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clinical therapeutics

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,

if they exist, are presented. The article ends with the author’s clinical recommendations.

Anti-CD20 Antibody Therapy

for B-Cell Lymphomas

David G. Maloney, M.D., Ph.D.

From the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle. Address reprint requests to Dr. Maloney at the Clinical Research Divi-sion, Transplantation Biology Program, Fred Hutchinson Cancer Research Cen-ter, 1100 Fairview Ave. N., D1-100, Seattle, WA 98104-1029, or at dmaloney@fhcrc.org. N Engl J Med 2012;366:2008-16.

Copyright © 2012 Massachusetts Medical Society.

A 62-year-old man is evaluated for abdominal pain. Computed tomography (CT) shows a 7-cm mesenteric mass. An incisional biopsy reveals a diffuse large B-cell lymphoma, and immunohistochemical staining is positive for the B-cell antigen CD20. The patient is referred to an oncologist. A positron-emission tomographic–CT (PET-CT) scan reveals involvement of additional nodes in the lower chest and abdo-men. The serum level of lactate dehydrogenase is twice the upper limit of the normal range. The results of bone marrow biopsy and aspiration are normal on pathological analysis and flow cytometry. The patient reports an unintentional weight loss of 1112 kg (25 lb) during the previous 6 months but no unexplained fevers or night sweats. He has no history of cardiac disease, and an echocardiogram shows a normal left ventricular ejection fraction. The oncologist recommends treatment with the anti-CD20 monoclonal antibody rituximab in combination with a chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

The Clinical Problem

More than 25 histologic subtypes of B-cell lymphoma, with a wide range of bio-logic and clinical features, are recognized in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues.1,2 The

Ameri-can Cancer Society estimates that in 2012, a total of 70,130 new cases of B-cell lymphoma will be diagnosed in the United States, and 18,940 patients will die from the disease.3 B-cell lymphomas account for 4% of all cancers and 3% of

cancer-related deaths among adults in the United States.

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin’s lymphoma (accounting for approximately 30% of cases) in Europe and North America. It is considered to be an aggressive cancer that requires immediate treat-ment. The goal of therapy is induction of a complete remission and cure.

Follicular lymphoma is the second most common histologic form of non-Hodgkin’s lymphoma (accounting for approximately 25 to 30% of cases). Follicular lymphoma is often clinically indolent initially but with a tendency for relapse to occur after standard treatments. The goals of therapy are to prolong progression-free survival and to improve quality of life and overall survival.

Pathophysiology and Effect of Ther apy

All lymphocytes are derived from a common progenitor cell that originates in the bone marrow. The process of lymphoid differentiation includes a series of DNA

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recombination steps to create the extensive rep-ertoire of immunoglobulins (for B cells) or T-cell receptors (for T cells). Lymphoid cancers develop as a result of the acquisition of genetic abnor-malities during differentiation.4 Most B-cell

lym-phomas are clonal descendants of distinct popu-lations of B-cell precursors.

The process of lymphoid differentiation has traditionally been characterized on histologic analysis by the identification of cell-surface markers that are expressed at specific stages in lymphoid-cell development. CD20 is a B-cell– specific differentiation antigen that is expressed on mature B cells and in most B-cell non-Hodg-kin’s lymphomas but not on early B-cell pro-genitors or later mature plasma cells.5 The

hu-man protein has multiple membrane-spanning domains; there is no known ligand. CD20 is part of a multimeric cell-surface complex that regu-lates calcium transport and is involved in the regulation of B-cell activation and prolifera-tion.6,7 However, studies involving disruption of

the gene encoding CD20 in mice do not demon-strate a critical function for this molecule in B-cell development or the generation of immune responses.6,8

Rituximab is a chimeric monoclonal antibody (incorporating human immunoglobulin G1 heavy-chain sequences and murine immuno-globulin variable regions) that recognizes the human CD20 antigen.9 It was the first antibody

approved by the Food and Drug Administration for use in the treatment of lymphoma. The rec-ognition that rituximab could have a substantial therapeutic effectin cases of relapsed, indolent non-Hodgkin’s lymphoma ushered in the era of monoclonal antibody therapy for cancer.10

Anti-CD20 antibodies cause the death of tu-mor cells through several mechanisms. Howev-er, the exact contribution of each mechanism to the observed clinical activity of these antibodies remains controversial7 (Fig. 1). Binding of

anti-body to CD20 may activate the complement cascade through C1q, leading to cell death or deposition of complement proteins on the cell membrane, a phenomenon known as comple-ment-dependent cytotoxicity. Antibody-coated cells may be killed by immune cells expressing Fcγ receptors through antibody-dependent cell-mediated cytotoxicity. Finally, antibody binding to CD20 may have direct antiproliferative effects or may actively induce cell death (apoptosis).

These effects appear to be additive and possibly synergistic when anti-CD20 antibody therapy is combined with chemotherapy.

All clinically active anti-CD20 antibodies bind to a small loop of the CD20 molecule containing approximately 40 amino acids expressed on the cell surface (Fig. 1). In vitro, these antibodies can be separated into two types on the basis of cellular effects observed on binding to CD20-expressing cells. Type I antibodies (rituximab and ofatumumab11) induce redistribution of

CD20 into large lipid rafts in the plasma mem-brane and have strong complement-dependent cytotoxicity and antibody-dependent cell-mediat-ed cytotoxicity but have minimal direct antitu-mor effects. Ofatumumab, a human antibody, may bind to a small region of CD20 that is closer to the cell membrane than the region that rituximab binds to, explaining the increased ability of ofatumumab to bind C1q and mediate complement-dependent lysis.7 Type II antibodies

(tositumomab12 and obinutuzumab13) do not

induce redistribution of cell-surface CD20 and have minimal complement-dependent cytotoxic-ity, strong antibody-dependent cell-mediated cy-totoxicity, and increased direct antitumor ef-fects. To date, none of the newer anti-CD20 antibodies have been shown to be clinically more effective than rituximab in a direct com-parison.

Clinical Ev idence

Rituximab has been investigated in both aggres-sive and indolent cases of non-Hodgkin’s lympho-mas, as either a single agent or in combination with standard chemotherapy regimens for lym-phoma, such as CHOP (immunochemotherapy). On the basis of preliminary studies,14-16 only

combi-nation regimens were selected for evaluation in advanced-phase trials involving patients with ag-gressive lymphomas, whereas both single-agent and combination regimens have been evaluated in patients with indolent forms of disease.

Several trials have evaluated the effect of adding rituximab to chemotherapy in aggressive forms of non-Hodgkin’s lymphoma, such as diffuse large B-cell lymphoma.15,17-21 The benefit of this

ap-proach is illustrated by the MabThera Interna-tional Trial,19 in which 824 patients with diffuse

large B-cell lymphoma were randomly assigned to receive either CHOP-like chemotherapy alone or

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CHOP-like chemotherapy plus rituximab. Radio-therapy was administered to sites of bulky disease and elsewhere at the physician’s discretion, and growth factors were administered for neutropenia. The 3-year rate of progression-free survival was 68% with chemotherapy alone versus 85% with the addition of rituximab. Overall survival rates at 3 years were 84% and 93%, respectively.

In indolent non-Hodgkin’s lymphoma (e.g., follicular lymphoma), both single-agent and combination rituximab regimens have been in-vestigated.14,16,22-25 The efficacy of single-agent

therapy was shown in a nonrandomized study involving 166 patients with low-grade or follicu-lar lymphomas.14 The initial overall response

rate (rate of complete or partial response) was

Figure 1. Mechanisms of Action of Anti-CD20 Antibodies.

Anti-CD20 antibodies bind to the CD20 molecule on the surface of the malignant B cell in non-Hodgkin’s lymphoma (NHL), leading to cell death. Three mechanisms of action of anti-CD20 antibodies have been proposed. In complement- dependent cytotoxicity, the first component of complement (C1) binds to the Fc portion of the anti-CD20 molecule, resulting in the activation of the complement cascade and cell lysis through the formation of membrane attack com-plexes (MAC). In antibody-dependent cell-mediated cytotoxicity (ADCC), effector cells, such as natural killer cells or macrophages, bind to the Fc portion of the anti-CD20 molecule through Fcγ receptors; the effector cells then re-lease effector molecules such as perforin, which cause cell lysis. In direct cytotoxicity, the anti-CD20 antibody induc-es internal signaling within the tumor cell, causing antiproliferative effects or cell death, which may involve apopto-sis or other cell-death pathways. In the top inset, anti-CD20 antibodies bind to an extracellular portion of the CD20 molecule. Most anti-CD20 antibodies, including rituximab, tositumomab, and obinutuzumab, bind to the larger of two extracellular loops within the CD20 molecule; this loop includes the alanine-N-proline (ANP) residues at positions 170 to 172. Ofatumu mab binds to two sites on the CD20 molecule: the smaller extracellular loop and positions 159 to 166 on the larger loop. This unique binding pattern of ofatumumab, which results in increased proximity of the anti-body to the cell membrane, may account for the greater potency of the drug in inducing complement-mediated lysis. In the lower inset, the structure of chimeric and human antibodies is shown.

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48%, which is similar to that for single-agent cytotoxic chemotherapy.

In one of the larger trials of rituximab com-bined with chemotherapy for indolent lymphoma, 428 patients with previously untreated, advanced-stage follicular lymphoma were randomly assigned to receive either CHOP or CHOP plus rituximab (R-CHOP).23 The rates of overall response were

90% with CHOP and 96% with R-CHOP. The estimated survival rates at 2 years were 90% and 95%, respectively.

Clinical Use

The most important procedure in confirming the diagnosis of non-Hodgkin’s lymphoma is a tissue biopsy, with the sample submitted for analysis by a hematopathologist, including immunohisto-chemical analysis and often flow cytometry and molecular studies. In general, samples obtained by means of fine-needle aspiration are insuffi-cient. After the diagnosis has been confirmed, a thorough staging of the disease is required, in-cluding physical examination, assessment of per-formance status, radiography (including CT and PET scanning), bone marrow biopsy, and labora-tory studies to determine the lactate dehydroge-nase level as well as renal, hepatic, and marrow function. Patients should be screened for hepati-tis B, and those with evidence of previous expo-sure need to be monitored closely (with serial measurements of liver enzyme levels and viral load) and treated with antiviral medications if they have reactivation of the virus. For patients over the age of 60 years and those with a history of cardiac disease, cardiac function should be evaluated by means of echocardiography or ra-dionuclide ventriculography. Those with signifi-cantly impaired cardiac function (ejection frac-tion, <45%) should be treated with alternative regimens that do not include bolus anthracy-clines.

For patients with aggressive non-Hodgkin’s lymphoma, the use of the international prognostic index (IPI) provides valuable information on the likelihood of survival with the use of conventional chemotherapy.26 This index has been shown to

maintain its prognostic usefulness in the ritux-imab era.27 In patients with localized aggressive

non-Hodgkin’s lymphoma (stage I or II), three cy-cles of R-CHOP followed by involved-field irradia-tion or six to eight cycles of R-CHOP alone may

be used.28 A regimen of six to eight cycles of

R-CHOP is considered the current standard of care for patients with advanced disease (stage III or IV). R-CHOP is usually administered every 21 days, and rituximab is typically given on the first day of each cycle (Table 1).

Rituximab is administered at a dose of 375 mg per square meter of body-surface area by intra-venous infusion after premedication with acet-aminophen and diphenhydramine. Because of the risk of infusion-related symptoms, the first dose is typically administered slowly, at an ini-tial infusion rate of 50 mg per hour, with incre-mental increases every 30 minutes thereafter. In subsequent cycles, rituximab can usually be ad-ministered faster with minimal symptoms, and premedication may not be necessary.

The goal of therapy is a complete remission, and it is critical to try to deliver all agents on schedule and at full doses. Growth-factor sup-port is used for patients with neutropenic fever or a delay in the recovery of white cellsbetween cycles and is recommended for patients over 65 years of age in order to prevent febrile neu-tropenia and infection.29 Patients who are

treat-ed with chemoimmunotherapy are at increastreat-ed risk for infection and need to be monitored and treated as necessary.

At 6 to 8 weeks after completion of therapy, PET scanning of all areas of previous disease is performed to confirm complete remission. Pa-tients with a confirmed, PET-negative remission after a full course of therapy are monitored for evidence of relapse by means of physical exami-nation, laboratory studies, and periodic imaging studies. Patients with aggressive non-Hodgkin’s lymphoma do not appear to benefit from main-tenance rituximab therapy after R-CHOP induc-tion therapy.30,31 Relapse is most common in the

first 3 years, but late relapses may occur.

Table 1. A Typical Regimen of Rituximab with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP).

Drug Dose

Rituximab Intravenous infusion (375 mg/m2 of body- surface area) on day 1

Cyclophosphamide Intravenous bolus (750 mg/m2) on day 1 Doxorubicin Intravenous bolus (50 mg/m2) on day 1 Vincristine Intravenous bolus (1.4 mg/m2) on day 1 Prednisone Oral administration (100 mg) on days 1 to 5

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Patients who do not have a complete remis-sion and those who have a relapse should be considered for salvage therapy. Patients who have a response to salvage therapy should then be considered for high-dose therapy with hema-tologic stem-cell support. Appropriate candidates for transplantation are generally patients with-out prohibitive coexisting illnesses who are un-der the age of 75 years. In most patients, rituximab has been added to salvage regimens, although there is no proof that it provides an additional benefit.

Patients with indolent, asymptomatic non-Hodgkin’s lymphoma may be monitored, with treatment administered at the time of disease progression or the development of symptoms. Antibody therapy has been used alone and in combination or in sequence with conventional chemotherapy. In a study involving patients with follicular lymphoma and a low tumor burden, treatment with a single course of rituximab alone led to a response rate of 73%, with a complete-response rate of 20%.32 Extending the treatment

course for 1 year led to a rate of event-free sur-vival of 45% at 8 years.33,34 For patients requiring

chemotherapy (typically, those with symptomat-ic or bulky disease), rituximab is combined with regimens such as CHOP, CVP (cyclophospha-mide, vincristine, and prednisone), FMC (fluda-rabine, mitoxantrone, and cyclophosphamide), or bendamustine.

In contrast to the treatment approach in pa-tients with aggressive non-Hodgkin’s lympho-ma, achievement of a complete response is not yet considered a mandatory goal of treatment in patients with indolent lymphoma, although those with a complete response to initial therapy have improved progression-free survival. Most patients with indolent non-Hodgkin’s lymphoma remain at risk for relapse after initial therapy. In one study, patients who received maintenance therapy with rituximab (one dose every 2 months for up to 2 years) had an improvement in pro-gression-free survival (74.9%, vs. 57.6% among patients who did not receive rituximab as main-tenance therapy), but at a median follow-up of 36 months, there was no significant difference in overall survival between the two groups.25

Maintenance therapy is associated with increased risks of neutropenia and infection requiring treatment.

Patients who do not have a response to anti-body therapy or who have a relapse or disease progression within 6 months after the discon-tinuation of treatment are said to have rituximab resistance. Currently, the molecular mechanism of this resistance is unclear. Among patients who have a relapse, immunochemotherapy is frequently administered again, with or without subsequent maintenance rituximab therapy.35,36

In patients with indolent non-Hodgkin’s lym-phoma, there have been studies of radiolabeled anti-CD20 antibodies, including ibritumomab tiuxetan (an yttrium-90–conjugated monoclonal antibody)37 and tositumomab (an iodine-131–

conjugated antibody).38 The use of radiolabeled

anti-CD20 antibodies is associated with substan-tial delayed hematologic toxicity related to non-specific targeting of the bone marrow. Because of such side effects, these antibodies should be used as single agents or in sequence with con-ventional chemotherapy.37,38 Despite high

re-sponse rates with these agents, concern about the risks of late myelodysplasia and acute my-elogenous leukemia, as well as the cumbersome logistics of coordinating with nuclear medicine for administration, have limited their wide-spread use.

A study of treatment costs that was based on 2003 data showed that the cost of rituximab therapy was $2,871 per infusion in the United States.39 Similar studies have shown cost

esti-mates of £1,170 (about $2,150 in 2004 dollars) per infusion in the United Kingdom40 and €2,088

(about $2,700 in 2005 dollars) per infusion in the Netherlands.41

Adver se Effects

Most of the clinical experience with anti-CD20 antibodies has been with rituximab. The initial dose is associated with infusion-related symp-toms (e.g., urticaria, fever, and chills) in more than half of patients. Although these symptoms are usually modest, more serious reactions can occur, including hypotension, rigors, broncho-spasm, and angioedema, in as many as 10% of patients.42 Cardiac arrhythmias and acute

coro-nary syndromes have been reported with the first dose. Rituximab has also been associated with the development of acute interstitial lung dis-ease, which can be fatal.43 The infusion should

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be slowed or stopped if acute symptoms occur and then resumed when the symptoms abate. Subsequent infusions are usually associated with fewer symptoms and can generally be adminis-tered at a faster rate. In patients with clinically significant type 1 hypersensitivity reactions and a positive skin test for rituximab, a 12-step rapid desensitization protocol can be considered for subsequent infusions.44

Bowel perforations have been reported with rituximab treatment; this may be of particular concern in patients with lymphomatous involve-ment of the gastrointestinal tract.45

Mucocuta-neous reactions such as the Stevens–Johnson syndrome have been described.46

Rituximab causes expected B-cell depletion and some degree of immunodeficiency, and in-fectious complications are therefore not uncom-mon. In an analysis of pooled data from 356 patients, 30% of patients had infectious events: 19% with bacterial infections, 10% with viral infections, and 1% with fungal infections.47

Ful-minant hepatitis B reactivation has been ob-served after therapy; patients should be screened for hepatitis B, and carriers of the virus should be monitored closely.48 Progressive multifocal

leukoencephalopathy from the JC virus is a rare but devastating complication that has been ob-served in patients receiving rituximab, most of whom received rituximab in combination with chemotherapy or hematopoietic stem-cell trans-plantation.49

Delayed-onset neutropenia (typically occur-ring 3 to 4 weeks after treatment) has been re-ported in 3 to 27% of patients.50 Several analyses

have suggested an association with a genetic polymorphism that results in higher-affinity FcγRIIIa receptors.51,52 Delayed-onset

neutrope-nia usually resolves with the administration of growth factors.

Ar e as of Uncertaint y

For patients with aggressive non-Hodgkin’s lym-phoma, R-CHOP is currently the standard thera-py. However, it is not clear that the optimal che-motherapy regimen has yet been defined. Many of the initial trials used eight cycles of therapy on a 21-day cycle, whereas subsequent studies using R-CHOP on a 14-day cycle showed that a regimen of six cycles was sufficient.18,20 Other

combina-tion chemotherapy regimens are also under in-vestigation. For example, a regimen in which eto-poside is added to the R-CHOP regimen, with infusion of etoposide, vincristine, and doxorubi-cin during a 96-hour period rather than bolus administration (designated DA-EPOCH-R), is be-ing compared with R-CHOP in an ongobe-ing clini-cal trial.

Molecular profiling has shown that morpho-logically identical cases of diffuse large B-cell lymphoma actually comprise several disease subtypes with different clinical behavior on the basis of the cell of origin. The two main sub-types are germinal-center B-cell–like and acti-vated B-cell–like diffuse large B-cell lympho-mas.53 Clinically, patients with the activated

B-cell–like molecular profile have had inferior outcomes with most treatments, including R-CHOP and DA-EPOCH-R, although the addition of antibody therapy has improved the outcomes for both groups of patients.54,55 To date, no

ac-cepted standard treatment has proved to have greater efficacy on the basis of molecular sub-type or surrogate immunohistochemical markers. For patients with indolent non-Hodgkin’s lymphoma requiring therapy, the major areas of uncertainty include the choice of initial chemo-therapy to combine with rituximab, the role of radioimmunotherapy, and the role of mainte-nance therapy in inducing rituximab resistance. In patients with rituximab resistance, the role of additional therapy with anti-CD20 antibodies alone or in combination with chemotherapy is unknown.

For patients with indolent disease who have a low tumor burden, there is uncertainty about the role of observation as compared with initial thera-py. A recent randomized trial showed high rates of response to single-agent rituximab, with or without maintenance therapy, as compared with observation, and a prolonged interval before subsequent therapy was required.56 Longer

fol-low-up will be necessary to assess the response to subsequent therapy and overall survival.

Multiple next-generation anti-CD20 antibodies have been designed with augmented effector function, as described above. The clinical role of such antibodies remains undefined. Two of these antibodies (ofatumumab and obinutuzumab) are being evaluated in phase 3 trials in comparison with rituximab or rituximab-containing regimens

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in both patients with indolent and those with aggressive non-Hodgkin’s lymphoma.

Guidelines

For patients of all ages who have advanced-stage, aggressive diffuse large B-cell non-Hodgkin’s lymphoma, the National Comprehensive Cancer Network (NCCN) guidelines recommend treat-ment with R-CHOP every 21 days for six cycles.57

For patients with early-stage disease, the guide-lines recommend R-CHOP for three cycles with involved-field radiation or R-CHOP for six cycles. The European Society for Medical Oncology (ESMO) guidelines are slightly different.58 They

recommend chemotherapy with R-CHOP every 21 days for six to eight cycles for patients under the age of 60 years who have low age-adjusted IPI scores; for patients with higher-risk IPI scores, they recommend enrollment in clinical trials. For patients between the ages of 60 and 80 years, the ESMO guidelines recommend R-CHOP every 21 days for eight cycles or R-CHOP every 14 days for six cycles. There is no recommendation for consolidation with involved-field irradiation.

For patients with indolent non-Hodgkin’s lymphoma requiring therapy, the NCCN guide-lines recommend treatment with rituximab in combination with any one of various chemo-therapy regimens, including bendamustine, CVP, or CHOP, or radioimmunotherapy.57 Patients in

remission may be offered consolidation treat-ment with radioimmunotherapy or maintenance rituximab therapy. Elderly or infirm patients, in whom the above regimens may have unaccept-able adverse effects, single-agent rituximab ther-apy or radioimmunotherther-apy may be administered. The recommendations in the ESMO guidelines59

are generally similar.

R ecommendations

The patient described in the vignette is an appro-priate candidate for a rituximab-containing regi-men. He has stage III disease (involvement on both sides of the diaphragm without extralym-phatic involvement) and an elevated lactate dehy-drogenase level, and he has no contraindication to bolus anthracycline therapy. He has a high to high-intermediate risk score. I would recom-mend that he receive R-CHOP every 21 days for six cycles. I would expect his likelihood of 3-year survival to be approximately 65%. I would obtain a PET-CT scan at the completion of therapy to confirm remission of disease. If a complete re-mission is confirmed, I would not recommend maintenance therapy but would instead monitor the patient for relapse. For persistent or relapsed disease, I would assess his ability to tolerate ag-gressive salvage therapy and high-dose treatment.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

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Copyright © 2012 Massachusetts Medical Society.

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