Antibody-Based Immunotherapeutic Agents for Treatment of Non-Hodgkin Lymphoma

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1 Antibody-Based Immunotherapeutic Agents for Treatment of Non-Hodgkin Lymphoma Steven I. Park, MD, 1* and Kristy L. Richards, PhD, MD 1 ABSTRACT Antibody-based immunotherapeutic agents have emerged as important treatment options for non-hodgkin lymphoma. Recent data suggest that use of these agents not only induces high response rates but also results in improved survival when combined with conventional chemotherapy in patients with non-hodgkin lymphoma. As a result, antibody-based immunotherapy has changed lymphoma therapy considerably and dramatically impacted the management of patients with non-hodgkin lymphoma. Several unmodified and radiolabeled antibodies, as well as antibody-drug conjugates, have been approved by the United States Food and Drug Administration (FDA) for treatment of non-hodgkin lymphoma. Also, more promising antibodies that target other epitopes are being developed in preclinical and clinical studies. This review presents the latest information on antibody-based immunotherapeutic agents for treatment of non-hodgkin lymphoma in various clinical settings and discusses current clinical and laboratory guidelines for the use of antibodies for treatment of different subtypes of non-hodgkin lymphoma. Keywords: hematology, blood banking, transfusion medicine, immunology Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy and the sixth most common cancer in the United States, with more than 65,000 new cases diagnosed annually. 1 Comprised of a heterogeneous group of malignant neoplasm, NHL DOI: /LMWAT6W5LT3TIPVX Abbreviations IPIT, individualized therapy; NHL, non-hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; CLL, chronic lymphocytic leukemia; SLL, small lymphocytic leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MoAbs, monoclonal antibodies; ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; FDA, United States Food and Drug Administration; RIT, radioimmunotherapy; IL-2, interleukin 2; OR, overall response; TTP, time to progression; CVP, cyclophosphamide, vincristine, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab plus CHOP; NCCN, National Comprehensive Cancer Network; CR, complete response; ECOG, Eastern Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; CNS, central nervous system; FR, rituxamine plus fludarabine; FCR, fludarabine plus cyclophosphamide; FC, fludarabine and cyclophosphamide; FCR, fludarabine plus cyclophosphamide plus rituximab; CMV, cytomegalovirus; PCR, polymerase chain reaction; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; tmds/ taml, treatment-related MDS/AML; HL, Hodgkin lymphoma; ALCL, anaplastic large cell lymphoma; NIH, National Institutes of Health; UNC, University of North Carolina; MCP, mitoxantrone, chlorambucil, and prednisolone; NA, not available; NR, not reached; ProMACE, prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide 1 Division of Hematology and Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill *To whom correspondence should be addressed. sipark@med.unc.edu originates from B- or T-lymphocytes and is clinically categorized as indolent or aggressive based on its morphologic characteristics and natural history. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and follicular lymphoma (FL) is the most common indolent lymphoma; they comprise approximately 30% and 20%, respectively, of all NHL cases. 2 Chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) are also types of indolent NHL, although they are usually treated as separate disease entities. CLL is the most common leukemia in the Western world, accounting for 40% of all leukemias in individuals older than 65 years. 3 Until recently, the treatment of NHL was limited mainly to the use of radiotherapy and conventional cytotoxic drugs. The most common first-line cytotoxic regimen for many subtypes of NHL, including DLBCL and FL, involved cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP). Numerous attempts during the past 2 decades to improve treatment outcomes using more aggressive chemotherapeutic regimens have achieved only minimal improvement in the survival of patients with NHL. 4 Since the introduction of antibody-based immunotherapy, however, survival rates for aggressive and indolent NHL have significantly improved. 5,6 Monoclonal antibodies (MoAbs) target specific antigens expressed on tumor cells, selectively attacking the targeted tumor cells without damaging most healthy cells. Antibody-based immunotherapy Downloaded from Lab Medicine Spring 2013 Volume 44, Number 2

2 Figure 1 Schematic representation of various antibody-based immunotherapeutic methods and their corresponding drugs, which have been approved by the United States Food and Drug Administration (FDA). Unmodified antibodies mediate cell death through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. Antibody-drug conjugate binds to the targeted antigen on the surface of tumor cells and allows internalization of drug inside the cell. Use of a radiolabeled antibody results in targeted delivery of radiation specifically at the tumor site. Antibody-Drug Conjugate Brentuximab vedotin Unmodified Antibody Rituximab Alemtuxumab Ofatumumab Lymphoma Cell Radiolabeled Antibody 131 I-tositumomab 90 Y-ibritumomab tiuxetan may use unmodified antibodies, radiolabeled antibodies, or antibodies conjugated to certain drugs (Figure 1). Unmodified antibodies by themselves can induce cytotoxicity in tumor cells. Although the exact mechanism of action is not known, it is thought that antibodies induce cell death through several different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis. Rituximab (Rituxan, Genentech Inc, South San Francisco, CA), alemtuzumab (Campath, Genzyme Corporation, Cambridge, MA), and ofatumumab (Arzerra, GlaxoSmithKline plc, Philadelphia, PA) are unmodified antibodies currently approved by the US Food and Drug Administration (FDA) for treatment of NHL. Rituximab is the only MoAb approved for use in combination with conventional chemotherapeutic drugs and is the second most commonly used oncology drug in the United States, with $5 billion in annual sales. Radioimmunotherapy (RIT) refers to the use of radiolabeled MoAbs directed against tumor-specific antigens for treatment of cancer. Radiolabeled antibodies carry therapeutic radionuclides directly to tumor cells while sparing most of the surrounding healthy tissues, resulting in targeted delivery of radiation at the tumor site. Radionuclides used in RIT generate beta emissions that penetrate approximately 1 to 5 mm (ie, 100 to 500 celldiameters) and result in killing not only the cell directly bound by the radiolabeled antibody but also the neighboring cells through cross fire effects. 7 The 2 radioimmunoconjugates currently approved by the FDA are 90 Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals, Inc, Henderson, NV) and 131 I-tositumomab (Bexxar, GlaxoSmithKline plc). Antibody-drug conjugates binding to the targeted antigen on the surface of tumor cells results in rapid internalization, release of drug from the antibody conjugate and, ultimately, cell death. Brentuximab vedotin (Adcetris, Seattle Genetics Inc, Bothell, WA) is currently the only antibody-drug conjugate approved by the FDA for treatment of lymphoma. The genetically engineered recombinant fusion protein denileukin difitox (Ontak, Eisai Co Ltd, Tokyo, Japan), an immunotoxin composed of interleukin 2 (IL-2) and diphtheria toxin fragment, recently received FDA approval for treatment of refractory or relapsed cutaneous T-cell lymphoma expressing the CD25 component of the IL-2 receptor. This agent works in a way similar to antibody-drug conjugates by delivering a toxin specifically to the targeted cell; however, because it is not a true antibody-drug conjugate, it will not be discussed further in this review. Immunotherapy With Unmodified Antibodies Rituximab for Treatment of Follicular Lymphoma Rituximab, a chimeric anti-cd20 MoAb, was the first drug in this class to be approved by the FDA (in 1997) with the initial indication limited to relapsed or refractory indolent lymphoma. In clinical trials rituximab was administered as a single agent at a dose of 375 mg per m 2 per week for 4 to 8 doses. Overall response (OR) rates ranged from 40% to 60% in these trials with a median time to progression (TTP) ranging from 10 to 13 months; higher response rates were reported in patients with FL compared with SLL. 8,9 Rituximab was also evaluated as a first-line therapy in patients with FL, with Downloaded from Spring 2013 Volume 44, Number 2 Lab Medicine 109

3 Table 1. Response and Survival Rates for Chemotherapeutic Regimens That Include Rituximab Versus Chemotherapeutic Agents Only in Patients With Indolent Non-Hodgkin Lymphoma a Treatment No. of Patients Overall Response Progression-Free Survival Overall Survival Rate R-MCP vs MCP % vs 75% NR vs 28.8 mo 87% vs 74% (4 y) R-CHOP vs CHOP % vs 90% NA NR R-CVP vs CVP % vs 57% NA NA R, rituximab; CVP, cyclophosphamide, vincristine, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MCP, mitoxantrone, chlorambucil, and prednisolone; NA, not available, NR, not reached. a Based on the results of randomized trials. a response rate of 47% at 6 weeks, increasing to 63% with repeated courses. 10 This rate further increased to 73% in a separate study in patients with FL with low tumor burden and favorable prognostic factors. 11 Several randomized trials used rituximab in conjunction with various chemotherapeutic agents, including cyclophosphamide, vincristine, and prednisone (CVP), CHOP, and mitoxantrone, chlorambucil, and prednisone (MCP) in patients with previously untreated FL (Table 1) All of these studies reported excellent response rates, with OR rates ranging from 85% to 96%. Moreover, the overall survival (OS) and progression-free survival (PFS) rates were significantly higher for patients who received the rituximab combinations compared with patients who received only chemotherapeutic agents. Rituximab did not add significant toxicity to chemotherapeutic regimens in these trials. Rituximab has also been tested as a component of maintenance therapy. In a phase III randomized trial, patients with relapsed or refractory FL who received maintenance rituximab therapy (375 mg/ m2 once every 3 months) for a maximum of 2 years after chemotherapy with a combination of rituximab plus CHOP (R-CHOP) had superior median PFS (51.9 months) compared with the observation (ie, nomaintenance) group (23.1 months). 15 A recent randomized multicenter study evaluated the role of maintenance rituximab in patients with previously untreated FL. 16 In this study of 1018 patients who received first-line chemotherapeutic treatment, PFS rates were 74.9% and 57.6% in the rituximab maintenance group and the observation group, respectively, with a median follow-up of 36 months. However, no significant difference in overall survival was observed between groups. The National Comprehensive Cancer Network (NCCN) currently recommends the use of rituximab as a single agent, in combination with chemotherapeutic agents, or in the maintenance of patients with previously untreated or relapsed FL. Rituximab for Treatment of Diffuse Large B-cell Lymphoma Clinical trials have evaluated R-CHOP in previously untreated stage I to IV aggressive NHL and reported excellent response rates, with OR and complete response (CR) rates greater than 90% and 60%, respectively. 17 Chemoimmunotherapeutic regimens that include R-CHOP have been effective in treating elderly patients with DLBCL. 18 When patients aged 60 to 80 years with previously untreated stage II to IV DLBCL received 8 cycles of R-CHOP, the OR rate was 82%, with a CR rate of 52%. 18 At a median of 5 years of follow-up, the addition of rituximab to the CHOP regimen was associated with a significant improvement in OS (58% vs 45%) and event-free survival (47% vs 29%). 19 Another large phase III trial of R-CHOP versus CHOP in stage I to IV DLBCL, conducted by the Eastern Cooperative Oncology Group (ECOG) and Cancer and Leukemia Group B (CALGB) in patients 60 years of age or older, reported a 3-year failure-free survival rate of 52% in the R-CHOP arm vs 39% in the CHOP arm. Further, the addition of rituximab to the CHOP regimen has been associated with a reduced risk of DLBCL recurrence in the central nervous system (CNS). In a randomized trial of R-CHOP vs CHOP, the estimated 2-year incidence of CNS recurrence of disease was 4.1% with R-CHOP, compared with 6.9% with CHOP only. 20 Rituximab is now indicated for the treatment of previously untreated and relapsed or refractory DLBCL in conjunction with CHOP or other chemotherapeutic regimens. Rituximab for Treatment of Chronic Lymphocytic Leukemia Rituximab has shown encouraging results in the treatment of CLL, although it has limited efficacy as Downloaded from Lab Medicine Spring 2013 Volume 44, Number 2

4 a single agent, with response rates of approximately 20% in patients with relapsed CLL. 9 Consequently, many investigators are exploring methods for enhancing the efficacy of rituximab in CLL, including combining it with chemotherapeutic regimens. Several large phase II studies of rituximab plus fludarabine (FR) 21 or fludarabine plus cyclophosphamide plus rituximab (FCR), 22,23 have demonstrated a much higher CR rate than previously observed with any other therapeutic approaches used in CLL. Also, FR, compared with fludarabine only, yields a longer time to progression and improved survival. 24 Robak et al 25 compared the efficacy of FCR with that of FC in patients with previously untreated CLL. In this randomized trial of 552 enrolled patients, the median PFS was 30.6 months for patients in the FCR group, compared with 20.6 months for patients treated with FC, with a median follow-up of 25 months. OR and CR rates were also significantly higher with the addition of rituximab. The NCCN currently recommends the use of rituximab as a single agent or in combination with chemotherapeutic regimens, such as FC, in patients with newly diagnosed, relapsed, or refractory CLL. Alemtuzumab for Treatment of Chronic Lymphocytic Leukemia Alemtuzumab is a recombinant humanized antibody that targets the cell-surface CD52 antigen, which is highly expressed in lymphoma cells. Similar to rituximab, alemtuzumab induces ADCC, CDC, and apoptosis when it binds CD52 antigen-expressing cells Alemtuzumab initially received accelerated FDA approval for the treatment of fludarabinerefractory CLL. In a phase II trial of CLL patients who failed to respond to fludarabine-based therapies, alemtuzumab resulted in an OR rate of 33%. 29 The median OS was 16 months for all patients and 32 months for responders. Response rates were even higher when alemtuzumab was given in first-line therapy for CLL. A phase III study evaluated the efficacy and safety of alemtuzumab in patients with previously untreated CLL. In this randomized trial of 297 patients, alemtuzumab was associated with significantly higher response rates than chemotherapeutic treatments using chlorambucil (OR rate, 83% vs 55%, respectively; CR rate, 24% vs 2%, respectively). Median PFS was significantly longer in the alemtuzumab group (14.6 vs 11.7 months). 30 Alemtuzumab showed superior response rates compared with chlorambucil in patients with deletion of chromosome 17p, which is associated with chemotherapy-refractory disease and poor clinical outcomes (OR rate, 64% vs 20%, respectively). Based on these data, alemtuzumab received full approval by the FDA and its indication was expanded to include the treatment of CLL. Alemtuzumab has been associated with opportunistic infections, such as cytomegalovirus (CMV) reactivation, because of prolonged B and T cell lymphopenia and impaired monocyte function. Surveillance using polymerase chain reaction (PCR) based CMV monitoring is recommended for patients treated with alemtuzumab. Ofatumumab for Treatment of Chronic Lymphocytic Leukemia Ofatumumab is a second generation MoAb that targets a novel epitope of the CD20 molecule on lymphoma cells. Once bound, ofatumumab releases from its target more slowly compared with rituximab; the results of preclinical studies 31,32 have shown that ofatumumab is more effective than rituximab in promoting CDC in malignant B cells. Because ofatumumab is a fully humanized MoAb, it has a theoretical advantage over rituximab by its lesser immunogenicity. 33 Ofatumumab has been approved by the FDA as a single agent for the treatment of patients with CLL that is refactory to fludarabine and alemtuzumab, based on durable objective responses reported in a pivotal phase II study. 34 This study evaluated 8 weekly infusions of ofatumumab followed by 4 monthly infusions in CLL patients who were previously treated with multiple chemotherapeutic agents. In this trial of 138 patients, ofatumumab resulted in OR rates of 58% in patients with CLL that was refractory to fludarabine and alemtuzumab. Ofatumumab was associated with an OR rate of 48% in patients with bulky (ie, >5 cm) lymphadenopathy, the conditions of these patients were believed to be less suitable for therapeutic treatment with alemtuzumab. Ofatumumab was also shown to be effective in patients with CLL, regardless of previous treatment with rituximab. 35 The OR rate was 44% in patients whose condition was refractory to rituximab; therefore, ofatumumab is a treatment option for patients with rituximab-refractory disease. The most common adverse reactions associated with ofatumumab are infusion reactions, which occur more commonly on the day of the first infusion, and neutropenia. Ofatumumab is currently being evaluated in various clinical settings for other types of NHL, including DLBCL and FL. Downloaded from Spring 2013 Volume 44, Number 2 Lab Medicine 111

5 Immunotherapy with Radiolabeled Antibody and Antibody-Drug Conjugate Radioimmunotherapy for Treatment of Follicular Lymphoma 90 Y-ibritumomab tiuxetan and 131 I-tositumomab use antibodies that recognize the CD20 antigen. 90 Y-ibritumomab tiuxetan is conjugated with yttrium-90 via the chelator tiuxetan; 131 I-tositumomab is labeled with iodine-131. At present, these drugs are indicated for the treatment of relapsed, refractory indolent, or transformed NHL. The efficacy of RIT in patients with relapsed or refractory indolent NHL has been established in a series of clinical trials. In these studies, patients achieved excellent OR rates of 50% to 80%, with CR rates of 20% to 40% In a randomized study comparing the efficacy of 90 Y-ibritumomab tiuxetan with that of rituximab in patients with relapsed or refractory indolent NHL, response rates were significantly higher in the 90 Y-ibritumomab tiuxetan group, with OR and CR rates of 80% and 30%, respectively, compared with 56% and 16%, respectively, in the rituximab group. 40 The primary toxic condition associated with 90 Y-ibritumomab tiuxetan and 131 I-tositumomab is moderate, reversible myelosuppression. A retrospective study by Fisher et al 41 evaluated 250 patients with relapsed or refractory indolent NHL who received 1 course of 131 I-tositumomab in 5 clinical trials. OR rates in these trials ranged from 47% to 68%, with CR rates ranging from 20% to 38%. The 5-year PFS was 17%, with a median follow-up of 5.3 years. Eighty-one of 250 patients (32.4%) had a longterm durable response, with a PFS of greater than 1 year; the median duration of response for those patients was 45.8 months. A long-term follow-up study was conducted in 153 patients receiving 90 Y-ibritumomab tiuxetan for relapsed or refractory NHL in 4 clinical trials. 43 Fifty-nine (38.6%) of the 153 patients with FL had a long-term response, defined as a TTP of longer than 1 year, with a median TTP of 30.9 months. The results of both studies demonstrated that induction of a CR after RIT was the best predictor of a long-term response. An increased risk of radiation-induced secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concern with RIT. A retrospective study conducted by Bennett et al 44 evaluated the incidence of treatment-related MDS/AML (tmds/ taml) in 1071 patients who received 131 I-tositumomab for the treatment of NHL. After a median follow-up of 2 years from RIT, tmds/taml was reported in 35 (3.5%) of 995 patients with relapsed or refractory NHL; this group had previously received a median of 3 other types of therapy. Thirteen of 25 subjects were confirmed to have developed tmds/taml after taking 131 I-tositumomab. The annualized incidence rate of confirmed tmds/taml was 1.1%, which was no higher than that expected based on the patients having previously undergone chemotherapeutic treatment. Czuczman et al 45 evaluated 746 patients with NHL who received a median of 3 types of therapy before taking 90 Y-ibritumomab tiuxetan. Seventeen (2.3%) of 746 patients were found to have tmds/taml after a median follow-up of 4 years following cessation of RIT, with an annualized incidence rate of 0.7%. The study revealed that previous treatment with a fludarabinecontaining regimen was a significant risk factor for tmds/taml; however, RIT was not associated with significant risk. The low incidences of tmds/taml reported in these studies are encouraging, although the true long-term risk of RIT will remain uncertain until data from longer follow-up studies become available. The role of RIT in clinical settings other than relapsed or refractory indolent NHL is currently undefined. However, recent data 46,47 have demonstrated benefits of RIT as a single agent or in consolidation therapy for patients with previously untreated indolent NHL. Further studies are needed to establish the optimal sequence of treatment with RIT for indolent NHL. Lastly, preliminary reports have shown encouraging results in the use of RIT for treatment of other lymphomas, including DLBCL, but its use remains investigational at this time. Brentuximab Vedotin for Treatment of Anaplastic Large-Cell Lymphoma Brentuximab vedotin is a MoAb-drug conjugate that targets the CD30 antigen expressed on the surface of activated T cells and certain other hematopoietic cells. It is comprised of monomethyl auristatin E, a potent antimicrotubule cytotoxin released from the conjugate after the bound antibody is internalized by the cell. A phase-1 dose escalation study evaluated the safety of brentuximab vedotin in patients with CD30-positive hematologic malignancies, including Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). 48 A total of 45 patients (42 with HL, 2 with systemic ALCL, and 1 with angioimmunoblastic T-cell lymphoma) were treated with brentuximab Downloaded from Lab Medicine Spring 2013 Volume 44, Number 2

6 vedotin doses of 0.1 to 3.6 mg per Kg administered intravenously once every 3 weeks. The most common adverse events were fatigue, pyrexia, diarrhea, nausea, peripheral neuropathy, and neutropenia. Peripheral neuropathy and neutropenia were reported to be doserelated. The maximally tolerated dose of brentuximab vedotin was 1.8 mg per Kg administered once every 3 weeks. Objective evidence of response based on investigator-assessed restaging in this study led to the initiation of a phase II study 49 in which patients were treated with brentuximab vedotin at a dosage of 1.8 mg per Kg every 3 weeks. A multicenter phase II study of 58 patients reported an OR rate of 86% and a CR rate of 53% in patients with highly chemorefractory, systemic ALCL. 49 Data from this trial led to the recent accelerated approval of brentuximab vedotin by the FDA for the treatment of relapsed or refractory systemic ALCL after failure of at least 1 previous multiagent chemotherapeutic regimen. Brentuximab vedotin is currently indicated for treatment of HL in patients whose disease has progressed after autologous stem-cell transplant and in those ineligible for transplant whose disease has failed to respond to at least 2 multiagent chemotherapeutic regimens. Novel Antibody-Based Immunotherapeutic Drugs for Treatment of Non-Hodgkin Lymphoma Despite advances in antibody-based immunotherapy, the disease of some patients does not respond to currently available treatments; a significant number of patients eventually become resistant to repeated treatments using the same antibody. 9,50 Therefore, novel antibodies are being developed to further improve clinical outcomes in patients with NHL. Many of these antibodies target the CD20 antigen, including veltuzumab, ocrelizumab, obinutuzumab, and others Some of these nextgeneration anti-cd20 antibodies have been designed to enhance ADCC, CDC, and apoptosis to achieve superior therapeutic efficacy compared with rituximab. Novel antibodies directed against other surface antigens have been developed. Epratuzumab is a humanized anti-cd22 antibody that has shown significant therapeutic effect in NHL. 54 Inotuzumab ozogamicin, an antibodydrug conjugate of a humanized anti-cd22 antibody conjugated to calicheamicin, effective against CD22- positive B-cell NHL. 55 The chimeric anti-cd23 antibody lumiliximab, when combined with FCR, showed favorable response rates and toxicity profiles. 56 Zanolimumab, a humanized anti-cd4 antibody, inhibits T-cell activation and induces the killing of CD4-expressing T cells via ADCC. The safety and efficacy of zanolimumab have been reported 57,58 in relapsed or refractory cutaneous T-cell lymphoma and peripheral T-cell lymphoma. Lastly, blinatumomab, a single-chain bispecific antibody construct, represents a new class of antibody-based immunotherapy. Blinatumomab has specificity for CD19 and CD3 antigens and engages CD3-expressing cytotoxic T lymphocytes for the killing of CD19- expressing tumor cells. 59 On binding of the antibody, cytotoxic T lymphocytes are activated and induce lysis of tumor cells. Blinatumomab has shown therapeutic potential for treatment of NHL and other hematologic malignancies, including acute lymphoblastic leukemia. 60,61 Conclusion The antibody-based immunotherapies developed for the treatment of NHL have targeted surface antigens such as CD20, CD30, and CD52. Several mechanisms have been proposed to mediate the eradication of tumor cells targeted by unmodified antibodies; the efficacy of antibody-based immunotherapeutic agents has been enhanced by conjugation of the antibody with various radionuclides and toxins. The results of clinical trials have demonstrated that therapeutic benefits are conveyed by antibody-based immunotherapeutic agents, singly or in combination with chemotherapeutic agents in patients with previously untreated, relapsed or refractory NHL. Because antibody-based immunotherapeutic agents have been shown to be relatively safe and well-tolerated compared with conventional chemotherapeutic agents, their use has changed the standard of care for patients with NHL. Advancements in novel antibody-based immunotherapeutic agents will continue to offer more effective treatment options, improving survival rates among patients with NHL. LM Acknowledgments This research was supported by grant 8KL2TR by the National Institutes of Health (NIH) University of North Carolina (UNC) KL-2 grant and financial gifts from Unifi, Inc. and the Golfers Against Cancer foundation. References Available in the full-length version of this article, which can be accessed at content/44/2.toc Downloaded from Spring 2013 Volume 44, Number 2 Lab Medicine 113