Advances in Follicular Lymphoma Management
Follicular lymphoma (FL), the second most common subtype of non-Hodgkin lymphoma (NHL) and the most common indolent NHL, accounts for 35 percent of NHLs in the U.S. FL arises from germinal center B cells, which are usually CD10 positive, CD5 negative, and CD20 and CD19 positive.
Approximately 85 percent of patients with FL have t(14;18), which results in overexpression of B cell leukemia/lymphoma 2 (BCL2), an oncogene that blocks apoptosis, leading to prolonged cell survival. Pathologic grading of FL (1, 2, 3A, 3B), which is based on an increasing number of centroblasts, is prognostic and predictive (Blood 2003;101:1149-1154). FL grade 3B is treated, as are aggressive lymphomas, with rituximab and anthracycline-based chemotherapy.
Although FL is not typically curable with conventional treatment, the prognosis for FL continues to improve, with current treatments extending median survival in excess of 14 years (Blood 2013;122:981-987). Overall, 75-85 percent of patients with FL present with advanced disease (stage II bulky, III/IV) at diagnosis and have been historically managed with chemoimmunotherapy when treatment is indicated (Ann Oncol 2013;24:441-448).
When to start treatment rests largely on symptoms, the presence of significant cytopenias, and the threat of end organ damage. The presence of high tumor burden often aids in the decision to initiate therapy and has been proposed as an indicator by the Groupe d'Etude des Lymphomes Folliculaires (GELF) (J Clin Oncol 1997;15(3):1110–1117).
If a patient does not have significant symptoms and has low tumor burden, close observation is often recommended. This recommendation is based on prospective trials that have demonstrated no difference in overall survival when therapy is deferred.
Certainly, in clinical practice a significant proportion of patients do not feel comfortable with the “watch and wait” approach, and initial single-agent therapy with rituximab is acceptable for patients with low tumor burden. A large international randomized trial comparing watchful waiting with initial treatment with rituximab suggested that initial treatment with rituximab may improve quality of life and allow postponement of cytotoxic chemotherapy (Lancet Oncol 2014;15(4):424-435).
First-Line Treatment
The addition of the anti-CD20 monoclonal antibody rituximab to conventional chemotherapy has improved outcomes in FL, including response rate (RR), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS).
The optimal standard chemotherapy regimen, or backbone, to partner with rituximab is unclear. R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, prednisone) was previously the most commonly used regimen in the U.S. prior to the introduction of the alkylating agent bendamustine.
A phase III trial from the Study Group of Indolent Lymphomas (StiL) comparing six cycles of bendamustine plus rituximab (BR) to six cycles of R-CHOP demonstrated superior efficacy and reduced toxicity with BR (Lancet 2013;381(9873):1203-1210). In the patients with FL alone, the median PFS was significantly longer after BR than after R-CHOP (69.5 vs. 31.2 months; HR 0.58), while OS did not differ significantly between groups at 10 years (70% vs. 66%).
A confirmatory phase III study (a follow-up to BRIGHT) also showed that BR was significantly superior to R-CHOP and R-CVP (rituximab combined with cyclophosphamide, vincristine, and prednisone) for PFS at 5 years (66% vs. 56%) for the group of indolent lymphomas as a whole; however, this difference lost statistical significance when the analysis was limited to FL (J Clin Oncol 2017;35(Suppl):abstract 7500). Once again, there was no difference in OS. The quality of life is somewhat better for patients taking BR because of the absence of alopecia, significant neuropathy, and steroid use. Limited data exists regarding the use of BR in patients with more clinically aggressive disease, such as histologic grade 3A or disease characterized by a high Ki-67 level (≥30%). In this subset of more aggressive FL, R-CHOP may be a preferred regimen.
For first-line treatment of patients with advanced FL, the FDA in November 2017 approved obinutuzumab in combination with chemotherapy, followed by obinutuzumab maintenance. The approval is based on data from the phase III GALLIUM study (N Engl J Med 2017; 377:1331-1344), in which combining obinutuzumab with chemotherapy in first-line treatment, rather than relying on rituximab plus chemotherapy, reduced the risk of disease progression or death by 28 percent in patients with FL. The RELEVANCE trial is a phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated FL of grades 1-3A. Findings recently presented at the 2018 ASCO Annual Meeting (J Clin Oncol 2018;36 (Suppl): abstract 7500) showed that neither coprimary endpoint of PFS or complete response/unconfirmed complete response (CR/CRu) favored R2. Efficacy was similar in both arms; however, safety data differed, with the chemotherapy plus rituximab arm registering higher levels of grade 3/4 neutropenia, febrile neutropenia, growth factor usage, nausea, vomiting, neuropathy, and alopecia than the R2 arm. Meanwhile, more frequent cutaneous reactions, tumor flare, and diarrhea were seen in R2.
Primary investigator Nathan Fowler, MD, concluded that R2 is a novel immunomodulatory approach, and with its improved safety and tolerability over chemotherapy plus rituximab, R2 is a potential first-line chemotherapy-free option for patients with FL requiring treatment.
Maintenance Therapy
The question of whether to give maintenance rituximab after frontline rituximab plus chemotherapy was addressed in the phase III PRIMA trial. Patients with newly diagnosed FL who responded to initial treatment with rituximab plus chemotherapy were randomized to either observation or a single dose of rituximab every 2 months for 2 years.
At median follow-up of 36 months, the 2-year PFS in the maintenance rituximab arm was 75 percent, much higher than the 58 percent in the observation arm. This benefit was seen irrespective of the induction chemotherapy backbone. No difference in OS was observed. Maintenance rituximab was associated with a slightly higher incidence of grade 3/4 adverse events (24% vs. 17%) (Lancet 2011;377(9759):4-6).
Long-term follow-up of the PRIMA trial was presented at the 2017 American Society of Hematology Annual Meeting, and findings indicated that rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS benefit over observation at 10 years (51% vs. 35%) (Blood 2017;130(Suppl1):abstract 486).
Relapsed & Refractory Disease
Relapse of FL commonly presents as asymptomatic enlargement of the lymph nodes, liver, or spleen. Asymptomatic patients can also be closely observed, and treatment should be based on the modified GELF criteria as in first-line therapy.
If histologic transformation or a change in biology is suspected (rising lactate dehydrogenase levels, disproportionate growth of single site, new extranodal disease, new B symptoms), a low threshold for a new biopsy is recommended, and PET scanning using fludeoxyglucose F 18 (FDG) may help identify suspicious sites of transformation if intense FDG avidity is seen.
Patients with relapsed or refractory FL will find physicians have no standard therapy to offer, and patients should be encouraged to participate in clinical trials. The choice of therapy at relapse should take into consideration the patient’s prior treatment and duration of response to initial therapy and his or her age, comorbidity, and goals for therapy.
Patients with early relapse within 2 years of initial diagnosis have poor outcomes. For example, the 5-year survival for patients with early relapse after rituximab plus CHOP was only 50 percent, whereas the rate was greater than 90 percent for patients who did not experience early relapse (J Clin Oncol 2015;33(23):2516-2522). These patients should be considered for more aggressive treatment, such as undergoing autologous hematopoietic stem cell transplant, or encouraged to participate in clinical trials.
For patients with later relapse, chemoimmunotherapy with an alternate chemotherapeutic or biologic backbone followed by maintenance is reasonable and can continue to provide long-term disease control. It should be noted that radioimmunotherapy has demonstrated response rates of 60-80 percent; however, it is not recommended for patients with poor bone marrow reserve or high marrow tumor burden (Cancer 2007;109(9):1804-1810). This modality is also not commonly used because of the complexity of administration.
Unmet Needs & Future Direction
In the era of precision and personalized medicine, FL lags behind some of its hematologic counterparts, which benefit from biomarkers that guide therapy. In CLL, for instance, fluorescence in situ hybridization or immunoglobulin heavy-chain variable mutational testing results can help tailor selection of frontline therapy. Testing for 17p deletion will identify patients who will derive more benefit from therapy with the Bruton tyrosine kinase inhibitor ibrutinib than with conventional chemotherapy. Unfortunately, routinely available prognostic and predictive biomarkers are not yet available in the management in FL.
The most powerful predictors of outcome today are the quality of response to initial therapy, as assessed by end-of-treatment PET imaging, or by durability of the first remission. Ongoing research will someday identify validated prognostic biomarkers capable of identifying high-risk patients and reliable predictive markers to select subgroups most likely to benefit from novel approaches. Such tools will prevent early relapse and further improve survival in FL.
Developing combinations that target driver mechanisms within lymphoma cells, minimizing drug resistance along pathways, and harnessing the potential of the immune system will be paramount to improving outcomes in FL.
Alan Tan, MD, is Director of Hematologic Malignancies and Clinical Research at Cancer Treatment Centers of America, Phoenix