life through peripheral tolerance mechanisms.22,23 One of these peripheral tolerance mechanisms is believed to involve CTLA-4 interactions with its ligands CD80 and CD86.23 During costimulation of nave T cells in the periphery through CD80-CD28 and CD86-CD28 interactions, it is thought that CTLA-4 is upregulated on these T cells. To maintain peripheral tolerance toward TAA, CTLA-4 on stimulated nave T cells could bind to CD80 on activated T cells or CD80 and CD86 on APCs presenting TAA. This could result in the inhibition of activation or deletion of stimulated nave anti-TAA T cells. If CTLA-4 induction is diminished by galiximab binding to CD80, it is possible that peripheral tolerance could be broken, allowing the proliferation of anti-TAA T cells by costimulatory molecules (eg, CD86, integrins, and so on) on APCs. Galiximab binding to CD80 on lymphoma cells may induce cell death, thereby increasing the number of TAA presented on APCs and enhancing the stimulation of anti-TAA T cells. Once activated, the expansion of nave anti-TAA T cells might proceed slowly because of limited stimulation through self-antigens and because of the blockade of CD28-CD80 interactions by galiximab. This may explain tumor reductions observed several months after treatment when galiximab concentrations are no longer detectable in the circulation. Although an increase in T-cell counts in this study was not observed, we would expect the majority of autoreactive cells to be found in tumor-associated tissues and not in the circulation.
Cmax and AUC increased proportionally with the administered dose of galiximab, and the mean terminal half-life ranged from 13 to 24 days. This is longer than the mean half-life observed with rituximab (approximately 9 days) administered at the standard dose (375 mg/m2) using the same treatment schedule (weekly for 4 weeks).1 This difference can be attributed to a higher CD20 antigen density on malignant and normal B cells.
Because galiximab's safety profile and mechanism of action differ from chemotherapies and other NHL antibody therapies, galiximab offers the potential for integration with other lymphoma therapies. In vitro and in vivo studies show that administering galiximab in combination with rituximab leads to enhanced antitumor activity in lymphoma models, supporting the rationale for a combination study.13,14 A phase I/II study of galiximab in combination with rituximab therapy in patients with relapsed or refractory patients is ongoing. Preliminary results show promising clinical activity without added toxicity compared with single-agent rituximab alone.24 Ongoing and future studies are warranted to further evaluate the therapeutic role of galiximab in the treatment of follicular lymphoma. Future studies in other CD80-positive hematologic malignancies (eg, diffuse large B-cell NHL, chronic lymphocytic leukemia, Hodgkin's disease, and multiple myeloma) are also under consideration.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Aron Thall, Biogen Idec; Baha Alkuzweny, Biogen Idec; Deborah M. Finucane, Biogen Idec; Bryan R. Leigh, Biogen Idec. Consultant/Advisory Role: Myron S. Czuczman, Biogen Idec; Thomas E. Witzig, Biogen Idec; Joseph O. Moore, Amgen, Biogen Idec; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec; John Sweetenham, Biogen Idec. Stock Ownership: Aron Thall, Biogen Idec; Baha Alkuzweny, Biogen Idec; Deborah M. Finucane, Biogen Idec; Bryan R. Leigh, Biogen Idec. Honoraria: Myron S. Czuczman, Biogen Idec; Anas Younes, Biogen Idec; Christos Emmanouilides, Biogen Idec; Thomas P. Miller, Biogen Idec; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec, Genentech; John Sweetenham, Biogen Idec. Research Funding: Myron S. Czuczman, Biogen Idec; Thomas E. Witzig, Biogen Idec; Christos Emmanouilides, Biogen Idec; Thomas P. Miller, Biogen Idec; Joseph O. Moore, Biogen Idec, Genta, Ligand; John P. Leonard, Biogen Idec; Leo I. Gordon, Biogen Idec, Genentech; John Sweetenham, Biogen Idec. Other Remuneration: Leo I. Gordon, Biogen Idec, Genentech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We would like to acknowledge the investigational site coordinators, the Biogen Idec 114 to 20 study management team and preclinical group, and the patients who participated in this study, without whom drug development would not advance.
NOTES
Supported by Biogen Idec Inc, San Diego, CA.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
Presented in part at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002; the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003; and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
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