Reassessment of Anti-CD20 Therapy in Lymphoid Malignancies: Impact, Limitations, and New Directions

May 16, 2017
Patrick M. Reagan, MD

,
Jonathan W. Friedberg, MD, MMSc

This review will highlight the survival impact that rituximab therapy has had on major lymphoid malignancies, such as diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma. We will also discuss alternative anti-CD20 monoclonal antibodies.

The addition of anti-CD20 monoclonal antibodies to the treatment of B-cell malignancies has dramatically affected the field as well as the lives of patients. Rituximab in particular has been combined safely with conventional chemotherapy and has resulted in improved overall survival in major histologic subtypes of B-cell lymphoma and chronic lymphocytic leukemia. It is incorporated into the standard initial treatment of nearly all of these diseases. Novel anti-CD20 antibodies are currently under development. Two of these agents, ofatumumab and obinutuzumab, have been approved for use in certain clinical settings. Research comparing these newer antibodies with rituximab is ongoing. As these newer antibodies are further studied and developed, improvements in response and progression-free survival need to be considered in the context of clinical benefit as well as toxicity, especially in indolent diseases. Research involving rituximab biosimilars is ongoing as well, and recent preliminary data demonstrate similar efficacy and tolerability when compared with rituximab. An additional focus of ongoing research is the use of extended schedules of anti-CD20 monoclonal antibodies, as the optimal duration of therapy remains ill-defined in many histologic subtypes. To maximize the use of these agents, well-validated clinical trial endpoints will need to be carefully considered.

Introduction

The introduction of the chimeric anti-CD20 monoclonal antibody rituximab has resulted in broad practice changes in a diverse group of illnesses. The contribution of rituximab and other anti-CD20 antibodies has been most pronounced in the treatment of B-cell lymphoproliferative disorders. Early studies of rituximab as a single agent by Maloney and colleagues showed favorable tolerability and considerable responses in patients with indolent lymphoma refractory to aggressive chemotherapy.[1,2] These responses, however, were rarely durable. Inclusion with chemotherapy in induction regimens for B-cell malignancies has had the largest impact on the field. In these disorders, the incorporation of rituximab into standard therapy has driven improvements in meaningful outcomes, such as progression-free survival (PFS) and overall survival (OS), and has redefined standards of care. National guidelines recommend the use of rituximab in the initial treatment of nearly every B-cell malignancy.[3]

Additional monoclonal antibodies, such as ofatumumab and obinutuzumab, were developed and studied in patients who were refractory to rituximab or rituximab-containing regimens. More recently, these two antibodies have been studied in frontline settings, and some trials have included direct comparisons with regimens that contain rituximab.[4-6] Results from studies involving rituximab biosimilars have been reported, and the European Medicines Agency (EMA) recently recommended one of these agents for approval.[7,8]

The success of rituximab and other anti-CD20 antibodies has resulted in part from the ability to integrate them into existing treatment regimens. The addition of an anti-CD20 monoclonal antibody rarely results in serious complications, and favorable tolerability of these combinations is generally preserved. There are, however, several serious complications of concern, such as reactivation of hepatitis B virus as well as a rare, but devastating, reactivation of the John Cunningham (JC) virus, which results in progressive multifocal leukoencephalopathy (PML).

This review will highlight the survival impact that rituximab therapy has had on major lymphoid malignancies, such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). We will also discuss alternative anti-CD20 monoclonal antibodies; however, we will focus on ofatumumab and obinutuzumab, which are the other unconjugated antibodies with approved indications. Finally, we will review the data regarding extended schedules of anti-CD20 therapy, as well as some limitations, including toxicity.

Mechanism of Action

A comprehensive review of the mechanisms of action of anti-CD20 monoclonal antibodies, as well as resistance mechanisms, is outside the scope of this review. Several excellent reviews are available that detail both mechanisms of action and mechanisms of resistance.[9,10] We will focus on the similarities and distinctions between the type I antibodies rituximab and ofatumumab and the type II antibody obinutuzumab (Table 1).

Rituximab is a type I chimeric anti-CD20 antibody with human immunoglobulin G1 (IgG1) heavy chain, human kappa light chain constant regions, and murine light and heavy chain variable regions. It causes cell death primarily through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[11] Ofatumumab is a fully human type I anti-CD20 monoclonal antibody that binds to a different epitope of CD20 than rituximab, which results in higher binding affinity and enhanced CDC.[12] Obinutuzumab is a humanized type II anti-CD20 monoclonal antibody. Several features distinguish obinutuzumab from rituximab and ofatumumab. In culture and xenograft models, it has demonstrated an improved ability to induce direct cell death, as well as ADCC, compared with rituximab. The factors that contribute to the increased ADCC include the glycoengineering of the Fc segment, which leads to enhanced binding to FcγRIIIA, as well as longer persistence on the B-cell surface. Obinutuzumab does not induce significant CDC.[13] Table 1 provides a summary of the mechanisms of the different anti-CD20 antibodies.

Impact of Anti-CD20 Therapy: OS Benefit in Many B-Cell Malignancies

The introduction of anti-CD20 therapeutics, particularly the monoclonal antibody rituximab, has transformed the landscape of therapy for B-cell lymphoid malignancies. Benefits in OS have been seen across both indolent and aggressive B-cell malignancies with the addition of rituximab. This section provides a comprehensive review of the randomized data that support the OS benefit of rituximab in major B-cell lymphoma subtypes and CLL. Table 2 contains a summary of the clinical trial treatments and endpoints.

DLBCL

DLBCL is the most common non-Hodgkin lymphoma. The addition of rituximab to combination chemotherapy has had a substantial impact on the OS of patients with DLBCL. Four large randomized controlled trials-LNH-85, MabThera International Trial (MInT), RICOVER-60, and US Intergroup Eastern Cooperative Oncology Group (ECOG) 4494/Cancer and Leukemia Group B (CALGB) 9793-have compared CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy with R-CHOP (rituximab-CHOP) chemoimmunotherapy. The addition of rituximab to CHOP chemotherapy has resulted in statistically significant OS benefits in older, high-risk patients, as well as in younger patients at lower clinical risk.

In a seminal study by the Groupe d’Etude des Lymphomes de l’Adulte (GELA), nearly 400 older patients were randomized to CHOP alone vs R-CHOP chemoimmunotherapy. Patients treated with R-CHOP had a statistically significant improvement in complete response (CR) rate (76% vs 63%), as well as sustained improvements in PFS and OS with long-term follow-up.[14,15] The MInT group randomized younger patients (18–60 years) to 6 cycles of R-CHOP or R-CHOEP (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) vs CHOP or CHOEP. When looking at pooled data for chemoimmunotherapy vs chemotherapy alone, there was a statistically significant improvement in the rate of CR or CR unconfirmed in favor of chemoimmunotherapy (86% vs 68%).[16] With long-term follow-up of these data, a sustained difference in OS was noted, with a 6-year OS rate of 90.1% in patients in the chemoimmunotherapy arm vs 80.0% in those in the chemotherapy-only arm.[17]

These results have been duplicated in older populations in both Germany and the United States. The RICOVER-60 trial, conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group, showed an improvement in both PFS and OS with R-CHOP-14 over CHOP-14.[18] The ECOG 4494/CALGB 9793 trial differed in study design, with a two-stage randomization to R-CHOP vs CHOP and then to maintenance rituximab in responders. The absence of an OS benefit likely resulted from the use of maintenance rituximab, which benefited the group assigned to CHOP induction.[19] Importantly, the severity and quantity of adverse events did not vary greatly between the chemotherapy and chemoimmunotherapy arms in these studies.[14,16,18,19] Despite extensive ongoing clinical research, for most patients R-CHOP has remained the standard of care, based on the efficacy it has demonstrated, as well as its toxicity profile.

CLL

CLL has a long natural history and is the most prevalent B-cell malignancy. Despite the low expression of CD20 in CLL and the relatively poor activity of rituximab as a single agent, rituximab has been highly effective when incorporated into therapy for CLL. CLL8 was a large, randomized, multicenter trial that compared FC (fludarabine and cyclophosphamide) with FCR (rituximab, fludarabine, and cyclophosphamide). Participants assigned to FCR had statistically significant improvements in CR rate (44% vs 22%), PFS (51.8 vs 32.8 months), and OS rate (87% vs 83%) compared with those who received FC.[20] Importantly, these deeper remissions and the OS benefit have been sustained. The median OS was 86 months in the FC group, and median OS was not reached in the FCR group, with a median follow-up of 5.9 years. This benefit was most prominent in patients with mutated IGHV; no benefit was seen in those with deletion of 17p.[21]

Minimal residual disease (MRD) negativity is an important endpoint in CLL and has proved to be an independent predictor of response duration and OS.[22-24] In CLL8, FCR induced MRD-negative remissions more frequently than FC. This was determined in the bone marrow, and MRD below 10-4 was observed in 44% of patients assigned to FCR vs 28% in the FC group.[23] Rituximab is currently a standard component of treatment for CLL; however, CLL has been an area of intensive study of alternative anti-CD20 antibodies, which will be discussed in detail further on.

FL

FL is the most common indolent B-cell lymphoma and, while it is incurable, has a long natural history. Several retrospective series have demonstrated that survival in FL is consistently improving. These series include analyses of randomized controlled trials conducted by cooperative groups in the United States and the European Union; a large single-institution experience; and a Surveillance, Epidemiology, and End Results (SEER) analysis.[25-28] While the study design and data sources may preclude the determination of the factors associated with the improvement in survival, the analyses of the clinical trials strongly support the addition of anti-CD20 monoclonal antibodies as a major driver of the improvement in OS. The analysis by the Southwest Oncology Group (SWOG) included trials with both rituximab and I131-tositumomab and demonstrated an improvement in 4-year OS when compared with previous combination chemotherapy studies.[26] A meta-analysis was performed on randomized trials that compared chemotherapy with rituximab vs chemotherapy alone in indolent B-cell lymphomas and MCL. The meta-analysis demonstrated an improved OS in all patients (hazard ratio [HR], 0.65; 95% CI, 0.54–0.78) who were treated with rituximab and chemotherapy, including those with FL (HR, 0.63; 95% CI, 0.51–0.79), compared with patients who received chemotherapy alone.[27]

Several prospective studies demonstrated the additive benefit of rituximab to chemotherapy in FL. Many of these studies also included other indolent lymphomas or MCL. These studies used similar criteria that included considerations of tumor bulk or need to treat based on symptomatic disease.

The German Low-Grade Lymphoma Study Group (GLSG) conducted a randomized controlled trial of R-FCM (rituximab, fludarabine, cyclophosphamide, and mitoxantrone) vs FCM in patients with FL or MCL. There was a significant PFS benefit in the FL group; however, there was no statistically significant OS benefit in these patients.[29] The East German Study Group conducted a randomized trial of MCP (mitoxantrone, chlorambucil, and prednisone) vs rituximab-MCP. The response rates were significantly higher in the rituximab arm: the overall response rate (ORR) was 92% vs 75% in the MCP-alone arm, and the CR rate was 50% vs 25%. Similarly, both the median PFS (not reached vs 28.8 months; P < .01) and the 4-year OS rate (87% vs 74%; P = .0096) were significantly improved in patients who received rituximab.[30] A randomized study of CVP (cyclophosphamide, vincristine, and prednisone) vs rituximab-CVP (R-CVP) also showed a statistically significant benefit in response rates: both the ORR (81% vs 57%) and the CR rate (41% vs 10%) were higher in the rituximab-containing arm than in the CVP-alone arm.[31] With long-term follow-up, there was a statistically significant improvement in the primary outcome of time to treatment failure in the rituximab-containing arm vs the CVP arm, as well as a statistically significant benefit in the 4-year OS rate (83% vs 77%; P = .029). R-CVP demonstrated a longer duration of response than CVP as well. The benefits seemed to be preserved across risk groups.[32] The GLSG conducted a randomized clinical trial of R-CHOP vs CHOP, which had impressive ORRs in both arms, but with a statistically better ORR in the R-CHOP group (96% vs 90%). More important clinically was the prolonged duration of response, as well as a small but statistically significant improvement in OS in the rituximab-containing arm.[33] In patients with FL who have a high tumor burden, chemoimmunotherapy that contains rituximab is recommended; however, research is ongoing to identify the optimal induction and maintenance strategies.

MCL

The addition of rituximab to chemotherapy is associated with an improvement in survival in patients with MCL. As previously mentioned, several of the original randomized studies of chemotherapy vs rituximab-containing chemoimmunotherapy in indolent lymphoma included patients with MCL. These analyses were somewhat limited by lack of power. The addition of rituximab to FCM chemotherapy resulted in an improved ORR (58% vs 46% with FCM alone) as well as median OS (not reached vs 11 months with FCM alone) in patients with MCL.[29] In a study that compared R-CHOP with CHOP chemotherapy in patients with MCL, the rituximab-containing arm had an improved ORR (94% vs 75%) and CR rate (34% vs 7%), but there was no difference in PFS or OS. This study was not powered for PFS or OS endpoints.[34] In a meta-analysis of the available randomized data, the OS in patients with MCL who received rituximab was improved (HR, 0.60; 95% CI, 0.37–0.98). A relatively high degree of heterogeneity was noticed among studies in this analysis.[27]

Alternative Anti-CD20 Agents: Ofatumumab, Obinutuzumab, and Biosimilars

Rituximab resistance has been variably defined in the literature and has been used as an inclusion criterion for various recent studies. In most cases, it has been defined as no response or a response duration of less than or equal to 6 months from the last rituximab-containing regimen.[35,36] Ofatumumab and obinutuzumab are the other unconjugated anti-CD20 antibodies that have indications approved by the US Food and Drug Administration (FDA). They have been studied in the setting of rituximab resistance, as well as in initial treatment of patients with CLL or B-cell lymphomas. We will discuss the data from major studies involving these two agents in this section. We will also describe recent data from trials involving rituximab biosimilar agents.

Ofatumumab is approved only for CLL, with specific indications for frontline treatment in combination with chlorambucil in patients who are ineligible for more intensive fludarabine-based therapy, for patients whose disease is refractory to fludarabine and alemtuzumab, and for extended treatment in patients who have had at least two lines of therapy and have had a partial response (PR) or a CR to their most recent treatment. The initial approval of ofatumumab in CLL was based on the results of a phase II study of patients with CLL refractory to treatment with fludarabine- or alemtuzumab-based regimens. In the fludarabine group, the ORR with single-agent ofatumumab was 58%, and in the alemtuzumab group, the ORR was 47%. The median PFS and OS were poor in both groups: 5.7 months and 13.7 months, respectively, in the fludarabine group, and 5.9 months and 15.4 months, respectively, in the alemtuzumab group.[37] Importantly, in a retrospective analysis of the participants in this trial, the benefit was seen not only in rituximab-naive patients, but also in those who had previous rituximab exposure, and in those whose disease was considered refractory to rituximab.[35]

Based on its efficacy in the relapsed setting, ofatumumab was studied in a randomized controlled trial in combination with chlorambucil vs chlorambucil alone. The patients in this study tended to be older (median age, 69 years) and were considered by the investigators to be ineligible for fludarabine-based treatment. The combination arm was superior in terms of ORR and CR rate, as well as the primary endpoint of PFS. The median PFS was 22.4 months in the combination arm and 13.1 months in the chlorambucil monotherapy arm.[38] These data were the basis for approval in the settings of relapse and induction treatment.

Like rituximab, ofatumumab has been studied in an extended schedule in a variety of settings. A phase III randomized controlled trial of observation vs 2 years of ofatumumab included patients who had achieved a PR or CR to second- or third-line treatment. The primary endpoint of PFS was met in a preplanned interim analysis, with a median PFS of 29.4 months in the extended ofatumumab group vs 15.2 months in the observation group (HR, 0.5; P < .0001).[39] In view of other recent developments in the targeted therapy of CLL, the clinical significance of this improvement is unclear.

Obinutuzumab also has been studied in B-cell malignancies and has been approved for use in combination with chlorambucil in untreated CLL, as well as in combination with bendamustine in patients with relapsed FL, on the basis of several randomized clinical trials. CLL11 was a large randomized trial that assigned patients with a high burden of comorbidities to chlorambucil monotherapy, chlorambucil and rituximab, or chlorambucil and obinutuzumab. The obinutuzumab and chlorambucil arm was superior to chlorambucil monotherapy in terms of response, PFS, and OS. Obinutuzumab and chlorambucil induced statistically significant higher overall response and CR rates compared with rituximab and chlorambucil (78.4% vs 65.1%, and 20.7% vs 7.0%, respectively). In addition, there was higher MRD negativity in the blood (37.7% vs 3.3%; P < .001) and bone marrow (19.5% vs 2.6%; P < .001) of those treated with obinutuzumab and chlorambucil vs rituximab and chlorambucil. Median PFS was also prolonged in the obinutuzumab group, and there was a trend toward improved OS.[5] This demonstrated the superiority of obinutuzumab over rituximab in combination with chlorambucil and led to the approval of obinutuzumab in this patient population.

Obinutuzumab is also approved for use in relapsed FL based on the results of the randomized GADOLIN study of obinutuzumab in combination with bendamustine vs bendamustine monotherapy in patients who were refractory to rituximab. Those who were randomized to obinutuzumab also received obinutuzumab maintenance therapy. With approximately 20 months of follow-up in both arms, the median PFS was not reached in the obinutuzumab and bendamustine arm and was 14.9 months in the monotherapy arm (HR, 0.55; P < .001).[36] This led to approval for obinutuzumab in rituximab-refractory FL and established a clear role for obinutuzumab in this group of patients. A longer-term follow-up study presented at the 2016 American Society of Hematology (ASH) Annual Meeting showed a statistically significant difference in OS, with an HR for death of 0.67 (95% CI, 0.47–0.96; P = .0269) in the obinutuzumab arm.[40]

Obinutuzumab is being investigated in lymphoma in the frontline setting, and results from studies in both DLBCL and FL were presented at the 2016 ASH Annual Meeting. The GALLIUM study enrolled patients who required treatment according to Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria and were randomized to chemoimmunotherapy with either rituximab or obinutuzumab. Induction chemotherapy regimens included bendamustine, CVP, and CHOP. There was no difference in ORR or CR rate. The median PFS has not been reached in either the rituximab or the obinutuzumab arm; however, the HR for progression or death was 0.66 (95% CI, 0.51–0.85; P = .001) for the obinutuzumab-chemotherapy arm. When this was analyzed by chemotherapy, the patients treated with obinutuzumab-CHOP or obinutuzumab-CVP clearly had a prolonged PFS compared with those treated with rituximab-containing counterparts, although the absolute difference was relatively small between obinutuzumab/bendamustine and BR (bendamustine/rituximab).[6] Based on the presented results, as well as the MRD findings in this study, the difference was most pronounced between obinutuzumab and rituximab when the chemotherapy used was CHOP or CVP. In patients with peripheral blood samples available for MRD testing who were treated with BR or obinutuzumab/bendamustine, the rate of MRD negativity after induction was the same. In the bone marrow, the rate of MRD negativity was slightly superior with obinutuzumab/bendamustine.[41] It is clear that obinutuzumab combined with CHOP or CVP is superior to R-CHOP or R-CVP; however, when combined with bendamustine, the benefit is modest. Based on these available data, we have not incorporated obinutuzumab into the initial therapy of patients universally, since we typically use bendamustine in patients with grade 1 or 2 FL. A much stronger case could be made to substitute obinutuzumab for rituximab in those receiving CHOP or CVP backbones.

Another important study presented at the meeting was the GOYA trial. This randomized patients with DLBCL between standard R-CHOP chemoimmunotherapy and obinutuzumab-CHOP. The two populations were well matched in terms of clinical and biological risk factors. There was no difference in the primary endpoints of 3-year PFS, ORR, CR, and OS.[42] The importance of this study is that it highlights that although obinutuzumab may be a more efficacious antibody as a single agent, the superiority may not necessarily be preserved across histologic subtypes.

Monoclonal antibodies are generally associated with high costs, and efforts are underway to study molecules that are biosimilars of rituximab. Data were presented at the 2016 ASH Annual Meeting on two such compounds. A multicenter controlled trial was presented that randomly assigned patients with advanced-stage FL to GP2013 and CVP or R-CVP. The primary endpoint was ORR, and equivalence was seen between the two regimens.[7] Data from another compound, CT-P10, were presented at the meeting from a multicenter controlled trial that randomized patients with advanced-stage FL to CT-P10 and CVP or R-CVP. This study was designed primarily to assess pharmacokinetic and pharmacodynamic endpoints. There was a high degree of similarity between the two agents in regard to these endpoints, as well as the safety profile.[8] These data contributed to the recent decision by the EMA to recommend approval of CT-P10.

Extended Schedules and Maintenance Therapy

Extended schedules of rituximab after induction therapy have demonstrated improved PFS, but in most lymphoid malignancies there has been no difference in OS after chemoimmunotherapy induction. The usefulness of maintenance in all patients, particularly those with a low tumor burden, remains unclear. The PRIMA study is a landmark trial that enrolled patients with FL who had a high tumor burden. It established the safety and PFS benefit of maintenance rituximab after induction chemoimmunotherapy. Participants received induction therapy with R-CHOP, R-FCM, or R-CVP and were randomized to observation vs maintenance rituximab for a total of 2 years. A PFS benefit was seen for rituximab maintenance, with an HR of 0.55 (95% CI, 0.44–0.68; P < .0001); however, no difference was seen in OS, with an HR of 0.87 (95% CI, 0.51–1.47; P = .60).[43] With long-term follow-up (median, 73 months), the PFS benefit is preserved, although there is no difference in OS, nor in the clinically important endpoint of histologic transformation.[44] Despite the lack of an OS benefit, rituximab maintenance after chemoimmunotherapy is considered an option for the treatment of patients with FL who have a high tumor burden.

Extended schedules and maintenance have been used in both relapsed and untreated patients with FL. The Swiss Group for Clinical Cancer Research (SAKK) conducted a randomized trial in patients with untreated or relapsed FL. Participants were randomized between weekly rituximab for 4 doses followed by 4 additional doses every 2 months vs observation. Among all participants, the median event-free survival was improved in those who received the extended schedule (23.2 months vs 11.8 months; P = .024).[45] With long-term follow-up, 27% of patients who received the extended schedule were without an event at 8 years compared with 5% of those in the induction-only arm.[46]

E4402, the RESORT study, is a randomized controlled trial in patients with low tumor burden as defined by the GELF criteria that compared induction followed by a retreatment strategy vs induction followed by rituximab every 13 weeks until treatment failure. In patients with FL, there was no difference in time to treatment failure or OS; however, there was a prolonged time to first cytotoxic therapy in the maintenance group. Far more antibody was used in the maintenance arm with less toxicity.[47]

In MCL, the role of maintenance remains unclear, and it appears that the efficacy of maintenance rituximab is dependent on the induction chemoimmunotherapy. A survival benefit with rituximab maintenance was demonstrated in a randomized trial conducted by the European Mantle Cell Network. This trial randomized patients to R-CHOP or FCR. Those who had a response to treatment underwent a second randomization to rituximab or interferon-α maintenance. An OS benefit was seen with rituximab maintenance when data from all participants were analyzed together; however, this was driven by improved survival in those who received R-CHOP induction, with no benefit in those who received FCR.[48]

BR became a standard frontline option in MCL based on randomized noninferiority trials that showed at least equivalent efficacy when compared with R-CHOP, and an improved safety profile. The role of maintenance rituximab after BR has been studied. Rummel et al reported at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2016 that there was no survival benefit in the arm receiving rituximab maintenance, with a median 4.5 years of follow-up.[49]

A strategy of preemptive rituximab has also been employed with some success in patients with MCL. The Nordic group has treated patients with rituximab at the time of MRD relapse after autologous stem cell transplant (ASCT). This has demonstrated efficiency in converting patients back to an MRD-negative state.[50] Maintenance rituximab appears to have a role following ASCT; recent data show an OS benefit for patients randomized to maintenance. The data supporting this are from the phase III LyMa study, which randomized patients to rituximab maintenance or to observation after an aggressive induction and ASCT. A statistically significant benefit in 4-year PFS and OS was seen in the rituximab maintenance arm compared with the observation arm.[51]

There is currently no clear role for maintenance in CLL or DLBCL. Rituximab maintenance has been studied in CLL, and the AGMT CLL-8a Mabtenance study demonstrated a statistically significant PFS benefit (47 months vs 35.5 months) compared with observation alone.[52] The clinical significance of this PFS benefit has been questioned given the long natural history of CLL and the duration of the benefit relative to the 2-year duration of maintenance. In DLBCL, rituximab maintenance has not shown a benefit after induction with R-CHOP.[19,53] There is, however, some evidence in a subgroup analysis to suggest that older men may benefit from prolonged exposure to rituximab.[53]

Toxicity

Overall, anti-CD20 antibodies are well-tolerated and have similar toxicity profiles. They rarely result in severe toxicities but can rarely cause viral reactivations, which will be discussed further on in this section. Hypersensitivity reactions, myelosuppression, immunosuppression, and infections are the most common toxicities of rituximab.[2,14,20,33,45] When combined with CHOP chemotherapy, rituximab adds little to the short-term toxicity of the regimen, with an increase in myelosuppression that has not been clinically significant, evidenced by higher rates of neutropenic fever or infection.[14,33] The addition of rituximab to FC has similarly added little to toxicity other than increased myelosuppression.[20] Increased toxicity can occur with extended schedules of rituximab.

In the PRIMA trial, which involved 2 years of rituximab maintenance after induction, there was an increase in grade 2–4 infections; 56% of patients in the maintenance arm and 37% of those in the observation arm experienced an infection, most of which involved the respiratory tract.[43] The toxicity of maintenance rituximab is related to the duration of therapy. In patients with FL who have a low tumor burden, the increase in toxicity with the SAKK schedule of rituximab is minimal.[45] In the RESORT trial, both the retreatment strategy and maintenance were well tolerated, but there were more grade 3–5 toxicities in the maintenance arm.[47]

Ofatumumab and obinutuzumab have similar safety profiles, with a few exceptions. The most common adverse events reported with ofatumumab include hypersensitivity reactions, infection, and neutropenia. The infusion reactions tend to be grade 1/2 in severity; grade 3 events are relatively rare. The most common grade 3 or higher adverse event associated with ofatumumab is neutropenia.[37-39] Compared with rituximab and chlorambucil, obinutuzumab and chlorambucil caused more grade 3 or higher infusion-related reactions, as well as myelosuppression.[5] This trend was also seen in the GOYA study, which compared R-CHOP and obinutuzumab-CHOP.[42]

Hepatitis B virus reactivation is a well-recognized risk with the use of anti-CD20 monoclonal antibodies, and guidelines recommend screening patients for hepatitis B.[3,54] Patients with a positive hepatitis B surface antigen (HBsAg) test are at high risk for severe hepatitis. With chemoimmunotherapy, patients who have a negative surface antigen test, but a positive core antibody test, are also at significant risk for reactivation. In patients treated with R-CHOP, this risk appears to be significantly higher than in those treated with CHOP alone.[55,56] The patients who are at highest risk for severe hepatitis appear to be those who have a serologic reactivation of hepatitis B with a positive hepatitis B antigen test.[57] Guidelines from the American Gastroenterological Association recommend that physicians provide antiviral prophylaxis to patients who are at high risk for reactivation during immunosuppressive therapy. The high-risk group includes patients who are HBsAg-positive and anti–hepatitis B core (HBc) antibody–positive, as well as those who are HBsAg-negative and anti-HBc antibody–positive, and who are receiving B-cell–depleting agents such as anti-CD20 monoclonal antibodies. These guidelines recommend giving prophylaxis for at least 12 months after the agents have been discontinued.[58] While the ASCO guidelines also recommend antiviral prophylaxis for patients who are HBsAg-positive and anti-HBc antibody–positive, they allow for close monitoring or prophylaxis for those who are anti-HBc antibody–positive but HBsAg-negative.[54]

A rare but catastrophic complication of rituximab therapy is reactivation of the JC virus, which leads to PML. A retrospective series of patients in whom PML developed after they received rituximab has been compiled using a multifaceted approach, including cases from several institutions, the FDA reporting system, the manufacturer’s database, and a search of the literature. While the absolute risk of PML is quite low in patients who receive rituximab, the case-fatality rate was 90% in this series, and all clinicians who use these therapies should be aware of this complication.[59] An analysis of the FDA reporting system also identified cases associated with ofatumumab and obinutuzumab use.[60] Despite these rare complications, anti-CD20 monoclonal antibodies have been a safe addition to chemotherapy and have redefined standards of care.

Conclusions

With multiple anti-CD20 monoclonal antibodies available, key issues will need to be addressed through research. Important issues include the determination of the most appropriate antibody for specific clinical scenarios and the role of extended schedules or maintenance therapy. While obinutuzumab and ofatumumab appear to be superior in certain clinical scenarios and more efficacious as single agents, the recent GOYA study is an example of the inability to generalize the success of a new anti-CD20 monoclonal antibody to another histologic subtype. The study and incorporation of rituximab biosimilar agents will also be important in controlling escalating costs associated with these agents.

The results of recent randomized clinical trials, particularly CLL11, GADOLIN, and GALLIUM, are provocative in that they are challenging current treatment paradigms. In CLL11 and GALLIUM, chemoimmunotherapy with obinutuzumab demonstrates superiority in direct comparison with therapy containing rituximab, and in GADOLIN, the benefit of the addition of obinutuzumab was demonstrated in rituximab-refractory patients.[5,6,36] The results from CLL11 and GADOLIN define a role for use of obinutuzumab in the treatment of CLL and FL patients, respectively, but the results of the GALLIUM study are somewhat more difficult to process. While it is clear that there is a statistical difference between obinutuzumab- and rituximab-containing chemoimmunotherapy, the choice of the chemotherapy backbone may influence the magnitude of that effect, with little difference evident when a bendamustine backbone is used. While CHOP and CVP backbones are also supported by category 1 evidence and are included in guidelines, bendamustine is our preferred agent and is used throughout the world for the initial treatment of patients with low-grade FL who have a high tumor burden.[3] It is our opinion that based on the available evidence, the benefit of obinutuzumab over rituximab in combination with bendamustine is questionable and requires further evaluation in the context of increased toxicity and higher costs. This is based on the abstracts presented, and we will certainly evaluate this when the final results of the GALLIUM study are published.

In current clinical practice, rituximab maintenance has a role in FL and other indolent lymphomas, as well as in MCL. The optimal schedule of rituximab and other anti-CD20 monoclonal antibodies will need to continue to be investigated, taking efficacy, toxicity, and cost into consideration. This will occur in the context of novel, targeted induction strategies, as well as maintenance with targeted agents. When researching questions involving maintenance treatment, especially with new antibodies and certain induction regimens, we feel that it is important to consider including treatment arms without maintenance. This is important because recent examples in the literature suggest that the type of induction regimen has an impact on the efficacy of maintenance.[48,49]

Appropriate endpoints for future clinical trials will need to be defined, particularly for indolent histologies and maintenance therapy. Certainly, it is indisputable that OS is a clinically relevant endpoint; however, in histologic subtypes with long natural histories, it can be very difficult to demonstrate a benefit in OS within a reasonable follow-up period. Prolongation of PFS is of questionable value and may not be a good surrogate for patient benefit. Benefits in PFS must be weighed against any added toxicity and cost. In indolent histologies, patient-reported outcomes such as health-related quality of life, which were studied as part of the RESORT trial,[47] may have increased importance as a measure of clinical benefit for patients and should be considered in clinical trial design.

Anti-CD20 monoclonal antibodies have been highly effective in B-cell malignancies and have transformed the therapeutic landscape. While initially studied in the relapsed and refractory setting, they have become an integral component of initial therapy. Rituximab, in particular, is a standard of care of all induction regimens for the majority of B-cell malignancies, based on national clinical practice guidelines.[3] Obinutuzumab has also become an important agent used in clinical practice, and studies are ongoing with these and other anti-CD20 antibodies.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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