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Review of Antibody-Based Immunotherapy in the Treatment of Non-Hodgkin Lymphoma and Patterns of Use

Clinical Lymphoma Myeloma and Leukemia

Abstract

The creation of new cancer immunotherapies represents 1 of the most exciting advances taking place this decade. Although clinical studies continue to indicate improvement in clinical outcomes, the speed of its diffusion into actual practice is not known. It is important to understand practice variation in the use of recommended immunotherapies as new and more effective immunotherapies are developed. Additionally, as the field continues to grow, immunotherapy will encounter new barriers that will hinder its rapid adoption into clinical practice. This review aims to present a brief summary of the mechanisms and uses of antibody-based immunotherapies used to treat lymphoma and to present available practice variation data, including factors associated with variation. Review of the available data implicated patient characteristics and health care systems as being associated with practice variation; however, in several instances, ease of use, cost, toxicity, and physician knowledge contributed to variation, regardless of efficacy. As new immunotherapies are developed, these factors must be considered to increase the rapid diffusion of effective immunotherapies into wide clinical use.

Keywords: Health services research, Immunotherapy, Non-hodgkin lymphoma, Practice variation.

Introduction

The meteoric success of rituximab inspired an upsurge in both the development of new immunotherapies and the methods used to test them. The newer approved immunotherapies exhibit a level of mechanistic complexity previously unseen in successful immunotherapies: rather than targeting antigens presented on the surface of malignant cells, these drugs serve to bolster the host's antitumor immune response.1 and 2 However, as new and more effective immunotherapies are developed, the field will encounter new barriers that can hinder the rapid adoption of these treatment modalities. Thus, data concerning the practice variation in the use of existing antibody-based immunotherapies are valuable for understanding the challenges that newly developed immunotherapies may face. The use of immunotherapy to treat non-Hodgkin lymphoma (NHL) offers a particularly important tool in that immunotherapy—in the form of rituximab—has been a core component of the standard of care for a large proportion of NHL cases for more than a decade. However, at the same time, many antibody-based immunotherapies designed to treat various forms of NHL continue to be underused despite, in some cases, very promising clinical trials. This review aims to present a brief summary of the mechanisms and specific uses of antibody-based immunotherapies ( Table 1 ) to treat NHL as well as available practice variation data, including the complex factors associated with variations.

Table 1 Summary of Mechanisms and Indications for Antibody-Based Immunotherapies for Non-Hodgkin Lymphoma

Drug Classification Mechanism of Action Indications/Uses References
Rituximab Type I anti-CD20 mAb
  • (1) ADCC and CMC
  • (2) Development of T-cell response against malignant clone
  • (3) Induction of direct, nonclassic programmed cell death
  • (1) First-line treatment, salvage, and maintenance therapy for CD20+ NHL
  • (2) Initial treatment of CLL or relapsed CLL in combination with fludarabine and cyclophosphamide
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 118, 119, 120, 121, 122, 123, 124, and 125 127
Ofatumumab Type I anti-CD20 mAb
  • (1) ADCC and CMC
  • (2) Induction of direct nonclassic programmed cell death
  • (1) Treatment of CLL refractory to fludarabine and alemtuzumab
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42
Obinutuzumab Type II anti-CD20 mAb
  • (1) ADCC and CMC (minor extent)
  • (2) Induction of direct nonclassic programmed cell death
  • (1) Treatment of previously untreated CLL in combination with chlorambucil
43, 44, 45, 46, 47, 48, 49, and 50
Alemtuzumab b Anti-CD52 mAb
  • (1) ADCC and CMC
  • (2) Signal transduction interference caused by glycolipid raft formation
  • (1) Treatment of fludarabine-refractory B-cell CLL
  • (2) Second-line treatment of peripheral T-cell lymphoma in patients not eligible for transplantation a
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, and 83
Yttrium-90 Ibritumomab Tiuxetan Radio-therapeutic type I anti-CD20 mAb
  • (1) CD20-targeted delivery of radiation
  • (1) Treatment of relapsed, refractory, low-grade, or follicular CD20+ NHL
84, 85, 86, 87, 88, 89, 90, 91, 92, and 93 128
Iodine-131 Tositumomab c Radiotherapeutic type II anti-CD20 mAb
  • (1) CD20-targeted delivery of radiation
  • (1) Treatment of relapsed, refractory, low-grade, follicular, or transformed CD20+ NHL
94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105 128
Denileukin Diftitox d CD25- targeted immunoconjugate
  • (1) IL-2 receptor–targeted (mainly CD25) delivery of diphtheria endotoxin e
  • (1) Treatment of persistent or recurrent T-cell lymphoma
106, 107, 108, 109, 110, 111, 112, and 113
Brentuximab Vedotin Anti-CD30 mAb immunoconjugate
  • (1) CD30-targeted delivery of mitotic inhibitor
  • (1) Treatment of relapsed/refractory HL and anaplastic large cell lymphoma
114, 115, 116, and 117

a National Comprehensive Cancer Network recommendation as opposed to US Food and Drug Administration (FDA) indication.

b Not commercially available.

c Discontinued.

d Temporarily not available.

e Non–antibody-based immunoconjugate.

Abbreviations: ADCC = antibody-dependent cell-mediated cytotoxicity; CLL = chronic lymphocytic leukemia; CMC = complement-mediated cytotoxicity; HL = Hodgkin lymphoma; IL-2 = interleukin 2; mAb = monoclonal antibody; NHL = non-Hodgkin lymphoma.

Rituximab

The US Food and Drug Administration (FDA) approval of rituximab in 1997 made it the first monoclonal antibody (mAb) approved for the treatment of human malignancy. Rituximab is a chimeric antibody with a mouse variable region from the α-CD20 antibody ibritumomab and the human IgG1 κ constant regions. 3 CD20 is not internalized or shed by the cell, and it is expressed by all B-cell malignancies except acute lymphoblastic leukemia and multiple myeloma.3 and 4 Finally, CD20 overexpression is associated with resistance to apoptosis. 3 This combination of characteristics makes CD20 an effective target for mAb-based immunotherapy.

Several different mechanisms have been attributed to the anticancer effects of rituximab. The chimeric antibody was chosen specifically for the purpose of increasing complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which are the main mechanisms through which rituximab produces its antitumor effect. 5 Additionally, reports of increased cytotoxic T-cell response against the malignant clone in patients treated with rituximab suggest that rituximab may induce vaccine-like effects. 6 Finally, there is considerable evidence that the binding of rituximab to CD20 has the capability of interfering with a variety of intracellular processes, including Bcl-2 signaling, BCR signaling, and caspase signal cascades. 5

As a single agent, rituximab treatment produced durable response rates (RRs) in a large variety of cancers, including treated and untreated follicular lymphoma (FL), relapsed indolent lymphoma, relapsed diffuse large B-cell lymphoma (DLBCL), relapsed and untreated mantle cell lymphoma (MCL), and relapsed and untreated chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL), among others. Dillman presented summaries of all single-agent rituximab trials. 7 Rituximab has also been used with some success in the maintenance, consolidation, or salvage therapy (or a combination) of FL and CLL/SLL after high-dose chemotherapy, 8 as well as DLBCL and MCL after autologous hematopoietic stem cell transplantation.9 and 10

The most important use of rituximab is in combination with chemotherapy. In patients with untreated CLL, RRs near 95% were observed in key trials of rituximab plus cyclophosphamide and fludarabine.11, 12, and 13 Additionally, rituximab was shown to improve outcomes of patients: 65% and 87% of the rituximab arm experienced 3-year progression-free survival (PFS) and overall survival (OS), respectively, compared with the control arm, which had 45% and 83% PFS and OS, respectively. For treatment of patients with relapsed or refractory CLL, RRs of 53% to 93% were observed for rituximab plus chemotherapy.12 and 13 This study also observed an increase in the median PFS of patients in the rituximab arm to 30.6 months compared with 20.6 months in the control arm.

When rituximab was used in combination with chemotherapy to treat previously untreated FL, RRs between 81% and 96% were observed depending on the chemotherapy regimen used.8, 13, 14, 15, 16, and 17 Furthermore, in each case, the overall RR was greater for rituximab plus chemotherapy than for chemotherapy alone.14, 15, 16, and 17 In phase III trials, the addition of rituximab to chemotherapy was shown to have a significant impact on overall survival; 3 phase III trials showed increases in OS ranging between 5% and 13% for the groups that received rituximab plus chemotherapy over the chemotherapy-alone groups.15, 16, and 17 Finally, another phase III trial of rituximab in relapsed or refractory FL showed an increase in PFS when rituximab was added to chemotherapy (median PFS not reached at 3 years vs. 21 months for chemotherapy alone). 18

In the first-line treatment of MCL, rituximab in combination with chemotherapy was capable of producing high RRs (ranging from 94%-97%), increasing the proportion of patients experiencing 3-year failure-free survival (64% chemotherapy plus rituximab vs. 10%-24% historical control) 19 and extending the time to treatment failure by approximately 7 months. 20 Trials focusing on relapsed MCL after CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) showed RRs of 60% to 70% and PFS ranging from 23 to 25.6 months.21, 22, and 23 One phase III trial showed that the addition of rituximab to chemotherapy compared with chemotherapy alone increased OS; the median OS of the chemotherapy plus rituximab cohort had not been reached at 3 years compared with 11 months for chemotherapy alone. 18

Initial treatment of DLCBL with rituximab plus chemotherapy was shown to have RRs ranging from 76% to 94%.24, 25, 26, and 27 Furthermore, the addition of rituximab to chemotherapy, compared with chemotherapy alone, for the treatment of DLBCL in young relatively healthy patients was shown to increase 3-year event-free survival (79% vs. 59%) and 3-year OS (93 vs. 84%). 26 Finally, addition of rituximab to chemotherapy for treatment of DLBCL in the elderly was shown to decrease the risk of death by 47% compared with chemotherapy alone. 25

Rituximab is now the standard first-line treatment for patients with CD20-positive (CD20+) B-cell malignancies and is frequently administered in maintenance, consolidation, and salvage settings for patients with FL and CLL (for information on common and serious adverse reactions to rituximab and other immunotherapies discussed here see Table 2 ).

Table 2 Summary of Most Common Adverse Reaction and Severe, Sometimes Fatal, Adverse Reactions of Approved Immunotherapy for the Treatment of NHL

Drug Common Adverse Reactions a Serious Adverse Reactions a
Rituximab Infusion reactions (≥25%), fever, chills, lymphopenia, infection, and asthenia Grade 3 and 4 infusion reactions, mucocutaneous reactions, hepatitis B virus (HBV) reactivation, and progressive multifocal leukoencephalopathy (PML)
Ofatumumab Infusion reactions, neutropenia, pneumonia, anemia, fever, cough, diarrhea, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (≥10%) HBV reactivation and PML
Obinutuzumab Infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, and musculoskeletal disorders (≥10%) HBV reactivation and PML
Alemtuzumab Infusion reaction, cytopenia, cytomegalovirus, and other infections, nausea, emesis, diarrhea, and insomnia (≥10%) Cytopenia, infections, and infusion reactions
Yttrium-90 Ibritumomab Tiuxetan Cytopenia, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and fever (≥10%) Infusion reactions, cytopenia, cutaneous and mucocutaneous reactions
Iodine-131 Tositumomab Neutropenia, thrombocytopenia, anemia and their sequelae (prolonged and severe) Allergic reactions, cytopenia, and sequelae
Denileukin Diftitox b Pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea, pruritus (≥20) Capillary leak syndrome (11%), infusion reaction (8%), and visual changes/loss of visual acuity (4%)
Brentuximab Vedotin Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough, and vomiting (≥20%) John Cunningham virus infection/reactivation, PML

a Information obtained from product inserts.

b Nonantibody.

Abbreviation: NHL = non-Hodgkin lymphoma.

Ofatumumab

Ofatumumab is a human IgG1 κ α-CD20 antibody. The sole difference regarding mechanism between rituximab and ofatumumab is the binding site. Of the 2 extracellular loops on CD20, rituximab binds 1, whereas ofatumumab binds the other in addition to an intracellular loop that transiently approaches the outer membrane.28 and 29 It is believed that these differences are in part responsible for tighter binding of ofatumumab compared with rituximab, resulting in increased exposure of the antibody Fc domain and thereby enhancing CMC and ADCC30, 31, and 32; in fact, in vitro studies show increased CMC induced by ofatumumab compared with rituximab.28, 29, 31, and 33

In 2009, ofatumumab was granted FDA approval for the treatment of CLL that is considered refractory to fludarabine and alemtuzumab. Early studies of ofatumumab in combination with chemotherapy for the treatment of relapsed or refractory CLL found RRs ranging from 40% to 77% depending on exposure to rituximab and chemotherapy regimen.34, 35, 36, and 37 Furthermore, these studies reported widely variable median PFS, ranging from 5.3 months to 23.6 months. However, these values appear to be similar if not better than those produced by rituximab under similar conditions. A head-to-head comparison of the 2 antibodies in CLL and other diseases would be interesting, but the already high RRs and PFS produced by rituximab would make it difficult to achieve statistical significance.

Ofatumumab has also been tried in the first-line treatment of CLL with some success. Two studies reported overall RRs of 77% and 96% when used in combination with fludarabine and cyclophosphamide or fludarabine and pentostatin and cyclophosphamide, respectively.38 and 39 In these trials, the complete remission (CR) rate was near 50%. Furthermore, comparison between chemoimmunotherapy with ofatumumab versus chemoimmunotherapy with rituximab in this study revealed that the ofatumumab group had greater 2-year treatment-free survival (86% vs. 68%). 39

Finally, ofatumumab has been tried in a variety of other settings with some success. One study evaluated ofatumumab in combination with CHOP as first-line treatment of FL. Here the authors reported an overall response between 90% and 100%, depending on dose, and a CR rate of 62%. 40 In relapsed FL in patients who initially responded to rituximab, treatment with ofatumumab in combination with chemotherapy resulted in an RR of 63% and time to progression of 8.8 months and 32.6 for the entire cohort and responders, respectively. 41 Finally, 1 study evaluated ofatumumab in combination with ifosfamide carboplatin and etoposide or dexamethasone, cytarabine, and cisplatin as second-line therapy (after failure of R-CHOP [rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisolone]) before autologous hematopoietic stem cell transplantation for intermediate grade lymphoma (DLBCL, grade III; FL; or transformed FL). 42 This study reported an RR of 61%, with 37% of those being CRs; furthermore, 45 of the 61 original patients were eligible for transplantation after ofatumumab-based chemoimmunotherapy. Stem cell mobilization was successful in 43 of the 45 eligible patients.

Obinutuzumab

GA101 (now obinutuzumab) was derived from the humanization of the parent murine antibody B-Ly1, an IgG1κ antibody. Unlike rituximab and ofatumumab, which are type I anti-CD20 antibodies, obinutuzumab is a type II anti-CD20 antibody. 43 Schematically, the difference between the 2 types of anti-CD20 antibodies is that type I antibodies stabilize CD20 in lipid rafts, thereby increasing the binding of C1q, which is the member of the complement 1 complex responsible for binding of the antibody Fc region.43 and 44 As a result, type I antibodies rely largely on CMC for their antineoplastic effects. In contrast, type II anti-CD20 antibodies do not stabilize CD20 into lipid rafts and thus do not initiate CMC to the same extent. Rather, type II antibodies rely on the induction of greater nonclassic programmed cell death in combination with ADCC for their antineoplastic activity.

Screening of antibody variants that ultimately led to the identification of obinutuzumab included the inability of the antibody to stabilize CD20 in triton X100 insoluble fractions representing lipid rafts and the ability to induce direct cell cytotoxicity in vitro. 44 On identification of GA101 as a type II anti-CD20 mAB, it was further modified by engineered glycosylation of asparagine 297 in the Fc region, resulting in higher affinity binding to FcγRIIIa, an Fc receptor expressed on NK cells, monocytes, and neutrophils. The net result of this glycosylation is enhanced ADCC induction by the antibody. Further characterization of GA101 showed decreased CMC activity in comparison to rituximab and sustained activity in the presence of cobra venom factor, an inhibitor of compliment.44 and 45 Despite decreased induction of CMC, both in vitro and in vivo models of obinutuzumab demonstrated greater activity than rituximab in induction of apoptosis and B-cell depletion.

Initial phase II clinical trials of obinutuzumab were quite promising. As a single agent used in the treatment of relapsed or refractory indolent lymphoma in which 95% of patients had previous exposure to rituximab, obinutuzumab produced an RR of 55% in the high-dose arm, 9% of which were CRs. 46 In this trial, the median PFS was 11.9 months in the high-dose treatment arm. Monotherapy with obinutuzumab also showed activity in relapsed or refractory DLBCL or MCL. 47 In the highest dose group, 37% of patients experienced clinical response. 48 Analysis of the rituximab-refractory subset of patients revealed a 20% RR. 47

Obinutuzumab was considerably more active and acceptably safe when combined with chemotherapy. In relapsed or refractory FL, obinutuzumab produced RRs of 96% and 93% when combined with CHOP and FC (fludarabine and cyclophosphamide), respectively. 49 CR rates were 39% for obinutuzumab plus CHOP and 50% for obinutuzumab plus FC. Most impressively, when obinutuzumab combined with chlorambucil was compared with rituximab plus chlorambucil for the treatment of patients with previously untreated CLL and preexisting conditions, obinutuzumab combined with chlorambucil produced a significantly longer median PFS (26.7 months compared with 16.3 months) and a higher CR rate (20% vs. 7%) than the rituximab plus chlorambucil group. 50 Based on these findings, obinutuzumab was granted FDA approval in November 2013 for the first-line treatment of CLL in combination with chlorambucil.

Alemtuzumab

Alemtuzumab is a humanized antibody with the hypervariable region of the rat α-CD52 antibody campath-1G with the variable and constant regions of a human IgG1 κ antibody.51 and 52 The human IgG1 Fc region was chosen specifically because it increased CMC and ADCC compared with campath-1G in vitro and in vivo.53, 54, and 55 Multiple studies have confirmed that ADCC is 1 of the means through which alemtuzumab induces antitumor effects.48, 52, and 56 There is also evidence that alemtuzumab induces caspase-independent cell death through the aggregation of glycolipid-enriched rafts at the cell surface, which is hypothesized to interfere with intracellular signaling. 57 Interestingly, this effect was shown to be greater in CLL cells compared with normal B lymphocytes.

In 2001, alemtuzumab earned FDA approval for the treatment of fludarabine-refractory CLL. In this setting, RRs ranged from 30% to 53%, with median duration of remissions between 5 and 20 months when administered to patients with relapsed CLL.58, 59, 60, 61, 62, 63, and 64 Most convincingly, a phase III trial showed that the addition of alemtuzumab to fludarabine increased PFS from 16.5 months (fludarabine alone) to 23.7 months. In this study, median OS of the alemtuzumab treatment group had not been reached but was significantly increased over the fludarabine control arm (P = .021). 65 Another study of alemtuzumab in the treatment of previously untreated CLL reported an RR of 87%. 66 These results in the first-line setting earned alemtuzumab the marketing indication for first-line treatment of CLL. However, a phase III study using alemtuzumab as a first-line treatment of CLL showed that alemtuzumab in combination with fludarabine produced RRs similar to that of rituximab and fludarabine (91% vs. 90% for rituximab and alemtuzumab, respectively). 67 However, alemtuzumab produced lower CR rates (33.75% vs. 19.2%) and decreased 3-year PFS rates (82.6% rituximab vs. 72.5% alemtuzumab) and decreased 3-year OS rates (90.1% rituximab vs. 86.4% alemtuzumab). Because of inferior clinical results and increased toxicity relative to rituximab, alemtuzumab is no longer considered as a first-line treatment for CLL.

Additionally, several studies of alemtuzumab showed it to be effective in the consolidation of CLL therapy. Although the initial study of alemtuzumab as a consolidation therapy for fludarabine or fludarabine and cyclophosphamide was halted because of a high number of severe infections, this study still showed an increase in PFS; at 21.5 months of median follow-up, the alemtuzumab group had no progression, whereas the chemotherapy-alone group had reached a median PFS of 24.7 months (P = .036). 68 Subsequent studies of alemtuzumab as a consolidation therapy confirmed benefit regarding RR but continued to struggle with complications associated with alemtuzumab.69, 70, 71, and 72 Ultimately, a phase III trial of fludarabine with or without alemtuzumab consolidation confirmed a benefit regarding 3-year survival—81.8% versus 30% for the alemtuzumab and fludarabine-alone groups, respectively. 73 However, these results published in 2009 lack applicability because they do not consider the use of rituximab in the treatment of CLL. As a maintenance therapy, a phase II study of alemtuzumab maintenance for heavily pretreated patients with CLL/SLL showed that low-dose (30 mg) alemtuzumab seemed to prolong PFS. 74

Alemtuzumab was shown to be active in the treatment of other CD52+ lymphoproliferative disorders. In the treatment of previously treated indolent B-cell NHL, alemtuzumab produced an RR of 14%, 75 whereas another study produced an RR of 44% in 18 patients with high-grade (n = 2) and low-grade (n = 16) NHL. 76 Finally, 4 studies reported RRs ranging from 38% to 85% when alemtuzumab was used to treat Sézary syndrome.75, 77, 78, and 79 One study reported an RR of 84% for alemtuzumab treatment of cutaneous T-cell lymphoma (CTCL), 80 2 studies reported RRs of 50% and 73% in T-prolymphocytic leukemia,81 and 82 and 1 study found a 36% RR in peripheral T-cell lymphoma. 83

Although alemtuzumab is active in a variety of malignancies, it is not as effective as rituximab in the treatment of B-cell malignancies. Furthermore, the increased toxicity/side effect profile of alemtuzumab—including infusion reactions, cytopenia, cytomegalovirus reactivation, and infections—in comparison to that of rituximab, serves to further limit the clinical potential of alemtuzumab. Because of this, alemtuzumab is no longer commercially available. However, it is still available free of charge for appropriate patients through the Campath distribution program. Information is available at the following site: http://www.campath.com .

Yttrium-90 Ibritumomab Tiuxetan

Yttrium-90 ibritumomab tiuxetan (Y90IT) is a mouse α-CD20 antibody conjugated with tiuxetan, a yttrium-90 chelator. It is believed that Y90IT has some immune-mediating effects, but the fully mouse Fc domain, chosen to ensure quick clearance of unbound antibody and radioactive isotope, attenuates CMC and ADCC immune response. 7 The main mechanism of action of Y90IT is the targeted delivery of the radioactive isotope to tumor masses.

Y90IT initially showed a great deal of promise; in phase I trials of the currently available product, RRs of ∼ 70% and a CR rate of 26% were observed in patients with indolent, refractory (2 previous treatments of anthracycline), low-grade, bulky lymphoma, or MCL. In this study, the median time to progression was 12.9 months for patients who experienced clinical response. 84  A phase III trial of Y90IT treatment versus rituximab with chemotherapy for the treatment of relapsed or refractory low-grade FL or transformed NHL demonstrated superior RRs and increased rates of durable response (≥ 6 months) for Y90IT over rituximab (RR, 80% vs. 56%; CR, 30% vs. 16%; durable response, 64% vs. 47%); however, time to progression and remission duration were not statistically different between the 2 groups. 85 The RR of Y90IT used in rituximab-refractory lymphoma was 74%, and in MCL refractory to previous treatment including rituximab, Y90IT produced RRs of 31%.86 and 87 However, in both of these trials, the time to progression 86 or event-free survival 87 were < 1 year.

Additionally, numerous studies have shown benefit to the use of Y90IT as a consolidation therapy. A small single-institution study involving 20 previously untreated patients with indolent lymphoma with at least a partial response to fludarabine and mitoxantrone therapy, normal platelet levels, and < 25% of the bone infiltrated by malignant cells, showed that 100% of patients treated with Y90IT achieved CR. 88 Furthermore, this study showed a 3-year PFS of 89.5%. 89 In a multicenter study of the same design with 61 patients who had previously untreated indolent lymphoma, 55 of 57 eligible patients achieved CR after consolidation with Y90IT; 3-year PFS was reported at 76%. 90 One single-institution study showed that Y90IT in the consolidation of a short course of R-CHOP increased CR (assessed by positron emission tomography) from 46% after R-CHOP to 86% after Y90IT consolidation in the 55 patients who completed therapy. 91 Another 41-patient trial of Y90IT used as consolidation therapy after R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) as first-line treatment of FL reported an increased CR rate (30% after immunochemotherapy to 76% after Y90IT consolidation) and a 5-year PFS and OS rate of 64% and 96%, respectively. 92 Most impressively, in a 414-patient randomized trial of first-line treatment in FL, 87% of the Y90IT consolidation group achieved CR and a median PFS of 36 months compared with 53% and 13 months in the control group. 93 The results of this clinical trial earned Y90IT FDA approval in 2002 for the treatment of indolent lymphoma.

Iodine-131 Tositumomab

Iodine-131 tositumomab (I-131T) is a murine IgG2a type II α-CD20 mAb conjugated to iodine-131 at tyrosine residues. 94 Like ibritumomab, there are several mechanisms proposed to account for the antitumor activity of I-131T, including increased apoptosis, CMC (to a much lesser extent), ADCC, and ionizing radiation. 95 Objective RRs of I-131T when used with chemotherapy to treat relapsed, refractory, or recurrent NHL, or all of these, ranged between 57% and 76%.88, 96, 97, 98, 99, and 100 This included an RR of 65% observed when I-131T was used to treat patients with progressive lymphoma after treatment with rituximab. 99 Similarly, 2 studies reported overall median PFS of 12 months and 10.4 months, but patients who experienced response had greater median PFS at 20 and 24.5 months96 and 99 Furthermore, a compilation of 5 trials with 250 patients with recurrent disease showed that 33% of patients treated with I-131T had PFS lasting longer than a year; 17% of patients experienced PFS ≥ 5 years. 101 Fifty-six percent of patients who had previously received and responded to I-131T responded again when retreated.

I-131T has also been tried in the consolidation setting. In a study involving 90 previously untreated patients with FL, 6 cycles of CHOP followed by I-131T resulted in an RR of 91%; 69% experienced CR and 67% experienced 5-year PFS. 102 A smaller study showed that I-131T after 6 cycles of CVP resulted in an RR of 100% and a 93% CR rate in patients with previously untreated FL; 5-year PFS was 56%. 103 Finally, 1 study examined I-131T as consolidation therapy after 3 cycles of fludarabine for the treatment of FL. 104 After fludarabine, 89% of patients had responded and 9% had experienced CR; after consolidation with I-131T, all patients had responded and 86% had achieved CR. This study also reported a 5-year PFS of 60%. It is important to note, however, that none of these trials included the first-line therapy of rituximab plus chemotherapy. When CHOP with I-131T consolidation therapy was compared with R-CHOP therapy in a phase III trial, there was no difference in 2-year PFS (80% I-131T vs. 76% rituximab) and OS (93% I-131T vs. 97% rituximab). 105 The current indication for I-131T is in the treatment of relapsed or refractory low-grade FL or transformed NHL, including patients with rituximab-refractory disease. However, GlaxoSmithKline has discontinued the manufacture and sale of I-131T as a result of low product use, and it is no longer available.

Denileukin-Diftitox

Denileukin diftitox (DD) is a recombinant fusion protein consisting of interleukin (IL)-2 linked to diphtheria endotoxin to produce the immunotoxin DAB389IL-2. 106 The premise of this immunotherapy is that the immunotoxin is taken into the high-affinity IL-2 receptor complex, which is overexpressed (especially CD25) in a variety of malignancies including B- and T-cell lymphomas.107 and 108 Inside the cell, the toxin is released and catalyzes the transfer of adenosine diphosphate ribose to elongation factor-2, thereby inhibiting protein synthesis and resulting in cell death.107 and 109

A 73-patient phase I trial of DD reported varying RRs in different diseases settings, including the mycosis fungoides stage of CTCL (13 out of 35), B-cell lymphoma (3 out of 17), and Hodgkin's disease (0 out of 21).110 and 111 A multicenter trial involving 71 patients with CTCL treated with DAB389IL2 showed a 30% RR, 33% of which were CRs. 112 The results of these trials earned DD FDA approval for the treatment of CTCL. After approval, a 144-patient randomized placebo-controlled trial of DD in patients with CTCL confirmed a 44% RR in the treatment group compared with 16% in the placebo group and a median PFS > 2 years for the 2 DD doses compared with a PFS of 124 days for the placebo group; however, it is likely that these patients received additional therapy. 113 As a final note on DD, as of 2011 there has been a break in the supply because of difficulties with manufacturing a consistent product.

Brentuximab Vedotin

Brentuximab vedotin (BV) is a mouse and human chimeric IgG1 antibody directed against the membrane-bound glycoprotein CD30 conjugated to an average of 4 monomethylauristatin A (MMAE) molecules through a protease-sensitive dipeptide linker. 114 CD30 is a member of the tumor necrosis factor receptor family. In normal physiologic function, CD30 is expressed only on subsets of activated B and T cells; in malignant cells, CD30 is expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma, and about 25% of CTCL cases.114 and 115 The exact function of CD30 is difficult to pinpoint because of its pleotropic effect on cells; however, expression of CD30 on B cells appears to be involved in B-cell proliferation and production of immunoglobulin. On T cells, CD30 is believed to regulate various populations of memory T cells. 115 In malignant cells, CD30 has been linked to both increased activation of nuclear factor kappa beta signaling and production of proinflammatory cytokines such as IL-6, both of which may be important for malignant cell survival and immune evasion. On binding of BV to CD30, the antibody-receptor complex is quickly internalized through endocytosis. 114 On exposure to lysosomal proteases, dipeptide bond linking MMAE molecules to the antibodies is cleaved, thereby releasing MMAE inside the cell. MMAE is then free to disrupt the microtubule network inside the cell by binding to tubulin. The end result of this is cell cycle arrest at the G2/M phase.

In clinical trials, BV was shown to be somewhat effective in the treatment of CD30+ lymphoproliferative disorders. A phase II trial of BV in the treatment of relapsed or refractory HL after autologous hematopoietic stem cell transplantation produced an RR of 75%, a CR rate of 34%, and a median PFS of 5.6 months. 116 When BV was used to treat systemic ALCL, 86% of patients experienced a clinical response. 117 Currently, BV is FDA approved for the treatment of relapsed or refractory HL and systemic ALCL.

Use of Immunotherapy in NHL

One of the most successful uses of immunotherapy is the treatment of NHL with rituximab, which is now a standard treatment for some forms of lymphoma. It also provides a great lesson in how immunotherapy diffuses into practice over time when its effectiveness is shown to dramatically change the course of a disease. A 2009 study by Shih et al showed that the use of rituximab increased from 2.12% in 1998% to 24.8% in 2004 compared with a change in the use of immunotherapy of only 2.1% to 5.43% in breast cancer and 0.61% to 4.19% in colorectal cancer (CRC) over the same period. 118 This change in the adoption of immunotherapy was associated with $285 million, $73 million, and $12 million increases in the cost of treating lymphoma, breast cancer, and CRC, respectively, in the United States. 119 Interestingly, a similar study focusing on the use of rituximab in the first-line treatment of elderly patients with DLBCL found that by 2002, 45% of patients received rituximab either alone or with chemotherapy as a first-line treatment. This finding indicates that the use of rituximab diffused more quickly into the treatment of elderly patients (for whom toxicity, frailty, and comorbidity are generally of greater concern), especially when the fact that rituximab in combination with anthracycline-based chemotherapy was not approved by the FDA for the first-line treatment of DLBCL until early 2006. 120

Despite its effectiveness, practice variation in the use of rituximab exists according to patient characteristics. In 2009, the results of the National LymphoCare Study evaluating treatment of newly diagnosed FL in the United States between 2004 and 2007 were published. 121 The study included 2728 participants enrolled from 265 sites, 80% of which were nonacademic sites. The treatment of choice for FL was chemotherapy plus rituximab (51.9%), followed by observation (17.7%), rituximab monotherapy (13.9%), clinical trials (6.1%), external beam radiotherapy (5.6%), and chemotherapy alone (3.2%). The choice to initiate therapy rather than observe was associated with age, stage of disease, prognostic index score, and histologic type. There are also regional variations noted across the United States in the decision to treat versus observe (northeastern United States more likely to observe). Of the patients observed initially, active therapy was initiated in 22% within 12 months and in 31.2% within 24 months; rituximab with or without chemotherapy was the treatment of choice in this setting (62.8%). The study concluded that despite the availability of rituximab as a low-morbidity therapeutic option, no change in threshold to initiate treatment in FL was observed.

In a subsequent study published in 2012 that focused on patients with stage I disease (n = 471), treatments varied according to how rigorous the staging was; rigorously staged patients (bone marrow aspirate plus biopsy plus imaging modality) received the following treatments: rituximab plus chemotherapy (28%), radiotherapy (27%), observation (17%), systemic therapy plus radiotherapy (13%), rituximab monotherapy (12%), and others (3%). The study concluded that variable treatment approaches resulted in similar excellent outcomes. Interestingly, it was shown that patients who received rituximab monotherapy did not differ in risk of progression/death compared with those who received rituximab plus chemotherapy, raising the possibility of immunotherapy as monotherapy in the treatment of early disease. 122

There are also several studies that evaluated the factors associated with the use of immunotherapy plus chemotherapy in other forms of NHL. In the treatment of DLBCL in the United States between the years 2001 and 2004, Flowers et al in 2012 evaluated the factors associated with the likelihood of receiving chemoimmunotherapy (n = 10,234) versus chemotherapy alone (n = 19,078) using the National Cancer Database. 123 This study showed that 27% of patients received some chemoimmunotherapy, whereas 50% received chemotherapy alone. The following were associated with increased likelihood of receiving chemoimmunotherapy: later year of diagnosis, white race/ethnicity, younger age, advanced disease stage, extranodal involvement, treatment in high-volume teaching/research hospital, and residency in the southern United States. A subsequent report from the LymphoCare Study showed that Hispanics were more likely to receive rituximab plus chemotherapy than either African Americans or whites (66% vs. 54% and 50%, respectively). 124 In a separate study of 207,581 patients with NHL diagnosed between 1998 and 2004, the use of immunotherapy varied significantly by age, race, insurance status, year of diagnosis, and type of treatment facility. 118 Interestingly, among patients 65 years or older, having another insurance plan along with Medicare is associated with a higher likelihood of receiving immunotherapy. Another study by Han et al. also found that having private insurance increased the likelihood of receiving chemoimmunotherapy over having no insurance and Medicaid; however, the difference between the 3 groups was not significant. 125 Patients with lymphoma were more likely to receive immunotherapy compared with patients with breast cancer or CRC over time.

As demonstrated by the articles discussed, the use of rituximab is dependent on a wide variety of factors. According to the Cabana model of barriers to physician adherence to recommended practices, a lack of knowledge pertaining to a given treatment can serve as barrier to the implementation of that treatment in the appropriate setting. 126 Despite the success and prevalence of rituximab in the treatment of NHL, practice variation in rituximab use can also be the result of gaps in physicians' knowledge. Incorrect answers after the 2010 session of the American Society of Clinical Oncology helped to elucidate these knowledge gaps, which ultimately have the potential to result in unwarranted practice variation. 127 The most prevalent example of 1 such knowledge gap is the fact that 23% of physicians surveyed replied that maintenance rituximab was indicated for patients with de novo DLBCL in CR after rituximab-containing chemoimmunotherapy. These incorrect answers highlight a lack of familiarity with the indications for rituximab, which may ultimately hinder its use in the settings in which it is warranted. Furthermore, the results of this survey indicate the need for continued educational efforts to eliminate unwarranted practice variation and ensure that immunotherapies are used in the most advantageous and cost-effective manner.

In contrast to rituximab, despite very promising results of I-131T and Y90IY in clinical trials that produced high overall and complete RRs in addition to substantially extending PFS, the use of these radioimmunotherapies has not diffused widely into clinical practice. In fact, use of these drugs is so poor that at the end of 2006, Idec Pharmaceuticals discontinued promotional and marketing efforts pertaining to Y90IT, and as of February 2014, the production of I-131T had been discontinued. 128 Underlying this underuse of I-131T and Y90IT are a variety of factors. For one, use of either drug requires the medical oncologist to refer the patient to a radiation oncologist or nuclear medicine specialist; the end result is a more complicated treatment plan in which both physicians must coordinate the care that they give, as well as decreased compensation for the medical oncologist and more complicated billing procedures.

Conclusion

The introduction of immunotherapy as an added tool in the armamentarium for the treatment of cancer is slowly finding its way into therapy for some of the most common malignancies like NHL. Approved immunotherapy use varies widely across broad types of NHL, as well as across provider and patient characteristics. In lymphoma, use of rituximab increased between 15% and 20% within 5 years of its FDA approval; rituximab is now widely used because of its effectiveness in this disease setting. In contrast, many immunotherapies with promising results in the treatment of NHL, such as I-131T and Y90IT, failed to be widely adopted in clinical practice. Adoption can be influenced by an immunotherapy's relative toxicity, ease of administration, and overall cost in addition to its overall effectiveness. These adoption factors may likely determine which immunotherapies being developed today, regardless of efficacy, will have an impact on the course of a disease and its treatment. This review has also shown that there are various factors that likely contribute to the use of immunotherapy in different diseases. The role of physician education is important in distinguishing unwarranted practice variation resulting from knowledge gaps and disparities in health care equity and access, as opposed to practice variation resulting from a clinician's effort to personalize treatments based on a patient's risk factors. These may prove to be critical as the field of immunooncology becomes increasingly established.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

This work was supported by an unrestricted educational grant from Bristol-Myers Squibb, grant No. 63313, to the University of Nebraska Medical Center, Center for Continuing Education and CE Outcomes, LLC.

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Footnotes

Section of Oncology/Hematology, Internal Medicine, University of Nebraska Medical Center, Omaha, NE

Address for correspondence: Fausto Loberiza, Jr, MD, MS, Section of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-6520, Fax: 402-559-6520