Originally published as JCO Early Release 10.1200/JCO.2006.05.6291 on July 24 2006

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Multicenter Phase II Trial of Immunotherapy With the Humanized Anti-CD22 Antibody, Epratuzumab, in Combination With Rituximab, in Refractory or Recurrent Non-Hodgkin's Lymphoma

Sandra J. Strauss, Frank Morschhauser, Juergen Rech, Roland Repp, Philippe Solal-Celigny, Pier L. Zinzani, Andreas Engert, Bernard Coiffier, Dieter F. Hoelzer, William A. Wegener, Nick K.W. Teoh, David M. Goldenberg, T. Andrew Lister

From the Cancer Research United Kingdom Medical Oncology Unit, St Bartholomew's Hospital, London, United Kingdom; Service des Maladies du Sang, Lille; Clinique Victor Hugo, Le Mans; Center Hospitalier Lyon-Sud, Lyon, France; University of Erlangen-Nuremberg, Erlangen; University Hospital, Koln; University Hospital, Frankfurt, Germany; Istituto di Ematologica Seragnoli, Bologna, Italy; Immunomedics Inc, Morris Plains; and the Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey.

Address reprint requests to T. Andrew Lister, MD, Cancer Research United Kingdom Medical Oncology Unit, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE United Kingdom; e-mail: andrew.lister{at}cancer.org.uk

	ABSTRACT

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PURPOSE: A multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma.

PATIENTS AND METHODS: Sixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m² intravenously over 60 minutes followed by infusion of 375 mg/m² rituximab, weekly for 4 consecutive weeks.

RESULTS: Combination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months.

CONCLUSION: Epratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

	INTRODUCTION

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The non-Hodgkin's lymphomas (NHL) are a heterogeneous group of diseases, the majority of which express B-cell antigens.¹ The prognosis of the most common of these, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), have changed dramatically with the incorporation of the monoclonal antibody, rituximab (Rituxan; Genentech, South San Francisco, CA; and Biogen Idec Pharmaceuticals, San Diego, CA) into treatment schedules. After demonstration of its efficacy as a single agent, it has been combined with chemotherapy, resulting in improved response rate, progression-free survival (PFS), event-free survival, and overall survival for patients with advanced, newly diagnosed, DLBCL and FL.^2-7

There remains, however, room for additional improvement in patients with these illnesses. The development of antibodies that target different B-cell antigens is a promising proposition because the combination of two antibodies with potentially differing mechanisms of antitumor action may lead to additive or synergistic effects and may overcome intrinsic single-antibody resistance. CD22 provides an attractive target for NHL antibody therapy, being expressed in 82% to 99% of follicular and DLBCL biopsies.⁸ CD22 is a 135-kD glycoprotein expressed in the cytoplasm of pro-B and pre-B cells, and then on the surface of B cells as they mature, with expression ceasing on B-cell differentiation into plasma cells.⁹ It is rapidly internalized when crosslinked with its natural ligand, producing a potent costimulatory signal in primary B cells.⁹ Animal experiments indicate that CD22 plays a key role in B-cell development and survival, with CD22-deficient mice having reduced numbers of mature B cells with shorter life span and enhanced apoptosis.¹⁰ More recent studies indicate how CD22 may regulate B-cell receptor activation by controlling calcium efflux.^11,12

Initially, an anti-CD22 mouse monoclonal antibody (mLL2, formerly EPB-2) was developed and characterized, with promising in vitro activity.^13,14 Epratuzumab, the resulting humanized monoclonal antibody (hLL2), is 90% to 95% of human origin, thus greatly reducing the potential for immunogenicity.¹⁵ In vitro studies demonstrated that the antitumor activity of epratuzumab was predominantly via antibody-dependent cytotoxicity,^16,17 and in vivo studies showed that combination therapy with epratuzumab and rituximab, or with another CD20 antibody, was more effective in controlling lymphoma growth and prolonging survival than either agent alone.^17,18

The single-agent activity of epratuzumab was assessed in two phase I/II trials, one in indolent and the other in aggressive lymphomas,^19,20 in which patients received increasing doses of epratuzumab administered weekly for 4 consecutive weeks. In both populations, epratuzumab was well tolerated, with more than 95% of infusions administered within 1 hour. Infusion toxicities were primarily mild (grade 1) and manageable with supportive measures, and no dose-limiting toxicity was seen for doses administered up to 1,000 mg/m². Encouraging efficacy was demonstrated, particularly in FL, with a 43% objective response (OR) rate in 14 patients treated at 360 mg/m².

On the basis of the excellent tolerance of single-agent epratuzumab and encouraging clinical antilymphoma activity, a single-center study of epratuzumab given with rituximab to 23 patients demonstrated that the combination is also well tolerated, with promising activity in both FL and DLBCL.²¹ Here, we report the results of a larger European multicenter study of combination therapy with epratuzumab and rituximab in patients with relapsed or recurrent B-cell NHL.

	PATIENTS AND METHODS

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This open-label, single-arm, phase II study was conducted to evaluate the safety and effectiveness of combination antibody therapy with epratuzumab and rituximab in patients with refractory or recurrent NHL in a multicenter setting. The study end points were safety and efficacy, defined as objective and complete response rates, duration of response (DR), and time-to-progression (analyzed as PFS). Immunogenicity and immunoglobulin modulation also were assessed. At each participating institution, the governing ethics committee approved the study, and written informed consent was obtained from all patients.

Patient Population
Eligible patients were 18 years of age or older with histologically confirmed B-cell NHL for whom one to four prior regimens of chemotherapy, and/or radiotherapy, and/or rituximab had failed. Patients required an adequate performance status (Karnofsky 60 or higher or Eastern Cooperative Oncology Group 0 to 2), serum chemistries (creatinine, bilirubin, alkaline phosphatase, ALT, AST; each < 1.5 institution upper limit of normal), and hematology (hemoglobin 8.0 g/dL or higher, neutrophils 1,000/µL or higher or 500/µL if due to bone marrow involvement, platelets > 50,000/µL, without ongoing transfusional support). Patients were required to have at least one measurable lesion (1.5 cm or larger) by computed tomography, but those with bulky disease (> 10 cm), pleural fluid cytologically positive for lymphoma, primary CNS lymphoma, or Richter's lymphoma were excluded. Patients who received cytotoxic chemotherapy, cytokine therapy, major surgery, or radiotherapy to the index lesion within 4 weeks, systemic corticosteroid therapy within 2 weeks, or were refractory to their last treatment with rituximab (defined as failure to achieve an OR and/or disease progression within 6 months from the start of rituximab therapy) also were excluded. Females who were pregnant or breastfeeding were excluded, as were patients with known human antichimeric antibody (HACA) positivity, known HIV positivity, active hepatitis B or C surface antigens, other primary malignancy (except squamous or basal cell skin cancer or cervical cancer in situ) within 5 years, or patients previously exposed to other human or humanized monoclonal antibodies unless being human antihuman antibody (HAHA)–negative.

Histological subtypes were classified according to the WHO classification.¹ International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) were assigned according to published criteria.^22,23

Treatment
Patients received combination antibody therapy weekly for 4 consecutive weeks, with an intravenous infusion of 360 mg/m² epratuzumab given first within 1 hour, followed by 375 mg/m² rituximab administered the first week at 50 mg/h for the first hour, 100 mg/h during the second hour, and then at 150 mg/h until completion, and then administered at 150 mg/h during subsequent weeks. All patients were premedicated each week with an antihistamine (eg, chlorphenyramine) and an antipyretic (eg, paracetamol).

Evaluation of Safety and Toxicity
Patients were monitored for adverse reactions during infusions, with vital signs obtained every 15 minutes until both infusions were complete, and then 30 minutes and 60 minutes later. Standard safety laboratories (serum chemistry, hematology, urinalysis) were obtained at baseline, 24 hours, and 4 weeks after the last infusion, and then every 3 months. Toxicity grading of adverse events and laboratories utilized National Cancer Institute Common Toxicity Criteria, initially version 2.0, but later updated version 3.0.

Immunologic and Antibody Laboratories
Blood samples for epratuzumab, B-cell counts (CD19+), and immunoglobulin levels, as well as HAHA, were obtained at baseline, 24 hours, and 4 weeks after the last infusion, with additional samples tested every 3 months as needed. Epratuzumab and HAHA determinations in the blood were performed by the sponsor using an enzyme-linked immunosorbent assay (ELISA).

Response Evaluation
Treatment responses were determined by each investigator using international workshop criteria,²⁴ and each patient's best response was classified as either complete response (CR), complete response unconfirmed (CRu), partial response (PR), stable disease, or progressive disease (PD). A physical examination was performed and computed tomography scans of the chest, abdomen, pelvis, and other sites of known disease were obtained at baseline, 4 weeks after last infusion, and then every 3 months for 2 years and semi-annually thereafter until progression. In patients with CR or CRu, those with bone marrow infiltration at baseline were required to have bone marrow biopsy repeated.

Statistical Analysis
Demographic, safety, and laboratory data were analyzed using descriptive statistics, while survival analysis methods based on Kaplan-Meier estimates and descriptive statistics were used for analyzing treatment responses including DR and PFS. The DR was calculated from onset of an OR (ie, CR, CRu, or PR) to subsequent disease progression, death, or last contact, whichever was earliest. For all patients, PFS was measured from the first infusion to disease progression, last contact or death, whichever was earliest. Patients were considered as censored if they never experienced disease progression or death. The Cochran-Armitage trend test was used to analyze for significant trends in the response profiles of the FL and DLBLC subgroups based on the patients' risk scores FLIPI and IPI, respectively.

	RESULTS

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Patient Characteristics
A total of 65 patients from eight institutions were enrolled between November 2001 and August 2003. Forty-six patients had indolent lymphomas, including 34 patients with FL, and 19 patients had aggressive lymphomas, including 15 patients with DLBCL. Demographics and patient characteristics are summarized in Table 1; histological classifications are presented in Table 2.

Efficacy
Efficacy results are summarized in Table 3. One FL patient who withdrew before completing the first infusion was deemed unassessable and excluded from the efficacy analysis in the ensuing discussions. The overall OR rate in assessable patients was 47% (30 of 64), including 22% (14 of 64) with CR/CRu (46%; 30 of 65 and 22%; 14 of 65, respectively, in all patients). Of the 33 assessable FL patients, 21 patients (64%) achieved an OR, including eight patients (24%) with CR/CRu. Seven (47%) of 15 patients with DLBCL achieved an OR including five patients (33%) with CR/CRu. There was a trend of FL patients with low FLIPI score or DLBCL patients with low IPI score to have a higher response rates than those with high scores. This was statistically significant in the FL subgroup (P = .03), but not in the smaller group of patients with DLBCL (P = .08). Of six patients with marginal zone lymphoma, two patients achieved an OR, including one CR. None of the 10 patients with other histologies responded to therapy.

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier duration of response (DR) curves for seven patients with diffuse large B-cell lymphoma (DLBCL) and 21 patients with follicular lymphoma (FL) who achieved an objective response (complete response, complete response unconfirmed, partial response) after combination antibody therapy. The median (95% CI) DR was 15.7 months (range, 6.3 months to 19.7 months) with FL and 6.4 months (interval not available due to small sample size) with DLBCL.

View larger version (13K): [in this window] [in a new window]   Fig 2. Kaplan-Meier progression-free survival (PFS) curves for the 15 patients with diffuse large B-cell lymphoma (DLBCL) and 33 assessable patients with follicular lymphoma (FL). The median (95% CI) PFS was 10.9 months (range, 3.8 months to 13.8 months) with FL and 5.7 months (range, 1.8 months to 6.7 months) with DLBCL.

Five patients had infections treated with antibiotics (infected intravenous access, pneumonia, cellulitis, urinary tract infection, upper respiratory tract infection), and one patient had herpes zoster treated with antivirals. Other reported infections included one patient with diverticulitis, another patient with folliculitis, and five patients with upper and lower respiratory illness. For standard safety laboratories, post-treatment increases in National Cancer Institute Common Toxicity Criteria version 3.0 toxicity grades were infrequent, and most were limited to changes of one grade level (Table 5). Hematological toxicity was rare, with one patient developing grade 4 neutropenia, which did not result in infectious complications, and two patients developing grade 3 to 4 thrombocytopenia, discussed herein. Abnormalities of serum chemistries were rare, with two patients having grade 3 liver function abnormalities after the completion of therapy.

B-Cell and Immunologic Changes
Peripheral blood levels of B cells (CD19+) were determined by local laboratories from samples obtained at 24 hours, 4 weeks, and 3 months after the last infusion, and then every 3 months while patients remained in follow-up. Of 47 patients with assessable baseline and post-treatment measurements, approximately 90% had B-cell levels depleted 75% or higher within 4 weeks of therapy (77% achieving 95% or higher depletion), with evidence of B-cell recovery often occurring 9 months to 12 months after the last infusion.

The majority of patients had changes in serum immunoglobulin levels assessed at 24 hours, 4 weeks, 3 months, and 6 months post-treatment, while a small number of patients also had evaluations at 12 months and 18 months. For IgG, IgA, and IgM, the mean percentage of change from baseline at each of these times all remained within two standard deviations. Thus, there was no evidence that a 4-week course of combination therapy significantly decreases serum immunoglobulin levels.

Immunogenicity (HAHA)
Forty-nine patients had at least one post-treatment serum sample analyzed by the sponsor for antiepratuzumab antibodies (ELISA), including one or more samples obtained from 44 patients at 0 to 4 weeks, 37 patients at 3 months, and 11 patients at 6 to 15 months. Only one patient had positive assay results (> 50 ng/mL) with a low-level value (260 ng/mL) of uncertain significance because it was not associated with any clinical events.

	DISCUSSION

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The introduction of rituximab monoclonal antibody therapy, initially as a single agent and subsequently with chemotherapy, has led to exciting improvements in the management of malignant lymphoma, and has paved the way for the routine use of targeted therapy in this group of diseases.^5-7 Chemotherapy has, however, been pushed almost to the limits of tolerance, and there remains much room for improvement. The CD22 antigen, like some others, such as CD-19 and CD80, is an attractive additional target to CD20 in follicular and diffuse large B-cell lymphoma, because potentially different mechanisms of antitumor action may lead to additive or synergistic effects and may overcome intrinsic single-antibody resistance. The concept of multiple antibody therapy, either with or without chemotherapy, is therefore an obvious possible further advance. Proving its benefit over and above rituximab remains the challenge today.

This multicenter study, including patients with previous rituximab exposure, brings the number of patients with recurrent or refractory B-cell lymphoma treated with the combination of epratuzumab and rituximab to more than 100.^21,25 Our larger group of patients consolidates the previous results of a single-center study with, generally, very similar findings. In particular, it draws additional attention to provocative results in DLBCL, and also focuses on the relevance of clinical prognostic features to outcome.

In the initial, single-center, combination study, four of six patients (67%) with DLBCL responded to treatment, three of whom achieved a CR.²¹ Here, where 15 patients with DLBCL were treated, an OR rate of 47% was observed with a 33% CR/CRu rate that included all three patients with low IPI scores. The results presented here appear superior to the initial study of single-agent rituximab despite only 4 weeks of treatment being given.⁴ The short DR notwithstanding, the impressive response rate, particularly that of CR/CRu, provides a strong rationale for investigating the efficacy of this combination of antibodies added to a conventional chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). To this end, a pilot study of CHOP, epratuzumab, and rituximab (CHOP-ER) is being conducted by the North Central Cancer Treatment Group. Favorable preliminary results have been reported, with 13 of 15 patients alive in remission at the last report.³¹

For patients with FL, the overall response rate of 64%, with 24% CR/CRu, appears superficially better than rituximab alone in patients with similar amounts of prior treatment.^27-29 However, it is difficult to directly compare phase II studies, compounded by the fact that neither the international workshop response criteria nor the FLIPI prognostic criteria were in use at the time of earlier rituximab studies. Indeed, without randomized data comparing the combination with single-agent rituximab, statistical comparisons cannot be made. Nevertheless, it is encouraging that the results of this multicenter study are comparable with that of the single-center study of the combination of epratuzumab and rituximab, which demonstrated an overall response rate of 67% in 15 patients with FL.²¹ Although a higher CR/CRu rate of 56% was reported in that study, all patients there were rituximab naïve, had received less prior therapy, and had a more prolonged time from previous treatment until entry into the study. Preliminary findings from a multicenter US study of this combination in indolent NHL patients also showed a high CR/CRu rate of 30%, which is important, because of the survival advantage associated with CR in patients with recurrent FL.^25,26 In addition, the median response duration of 16 months obtained here appears longer than the 11- to 12-month durations reported in single-agent rituximab studies.^27-29 Patients with low-risk FLIPI scores had a particularly encouraging OR rate of 83% and durable CR/CRus were observed in 30% and 33% of patients with low- and intermediate-risk disease, respectively. Patients with high-risk disease obtained less benefit from the combination therapy, with only one of 11 patients achieving a CR/CRu. This is in contrast to the single-center study, where all patients had intermediate- or high-risk disease, and where five of 13 patients with a high FLIPI achieved a CR/CRu.²¹ Patients in that study did, however, have other favorable characteristics, as described herein. Five (50%) of 10 patients who had previously received rituximab responded to therapy, which is at least comparable with the 40% rate reported when retreating patients with recurrent indolent lymphomas who had responded previously to rituximab.³⁰

As far as toxicity is concerned, epratuzumab given before the infusion of rituximab weekly for 4 weeks was tolerated well when infused within an hour, with only one patient having an infusion-related reaction to epratuzumab that required termination of therapy. Overall, infusion-related toxicity and adverse events were comparable with that observed with single-agent rituximab, as was also experienced in the other two studies of combined epratuzumab/rituximab therapy.^21,25 The addition of a second antibody to therapy without a commensurate increase in toxicity provides reassurance that combining these antibodies with chemotherapy is likely to be feasible, and that they may also be of value in patients not considered to be suitable for cytotoxic therapy.

Within the limits of the interpretation of open phase II studies, this combination antibody study is suggestive of greater efficacy than single-agent anti-CD20 therapy without an increase in toxicity, and encourages additional investigation in both FL and DLBCL. Epratuzumab is one of a number of new biologic agents with promising activity in malignant lymphoma, and all face similar challenges in investigating the optimal setting for their development. Other novel agents are undergoing similar investigation, including a primatized anti-CD80 monoclonal antibody, which also has promising preliminary phase II data in combination with rituximab.³² Prospective, randomized clinical trials are warranted to definitively answer whether any such combinations provide additional benefit over single-agent rituximab. The current results of a this multicenter trial, in support of the findings of an earlier single-center study,²¹ justify a randomized trial, possibly including conventional chemotherapy in both study arms. Investigation of other schedules, including maintenance combination antibody therapy, may also be warranted in patients with FL.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Sandra J. Strauss Immunomedics Inc (B) Frank Morschhauser Immunomedics Inc (B) Juergen Rech Immunomedics Inc (B) Philippe Solal-Celigny Immunomedics Inc (B) Pier L. Zinzani Immunomedics Inc (B) Andreas Engert Immunomedics Inc (B) Bernard Coiffier Immunomedics Inc (B) Dieter F. Hoelzer Immunomedics Inc (B) William A. Wegener Immunomedics Inc (N/R) Immunomedics Inc (C) Nick K.W. Teoh Immunomedics Inc (N/R) Immunomedics Inc (B) David M. Goldenberg Immunomedics Inc (N/R) Immunomedics Inc (C) Immunomedics Inc (C) T. Andrew Lister Immunomedics Inc (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: William A. Wegener, David M. Goldenberg, T. Andrew Lister Administrative support: William A. Wegener Provision of study materials or patients: Sandra J. Strauss, Frank Morschhauser, Juergen Rech, Roland Repp, Philippe Solal-Celigny, Pier L. Zinzani, Andreas Engert, Bernard Coiffier, Dieter F. Hoelzer, William A. Wegener, T. Andrew Lister Collection and assembly of data: Sandra J. Strauss, Frank Morschhauser, Juergen Rech, Roland Repp, Philippe Solal-Celigny, Pier L. Zinzani, Andreas Engert, Bernard Coiffier, Dieter F. Hoelzer, T. Andrew Lister Data analysis and interpretation: Sandra J. Strauss, William A. Wegener, Nick K.W. Teoh, T. Andrew Lister Manuscript writing: Sandra J. Strauss, William A. Wegener, David M. Goldenberg, T. Andrew Lister Final approval of manuscript: Sandra J. Strauss, Frank Morschhauser, Juergen Rech, Roland Repp, Philippe Solal-Celigny, Pier L. Zinzani, Andreas Engert, Bernard Coiffier, Dieter F. Hoelzer, William A. Wegener, Nick K.W. Teoh, David M. Goldenberg, T. Andrew Lister

 

	ACKNOWLEDGMENTS

 
We thank the patients who participated in this clinical trial and the doctors and nurses who cared for them.

	NOTES

 
published online ahead of print at www.jco.org on July 24, 2006.

Supported by Cancer Research United Kingdom and grants from Immunomedics Inc. T.A.L. and S.J.S. are supported by Cancer Research United Kingdom.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted January 7, 2006; accepted June 19, 2006.

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