Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

How to Manage…

How we manage follicular lymphoma

Abstract

Major changes have taken place within the last few years in the management of follicular lymphoma (FL) leading to substantial improvement in prognosis and overall survival. For some patients with limited disease stages I and II, radiotherapy may be associated with durable responses; however, it is unclear whether patients are cured and new approaches such as the combination of irradiation with rituximab or even single-agent rituximab need to be explored. Whereas watch and wait is the current standard for stage III and IV disease with low tumour burden, better indices are warranted to potentially select patients for whom early intervention is preferred. For advanced stages with a high tumour burden, immunochemotherapy followed by 2 years of rituximab maintenance is widely accepted as standard therapy, although re-treatment at recurrence may be an alternative option. Highly attractive new therapeutic options have recently arisen from new antibodies, and from new agents targeting oncogenic pathways such as B-cell receptor signalling pathways or inhibition of bcl 2. Furthermore, immunomodulatory drugs may add to the therapeutic armamentarium and may lead to ‘chemotherapy-free’ therapies in the near future. Hence, the management of FLs has become a moving target and the hope is justified that the long-term perspectives of patients suffering from the disease will be further improved in the near future.

Introduction

Follicular lymphoma (FL) is the second most frequent type of lymphoma subtype worldwide, with a rising incidence particularly in Western countries.1, 2 Biologically, tumour cells are malignant counterparts of normal germinal centre B-cells. Together with a heterogeneous group of cells, including macrophages, follicular dendritic cells, fibroblasts, endothelial cells and T lymphocytes, FL cells form a disease-specific microenvironment allowing a dynamic and bidirectional feedback process between cancer cells and the complex network of reactive cells.3, 4

On the basis of the relative proportion of centrocytes to centroblasts, FL grades 1 to 3 are discriminated with a further separation of grade 3A and 3B.5 Whereas FL grades 1 to 3A share common histologic and molecular features and have an indolent clinical course, FL grade 3B histologically resembles diffuse large B-cell lymphoma, reveals different molecular characteristics and is clinically more aggressive.

The genetic hallmark of FL, the translocation t(14;18)(q32;q21), results in the constitutive overexpression of the bcl 2 protein, which impairs the normal germinal centre apoptotic programme. Almost all cases of FL carry additional genetic alterations such as gains, losses or mutations of genes such as MLL2, EPHA7, TNFRSF14, BCL6, CREBBP, EZH2 and many others. However, the level of B-cell development at which these alterations occur, their sequence, their relation to the translocation t(14;18) and their impact on the pathogenesis of FL, remains unclear.3, 4 Weigert and Weinstock recently proposed a model for the molecular ontogeny of FL that considers different possibilities for the initial steps of malignant transformation within the hierarchy of lymphomagenesis.6, 7

Clinically, FL is usually characterised by an indolent course, and many patients remain asymptomatic despite extended disease. In fact, the vast majority of patients are diagnosed at advanced stages III and IV. Although FL is still considered incurable, substantial progress has been achieved in the last decades, particularly through the introduction of monoclonal antibodies and of rituximab in particular into FL therapy and its combination with conventional chemotherapeutic regimens. In addition, diagnostic workup has been refined, including molecular markers, immunophenotyping and positron emission tomography (PET) imaging.

Therapy of FLs at limited stages I and II

Approximately 15–25% of FL patients are diagnosed at early stages I and II. Because of the high radiosensitivity of FL and the potential for cure, national and international guidelines uniformly recommend radiotherapy for these patients.8, 9 In the past a series of studies have suggested that radiotherapy by way of involved or even extended field irradiation may achieve long-term disease-free survival and possibly cure.10, 11, 12, 13, 14, 15 However, these studies have been performed in the pre-rituximab era; most of them were retrospective and none of them compared the respective radiotherapeutic approach with other alternatives. Furthermore, the dose and field size of radiation are still not clearly defined, although a recent study suggests that 24 Gy may be sufficient.16 Hence, the definition of radiotherapy as the standard treatment for localised stages of FL was not based on solid scientific evidence.

A recent survey of the National LymphoCare Study consequently demonstrated that adherence to the standard is low.17 Less than a third of 471 patients with stage I FL were actually treated with radiotherapy alone, whereas the rest were either only observed, received single-agent rituximab, or received a combination of rituximab plus chemotherapy with or without subsequent irradiation. In addition, only 206 patients were adequately staged by carrying out a mandatory bone marrow biopsy. Although this study was not designed to compare different therapeutic options in early-stage FL and the selection of treatment was not based on predefined entry criteria, it clearly illustrates that in clinical practice radiotherapy is not considered standard therapy in the majority of cases. Similar results also emerged from an analysis of guidance adherences in patients with malignant lymphomas from the Netherlands.18 This obvious uncertainty about the most adequate therapy for early-stage FL may in part result from the observation that a watch-and-wait approach for these patients may not be inferior to radiation therapy.19 Furthermore, the question remains whether clinically defined stages I and II really represent a localised disease or whether FL is primarily a disseminated disease even if no widespread clinical manifestations can be detected. On the other hand, the LymphoCare study reported that adequately staged patients had a better outcome compared with patients with insufficient staging at diagnosis. Remarkably, the different treatment modalities that were chosen all resulted in a comparably favourable outcome.

Which conclusion can be drawn from these data and how can we use them for the management of our FL patients with early stages of the disease today?

First, we have to admit that there is currently no generally accepted and scientifically validated standard therapy for patients with early-stage FL. Second, we have to re-emphasise the need for adequate staging at diagnosis to ensure the precise definition of the extent of the disease before taking a therapeutic decision. In this context, the role of 18FDG PET needs to be better defined. Third, there is an urgent need to compare the different treatment options, such as rituximab followed by radiotherapy, immunochemotherapy followed by radiotherapy, or single-agent rituximab, in prospective randomized trials, some of which have already been initiated.20, 21 Fourth, new markers need to be developed to distinguish patients who need to be treated immediately from those who might be observed because of an indolent course of their disease.

Patients with early stages of FL should, therefore, preferentially be treated within prospective clinical studies. For patients outside clinical trials, an individual decision needs to be made that should consider the patient's age and general condition, symptoms of the disease such as B symptoms or bulky disease and other risk factors such as elevated lactate dehydrogenase or beta-2-microglobulin levels. On the basis of these criteria a combination of rituximab plus radiotherapy or even rituximab plus chemotherapy followed by irradiation may be adopted in younger and medically fit patients with a long life expectancy, whereas single-agent rituximab or even a watch-and-wait approach may be appropriate for older or medically unfit patients.

Therapy of FLs at advanced stages III and IV

Patients without symptoms and low tumour burden

Because of the indolent course of FL and the lack of life-prolonging or even curative therapy, the strategy of withholding treatment in asymptomatic patients with a low tumour burden until the occurrence of disease-related symptoms was established in the 1990s. This ‘watch-and-wait’ approach was confirmed in a few prospective randomized studies demonstrating that the application of systemic cytostatic therapy could be safely delayed until treatment became necessary without any negative impact on patients’ outcome.22, 23

However, as for radiotherapy in limited stages I and II, these results were generated in the pre-rituximab era and need to be re-assessed on the basis of newer treatment modalities. In this respect, long periods of event-free survival were shown after single-agent rituximab therapy in patients with a low tumour burden.24, 25 Preliminary results of a prospective randomized trial were recently reported by Ardeshna et al.26 Their study compared the three different strategies of watch-and-wait versus four weekly doses of rituximab versus four weekly doses of rituximab followed by 2 years of rituximab maintenance. Whereas the 4-week application of rituximab was stopped early, the analysis of the other two study arms revealed a significant prolongation of the time to initiation of chemo- or radiotherapy in favour of the early rituximab intervention. No relevant side effects were encountered in the rituximab-treated patients. However, follow-up is still relatively short and data on overall survival will not become available within the next few years. There was also an imbalance in design with one arm measuring time to first treatment and the other measuring time to second treatment, favouring the latter.

Longer follow-up is also required to evaluate whether early treatment with rituximab might impair the response to subsequent immunochemotherapy, which might become necessary at later disease progression.

On the basis of the currently available data, the question arises whether we should change the paradigm of watch-and-wait today. Given the many open questions on the unknown long-term outcome of early intervention, the most relevant justification for a change could be based on the assumed high level of anxiety that patients may encounter when they are faced with the fact that they suffer from a malignant disorder but remain untreated. Watch-and-wait has therefore frequently also been called ‘watch-and-worry’. A recent evaluation of the study by Ardeshna et al.,27 however, revealed that the proportion of patients suffering from high anxiety is surprisingly low and that patients assigned to watch-and-wait adjust to this approach in the vast majority of cases.

In addition, several other questions remain. When analysing the watch-and-wait arm of the study by Ardeshna in more detail it appears that 46% of patients did not require therapy within the first 3 years. Does that mean that almost half of the patients randomized for immediate intervention were treated too early and received an overtreatment? Is the benefit of delaying the onset of cytostatic therapy well balanced against a 2-year exposure to maintenance therapy? Is it really necessary to apply rituximab for 2 years to achieve this beneficial effect?

Results from the so-called RESORT study suggest that shorter courses of rituximab may lead to similar effects. In this study from the Eastern Cooperative Oncology Group, patients were initially treated with a 4-week course of rituximab after which one group of cases continued on rituximab maintenance until progression while the other group received no further therapy and was re-treated upon the recurrence of lymphoma manifestations.28 After a median follow-up of almost 4 years, time to treatment failure was similar at 3.9 and 3.6 years, respectively. Five per cent of patients in the first group required subsequent chemotherapy, whereas this was necessary in 86% of patients in the second group. However, the first group received 15.8 applications of rituximab as compared with only 4.5 doses in the second group.

Further support for not changing the current watch-and-wait strategy is gained from the F2 study database that revealed no disadvantages in patients with a low tumour burden in whom immediate treatment was withheld.29

Hence, at present, watch-and-wait should still be the preferred choice for patients with asymptomatic, low tumour burden FL.30 This recommendation is further supported by the perspective that the increasing insight into the biology of the disease will most certainly result in molecular markers that will allow the discrimination between patients with a rapidly progressive and those with a more indolent course of their disease. In addition, new and more specific anti-lymphoma therapies are rapidly emerging, which will most probably change the therapeutic approaches substantially.

Patients with symptoms or a high tumour burden—front-line therapy

For patients with a high tumour burden and/or with symptoms in need of therapy, the combination of rituximab plus chemotherapy (R-chemotherapy) has become the standard of care for frontline treatment. Four major prospective randomized studies uniformly demonstrated a significant increase in response rates, progression-free survival and particularly overall survival when comparing R-chemotherapy with chemotherapy alone.31, 32, 33, 34, 35 Whether any of the different chemotherapeutic regimens has advantages over the alternatives remains currently unanswered. Indirect evidence from the PRIMA study and from a prospective randomized trial of the Italian FIL group indicates that R-CVP has a lower response rate as compared with R-CHOP or R-FM, whereas R-FM is substantially more toxic than R-CHOP.36, 37 Recently, Rummel et al.38 reported the results of a prospective randomized trial comparing R-CHOP with R-bendamustine and described a significantly higher response rate and a longer progression-free survival in favour of R-bendamustine, which also had lower toxicity. However, no differences in overall survival were observed.38 In contrast, a subsequently performed open label randomized comparison of R-bendamustine versus R-CHOP or R-CVP revealed no significant differences in response rates and time to progression and observed more side effects after R-bendamustine.39 Still, R-bendamustine was not inferior to R-CHOP or R-CVP and therefore can be added to the currently available treatment options for initial therapy of patients with advanced-stage FL.

With modern R-chemotherapeutic regimens, overall response rates of more than 90% with complete remissions in the range of 20–60% can be expected with subsequent periods of median progression-free survival exceeding 4 to 5 years. Hence, the introduction of rituximab into frontline therapy of advanced FL represents an important step forward in the treatment of this disease (Figure 1).

Figure 1
figure 1

Key steps in the treatment of follicular lymphomas.

Patients with symptoms or a high tumour burden—therapy in remission

Despite the high efficacy of initial anti-lymphoma therapy, the majority of patients with advanced-stage FL still suffer from a progression of their disease after a period of several years. Several attempts were made to prolong the time to progression, including consolidation with radio-immunotherapy or even autologous stem cell transplantation or prolonged rituximab maintenance.

Considering the high radiosensitivity of FL and the possibility of directing a radioactive tracer specifically to lymphoma cells, radio-immunotherapy is a highly attractive option for consolidation of first remission. In fact, promising data were reported by several phase II studies.40, 41, 42, 43 A randomized phase III study reported by Morschhauser et al.44 compared 90Yi-ibritumomab treatment versus observation in patients in CR or PR after initial therapy and found a significantly longer progression-free survival in favour of radio-immunotherapy. However, only a minority of patients received rituximab during induction, thus limiting the significance of these findings. In a most recent study by Press et al.45 patients with untreated FL were randomized for initial therapy with R-CHOP versus CHOP followed by 131iodine-tositumomab . After a median follow-up of 4.9 years no differences in progression-free or overall survival were observed with high estimated 2-year progression-free survival rates of 76% for R-CHOP and 80% for CHOP-RIT. Although a longer follow-up is needed to judge the long-term effects of the different approaches of this study, it will not answer the question whether and how radio-immunotherapy could further improve the outcome of patients with advanced-stage FL. Hence, radio-immunotherapy remains investigational at this time in this setting.

The high radiosensitivity of FL was at least in part also one of the arguments using myeloablative (radio)-chemotherapy followed by autologous stem cell transplantation (ASCT) for consolidation of first remission in patients with advanced-stage FL. In three of the four published major randomized trials a significant improvement in progression-free survival was reported but in all studies overall survival was not prolonged.46, 47, 48, 49, 50 Although it may still be possible that a certain proportion of patients are cured by ASCT as consolidation therapy, ASCT has lost its relevance as first-line therapy for advanced-stage FL as similar results are nowadays achieved by less toxic and more easily applicable R-chemotherapeutic regimens.51 ASCT, however, retains its role as a therapeutic option in the relapse setting where long-lasting remissions can be achieved.52, 53, 54, 55, 56 Whether and when ASCT should be applied, that is, at first, second or third relapse, is not defined and must currently remain an individual’s decision, which may be based on the patient's age and general condition, type and intensity of prior therapy and actual lymphoma manifestations including risk factors such as bulky disease, extranodal involvement, lactate dehydrogenase and beta-2-microglobulin levels.

After several prospective randomized studies had suggested a beneficial effect of rituximab maintenance in patients with untreated and relapsed FL,57, 58, 59, 60, 61 the PRIMA study established rituximab maintenance as a new standard of care for first-line therapy of patients achieving first remission after initial therapy with either R-CHOP, R-CVP or R-FCM.62 The data were recently updated at a median follow-up of 73 months and showed that rituximab maintenance resulted in a highly significant prolongation of progression-free survival at 6 years of 59.2% as compared with 42.7% of patients without maintenance (P<0.0001).63 The beneficial effect of R-maintenance was seen across all ages and the Follicular Lymphoma International Prognostic Index (FLIPI) risk groups and leads further to an increase in the rate of complete remissions at the end of the 2-year maintenance.

Although no data are yet available on the impact of rituximab maintenance on overall survival, 2 years of rituximab maintenance following successful initial R-chemotherapy is broadly considered a new standard for first-line therapy of patients with advanced-stage FL (Figure 2).

Figure 2
figure 2

The current strategy of therapy in follicular lymphomas with a high tumour burden comprises initial immunochemotherapy for achieving a complete or partial remission, followed by 2 years of rituximab maintenance.

However, maintenance is associated with increased expense and toxicity. In addition, major questions remain or even arise: is continuous maintenance really necessary or is re-treatment at progression equally effective and possibly more cost-efficient64 as also suggested by the results of the RESORT study?28 Is 2 years of rituximab maintenance adequate, too short or too long? What can actually be achieved by maintenance—lymphoma control or even eradication? Can maintenance be adjusted to pretherapeutic risk factors such as the FLIPI or the quality of remission that is achieved by initial R-chemotherapy? Can maintenance be adjusted to minimal residual disease (MRD) in remission? Is the efficacy of rituximab maintenance dependent on the type of initial chemotherapy as suggested by Vitolo et al.?65 These and other questions must be addressed in subsequent studies.

Future perspectives in the treatment of FLs—new agents

The aforementioned discussion about the most appropriate chemotherapy to be combined with rituximab will most certainly soon be replaced by the more relevant question of which of the new agents that are currently under development should be incorporated into first-line therapy and how should these new drugs be combined with each other.

Actually, a real plethora of new agents is currently explored, some of which have entered clinical phase III evaluation already.66, 67

New CD20 antibodies

CD20 remains an attractive target in FL and several second- and third-generation monoclonal antibodies have been developed to target that antigen. One of these is ofatumumab, which demonstrated a high single-agent activity in relapsed FL but failed to induce a significant response rate in rituximab refractory patients.68, 69 Obinutuzumab or GA 101, on the other hand, proved effective in relapsed, rituximab refractory FL as well, both in a single-agent setting70, 71 and when combined with chemotherapy.72 Obinutuzumab is currently randomly compared with rituximab in combination with chemotherapy for first-line therapy within the so-called international GALLIUM study.

Other B-lineage antigen-directed antibodies

Although targeting CD22 and CD23 by antibodies such as epratuzumab or lumiliximab was less successful when applied as single agents, the combination of epratuzumab with rituximab induced considerable response rates both in relapse and front-line therapy.73, 74 A similar activity was found when the CD22 antibody inotuzumab was conjugated with ozogamicin and its combination with rituximab.75, 76 Promising data were also achieved by combining the anti-CD 80 antibody galiximab with rituximab in patients with untreated FL.77 A further highly attractive approach is the application of the bi-specific T-cell engaging antibody blinatumomab targeting CD19 and CD3. Although the development of this bi-specific T-cell engager antibody is currently focussed on B-precursor acute lymphoblastic leukaemia, promising early results were also obtained in B-cell lymphomas, although considerable neurotoxicity with encephalopathy was observed.78, 79

Drugs targeting oncogeneic pathways

Crucial pathways in the pathogenesis of malignant lymphomas comprise the PI3K/Akt/mTOR pathway as well as B-cell receptor signalling. mTOR inhibitors such as temsirolimus and everolimus revealed a significant single-agent activity predominantly in mantle cell lymphoma but also in FL and are currently explored in combination with different chemotherapeutic regimens.80, 81, 82 Promising data were also achieved by targeting PI3K with drugs such as idelalisib, which showed a high single-agent activity in refractory FL.83, 84 Most interesting are recent data on the impairment of B-cell receptor signalling pathways through drugs such as fostamatinib or Brutońs tyrosine kinase inhibitors such as ibrutinib.85, 86

Bcl 2 inhibitors

Interesting data also emerged from agents interfering with the bcl 2 family of proteins. Hence, promising response rates were initially reported from phase I studies with ABT-263 (navitoclax), which is, however, associated with thrombocytopenia. A better efficacy-toxicity profile is revealed by the BH3 mimetic ABT-199 (GDC-0199),87, 88 which is currently being actively developed.

Immunomodulatory drugs

One of the most promising new agents in the treatment of FL is lenalidomide. Its mechanism of action is not fully understood but probably includes a modulation of the lymphoma microenvironment and an enhanced anti-lymphoma immune response.89 After promising single-agent activity was seen particularly in patients with refractoriness to prior therapies,90 lenalidomide was combined with rituximab and achieved high response rates in first-line therapy.91, 92 An international prospective randomized phase III trial (RELEVANCE) currently compares the so-called R2 combination of lenalidomide and rituximab against conventional R-chemotherapies, both arms being followed by a respective maintenance in remission.

Overall, a large number of promising new agents are currently being explored for the treatment of patients with FL. On the basis of available data the expectation seems to be highly justified that further improvements in the outcome of patients with FL can be achieved in the near future.

Future perspectives in the treatment of FLs—better use of currently available therapies

While waiting for the exploration of new agents we may make better use of currently available therapies—for example, by adjusting them to prognostic factors or distinct response parameters.

The FLIPI is mainly based on age and clinical characteristics, including lactate dehydrogenase, and classifies patients into three major prognostic subgroups with 10-year overall survival rates of 71, 51 and 36%, respectively.93 Although the FLIPI was developed in the pre-rituximab era its relevance could also be demonstrated for rituximab-based therapies.94 The FLIPI as well as the subsequently reported modified FLIPI295 is a valuable tool for patient stratification in clinical trials and for evaluating treatment effects in the respective prognostic subgroups. However, owing to the marked variation in outcome within each subgroup, FLIPI does not allow for an adjustment of individual treatment decisions.

Modern cell biologic and genetic techniques including gene sequencing provide deeper insights into the pathobiology of FL and may allow the discrimination of distinct biologic subgroups. Indeed, associations between certain gene signatures or compositions of the microenvironment and clinical outcome have been described.96, 97, 98, 99 Data are inconsistent, however, and cannot be applied for guidance of treatment today.

In contrast, early assessment of treatment response by PET appears to be closely associated with patient outcome. Whereas the prognostic relevance of PET is already well established in Hodgkin’s disease and diffuse large B-cell lymphoma, its role in FL remained undetermined. Several recent reports, however, describe a highly significant correlation between the results of PET imaging after R-chemotherapy for advanced-stage FL and progression-free and even overall survival.100, 101, 102 In these studies PET negativity or positivity, respectively, proved superior to conventional definitions of complete or partial response and therefore support the incorporation of PET into routine response assessment as already suggested in 2007 by the revised response criteria for malignant lymphoma.103

Individualised adaptation of therapy seems also possible by molecular monitoring of treatment response using PCR for the detection and quantification of the BLC2-IGH rearrangement that results from the translocation t(14;18).104 PCR monitoring of MRD after successful cytoreductive therapy proved highly predictive for response duration104, 105, 106, 107 and was even used for pre-emptive therapy in patients with persistent MRD after ASCT.108, 109, 110, 111 Hence, monitoring of MRD may allow optimisation of the currently available treatment options by their adaptation to the MRD status in individual patients. This means that rituximab maintenance, for example, may be stopped when MRD negativity is achieved and restarted upon re-occurrence of the MRD signal.

Early assessment of treatment response by PET and molecular monitoring of MRD therefore provide the perspectives to further improve the management of patients with FL by adapting currently available therapeutic options to the status of the disease in individual patients.

Conclusions

After decades of stagnation until the mid 1990s the perspectives of patients with FL have changed substantially. The introduction of rituximab into FL therapy has led to significant improvement in long-term outcome and has challenged prior therapeutic paradigms such as radiotherapy for limited stages of the disease or the watch-and-wait approach for asymptomatic patients with low tumour burden. Hence, we are faced with the challenge to re-evaluate our therapeutic directives and to also take advantage of the large number of new agents that are currently entering clinical phase I to III studies. These developments are highly encouraging and justify the expectation that the management of patients with FL will further improve within the coming years. In this context we are also faced with the challenge to re-define our therapeutic goals. Are we aiming at cure and final disease eradication or are we aiming at making FL a chronic disease that we can control and re-treat with as little therapy as necessary upon potential re-occurrences to allow patients to live with their disease but experience ideally a normal life expectancy?

Considering that the majority of patients are at higher age, the latter approach may be most appropriate. Hence, therapy for FL remains a moving target and a challenge for basic researchers and clinicians.

References

  1. National Cancer Institute. SEER Cancer Statistics Review. NIH: Bethesda, Maryland, USA, 2008; 23.

  2. Anderson JR, Armitage JO, Weissenburger DD . Epidemiology of the non-Hodgkińs lymphomas: distribution of the major subtypes differ by geographic locations. Non-Hodgkińs Lymphoma Classification Project. Ann Oncol 1998; 7: 717–720.

    Article  Google Scholar 

  3. Kridel R, Sehn LH, Gascoyne RD . Pathogenesis of follicular lymphoma. J Clin Invest 2012; 122: 3424–3431.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Stevenson FK, Stevenson GT . Follicular lymphoma and the immune system: from pathogenesis to antibody therapy. Blood 2012; 119: 3659–3667.

    CAS  PubMed  Article  Google Scholar 

  5. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn. WHO: Geneva, Siwtzerland, 2008.

    Google Scholar 

  6. Weigert O, Kopp N, Lane AA, Yoda A, Dahlberg SE, Neuberg D et al. Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation. Cancer Dis 2012; 2: 47–55.

    Article  Google Scholar 

  7. Weigert O, Weinstock DM . The evolving contribution of hematopoietic progenitor cells to lymphomagenesis. Blood 2012; 120: 2553–2561.

    CAS  PubMed  Article  Google Scholar 

  8. Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Byrd JC, Czuczman MS et al. NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. J Natl Compr Canc Netw 2010; 8: 288–334.

    PubMed  Article  Google Scholar 

  9. Ghielmini M, Vitolo U, Kimby E, Montoto S, Walewski J, Pfreundschuh M et al. ESMO guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). Ann Oncol 2013; 24: 561–576.

    CAS  PubMed  Article  Google Scholar 

  10. Mac Manus MP, Hoppe RT . Is radiotherapy curative for stage I and II low-grade follicular lymphoma? results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996; 14: 1282–1290.

    CAS  PubMed  Article  Google Scholar 

  11. Stuschke M, Hoederath A, Sack H, Pötter R, Müller RP, Schulz U et al. Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic-centrocytic lymphomas: results of a prospective multicenter study. Study Group NHL-frühe Stadien. Cancer 1997; 80: 2273–2284.

    CAS  PubMed  Article  Google Scholar 

  12. Wilder RB, Jones D, Tucker SL, Fuller LM, Ha CS, McLaughlin P et al. Long-term results with radiotherapy for stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 2001; 51: 1219–1227.

    CAS  PubMed  Article  Google Scholar 

  13. Guadagnolo BA, Li S, Neuberg D, Ng A, Hua L, Silver B et al. Long-term outcome and mortality trends in early-stage, grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 2006; 64: 928–934.

    PubMed  Article  Google Scholar 

  14. Pugh TJ, Ballonoff A, Newman F, Rabinovitch R . Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a surveillance, epidemiology, and end results database analysis. Cancer 2010; 116: 3843–3851.

    PubMed  Article  Google Scholar 

  15. Campbell BA, Voss N, Woods R, Gascoyne RD, Morris J, Pickles T et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy. Cancer 2010; 116: 3797–3806.

    PubMed  Article  Google Scholar 

  16. Lowry L, Smith P, Qian W, Falk S, Benstead K, Illidge T, Linch D et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol 2011; 100: 86–92.

    PubMed  Article  Google Scholar 

  17. Friedberg JW, Byrtek M, Link BK, Flowers C, Taylor M, Hainsworth J et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 2012; 30: 3368–3375.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Wennekes L, Ottevanger PB, Raemaekers JM, Schouten HC, de Kok MW, Punt CJ et al. Development and measurement of guideline-based indicators for patients with non-Hodgkin's lymphoma. J Clin Oncol 2011; 29: 1436–1444.

    PubMed  Article  Google Scholar 

  19. Advani R, Rosenberg SA, Horning SJ . Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22: 1454–1459.

    PubMed  Article  Google Scholar 

  20. Ruella M, Filippi A, Di Russo A, Caracciolo D, Matteucci P, Magni M et al. Rituximab followed by involved field radiotherapy (IF-RT) in stage I-II follicular lymphoma (FL): long term results. Blood (ASH Annual Meeting Abstracts) 2011; 118: a3699.

    Google Scholar 

  21. Herfarth K, Engelhard M, Borchmann P, Hohloch K, Budach V, Viardot A et al. Treatment of early stage nodal follicular lymphoma using involved-field radiotherapy and rituximab: preliminary results of the MIR trial (phase II study of the German Low Grade Lymphoma Study Group (GLSG). Blood (ASH Annual Meeting Abstracts) 2012; 120: a1634.

    Google Scholar 

  22. Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997; 15: 1110–1117.

    CAS  PubMed  Article  Google Scholar 

  23. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA 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.

    CAS  PubMed  Article  Google Scholar 

  24. Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S 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.

    CAS  PubMed  Article  Google Scholar 

  25. Colombat P, Brousse N, Salles G, Morschhauser F, Brice P, Soubeyran P 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.

    CAS  PubMed  Article  Google Scholar 

  26. Ardeshna K, Qian W, Smith P, Warden J, Stevens L, Pocock CFE et al. An Intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A preliminary analysis. Blood 2010; 116: a6.

    Article  Google Scholar 

  27. Ardeshna K, Qian W, Stephens R, Smith P, Warden J, Lowry L et al. Preliminary results of quality of life analyses from the Intergroup phase III randomized trial of rituximab vs. a watch and wait approach in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma. Ann Oncol 2011; 22 (Suppl. 4): a019.

    Google Scholar 

  28. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC et al. Results of the Eastern Cooperative Oncology Group protocol E 4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Blood 2011; 118: LBA6.

    Article  Google Scholar 

  29. Solal-Céligny P, Bellei M, Marcheselli L, Pesce EA, Pileri S, McLaughlin P 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: 848–853.

    Article  Google Scholar 

  30. Cheson BD . Waiting is the hardest part. J Clin Oncol 2012; 30: 3781–3782.

    PubMed  Article  Google Scholar 

  31. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R et al. 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.

    CAS  PubMed  Article  Google Scholar 

  32. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–1423.

    CAS  Article  PubMed  Google Scholar 

  33. Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A 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.

    CAS  Article  PubMed  Google Scholar 

  34. Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008; 112: 4824–4831.

    CAS  PubMed  Article  Google Scholar 

  35. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC 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.

    CAS  PubMed  Article  Google Scholar 

  36. Morschhauser F, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A, Bouabadallah R et al. Impact of induction chemotherapy regimen on response, safety and outcome in the PRIMA study. Ann Oncol 2011; 22 (suppl 4): iv88.

    Google Scholar 

  37. Federico M, Luminari S, Dondi A, Sacchi S, Tucci A, Vitolo U 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 (FIL). J Clin Oncol 2013; 31: 1506–1513.

    CAS  PubMed  Article  Google Scholar 

  38. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C 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 non-inferiority trial. Lancet 2013; 381: 1203–1210.

    CAS  Article  PubMed  Google Scholar 

  39. Flinn IW, Van der Jagt RH, Kahl BS, Wood P, Hawkins TE et al. An open-label, randomized study of bendamustine and rituximab (BR) compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL): the Bright study. Blood 2012; 120: a 902.

    Article  Google Scholar 

  40. Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352: 441–449.

    CAS  PubMed  Article  Google Scholar 

  41. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, Leblanc M et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006; 24: 4143–4149.

    CAS  PubMed  Article  Google Scholar 

  42. Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR et al. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14: 7088–7094.

    CAS  PubMed  Article  Google Scholar 

  43. Link BK, Martin P, Kaminski MS, Goldsmith SJ, Coleman M, Leonard JP . Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight-year follow-up of a multicenter phase II study. J Clin Oncol 2010; 28: 3035–3041.

    CAS  PubMed  Article  Google Scholar 

  44. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008; 26: 5156–5164.

    CAS  PubMed  Article  Google Scholar 

  45. Press OW, Unger JM, Rimsza LM, Friedberg JW, LeBlanc M, Czuczman MS et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol 2013; 31: 314–320.

    CAS  PubMed  Article  Google Scholar 

  46. Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M 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.

    CAS  PubMed  Article  Google Scholar 

  47. Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre 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 GOELAMS. Blood 2005; 105: 3817–3823.

    CAS  PubMed  Article  Google Scholar 

  48. Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C 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.

    CAS  PubMed  Article  Google Scholar 

  49. Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A 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.

    CAS  PubMed  Article  Google Scholar 

  50. Al Khabori M, de Almeida JR, Guyatt GH, Kuruvilla J, Crump M . Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2012; 104: 18–28.

    PubMed  Article  Google Scholar 

  51. Hiddemann W, Dreyling MH, Metzner B, Pfreundschuh M, Wilhelm M et al. Evaluation of myeloablative therapy followed by autologous stem cell transplantation in first remission in patients with advanced stage follicular lymphoma after initial immuno-chemotherapy (R-CHOP) or chemotherapy alone: analysis of 940 patients treated in prospective randomized trials of the German Low Grade Lymphoma Study Group (GLSG). Blood 2013; 223: a419.

    Article  Google Scholar 

  52. Rohatiner AZ, Nadler L, Davies AJ, Apostolidis J, Neuberg D, Matthews J et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 2007; 25: 2554–2559.

    PubMed  Article  Google Scholar 

  53. Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier N et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 2008; 26: 3614–3620.

    CAS  PubMed  Article  Google Scholar 

  54. Weigert O, Uysal A, Metzner B, Pfreundschuh M, Schmitz N, Wandt H et al. Impact of autologous stem cell transplantation and/or rituximab on outcome of patients with relapsed follicular lymphoma- retrospective analysis of 2 randomized trials of the German Low Grade Lymphoma Study Group (GLSG). Blood 2008; 112: a 2189.

    Article  Google Scholar 

  55. Le Gouill S, De Guibert S, Planche L, Brice P, Dupuis J, Cartron G et al. Impact of the use of autologous stem cell transplantation at first relapse both in naive and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study. Haematologica 2011; 96: 1128–1135.

    PubMed  PubMed Central  Article  Google Scholar 

  56. Montoto S, Matthews J, Greaves P, Lillington D, Anderson D, Gribben JG et al. Myeloablative chemotherapy for chemo-sensitive recurrent follicular lymphoma: potential benefit in second relapse. Haematologica 2013; 98: 620–625.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Hainsworth JD, Litchy S, Burris 3rd HA, Scullin Jr DC, Corso SW, Yardley DA et al. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 2002; 20: 4261–4267.

    CAS  PubMed  Article  Google Scholar 

  58. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103: 4416–4423.

    CAS  PubMed  Article  Google Scholar 

  59. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108: 3295–3301.

    CAS  PubMed  Article  Google Scholar 

  60. Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006; 108: 4003–4008.

    CAS  PubMed  Article  Google Scholar 

  61. Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009; 27: 1607–1614.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L 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.

    CAS  Article  PubMed  Google Scholar 

  63. Salles G, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A 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. Blood 2013; 223: a509.

    Article  Google Scholar 

  64. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA . Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma—a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2005; 23: 1088–1095.

    CAS  PubMed  Article  Google Scholar 

  65. Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F et al. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol 2013; 31: 3351–3359.

    CAS  PubMed  Article  Google Scholar 

  66. Cheson BD . New agents in follicular lymphoma. Best Pract Res Clin Haematol 2011; 24: 305–312.

    PubMed  Article  Google Scholar 

  67. Younes A . Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol 2011; 8: 85–96.

    CAS  PubMed  Article  Google Scholar 

  68. Hagenbeek A, Gadeberg O, Johnson P, Pedersen LM, Walewski J, Hellmann A et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008; 111: 5486–5495.

    CAS  PubMed  Article  Google Scholar 

  69. Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 2012; 119: 3698–3704.

    CAS  PubMed  Article  Google Scholar 

  70. Sehn LH, Assouline SE, Stewart DA, Mangel J, Gascoyne RD, Fine G et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood 2012; 119: 5118–5125.

    CAS  PubMed  Article  Google Scholar 

  71. Salles G, Morschhauser F, Solal-Celigny P, Thieblemont C, Lamy T, Tilly H et al. Obinutuzumab (GA 101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGIN study. J Clin Oncol 2013; 31: 2920–2926.

    CAS  PubMed  Article  Google Scholar 

  72. Radford J, Davies A, Cartron G, Morschhauser F, Salles G, Marcus R et al. Obinutuzumab (GA 101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood 2013; 122: 1137–1143.

    CAS  PubMed  Article  Google Scholar 

  73. Strauss SJ, Morschhauser F, Rech J, Repp R, Solal-Celigny P, Zinzani PL et al. Multicenter phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin's lymphoma. J Clin Oncol 2006; 24: 3880–3886.

    CAS  PubMed  Article  Google Scholar 

  74. Grant BW, Jung SH, Johnson JL, Kostakoglu L, His E, Byrd JC et al. A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer 2013; 119: 3797–3804.

    CAS  PubMed  Article  Google Scholar 

  75. Advani A, Coiffier B, Czuczman MS, Dreyling M, Foran J, Gine E et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study. J Clin Oncol 2010; 28: 2085–2093.

    CAS  PubMed  Article  Google Scholar 

  76. Fayad L, Offner F, Smith MR, Verhoef G, Johnson P, Kaufman JL et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol 2013; 31: 573–583.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Czuczman MS, Leonard JP, Jung S, Johnson JL, Hsi ED, Byrd JC et al. Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol 2012; 23: 2356–2362.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321: 974–977.

    CAS  Article  PubMed  Google Scholar 

  79. Nagorsen D, Zugmaier G, Viardot A, Goebeler M, Noppeney R, Schmidt M et al. Confirmation of safety, efficacy and response duration in non-Hodgkin lymphoma patients treated with 60 μg/m2/d of BiTE® antibody Blinatumomab. Blood 2009; 114: a 2723.

    Article  Google Scholar 

  80. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009; 27: 3822–3829.

    CAS  PubMed  Article  Google Scholar 

  81. Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A et al. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: the University of Chicago phase II consortium. J Clin Oncol 2010; 28: 4740–4746.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukaemia 2011; 25: 341–347.

    CAS  Article  Google Scholar 

  83. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL et al. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012; 119: 1897–1900.

    CAS  PubMed  Article  Google Scholar 

  84. Gopal A, Kahl BS, De Vos S, Wagner-Johnston ND, Schuster SJ, Blum KA et al. Mature response data from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (rituximab and alkylating agent)-refractory indolent B-cell non-Hodgkin lymphoma (iNHL). Blood 2013; 223: a85.

    Article  Google Scholar 

  85. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukaemia. Blood 2010; 115: 2578–2585.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88–94.

    CAS  Article  PubMed  Google Scholar 

  87. Kahl B, Roberts AW, Seymour JF, Advani RH, Persky DO, Yang J et al. Navitoclax (ABT-263) plus rituximab: Interim results of a phase I study in patients with CD 20-positive lymphoid malignancies. Blood 2010; 116: a3943.

    Article  Google Scholar 

  88. Davids MS, Roberts AW, Anderson MA, Pagel JM, Kahl BS, Gerecitano JF et al. The bcl2 specific BH3-mimetic ABT-199 (GDC-0199) is active and well tolerated in patients with relapsed non-Hodgkin lymphoma: interim results of a phase I study. Blood 2012; 120: a304.

    Article  Google Scholar 

  89. Chanan-Khan AA, Cheson BD . Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008; 26: 1544–1552.

    CAS  Article  PubMed  Google Scholar 

  90. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 2009; 27: 5404–5409.

    CAS  PubMed  Article  Google Scholar 

  91. Dutia M, DeRoock I, Chee K, O'donnell R, Quirch C, Reed-Pease C et al. R2: Preliminary results of a phase II study of lenalidomide and rituximab in relapsed / refractory indolent Non-Hodgkin's Lymphoma (NHL). Blood 2009; 114: a 1679.

    Article  Google Scholar 

  92. Fowler NH, Neelapu SS, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE et al. Lenalidomide and rituximab for untreated indolent lymphoma: final results of a phase II study. Blood 2012; 120: a 901.

    Article  Google Scholar 

  93. Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–1265.

    Article  CAS  PubMed  Google Scholar 

  94. Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W . The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 2006; 108: 1504–1508.

    CAS  PubMed  Article  Google Scholar 

  95. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 2009; 27: 4555–4562.

    PubMed  Article  Google Scholar 

  96. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351: 2159–2169.

    CAS  PubMed  Article  Google Scholar 

  97. Glas AM, Kersten MJ, Delahaye LJ, Witteveen AT, Kibbelaar RE, Velds A et al. Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 2005; 105: 301–307.

    CAS  PubMed  Article  Google Scholar 

  98. Schwaenen C, Viardot A, Berger H, Barth TF, Bentink S, Döhner H et al. Microarray-based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status. Genes Chromosomes Cancer 2009; 48: 39–54.

    CAS  PubMed  Article  Google Scholar 

  99. Farinha P, Al-Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD . The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood 2010; 115: 289–295.

    CAS  PubMed  Article  Google Scholar 

  100. Trotman J, Fournier M, Lamy T, Seymour JF, Sonet A, Janikova A et al. Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol 2011; 29: 3194–3200.

    PubMed  Article  Google Scholar 

  101. Dupuis J, Berriolo-Riedinger A, Julian A, Brice P, Tychyj-Pinel C, Tilly H et al. Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. J Clin Oncol 2012; 30: 4317–4322.

    CAS  PubMed  Article  Google Scholar 

  102. Luminari S, Biasoli I, Versari A, Rattotti S, Bottelli C, Rusconi C et al. The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL). Ann Oncol 2014; 25: 442–447.

    CAS  PubMed  Article  Google Scholar 

  103. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586.

    PubMed  Article  Google Scholar 

  104. Pott C, Brüggemann M, Ritgen M, van der Velden VH, van Dongen JJ, Kneba M . MRD detection in B-cell non-Hodgkin lymphomas using Ig gene rearrangements and chromosomal translocations as targets for real-time quantitative PCR. Methods Mol Biol 2013; 971: 175–200.

    CAS  PubMed  Article  Google Scholar 

  105. Freedman AS, Neuberg D, Mauch P, Soiffer RJ, Anderson KC, Fisher DC et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999; 94: 3325–3333.

    CAS  Article  PubMed  Google Scholar 

  106. Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood 2002; 99: 856–862.

    CAS  PubMed  Article  Google Scholar 

  107. Ladetto M, Lobetti-Bodoni C, Mantoan B, Ceccarelli M, Boccomini C, Genuardi E et al. Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive programme. Blood 2013; 122: 3759–3766.

    CAS  PubMed  Article  Google Scholar 

  108. Hirt C, Schüler F, Kiefer T, Schwenke C, Haas A, Niederwieser D et al. Rapid and sustained clearance of circulating lymphoma cells after chemotherapy plus rituximab: clinical significance of quantitative t(14;18) PCR monitoring in advanced stage follicular lymphoma patients. Br J Haematol 2008; 141: 631–640.

    CAS  PubMed  Article  Google Scholar 

  109. Mangel J, Buckstein R, Imrie K, Spaner D, Franssen E, Pavlin P et al. Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as ‘in vivo purge’ and consolidative immunotherapy following autologous stem cell transplantation. Ann Oncol 2003; 14: 758–765.

    CAS  PubMed  Article  Google Scholar 

  110. Hicks LK, Woods A, Buckstein R, Mangel J, Pennell N, Zhang L 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.

    CAS  PubMed  Article  Google Scholar 

  111. Morschhauser F, Recher C, Milpied N, Gressin R, Salles G, Brice P 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.

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W Hiddemann.

Ethics declarations

Competing interests

WH serves as a member of the International Advisory Board of Roche AG and receives research grants from Roche for the support of clinical trials.

Rights and permissions

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Reprints and Permissions

About this article

Cite this article

Hiddemann, W., Cheson, B. How we manage follicular lymphoma. Leukemia 28, 1388–1395 (2014). https://doi.org/10.1038/leu.2014.91

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.91

Further reading

Search

Quick links