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Rituximab for indolent lymphomas before and after allogeneic hematopoietic stem cell transplantation

Cieri, Nicolettaa,b; Di Bartolo, Orazioc; Corradini, Paoloa,d

doi: 10.1097/MOH.0000000000000180
HEMATOPOIETIC STEM CELL TRANSPLANTATION: Edited by Andrea Bacigalupo
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Purpose of review The most substantial advancement in the treatment of indolent B-cell non-Hodgkin lymphoma (NHL), since the advent of combination chemotherapy, has been the introduction of the monoclonal anti-CD20 antibody rituximab. However, the optimal schedule, timing, and duration of rituximab therapy remain controversial.

Recent findings Since its initially reported single-agent activity in 1997, the role of rituximab has greatly expanded and it is now ubiquitously integrated in all treatment phases of indolent NHL. Yet, several questions remain to be addressed: should asymptomatic patients be treated at diagnosis with single-agent rituximab or still kept in watchful waiting, what are the optimal first-line treatments to combine with rituximab, what is the role of maintenance therapy, and is there a benefit in incorporating rituximab in autologous and allogeneic stem cell transplantation schemes for these diseases? Recent and ongoing clinical trials tackling these relevant issues will be presented and critically discussed in this article.

Summary Excellent outcomes are reported with rituximab therapy in indolent NHL, both early and late in the disease course. Continued study of this most valuable therapeutic agent is warranted to set the optimal treatment approach leading to cure the majority of patients.

aDivision of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

bUniversità degli Studi di Milano, Milano, Italy

cUniversità degli Studi di Palermo, Palermo, Italy

dChair of Hematology, School of Medicine, Università degli Studi di Milano, Milano, Italy

Correspondence to Prof Paolo Corradini, MD, Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy. E-mail: paolo.corradini@unimi.it

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INTRODUCTION

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 [1]. Other iNHL subtypes include marginal zone lymphoma, lymphoplasmacytic lymphoma and small lymphocytic lymphoma [2]. Collectively, iNHL rivals their aggressive NHL counterparts in incidence, with approximately 30 000 new cases diagnosed each year [3].

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 [4]. 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.

Box 1

Box 1

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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 [10]. 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 [11], 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 [14], 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 [15]. 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 [18].

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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 [19]. 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 [24]. 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)] [25], 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 [28], although even the extended 6-year follow-up of this study, reported in abstract form at the 2013 American Society of Hematology (ASH) meeting [29], 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 [30]. 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.

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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 [35]. A common finding of HDC-ASCT studies, confirmed by a large meta-analysis [36], 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 [43] 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 [48]. 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.[51] 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].

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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 [55]. 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 [56]. 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 [57]. The use of peri-allo-HSCT rituximab was first reported by the M.D. Anderson Cancer Center group [58]. 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) [59]. 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 [60]. 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 [61] 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 [62]. 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.[63]. 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 [64] are expected to further raise the bar of allo-HSCT curative potential for iNHL, with the goal of obtaining sustained molecular remissions [65].

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CONCLUSION

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.

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Acknowledgements

None.

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Financial support and sponsorship

This study was supported in part by Associazione Italiana per Ricerca sul Cancro (AIRC).

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Conflicts of interest

All authors have no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16:2780–2795.
2. IARC, Jaffe ES, Harris NL, Stein H, Vardiman JW. WHO classification: pathology and genetics of tumors of haematopoietic and lymphoid tissues. 2001.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5–29.
4. Horning SJ. Follicular lymphoma, survival, and rituximab: is it time to declare victory? J Clin Oncol 2008; 26:4537–4538.
5. Zelenetz AD, Gordon LI, Wierda WG, et al. Non-Hodgkin's lymphomas, version 4.2014. J Natl Compr Canc Netw 2014; 12:1282–1303.
6. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma. Ann Oncol 2013; 24:857–877.
7. Ghielmini M, Vitolo U, Kimby E, et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol 2013; 24:561–576.
8. Zinzani PL, Marchetti M, Billio A, et al. SIE, SIES, GITMO revised guidelines for the management of follicular lymphoma. Am J Hematol 2013; 88:185–192.
9. Tarella C, Arcaini L, Baldini L, et al. Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation guidelines for the management of indolent, nonfollicular B-cell lymphoma (marginal zone, lymphoplasmacytic, and small lymphocytic lymphoma). Clin Lymphoma Myeloma Leuk 2015; 15:75–85.
10. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362:516–522.
11. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16:2825–2833.
12. Colombat P, Brousse N, Salles G, et al. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol 2012; 23:2380–2385.
13. Hainsworth JD, Burris HA, Morrissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 2000; 95:3052–3056.
14. Martinelli G, Schmitz S-FH, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28:4480–4484.
15. Solal-Céligny P, Bellei M, Marcheselli L, et al. Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database. J Clin Oncol 2012; 30:3848–3853.
16▪. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, nonbulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 2014; 15:424–435.
17▪. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol 2014; 32:3096–3102.

These two randomized studies investigated two different approaches to early treatment of low-tumor burden follicular lymphoma, which is a matter of great debate. Both studies found single-agent rituximab highly effective in extending PFS and time to next treatment; however, this was not accompanied by a significant benefit on overall survival. These practice-changing results have substantial implications on resource use in indolent NHL management.

18. Prica A, Chan K, Cheung M. Frontline rituximab monotherapy induction versus a watch and wait approach for asymptomatic advanced-stage follicular lymphoma: a cost-effectiveness analysis. Cancer 2015; 15:2637–2645.
19. Fisher RI, LeBlanc M, Press OW, et al. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 2005; 23:8447–8452.
20. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25:1986–1992.
21. Hiddemann W. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106:3725–3732.
22. Marcus R, Imrie K, Solal-Céligny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008; 26:4579–4586.
23. Salles G, Mounier N, De Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008; 112:4824–4831.
24. Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma. Cochrane Database Syst Rev 2007; 4:CD003805.
25. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013; 31:1506–1513.
26. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 noninferiority trial. Lancet 2013; 381:1203–1210.
27. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014; 123:2944–2952.
28. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377:42–51.
29. Seymour JF, Feugier P, Offner F, et al. Updated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy [abstract]. Blood 2013; 122:509.
30. Byrtek M, Dawson KL, Zhou X, et al. Early relapse of follicular lymphoma after R-CHOP uniquely defines patients at high risk for death: an analysis from the national lymphocare study [abstract]. Blood 2013; 122:510.
31▪▪. Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014; 15:1311–1318.

This Phase II study demonstrates the safety and remarkable effectiveness of the combination of lenalidomide and rituximab as first-line treatment of advanced indolent NHL. If validated by the ongoing Phase III RELEVANCE study, these results will challenge the current standard treatment for advanced stage indolent lymphomas and will set chemotherapy-free approaches as the new treating paradigm for these diseases.

32. Gyan E, Foussard C, Bertrand P, et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113:995–1001.
33. Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104:2667–2674.
34. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 2006; 108:2540–2544.
35. Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111:4004–4013.
36. Schaaf M, Reiser M, Borchmann P, et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012; 1:CD007678.
37. Corradini P, Ladetto M, Zallio F, et al. Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol 2004; 22:1460–1468.
38. Brown JR, Feng Y, Gribben JG, et al. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. Biol Blood Marrow Transplant 2007; 13:1057–1065.
39. Jiménez Ubieto A, Grande García C, Yáñez L, et al. High dose therapy with autologous stem cell transplantation (HDT/ASCT) support in follicular lymphoma (FL) a very long follow-up analysis of 640 patients of geltamo spanish group suggests that FL might be cured even in high-risk patients [abstract]. Blood 2014; 124:675.
40. Corradini P, Astolfi M, Cherasco C, et al. Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin's lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting. Blood 1997; 89:724–731.
41. Montoto S, Canals C, Rohatiner AZS, et al. Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study. Leukemia 2007; 21:2324–2331.
42. Kornacker M, Stumm J, Pott C, et al. Characteristics of relapse after autologous stem-cell transplantation for follicular lymphoma: a long-term follow-up. Ann Oncol 2009; 20:722–728.
43. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP Trial. J Clin Oncol 2003; 21:3918–3927.
44. Belhadj K, Delfau-Larue M-H, Elgnaoui T, et al. Efficiency of in vivo purging with rituximab prior to autologous peripheral blood progenitor cell transplantation in B-cell non-Hodgkin's lymphoma: a single institution study. Ann Oncol 2004; 15:504–510.
45. Arcaini L, Montanari F, Alessandrino EP, et al. Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma. Ann Oncol 2008; 19:1331–1335.
46. Tarella C, Zanni M, Magni M, et al. Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innnovative nei linfomi survey. J Clin Oncol 2008; 26:3166–3175.
47. Magni M, Di Nicola M, Carlo-Stella C, et al. Efficacy and safety of high-dose chemotherapy with in vivo purged auto-SCT in relapsed follicular lymphoma: long-term follow-up. Bone Marrow Transplant 2010; 45:1119–1120.
48. Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 2013; 31:1624–1630.
49. Brugger W, Hirsch J, Grünebach F, et al. Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study. Ann Oncol 2004; 15:1691–1698.
50. Hicks LK, Woods A, Buckstein R, et al. Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma. Bone Marrow Transplant 2009; 43:701–708.
51. Morschhauser F, Recher C, Milpied N, et al. A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma. Ann Oncol 2012; 23:2687–2695.
52. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012; 12:443–458.
53. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, Bergwelt-Baildon von MS. The role of B cells in the pathogenesis of graft-versus-host disease. Blood 2009; 114:4919–4927.
54. Sarantopoulos S, Ritz J. Aberrant B-cell homeostasis in chronic GVHD. Blood 2015; 125:1703–1707.
55. Rezvani AR, Sandmaier BM. Allogeneic hematopoietic cell transplantation for indolent non-Hodgkin lymphoma: indications and outcomes. Curr Opin Hematol 2013; 20:509–514.
56. Khouri IF. Reduced-intensity regimens in allogeneic stem-cell transplantation for nonhodgkin lymphoma and chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program 2006; 2006:390–397.
57. Ratanatharathorn V, Logan B, Wang D, et al. Prior rituximab correlates with less acute graft-versus-host disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation. Br J Haematol 2009; 145:816–824.
58. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98:3595–3599.
59. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008; 111:5530–5536.
60. Khouri IF, Saliba RM, Erwin WD, et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 2012; 119:6373–6378.
61. Laport GG, Wu J, Logan BR, et al. Reduced intensity conditioning (RIC) with rituximab yields excellent outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for relapsed follicuar lymphoma (FL): A Phase II Multicenter Trial from the blood and marrow transplant network (BMT CTN 0701) [abstract]. Blood 2014; 124:682.
62. Dodero A, Spina F, Sarina B, et al. High-dose rituximab in the conditioning regimen before allogeneic stem cell transplantation decreases deaths related to gvhd without affecting the anti-lymphoma effect [abstract]. Blood 2013; 122:2059.
63. Sauter CS, Barker JN, Lechner L, et al. A phase II study of a nonmyeloablative allogeneic stem cell transplant with peritransplant rituximab in patients with B cell lymphoid malignancies: favorably durable event-free survival in chemosensitive patients. Biol Blood Marrow Transplant 2014; 20:354–360.
64. Khouri IF, Wei W, Korbling M, et al. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood 2014; 124:2306–2312.
65. Corradini P, Dodero A, Farina L, et al. Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pretransplant disease status and histotype heavily influence outcome. Leukemia 2007; 21:2316–2323.
66▪. Davies A, Merli F, Mihaljevic B, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol 2014; 15:343–352.
Keywords:

follicular lymphoma; hematopoietic stem cell transplantation; immunotherapy; indolent non-Hodgkin lymphoma

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