March 2017, Vol. 6, No. 1
Follicular Lymphoma: An Overview of Current Treatments and Unmet Patient Needs
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) after diffuse large B-cell lymphoma (DLBCL), with an estimated 16,000 new cases diagnosed annually in the United States.1,2 However, unlike DLBCL, which is a histologically aggressive lymphoma, FL has a long natural history, with 15% to 20% of patients requiring no intervention over the course of 10 to 15 years, and is therefore considered the archetype of indolent disease.1 Treatment options for patients with FL vary based on stage of disease, patient age, performance status, comorbidities, and therapeutic goals.
This article provides a brief overview of the biology of FL, as well as the disease’s clinical course and prognostic indicators. We also discuss current and future treatment modalities, with the goal of highlighting unmet patient needs.
Pathogenesis of FL
FL is characterized by the overproliferation of malignant germinal center B cells that are thought to have acquired a translocational error during V(D)J recombination.3,4 The t(14;18)(q32;q21) translocation found in 85% of FL cases results in the dysregulation and overexpression of the antiapoptotic BCL2 protein and is considered a hallmark of the disease.3,4 However, it should be noted that the t(14;18) translocation is neither necessary nor sufficient to induce FL, and that subsequent mutations found with high frequency, such as inactivating mutations in the MLL2 gene (≥80% of cases), or in EPHA7 (70% of cases), are likely required to fully transform germinal center B cells into FL cells.3,4 Other commonly occurring genetic alterations include mutations in BCL6 (47% of cases), TNFRSF14 (18%-46% of cases), CREBBP (33% of cases), MEF2B (15% of cases), EP300 (9% of cases), EZH2 (7% of cases), TNFAIP3/A20 (2%-26% of cases), FAS (6% of cases), and TP53 (<5% of cases).3 Despite expanding knowledge of the mutational landscape of FL, the order in which these mutations occur remains unknown and is the focus of ongoing research.
Clinical Course and Prognosis
As evidenced by the variability in genetic markers, FL is a biologically heterogeneous disease, and its clinical course and prognosis may vary greatly among individual patients. FL occurs most frequently in middle-aged and elderly patients, although pediatric cases have been reported.5 Patients are generally diagnosed at an advanced stage, with only 26% to 33% of patients being diagnosed with stage I or II FL.5 Because of the slow natural history of the disease, median overall survival (OS) is estimated at 6 to 10 years.5 Approximately 20% of FL cases undergo spontaneous remission without treatment,5 whereas ≤45% of cases undergo histologic transformation into the more aggressive DLBCL tumor type, at a rate of 2% to 3% of patients per year.4 Historically, the transformation of FL to DLBCL has resulted in a reduction in median OS to 1 or 2 years, although recent advances in treatment have extended the median OS of transformed FL to 5 years.6
The disparities observed in the clinical course of FL have prompted the search for early prognostic indicators of disease progression. The Follicular Lymphoma International Prognostic Index (FLIPI) was derived using clinical and laboratory findings from 4167 patients. The 5 adverse prognostic factors identified were number of nodal areas (>4); serum lactate dehydrogenase above the normal range; age >60 years; stage III or IV disease; and hemoglobin level <120 g/L. The development of this tool has allowed for identification of 3 risk strata (low, intermediate, and high).7
Although FLIPI showed utility in the clinic, it was unable to reliably identify patients at highest risk for treatment failure.8 More recently, a clinicogenetic model (m7-FLIPI) has incorporated the mutation status of 7 genes (EZH2, ARID1A, EP300, FOXO1, MEF2B, CREBBP, and CARD11), as well as Eastern Cooperative Oncology Group performance status, into the FLIPI model, resulting in improved identification of high-risk patients.9 Although m7-FLIPI has proven to be useful in identifying patients who may require earlier or more intensive interventions, the best prognostic indicator in terms of long-term outcomes may be the length of first remission after standard immunochemotherapy.
In an analysis of 588 patients receiving first-line treatment with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the National LymphoCare Study (NLCS), an association between time to disease progression and OS was identified.10 Specifically, the analysis showed that 19% of patients experienced progressive disease within 2 years of diagnosis, and this subgroup of patients had a 5-year OS rate of 50% compared with 90% for patients without early progressive disease. Given that the patients receiving R-CHOP in this study were relatively young (57% were ≤60 years)10 and the fact that neither the FLIPI nor the m7-FLIPI can identify a group of young patients (<60 years) at such high risk for early death,4 it is likely that these patients may be underserved by current prognostic and treatment strategies.
Current Management Strategies for Patients with FL
Current treatment paradigms for patients with FL are broken down by disease stage, whether patients are symptomatic, and the extent of tumor burden, as commonly defined by Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria.1,4,11,12 For high-tumor-burden FL, GELF criteria require at least 1 of the following: 3 distinct nodal sites (each ≥3 cm); single nodal site (≥7 cm); symptomatic splenomegaly; organ compression or compromise; pleural effusions, ascites; B symptoms or any systemic symptoms; or serum lactate dehydrogenase or beta-2 microglobulin above the upper limit of normal.4Early Disease
For patients with early-stage FL (Ann Arbor stages I or II) and nonbulky, asymptomatic lesions, treatment guidelines suggest radiation therapy as a potentially curative first-line therapy.12 However, it should be noted that the prospective NLCS registry found no difference between external beam radiation therapy, rituximab-containing chemotherapeutic regimens, rituximab alone, observation, or combined-modality therapy with regard to OS in patients with stage I disease.13 Therefore, each modality may potentially be used for first-line therapy, with consideration given to patient-specific factors such as age, comorbidities, and treatment goals. For older patients with life expectancies ≤15 years, observation combined with palliative care is often most appropriate, given that aggressive therapy is unlikely to improve life expectancy and carries the risk for diminished quality of life. For younger patients with longer life expectancies, radiation treatment with curative intent has been suggested to be most appropriate.4 For patients with early-stage disease who have high tumor burden or adverse clinical or biologic features, or when local radiation therapy is not applicable, systemic therapies indicated for advanced stages should be considered.12Advanced Disease
Because of the variability in the clinical course of FL, and the possibility of spontaneous remission, it is suggested that even for advanced disease states, therapy should commence only upon the occurrence of symptoms or when GELF criteria for high tumor burden are met.12 For patients with stage III or IV disease, first-line rituximab-based chemotherapy has been shown to improve overall response rate (ORR), progression-free survival (PFS), and/or OS compared with chemotherapy alone and is therefore recommended as initial treatment.12 Although R-CHOP remains the most commonly used rituximab-based chemotherapeutic regimen in the United States, likely due to its efficacy-to-toxicity ratio, other commonly used combinations include rituximab, cyclophosphamide, vincristine, and prednisone, and regimens that combine rituximab with fludarabine.4
Recent clinical trials have shown that, in the first-line setting, treatment with a combination of rituximab plus the alkylating agent bendamustine leads to improved ORR, complete response rates, and PFS compared with R-CHOP.14 Currently, bendamustine is approved by the US Food and Drug Administration (FDA) for the treatment of indolent B-cell NHL, but only as a second-line therapy for patients whose disease has progressed during or within 6 months of treatment with a rituximab-containing combination regimen.15Maintenance and Consolidation Therapy
Maintenance therapy with rituximab after induction treatment with first-line rituximab-containing chemotherapy is a common practice, because it has been shown to significantly improve PFS.4,16 Regarding the duration of maintenance rituximab, available data suggest that 2 years is safe, but data beyond 2 years is lacking.4 Other consolidation strategies, including radioimmunotherapy17 and myeloablative consolidation followed by autologous stem-cell transplantation,18 have also been shown to prolong PFS after chemotherapy; these approaches continue to be evaluated in prospective trials.Relapsed and Refractory Disease
The choice of second-line therapy for patients with FL is based on several factors, including previous treatment used, duration of first response, patient age, comorbidities, and therapeutic goals.4 At the time of relapse, it is strongly recommended that patients undergo a repeat biopsy to ensure that their disease has not transformed into a more aggressive type of lymphoma, as this may also affect treatment strategies.12
For patients with FL who require second-line treatment, options include rituximab-based chemotherapy regimens used in the first-line setting.4 Rituximab monotherapy may also be considered for the minority of patients who are still sensitive to this drug after receiving it as first-line therapy and maintenance; this is an attractive option for elderly patients who cannot tolerate more toxic therapies.4 Radioimmunotherapy with 90yttrium-ibritumomab tiuxetan may also be an effective strategy for elderly patients with comorbidities that contraindicate the use of chemotherapy.4,12 For patients whose disease becomes refractory to rituximab, the combination of bendamustine plus obinutuzumab (an anti-CD20 monoclonal antibody) has been approved by the FDA for use as second-line therapy.4,19
Treatments that specifically target the B-cell receptor (BCR) signaling axis, which is crucial for B-cell lymphomagenesis, represent the most recent advances in the management of patients with FL.20 Idelalisib, a kinase inhibitor that targets phosphatidylinositol 3-kinase delta downstream of BCR, was granted accelerated approval by the FDA for the treatment of patients with FL who have received at least 2 prior systemic therapies.20-22 In a pivotal phase 2 trial, 123 patients with indolent NHLs who were refractory to rituximab and an alkylating agent received idelalisib 150 mg orally twice daily until evidence of disease progression or unacceptable toxicity. Among the 72 patients with FL, the ORR was 54%, with a complete response rate of 8% and a partial response rate of 46%.22Ongoing phase 3 studies are evaluating the clinical benefit and safety profile of idelalisib in refractory FL.23
New Treatments on the Horizon
For symptomatic patients with FL, the standard of care includes the repeated administration of therapies until the disease becomes resistant to treatment.22 This therapeutic paradigm makes it clear that new agents are needed to manage patients with the disease. Drugs such as bendamustine and obinutuzumab, which are already approved for relapsed FL, are now being studied in the first-line setting.24,25 In fact, due to encouraging preliminary results in treatment-naïve patients, some European centers have already begun the compassionate use of first-line bendamustine, which may portend its future approval as a primary therapy in Europe and the United States.14,26,27
As the genetic and molecular changes leading to the pathogenesis of FL continue to be unraveled, other novel therapeutic targets are being explored. Some of the candidate drugs and targets currently in FL clinical trials include ibrutinib, an inhibitor of Bruton’s tyrosine kinase in the BCR signaling pathway28; venetoclax, a small-molecule inhibitor of the antiapoptotic BCL-2 protein29; lenalidomide, an immunomodulatory drug30; bortezomib, a proteasome inhibitor31; alisertib, an investigational selective aurora A kinase inhibitor32; and buparlisib, an investigational pan-class I phosphatidylinositol 3-kinase inhibitor.33 These compounds are being evaluated in combination with other drugs (eg, rituximab) and as first-line and salvage treatments.
As new drugs and combination regimens for FL continue to be identified, detailed analysis of ideal patient subpopulations will need to be considered. The continued development of prognostic indices, such as the m7-FLIPI, and posttreatment patient evaluation using positron emission tomography–computed tomography and/or minimal residual disease analysis by polymerase chain reaction, may allow the tailoring of therapy for patients most likely to benefit from a particular regimen.12
Ongoing discoveries regarding the biology of FL have led to the development of targeted treatment options that are likely to redefine care for this disease in the near future. The personalized treatment of FL, which will be facilitated by identifying better prognostic indicators and through the application of new therapies, has the potential to eradicate the disease for some patients and make it a chronic but controlled disease for many others.
- National Institute for Health and Care Excellence. Non-Hodgkin’s Lymphoma: Diagnosis and Management. NICE Guideline NG52. www.nice.org.uk/guidance/ng52. July 2016. Accessed February 24, 2017.
- American Cancer Society. Cancer Facts & Figures 2017. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Accessed February 24, 2017.
- Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122:3424-3431.
- Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127:2055-2063.
- Takata K, Miyata-Takata T, Sato Y, Yoshino T. Pathology of follicular lymphoma. J Clin Exp Hematop. 2014;54:3-9.
- Wagner-Johnston ND, Link BK, Byrtek M, et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood. 2015;126:851-857.
- Solal-Céligny P, Roy P, Colombat P, et al. Follicular Lymphoma International Prognostic Index. Blood. 2004;104:1258-1265.
- LaCasce AS. M7FLIPI: a follicular lymphoma prognostic model for the 21st century. The Hematologist: ASH News and Reports. www.hematology.org/Thehematologist/Diffusion/4482.aspx. October 19, 2015. Accessed February 24, 2017.
- Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16:1111-1122.
- Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33:2516-2522.
- Chen Q, Ayer T, Nastoupil LJ, et al. Initial management strategies for follicular lymphoma. Int J Hematol Oncol. 2012;1:35-45.
- Dreyling M, Ghielmini M, Rule S, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl_5):v83-v90.
- Friedberg JW, Byrtek M, Link BK, 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.
- Gil L, Kazmierczak M, Kroll-Balcerzak R, Komarnicki M. Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma. Med Oncol. 2014;31:944-947. doi:10.1007/s12032-014-0944-1.
- Treanda (bendamustine hydrochloride) injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2016.
- 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.
- Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the international, randomized, phase III First-Line Indolent Trial. J Clin Oncol. 2013;31:1977-1983.
- Jurinovic V, Metzner B, Pfreundschuh M, et al. Autologous stem cell transplantation for patients with early progression of follicular lymphoma: retrospective analysis of 2 randomized trials of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2016;128(22). Abstract 3464.
- Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; 2016.
- Graf SA, Gopal AK. Idelalisib for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother. 2016;17:265-274.
- Zydelig (idelalisib) tablets, for oral use [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2016.
- Miller BW, Przepiorka D, de Claro RA, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21:1525-1529.
- Barrientos JC. Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential. Onco Targets Ther. 2016;9:2945-2953.
- ClinicalTrials.gov. Bendamustine in combination with rituximab as a first-line therapy followed by maintenance therapy with rituximab in patients with follicular lymphoma (BRiF). https://clinicaltrials.gov/ct2/show/NCT02423837. Accessed March 3, 2017.
- ClinicalTrials.gov. A study of obinutuzumab (RO5072759) plus chemotherapy in comparison with MabThera/Rituxan (rituximab) plus chemotherapy followed by GA101 or MabThera/Rituxan maintenance in patients with untreated advanced indolent non-Hodgkin’s lymphoma (GALLIUM). https://clinicaltrials.gov/ct2/show/NCT01332968. Accessed March 3, 2017.
- Knauf WU, Abenhardt W, Nusch A, et al. Bendamustine-rituximab (BR) replaces R-CHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma in German hematology outpatient centres. Blood. 2012;120(21). Abstract 3666.
- Solorzano S, Martinez-Chamorro C, Panizo C, et al. Bendamustine in combination with rituximab as first-line treatment for indolent non-Hodgkin lymphoma: retrospective analysis of an Spanish registry. Blood. 2013;122(21). Abstract 5094.
- ClinicalTrials.gov. A long-term extension study of PCI-32765 (ibrutinib). https://clinicaltrials.gov/ct2/show/NCT01804686. Accessed March 3, 2017.
- ClinicalTrials.gov. A study of obinutuzumab, polatuzumab vedotin, and venetoclax in relapsed or refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). https://clinicaltrials.gov/ct2/show/NCT02611323. Accessed March 3, 2017.
- ClinicalTrials.gov. A phase 3 open label randomized study to compare the efficacy and safety of rituximab plus lenalidomide (CC-5013) versus rituximab plus chemotherapy followed by rituximab in subjects with previously untreated follicular lymphoma (RELEVANCE). https://clinicaltrials.gov/ct2/show/NCT01650701. Accessed March 3, 2017.
- ClinicalTrials.gov. Ofatumumab and bendamustine hydrochloride with or without bortezomib in treating patients with untreated follicular non-Hodgkin lymphoma. https://clinicaltrials.gov/ct2/show/NCT01286272. Accessed March 3, 2017.
- ClinicalTrials.gov. Alisertib, bortezomib, and rituximab in treating patients with relapsed or refractory mantle cell lymphoma or B-cell low grade non-Hodgkin lymphoma. https://clinicaltrials.gov/ct2/show/NCT01695941. Accessed March 3, 2017.
- ClinicalTrials.gov. Safety and efficacy of BKM120 in relapsed and refractory NHL. https://clinicaltrials.gov/ct2/show/NCT01693614. Accessed March 3, 2017.
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