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Originally published as JCO Early Release 10.1200/JCO.2006.05.6291 on July 24 2006 © 2006 American Society of Clinical Oncology. 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
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
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.
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.
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 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
Evaluation of Safety and Toxicity
Immunologic and Antibody Laboratories
Response Evaluation
Statistical Analysis
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.
Study Drug Administration Sixty-three of 65 patients completed therapy, while two did not (one patient with FL due to a reaction during the first infusion and one DLBCL patient due to overt clinical progression after the second infusion). Infusion times (mean ± standard deviation) for epratuzumab and rituximab were respectively: 67 ± 27 minutes and 357 ± 124 minutes for initial infusions, and 64 ± 15 minutes and 266 ± 99 minutes for subsequent infusions.
Efficacy
For patients with FL and DLBCL, Kaplan-Meier estimates of DR and PFS curves are shown in Figures 1 and 2, respectively. With a median follow-up duration of 11 months, the median DR and PFS were, respectively, 16 and 11 months for FL and 6 and 6 months for DLBCL. Seven patients with continuing responses (five CR, one CRu, and one PR) are still in long-term monitoring, including five patients with FL currently progression free for 18 months to 30 months, and two patients with DLBCL currently progression free for 12 months and 18 months.
Adverse Events Fifty-four patients (83%) experienced one or more adverse events that were typically mild-moderate (National Cancer Institute [NCI] toxicity grade 1-2), self-limiting, infusion-related events (Table 4).
There were no deaths attributable to the therapy. Serious adverse events considered at least possibly related to combination therapy by the investigators were reported in eight patients (12%). One patient had an allergic reaction with severe hypotension during the first epratuzumab infusion. Three patients had uneventful epratuzumab infusions, but one patient subsequently developed hypotension before starting first rituximab administration, and two patients became hypotensive during their first rituximab infusions. Two patients had dyspnea, one considered an exacerbation of known asthma, during the first infusion as well as later during the trial, and the second 1 month after treatment, subsequently diagnosed as pulmonary embolism. The two remaining patients developed grade 3 and 4 thrombocytopenia that recovered spontaneously without serious bleeding. 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.
Pharmacokinetics Median serum levels of epratuzumab determined by the sponsor (ELISA) at 24 hours (n = 52), 4 weeks (n = 58), and 3 months (n = 24) after treatment were 265 µg/mL (range, 101 µg/mL to 604 µg/mL), 80 µg/mL (range, 13 µg/mL to 362 µg/mL), and 37 µg/mL (range, 3 µg/mL to 147µg/mL), respectively, and five samples analyzed even at 6 months had low but detectable levels (max, 13 µg/mL). A noncompartmental estimate based on 12 patients with at least four samples resulted in a serum half-life (mean ± standard deviation) after the fourth infusion of 31 ± 8.9 days.
B-Cell and Immunologic Changes 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)
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.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank the patients who participated in this clinical trial and the doctors and nurses who cared for them.
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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Czuczman MS, Weaver R, Alkuzweny B, et al: Prolonged clinical and molecular remissions in patients with low-grade follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow up. J Clin Oncol 23: 4711-4716, 2004 6. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346: 235-242, 2002 7. Pfreundschuh MG, Trümper L, Ma D, et al: Randomized intergroup trial of first line treatment for patients 8. Cessano A, Gayko, U, Braman C, et al: Differential expression of CD22 indolent and aggressive non-Hodgkin's lymphoma (NHL): Implications for targeted therapy. Blood 100: 350a, 2002 (abstr) 9. Clark EA: CD22, a B cell-specific receptor, mediates adhesion and signal transduction. J Immunol 150: 4715-4718, 1993[Medline] 10. Otipoby KL, Andersson KB, Draves KE, et al: CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384: 634-637, 1996[CrossRef][Medline] 11. Sato S, Tuscano JM, Inaoki M, et al: CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor. Semin Immunol 10: 287-297, 1998[CrossRef][Medline] 12. Chen J, McLean PA, Neel BG, et al: CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat Immunol 5: 651-657, 2004 [Epub 2004 May 09][CrossRef][Medline] 13. Pawlak-Byczkowska EJ, Hansen HJ, Dion AS, et al: Two new monoclonal antibodies, EPB-1 and EPB-2, reactive with human lymphoma. Cancer Res 49: 4568-4577, 1989 14. Stein R, Belisle E, Hansen HJ, et al: Epitope specificity of the anti-(B cell lymphoma) monoclonal antibody, LL2. Cancer Immunol Immunother 37: 293-298, 1993[CrossRef][Medline] 15. Leung SO, Goldenberg DM, Dion AS, et al: Construction and characterization of a humanized, internalizing, B-cell (CD22)-specific, leukemia/lymphoma antibody, LL2. Mol Immunol 32: 1413-1427, 1995[CrossRef][Medline] 16. Gada P, Hernandez-Ilizaliturri F, Repasky EA, et al: Epratuzumab's predominant antitumor activity in vitro/in vivo against non-Hodgkin's lymphoma (NHL) is via antibody-dependent cellular cytotoxicity (ADCC). Blood 100: 353a, 2002 (abstr 1367) 17. Stein R, Qu Z, Chen S, et al: Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin Cancer Res 10: 2868-2878, 2004 18. Hernandez-Ilizaliturri F, Gada P, Repasky EA, et al: Enhancement in anti-tumor activity of rituximab when combined with epratuzumab or apolizumab (Hu1D10) in a B-cell lymphoma severe combined immunodeficiency (SCID) mouse model. Blood 100: 158a, 2002 (abstr 6591) 19. Leonard JP, Coleman M, Ketas JC, et al: Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma. 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Emmanouilides C, Leonard JP, Schuster SJ, et al.: Multi-center phase 2 study of combination antibody therapy with epratuzumab plus rituximab in recurring low-grade NHL. Blood 102: 69a, 2003 (abstr 233) 26. Johnson PW, Rohatiner AZ, Whelan JS, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13: 140-147, 1995 27. Foran JM, Gupta RK, Cunningham D, et al: A UK multicenter phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 109: 81-88, 2000[CrossRef][Medline] 28. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20: 2453-2463, 2002 29. Genentech: Rituxan (Rituximab) full prescribing information. http://www.gene.com/gene/products/information/oncology/rituxan/insert.jsp 30. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18: 3135-3143, 2000 31. Micallef IN, Kahl BS, Gayko U, et al: Initial results of a pilot study of epratuzumab and rituximab in combination with CHOP chemotherapy (ER-CHOP) in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). J Clin Oncol 23: 577s, 2004 (abstr 6580) 32. Friedberg JW, Leonard JP, Younes A, et al: Updated results from a phase II study of galiximab (anti-CD80) in combination with rituximab for relapsed or refractory, follicular NHL. Blood 106: 685a, 2005 (abstr 2435) Submitted January 7, 2006; accepted June 19, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody rituximab: Early stopping after the first interim analysis. J Clin Oncol 23: 558s, 2004 (abstr 6500)
