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.
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). 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. 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. 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 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%). 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.
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. 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. 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 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. 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.
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. 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 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. 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.
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. 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. 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. 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. 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. 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.
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. 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. 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.
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