Indolent non-Hodgkin lymphomas (iNHLs) encompass a group of incurable, generally slow growing B-cell lymphomas that are highly responsive to initial therapy, yet characterized by a relapsing and progressing course. The most frequent iNHL is follicular lymphoma, accounting for 20% of all NHLs and as many as 70% of the indolent lymphomas reported in American and European clinical trials . Other iNHL subtypes include marginal zone lymphoma, lymphoplasmacytic lymphoma and small lymphocytic lymphoma . Collectively, iNHL rivals their aggressive NHL counterparts in incidence, with approximately 30 000 new cases diagnosed each year .
As patients with iNHL met with an incurable yet highly treatable disease, the goal of therapy has traditionally been to preserve the best quality of life and treat patients only when symptoms develop. Modifications to this approach require demonstration of a significant improvement of life expectancy with institution of therapy, cost-effectiveness or identification of prognostic criteria to justify a therapeutic change. Indeed, the treatment landscape of iNHL has dramatically changed with the introduction of rituximab, the first monoclonal antibody directed against CD20 (a transmembrane protein expressed by virtually all B-cell lymphomas) and the first approved monoclonal antibody for the treatment of lymphoma. Because of its high antitumor activity coupled with a favorable toxicity profile, rituximab has transformed the outcome of patients with iNHL . In the rituximab era, response rates are approaching 90% with rituximab along with chemotherapy, and time to next treatment is beginning to be measured in years.
In this article, we will tackle the role of rituximab in the management of iNHL, including initial approaches to newly diagnosed patients, approaches to first chemotherapy, maintenance and consolidation strategies, autologous and allogeneic stem cell transplantation, as well as novel promising rituximab-based treatments on the pipeline for iNHL.
RITUXIMAB IN THE FIRST-LINE TREATMENT OF INDOLENT NON-HODGKIN LYMPHOMAS
First-line treatment for low-tumor burden, advanced disease
The overwhelming majority of iNHL patients have advanced stage disease at diagnosis. According to international guidelines [5–9][5–9][5–9][5–9][5–9], patients with low-tumor burden, asymptomatic disease, do not require immediate treatment in an attempt to delay the side-effects of chemotherapy, and this approach is supported by randomized prospective trials of observation versus immediate treatment performed in the prerituximab era . A major question is hence whether rituximab might shift such a paradigm in favor of early treatment. Following the promising results of single-agent rituximab in the setting of relapsed disease , rituximab monotherapy has been explored as initial therapy in the common scenario of asymptomatic follicular lymphoma [12,13][12,13]. In the Swiss Group for Clinical Cancer Research trial , both previously untreated and relapsed follicular lymphoma patients responding to weekly rituximab for 4 weeks were randomly assigned to observation or an extended schedule consisting of four additional rituximab doses administered every 2 months (maintenance rituximab). With a median follow-up of 9 years, event-free survival (EFS) was 13 months for the standard and 24 for the maintenance rituximab arm, with a trend toward an overall survival (OS) benefit in the latter. Subsequently, a large retrospective analysis of follicular lymphoma patients who were either observed or received single-agent rituximab found no deleterious impact of watchful waiting, with a 4-year freedom from treatment failure of 87% in the observation-only group versus 79% in the maintenance rituximab group . Two recent randomized trials support these observations. In the trial reported by Ardeshna et al.[16▪], patients with low-tumor burden follicular lymphoma were randomly assigned to a wait and watch approach or treatment with four doses of rituximab followed by 12 doses of maintenance rituximab over the next 2 years. As expected, time to initiation of next treatment and progression-free survival (PFS) were better in the maintenance rituximab arm than in the watchful waiting arm. However, there was no difference in 3-year OS or in the likelihood of transformation. Notably, the original study design also included a third arm of single-agent rituximab, prematurely closed because of slow accrual. Despite the limited number of patients treated, outcomes in this group paralleled those of the maintenance rituximab arm, suggesting that maintenance rituximab addition does not induce additional benefits to PFS. In the Rituximab Extended Schedule or Re-Treatment trial [17▪], 408 patients with low-tumor burden follicular lymphoma were treated with weekly rituximab for 4 weeks, and responder patients were subsequently randomized to two different strategies. In the retreatment rituximab group, patients were observed and retreated with rituximab at progression, whereas in the maintenance rituximab group patients received a single-dose rituximab every 13 weeks until progression. With a median follow-up of 4.5 years, there was no difference in time to treatment failure between the two strategies, and OS was remarkable in both arms (94% at 5 years). Again, no difference in the rate of histologic transformation was observed. Overall, results from these randomized trials suggest that an aggressive maintenance rituximab strategy does not significantly impact OS compared with initial observation or first-line rituximab treatment without maintenance, at least within the reported timeframe of follow-up. From a pharmacoeconomics point of view, the implications of these trials on resource use are likely to be substantial .
First-line treatment for high-tumor burden indolent non-Hodgkin lymphomas
Although the utility of front-line rituximab in asymptomatic patients remains controversial, rituximab has undoubtedly changed the paradigm of treating high-tumor burden, symptomatic iNHL . The benefit of adding rituximab to combination chemotherapy has been demonstrated across multiple randomized trials of chemotherapy with or without rituximab [20–23][20–23][20–23][20–23], and has been confirmed by a large meta-analysis . All of these Phase III trials demonstrated major improvements in EFS and PFS for patients treated in the rituximab-containing arms and, importantly, three of the four studies also demonstrated improvement in OS. Thus, these trials represent practice-changing milestones in the clinical management of iNHL, and it is now inconceivable to administer induction chemotherapy without rituximab. However, which chemotherapy regimen should be coupled with rituximab during induction remains a matter of debate. The Italian FOLL05 Phase III trial compared the efficacy of the three most common first-line regimens [rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP), rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and rituximab-fludarabine and mitoxantrone (R-FM)] , and found both R-CHOP and R-FM superior to R-CVP in 3-year PFS and time to treatment failure, with R-CHOP displaying a more favorable toxicity profile. However, no difference in OS was observed. Two recent randomized Phase III trials have challenged the superiority of anthracycline-containing regimens, by comparing R-CHOP with bendamustine along with rituximab [26,27][26,27]. Both studies suggest that bendamustine along with rituximab is at least as effective as (if not superior to) R-CHOP in terms of PFS and may be less toxic. However, to definitively declare bendamustine along with rituximab superiority, longer follow-up and comparison of OS and incidence of long-term toxicities are required. Although bendamustine has been used for decades in East Germany, little evidence on its long-term toxicity is available, and concerns about stem cell mobilization and secondary tumors have not been addressed.
The concept of maintenance rituximab has also been explored in the setting of high-tumor burden iNHL upon first-line therapy. The Primary RItuximab and MAintenance (PRIMA) study has demonstrated substantial PFS benefit with a maintenance rituximab strategy compared with observation , although even the extended 6-year follow-up of this study, reported in abstract form at the 2013 American Society of Hematology (ASH) meeting , did not reveal differences in OS or rates of transformation between the two groups. Despite the lack of OS benefit, in the high-tumor burden setting 2-year PFS appears a satisfying endpoint, as the risk of relapse upon first-line R-CHOP is highest within the first 2 years after treatment . Yet, in the PRIMA trial, the advantage in PFS with maintenance rituximab mainly occurred after 2 years. Therefore, direct comparison of maintenance rituximab and retreatment rituximab strategies upon first-line therapy is needed before integrating maintenance rituximab in clinical practice.
Clearly, much effort still needs to be dedicated on how to dose rituximab for the optimal blend of efficacy, toxicity, and resource use. To date, the success of rituximab in iNHL has largely relied on R-chemo combinations, single-agent rituximab being much less effective as induction therapy. We anticipate that in the future, smart molecules such as immunomodulatory agents and kinase inhibitors will represent the perfect partners for rituximab, conjugating selective antilymphoma activity and low toxicity in chemotherapy-free approaches. Phase II trials are convincingly demonstrating the potential of such approaches [31▪▪], and the Rituximab Lenalidomide Versus Any Chemotherapy trial is expected to definitively unleash the potential of chemotherapy-free strategies for the initial treatment of iNHL.
RITUXIMAB AND AUTOLOGOUS STEM CELL TRANSPLANTATION
Despite the incorporation of rituximab into conventional chemotherapy significantly improving the outcomes of iNHL, there is no plateau on the PFS curves, with patients continuing to relapse. High-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) has been attempted to consolidate first remission; however, most of these studies preceded the widespread use of rituximab [32–34][32–34][32–34], with only one exception . A common finding of HDC-ASCT studies, confirmed by a large meta-analysis , was a significant improvement in PFS without impact on OS, partly explained by the excess number of second malignancies. Nevertheless, retrospective analyses of HDC-ASCT for follicular lymphoma in first remission suggest that a PFS plateau appears beyond 12 years, with more than 40% of patients being disease-free at this time [37–39][37–39][37–39]. Such long-term disease survivorship for a subset of patients, who have completely discontinued therapy and possibly maintained minimal residual disease (MRD) negativity [37,40][37,40], should be emphasized, even if OS for treatment cohorts proves similar.
In contrast to patients in first remission, HDC-ASCT has a more definitive role in patients with relapsed disease, as response rates and duration of remission to subsequent salvage chemotherapies steadily decrease. In the prerituximab era, two large retrospective studies [41,42][41,42] and the prospective CUP trial  demonstrated a PFS but not OS benefit for HDC-ASCT in the setting of relapsed follicular lymphoma. After the introduction of rituximab, several groups have investigated the value of its incorporation into HDC-ASCT schemes, either as in-vivo purging, integrated into the conditioning or as maintenance therapy. With the goal of eliminating autograft contamination and increasing the probability of obtaining a molecular remission, rituximab has been employed as in-vivo purging agent in several Phase II trials with promising results [44–47][44–47][44–47][44–47], though only one Phase III trial tested its efficacy . In this trial, rituximab-naive relapsed follicular lymphoma patients were randomly assigned to receive HDC-ASCT coupled with in-vivo purging, 2-year maintenance rituximab or the combination of both. Disappointingly, in-vivo purging did not improve outcomes, whereas maintenance rituximab improved PFS but not OS, at least at the time of publication. Thus, although a convincing benefit of autograft purging was missing, this trial, together with previous Phase II studies [49,50][49,50], implies a role for maintenance rituximab after ASCT. Nonetheless, it should be considered that patients in this study were all rituximab-naive, limiting its current applicability. A tailored application of maintenance rituximab, based on close MRD monitoring, might be an acceptable resource-sparing compromise to intensify treatment in high-risk patients. Morschhauser et al. prospectively explored the use of four consecutive weekly doses of rituximab given 3 months after ASCT in patients with clinically detectable or polymerase chain reaction-detectable disease. Short-course maintenance rituximab induced a high rate of durable remissions, without causing infections or hypogammablobulinemia, which were frequently associated with non-MRD-oriented maintenance rituximab upon ASCT [49,50][49,50].
RITUXIMAB AND ALLOGENEIC STEM CELL TRANSPLANTATION
The incorporation of rituximab into allogeneic hematopoietic stem cell transplantation (allo-HSCT) has occurred at a slower pace than the combination of rituximab with conventional chemotherapies, owing to the inherent immunological complexities. With the growing understanding of the role of B cells in graft-versus-host disease (GvHD) pathogenesis [52–54][52–54][52–54], rituximab inclusion in allo-HSCT preparative regimens has the dual goal of improving disease control and reducing nonrelapse mortality (NRM). allo-HSCT is a highly effective treatment for iNHL and represents the only curative approach for these diseases exquisitely sensitive to immunologic graft-versus-lymphoma effect . Fortunately, the NRM associated with allo-HSCT has declined with the use of reduced-intensity conditioning regimens, and plateaus in survival and relapse are now evident . Rituximab use in allo-HSCT stems from the retrospective observation that prior exposure to rituximab resulted in lower incidence and severity of acute GvHD (aGvHD) and lower NRM . The use of peri-allo-HSCT rituximab was first reported by the M.D. Anderson Cancer Center group . Nine of 20 patients treated received rituximab at the dose of 375 mg/m2 (day 6) and 1000 mg/m2 (days 1, 8, 15 postallografting). Interestingly, the cumulative incidence of grade II–IV aGvHD was only 20%. However, addition of rituximab did not show a similar benefit on chronic GVHD (cGvHD), whose cumulative incidence was 64%. A follow-up study by the same group reported similar outcomes in 47 consecutive relapsed follicular lymphoma patients undergoing allo-HSCT from matched related or unrelated donors using the same regimen of fludarabine, cyclophosphamide, and rituximab (FCR) . Rituximab was administered at a dose of 375 mg/m2 (day 13) and 1000 mg/m2 (days 6, 11, and 18). GvHD prophylaxis consisted of tacrolimus and short-course methotrexate plus antithymocyte globulin (ATG) in case of unrelated donor grafts. PFS and OS were 83% and 85% at 5 years, and impressively 72% and 78 at 11 years . Notably, grade II–IV aGVHD cumulative incidence was only 11%. Once again, adding rituximab did not show a protective effect against cGVHD. Building on these results, two ongoing prospective Phase II multicenter studies are evaluating the value of rituximab in allo-HSCT conditioning for iNHL. The American BMT CTN-0701 trial is testing the FCR platform in patients with follicular lymphoma beyond first remission. Results on 62 patients reported as an abstract at the 2014 ASH meeting  showed 2-year PFS and OS of 75% and 83%, with a favorable relapse and NRM profile. The 2-year cumulative incidence of grade II–IV aGvHD was 27%, but incidence of cGvHD was 55%. Differently, we have reported the preliminary results of an ongoing prospective multicenter Italian study in which 82 consecutive NHL patients received a single high-dose (500 mg/m2) rituximab administration on day –6 and were compared with 71 patients, part of a previous study without rituximab . All patients received the same conditioning (thiotepa, cyclophosphamide, and fludarabine) and cyclosporine plus short-course methotrexate as GvHD prophylaxis. ATG was added in case of unrelated-donor grafts. The 2-year NRM cumulative incidence was 16% in the rituximab group and 18% in the control group, with the main cause of death being infections without GvHD in the first group, and extensive GvHD in the latter. Despite similar incidences of aGvHD and cGvHD, deaths associated to GvHD were significantly lower in the rituximab group. However, rituximab administration resulted in delayed B-cell immune reconstitution, still evident 2 years after allo-HSCT. Similar results, including low cGVHD incidence, with a slightly different peritransplant rituximab schedule have been recently reported by Sauter et al.. Overall, these studies highlight the feasibility of rituximab incorporation in allo-HSCT platforms, and convincingly show a protective effect on aGvHD, suggesting that CD20 blockade might primarily interfere with B-cell antigen presentation in the early post-HSCT phase. Larger randomized studies are needed to better establish rituximab role in cGvHD prevention. Finally, novel bendamustine-based conditioning regimens  are expected to further raise the bar of allo-HSCT curative potential for iNHL, with the goal of obtaining sustained molecular remissions .
Rituximab has greatly changed the approach to iNHL, given its efficacy, tolerability and ease of administration, doomed to further increase with the advent of subcutaneous formulation [66▪]. Rituximab represents a paradigm shift in the treatment of iNHL, having marked the beginning of the era of targeted therapies in oncology. Nonetheless, questions remain and more research is under way to establish the optimal schedule, timing, and duration of rituximab-based therapies. We anticipate that soon a plethora of clinical trials combining rituximab with targeted therapies will further improve outcomes while minimizing toxicity, with the aim of rendering these incurable diseases finally curable.
Financial support and sponsorship
This study was supported in part by Associazione Italiana per Ricerca sul Cancro (AIRC).
Conflicts of interest
All authors have no conflicts of interest.
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