Current and future management of follicular lymphoma
Follicular lymphoma is usually considered as incurable, but patient’s outcome has been steadily improving over the last decade. The introduction of anti-CD20 monoclonal antibodies represented a major step. Treatment of patients should take into account accurate staging results, symptoms related to lymphoma, tumor burden, age and comorbidities. Several options are still available for patients with localized or asymptomatic low risk disease, and randomized studies should be developed for those patients. When a systemic therapy is needed, the combination of rituximab with a few of the available cytotoxic regimens clearly provides the best results. Rituximab maintenance appears to further improve the progression-free interval. Since most patients will likely survive for many years, the quality and duration of response as well as the short- and long-term side effects of the treatments should be carefully weighted during this prolonged therapeutic management.
KeywordsFollicular lymphoma Rituximab Chemotherapy
Current unresolved clinical questions regarding the upfront treatment of follicular lymphoma patients
1. Patients with Ann Arbor stage 1
Is radiation therapy still the standard of care?
2. Patients with a low tumor burden
Is watchful waiting still an acceptable option in 2012?
3. Patients with a high tumor burden
Is there an optimal chemotherapy regimen to be combined with rituximab?
The management of follicular lymphoma patients with stage I disease
Patients with Ann Arbor stage I (or very limited stage II) disease may still represent 15–25 % of patients at diagnosis . According to North American and European guidelines, the usual therapeutic recommendation, for those patients consists in localized radiation therapy [4, 5]. One randomized study comparing different doses of radiation indicated that 24 Gy may be optimal . The long-term disease control achieved with this strategy has suggested that some patients may be cured with this approach . However, retrospective series indicate that many patients do not receive radiation therapy, being either managed with observation (or watchful waiting, see below), with single agent rituximab, or with chemotherapy combined with rituximab and/or radiation therapy . This could be related to the fear of toxicities associated with radiation therapy as well as the assumption that follicular lymphoma is always a disseminated disease with low levels of circulating lymphoma cells . Unfortunately, there is a lack of systematic prospective or randomized study in this patient population, pre-empting the use of high level evidence-based recommendations. A recent analysis was performed in the United States, including 471 patients with stage I follicular lymphoma, and may help to optimize the management of this patients . First, this study indicates that patients with incomplete staging (lack of bone marrow biopsy or complete scanning using CT or 18FDG PET-CT) had an inferior outcome, emphasizing the need of rigorous patient check-up. Second, this study indicates that therapeutic approaches such as watchful waiting or single agent rituximab did not result in inferior results as compared to radiation therapy only. In fact, the best outcome was observed in patients receiving systemic treatment, either chemotherapy plus rituximab or combined modality approach (abbreviated rituximab chemotherapy followed by radiation therapy). Although this study is limited by its retrospective nature , these data clearly suggest that systemic treatments should be further evaluated in patients with limited stage follicular lymphoma patients.
The management of patients with disseminated disease and a low tumor burden
Tumor burden criteria
Criteria related to the tumor: patients should not present with:
Lymph nodes or tumor mass (except spleen) larger than 7 cm
Nodes greater than 3 cm in 3 distinct areas
Symptoms related to organ compression, pleural effusion or ascites, spleen enlargement; renal, liver or bone involvement
Biological criteria: patients should present with:
Serum LDH and serum beta2-microbulin below the upper normal values
Cytopenia (hemoglobin <10 g/dL or WBC <3.0 × 109/L or platelet counts <100 × 109/L) related to bone marrow infiltration
Criteria related to the effect of lymphoma on patient general status: patient should not present with
Systemic symptoms (fever, night sweats, weight loss)
Altered performance status (>1 on the WHO scale)
Time dependant related criteria:
Lack of generalized lymphoma progression over the last 3 months
The management of patients symptomatic or with a high tumor burden
When patients with follicular lymphoma present with a high tumor burden or develop symptoms after a watchful waiting period, the use of cytotoxic chemotherapy combined with rituximab has been established as the standard of care in the last decade [20, 21, 22, 23]. Several randomized studies have clearly demonstrated that this treatment improves response rates, progression-free and overall survival, as compared to chemotherapy alone. It was estimated that the risk of death was reduced by about 30 % in these patients with such strategies .
Retrospective analysis of patients receiving the R–FCM regimen (rituximab, fludarabine, cyclophosphamide and mitoxantrone) in the PRIMA study  as well as data originating from the FL-05 Italian study  regarding the R–FM regimen (rituximab, fludarabine, mitoxantrone), demonstrated that these fludarabine-containing regimens were as efficient as R–CHOP but significantly more toxic. This toxicity included severe infections and secondary neoplasia and the overall survival of patients was inferior to that achieved with other regimens.
The response rates and progression-free survival associated with the use of R–CHOP were found to be significantly better than those observed with the use of R–CVP [25, 26]. However, so far, no study has demonstrated that the overall survival of patients was significantly better when R–CHOP was used. Indirect non-randomized data originating from the PRIMA study  or from the North American Lymphocare study  suggested, however, that R–CHOP may lead to a prolonged survival in patients with adverse features (those with a high FLIPI score, for instance).
Finally, the German Stil NHL 1-2003 study compared the use of R–CHOP and R–bendamustine in patients with indolent lymphoma, and included 279 patients with follicular lymphoma . R–bendamustine appeared significantly less toxic than R–CHOP, with less hematopoietic, infectious and neurological toxicities. Furthermore, in patients with follicular lymphoma, complete response rates and progression-free survival were significantly better in the R–bendamustine arm. However, this benefit did not translate into an overall survival difference. It was also pointed by some investigators that the results obtained with R–CHOP in this trial were inferior to those of other studies [25, 26].
In conclusion, it seems that with the exception of fludarabine combination, at this time, the three R–CVP, R–CHOP and R–bendamustine regimens all appear to be acceptable options. Preliminary data indicate that R–CHOP should be preferred over R–CVP in patients with adverse prognostic features. In the wait for definitive results and confirmative studies, it might appear premature to conclude that R–bendamustine should always be preferred to R–CHOP, although the low toxicity profile of the former made it a very attractive option.
The role of consolidation after achieving a response to rituximab chemotherapy
Despite the efficacy of rituximab chemotherapy combinations, most patients will progress within 3–6 years after achieving a response to their induction regimen. Several studies have therefore attempted to consolidate remission using radio-immunotherapy or rituximab maintenance.
One randomized study evaluated the role of 90Y-labeled ibritumomab tiutexan administration after chemotherapy . The results indicated higher response rates and prolonged progression-free survival with the use of radio-immunotherapy. However, only a few patients had received rituximab in combination with chemotherapy before this treatment, indicating that it is difficult to extend these results in the modern treatment era. Furthermore, a higher number of secondary malignancies were observed with the use of radio-immunotherapy . Another study compared the use of rituximab–CHOP versus rituximab–CHOP followed by the administration of 131I tositumomab . No significant differences were observed for progression free or overall survivals. Again, a slight excess of haematological malignancies was also observed after radio-immunotherapy. Altogether, these data indicate that radio-immunotherapy should be further evaluated for its efficacy and toxicity before it can be routinely used in the first line treatment of follicular lymphoma patients.
The role of rituximab maintenance in patients with follicular lymphoma responding to an induction immuno-chemotherapy has been evaluated in the PRIMA study . Patients responding to R–CVP, R–CHOP or R–FCM were randomized to receive either one infusion of rituximab every 2 months for 2 years or no further treatment (observation). The risk of lymphoma progression was significantly reduced for those patients receiving maintenance rituximab (hazard ratio 0.55; 95 % confidence interval [CI] 0.39–0.64). Furthermore, a significantly higher proportion of patients (72 vs. 52 %; P = 0.0001) had reached a complete response 2 years after completing induction in the rituximab maintenance arm. The benefit of rituximab maintenance was observed whatever the patients’ age, the quality of response after induction (complete vs. partial response) or the FLIPI groups, or the isoforms of the FcGRIIIA receptor [23, 32]. The best results with maintenance were also observed in patients that had received R–CHOP induction (3-year progression-free survival 70 vs. 60 % with R–CVP). However, no significant difference in term of overall survival was observed. Patients experienced more frequently adverse events during rituximab maintenance (24 vs. 17 % WHO grade 3/4 events, P = 0.0026) and more frequently infections, which were predominantly of grade 2. But only 4 % of the patients randomized in the rituximab maintenance arm withdrew from study for treatment-related toxicities.
A recent meta-analysis considering 9 studies and more than 2500 patients demonstrated that the use of rituximab maintenance was associated with a significant reduction of the risk of death (hazard ratio 0.76; 95 % CI 0.62–0.92) . Although this findings were predominant in patients treated with rituximab maintenance in second line, a similar trend was observed for those receiving maintenance after first line treatment (hazard ratio 0.86, 95 % CI 0.60–1.25).
The management of patients at the time of lymphoma progression
When the first line treatment has failed, many options are available, including at least immunotherapy, chemo-immunotherapy, autologous or allogeneic transplant. Therapeutic decision should take into account patient age, fitness and priorities. Additional important considerations are: type of previous treatment, depth and duration of previous response and tolerability, as well histological transformation. This possibility should be systematically explored since it will prompt treatment strategies used in diffuse large B cell lymphoma.
Randomized studies performed at the time of progression have evaluated the use of rituximab maintenance after chemotherapy [34, 35], as well as the use of rituximab in the context of autologous transplant . But treatment strategies have not been compared, with the exception of a small underpowered study evaluating autologous transplantation .
The role of this latter option remains controversial , although several retrospective studies suggested its benefit, even the rituximab era [39, 40]. It is worth mentioning that the median progression-free survival achieved in the recent European Bone Marrow Transplant study of rituximab for induction and maintenance in the context of autologous transplant exceeded 5 years (in the rituximab containing arms) . Such results are usually not attained using other options in the same setting.
Future perspectives and conclusions
Although many progresses have been made to understand the origin and biology of follicular lymphoma [41, 42], we are still essentially relying on clinical-related factors to guide our therapeutic decisions. We may hope that some biomarkers will provide useful insights into the future. Another field of interest is the monitoring of treatment efficacy, with the use of 18FGD PET–CT. Recent retrospective and prospective studies demonstrated that PET–CT results can predict the outcome of patients at the end of induction immune-chemotherapy [43, 44].
Given the success of the first anti-CD20 antibody used, rituximab, several other antibodies targeting the same antigen are being developed, including ofatumomab, veltuzumab or obinutuzumab (also called GA101) . This latter molecule is a new type II glyco-engineered humanized anti-CD20 recognizing a distinct epitope of this cell surface antigen. In in vitro and animal models, obinutuzumab was shown to have a very potent direct cell killing effect against malignant B cell, and an increased ability to induce antibody-dependent cellular cytotoxicity  Promising clinical data were obtained in phase I and II trials, suggesting a good safety and efficacy profile of this new antibody in follicular lymphoma patients . The combination of obinutuzumab plus chemotherapy followed by obinutuzumab maintenance is then currently being compared to the standard approach, rituximab plus chemotherapy induction followed by rituximab maintenance (GALLIUM study, NCT01332968). The use of immunomodulating agents to increase the efficacy of anti-CD20 antibodies has also been explored with very promising results , leading to the recent launch of a large international phase III study (RELEVANCE) testing this chemotherapy-free regimen against the standard rituximab-chemotherapy induction followed by rituximab maintenance (NCT01650701). Other new treatments are actively being developed with antibody drug conjugates or targeted therapies directed against key pathways involved in B cell signaling .
Firm data obtained in randomized clinical trials are available to choose some of our strategies for the benefit of the patients. But individualized therapy will become increasingly important with the new therapeutic tools in the future.
- 1.Pulte D, Gondos A, Brenner H, editors. Expected long-term survival of older patients diagnosed with non-Hodgkin lymphoma in 2008–2012. Netherlands; 2012.Google Scholar
- 4.Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):vi59–63.Google Scholar
- 5.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 Cancer Netw. 2010;8(3):288–334.Google Scholar
- 9.Friedberg JW, Byrtek M, Link BK, Flowers C, Taylor M, Hainsworth J, Cerhan JR, Zelenetz AD, Hirata J, Miller TP. Effectiveness of first-line management strategies for stage i follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol. 2012;30(27):3368–75.PubMedCrossRefGoogle Scholar
- 11.Brice P, Bastion Y, Lepage E, Brousse N, Haioun 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(3):1110–7.PubMedGoogle Scholar
- 15.Ghielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, et al. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005;23(4):705–11.PubMedCrossRefGoogle Scholar
- 16.Colombat P, Brousse N, Salles G, Morschhauser F, Brice P, Soubeyran P, Delwail V, Deconinck E, Haioun C, Foussard C, Sebban C, Tilly H, Thieblemont C, Bergougnoux L, Lazreg F, Solal-Celigny P. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol. 2012;23(9):2380–5.PubMedCrossRefGoogle Scholar
- 17.Ardeshna KM, 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. ASH annual meeting 2010, Abstracts;116(21):6.Google Scholar
- 18.Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. ASH Annual Meeting 2011, Abstracts;118(21):LBA-6.Google Scholar
- 19.Ardeshna KM, Qian W, Stephens R, Smith P, Warden J, Lowry L, et al. Preliminary results of quality of life (Qol) analyses from the intergroup phase Iii randomised trial of rituximab vs a watch and wait approach in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma (FL). Ann Oncol. 2011;22(Suppl 4):iv88.Google Scholar
- 20.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(28):4579–86.PubMedCrossRefGoogle Scholar
- 21.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(15):1986–92.PubMedCrossRefGoogle Scholar
- 22.Hiddemann W, Kneba M, Dreyling M, 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(12):3725–32.PubMedCrossRefGoogle Scholar
- 23.Salles G, Seymour JF, Offner F, Lopez-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.PubMedCrossRefGoogle Scholar
- 24.Schulz H, Bohlius J, Skoetz N, Trelle S, Kober T, Reiser M, Dreyling M, Herold M, Schwarzer G, Hallek M, Engert A. Chemotherapy plus rituximab versus chemotherapy alone for B-cell non-Hodgkin’s lymphoma. Cochrane Database Syst Rev. 2007;17(4):CD003805.Google Scholar
- 25.Morschhauser F, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A, Bouabdallah 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
- 26.Federico M, et al. R–CVP versus R–CHOP versus R–FM as first-line therapy for advanced-stage follicular lymphoma: final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL). ASCO meeting abstracts, May 2012; 30:8006.Google Scholar
- 27.Nastoupil L, Sinha R, Byrtek M, Taylor M, Cerhan JR, Friedberg J, et al. A comparison of the effectiveness of first-line chemoimmunotherapy regimens for follicular lymphoma (FL) used in the United States. ASH annual meeting 2011, Abstracts;118(21):97.Google Scholar
- 28.Rummel MJ, et al. Bendamustine plus rituximab (B–R) versus CHOP plus rituximab (CHOP–R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. ASCO Meeting Abstr. 2012;30:3.Google Scholar
- 29.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(32):5156–64.PubMedCrossRefGoogle Scholar
- 30.Hagenbeek A, Radford J, Van Hoof A, Vitolo U, Rohatiner AZS, Salles G, et al. 90Y-Ibritumomab tiuxetan (Zevalin(R)) consolidation of first remission in advanced-stage follicular non-Hodgkin’s lymphoma: updated results after a median follow-up of 66.2 months from the international, randomized, phase III first-line indolent trial (FIT) in 414 patients. ASH annual meeting abstracts 2010;116(21):594.Google Scholar
- 31.Press OW, Unger JM, Rimsza LM, Friedberg J, LeBlanc M, Czuczman MS, et al. A phase III randomized intergroup trial (SWOG S0016) of CHOP chemotherapy plus rituximab vs. CHOP chemotherapy plus iodine-131-tositumomab for the treatment of newly diagnosed follicular non-Hodgkin’s lymphoma. ASH Annual Meeting Abstracts 2011;118(21):98.Google Scholar
- 32.Ghesquières H, Cartron G, Seymour JF, Delfau-Larue MH, Offner F, Soubeyran P, Perrot A, Brice P, Bouabdallah R, Sonet A, Dupuis J, Casasnovas O, Catalano JV, Delmer A, Jardin F, Verney A, Dartigues P, Salles G. Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms. Blood. 2012;120(13):2650–7.PubMedCrossRefGoogle Scholar
- 34.van Oers MH, Klasa R, Marcus RE, 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(10):3295–301.PubMedCrossRefGoogle Scholar
- 35.Forstpointner R, Unterhalt M, Dreyling M, 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(13):4003–8.PubMedCrossRefGoogle Scholar
- 36.Pettengell R, Schmitz N, Gisselbrecht C, et al. Randomized study of rituximab in patients with relapsed or resistant follicular lymphoma prior to high-dose therapy as in vivo purging and to maintain remission following high-dose therapy. J Clin Oncol. 2010;28(15 s):suppl;abstr 8005.Google Scholar
- 40.Le Gouill S, De Guibert S, Planche L, et al., eds. 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; 2011. Haematologica; No. 96.Google Scholar
- 43.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;29:3194–200.PubMedCrossRefGoogle Scholar
- 44.Dupuis J, Meignan M, Julian A, Tychyj-Pinel C, Berriolo-Riedinger A, Brice P, et al. Significant prognostic impact of [18F]fluorodeoxyglucose-PET scan performed during and at the end of treatment with R–CHOP in high-tumor mass follicular lymphoma patients: a GELA–GOELAMS Study. ASH annual meeting abstracts;118(21):877.Google Scholar
- 47.Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012;119(22):5126–32.PubMedCrossRefGoogle Scholar
- 48.Samaniego F, Hagemeister F, Mclaughlin P, et al. High response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin lymphoma, including those meeting GELF criteria. J Clin Oncol. 2011;29:suppl; abstr 8030.Google Scholar