Balancing the goal of obtaining a durable remission and that of avoiding a negative impact on quality of life argues against the routine use of chemotherapy in follicular lymphoma.
Follicular lymphoma is a common non-Hodgkin lymphoma subtype characterized by an indolent clinical course and heterogeneous clinical outcomes. Most patients present with advanced-stage disease and will experience high initial response rates and favorable remissions, coupled with recurrent relapse. Given the heterogeneity and chronicity of follicular lymphoma, many patients can anticipate a normal life expectancy despite the relapsing nature of this disease. Therefore, clinicians are tasked with balancing the efficacy of a treatment option with its impact on quality of life and potentially life-threatening toxicities. The goal of therapy, despite these challenges and the rapidly evolving treatment landscape, is to achieve a durable, quality remission for all patients.
The typical clinical course of follicular lymphoma has improved significantly over the past several decades.[3,4] Improvement in survival was not achieved with the evolution or intensification of chemotherapy regimens, but largely through the incorporation of monoclonal antibodies such as rituximab and novel targeted agents. Despite marked improvements in overall survival (OS) for the majority of patients, outcomes remain poor for approximately 20% of patients, who experience early relapse within 24 months of frontline chemoimmunotherapy.[2,5] Median survival for this poor-risk group is approximately 5 years, far short of the nearly 20-year projections of others.[2,4] Early relapse is a robust predictor of survival in follicular lymphoma and identifies a high-risk subset of patients in need of novel (non-chemotherapy) approaches.
The available clinical prognostic models, such as the Follicular Lymphoma International Prognostic Index (FLIPI) or FLIPI-2 cannot adequately identify patients likely to relapse early, nor can these models inform the preferred alternative treatment. An attempt to incorporate genetic heterogeneity into risk stratification led to the development of the m7-FLIPI risk model, which incorporates the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), in addition to the FLIPI and Eastern Cooperative Oncology Group (ECOG) performance status scores. Applying this model allowed for improved risk stratification of patients with a high-risk FLIPI score, mostly through identification of EZH2 mutations, which correlated with significantly improved outcomes. The model also identified a smaller subset of high-risk patients who face very poor outcomes with frontline chemotherapy-based approaches. Thus, we have another robust prognostic tool, but still lack predictive biomarkers to inform treatment selection.
OS remains the most important endpoint when measuring progress in follicular lymphoma. For asymptomatic, low-tumor-burden, advanced-stage patients, observation remains a viable option in the modern era, since neither chemoimmunotherapy nor rituximab monotherapy has demonstrated a survival advantage over observation in this setting.[7,8] Therefore, cytoreduction in a low-tumor-burden state does not translate into improved survival and can potentially be deleterious, given the increased risk of morbidity, which reduces the role that chemotherapy can play in a high-tumor-burden state.
Among high-tumor-burden patients, improvement in survival was only achieved with the addition of rituximab to chemotherapy, and not via the evolution of chemotherapy regimens.[9-11] Additionally, the largest impact on frontline management was not from intensification of chemotherapy, but from extended dosing of rituximab (1 dose every 2 months for 2 years), explored in the PRIMA study. Though no difference in OS has been observed to date, the improvement in initial remissions with immune therapy alone has been practice changing. One possible explanation for the similarity in OS is that the limitation of chemotherapy in the observation arm can be overcome by retreatment with rituximab-containing therapies at relapse; this highlights the impact of sequential therapy on this disease and the limited role of chemotherapy on its history.
A limitation of the PRIMA study was the absence of bendamustine among the chemotherapy regimens used in induction. Bendamustine in combination with rituximab was associated with a significantly longer progression-free survival (PFS) compared with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone),[13,14] and this regimen quickly replaced most frontline chemoimmunotherapy options in the United States. The GALLIUM study was designed to address whether obinutuzumab (a fully humanized type II glycoengineered monoclonal anti-CD20 antibody) is superior to rituximab in combination with CHOP, CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine followed by 24 months of maintenance in patients with high-tumor-burden, untreated follicular lymphoma. After 34.5 months of follow-up, obinutuzumab-based treatment was associated with a significant improvement in PFS compared with rituximab-based treatment. Fatal adverse events occurred in approximately 4% of patients, and significant differences in the toxicity profiles of the chemotherapy backbones were apparent. Bendamustine was associated with higher rates of grade 3–5 infections and second neoplasms compared with CHOP. Though this study was conducted to address the preferred monoclonal antibody, the safety of chemotherapy has drawn attention and once again raises the question of the preferred frontline approach for follicular lymphoma. Do the robust outcomes associated with chemoimmunotherapy outweigh the potential risks, and is bendamustine as safe as once perceived?
The microenvironment has been implicated in the pathogenesis and prognosis of follicular lymphoma.[16,17] Targeting the microenvironment, therefore, is desirable, with lenalidomide seen as an agent that could potentially accomplish this. Single-arm phase II studies have suggested that the combination of lenalidomide and rituximab (R2) in untreated follicular lymphoma is associated with a favorable safety and efficacy profile.[18,19] The RELEVANCE trial is an ongoing randomized phase III study examining lenalidomide in combination with rituximab vs rituximab in combination with chemotherapy followed by maintenance therapy in patients with untreated, high-tumor-burden follicular lymphoma. The preliminary results suggest that the lenalidomide and rituximab regimen has outcomes similar to those seen with rituximab plus chemotherapy (R-chemo). At a median follow-up of 37.9 months, the complete response rate was 84% (R2) vs 89% (R-chemo), and the PFS rate was 77% vs 78%. Less nonhematologic toxicity (with the exception of rash), less neutropenia and febrile neutropenia, and fewer infections were observed with R2. Though the study failed to meet the primary endpoint of significant improvement in PFS and complete response rates at 30 months, the findings suggest that R2 may be a reasonable option for patients who are not appropriate candidates for chemotherapy. Since the first remission is still anticipated to be the longest, achieving this with a safe, non–chemotherapy-based approach, if possible, is preferred.
The relapsed setting poses more challenges for clinicians, given the greater heterogeneity in presentations and outcomes. The preferred approach for high-risk patients is unknown, including whether intensification of chemotherapy (ie, myeloablative therapy) or a targeted approach should be pursued. Several phase II studies in the pre-rituximab era suggested that high-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) is associated with longer remission duration than can be expected with conventional therapy; however, the best results were achieved when the treatment was administered earlier in the course of the disease and in the setting of remission.[21-24] Concerns regarding mortality from secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) curbed initial enthusiasm for this approach. A retrospective analysis attempted to address the utility of HDT/ASCT in the modern era and reported similar findings: nearly half of patients achieved meaningful remissions when treated early in the course of the disease. The rates of secondary MDS/AML were not insignificant (12.4%). If the risk is high, but the reward is a prolonged second remission, then this approach should be restricted to the highest-risk patients-those who experience early relapse following frontline chemoimmunotherapy.
A separate retrospective analysis examined the outcomes among patients with early treatment failure (lymphoma progression within 24 months of frontline therapy) who underwent HDT/ASCT. There was no difference in 5-year OS between the non-HDT/ASCT and the HDT/ASCT group. However, in a planned subgroup analysis, patients who received HDT/ASCT soon after treatment failure (≤ 1 year) had higher 5-year OS rates than those who did not undergo HDT/ASCT (73% vs 60%; P = .05). If HDT/ASCT is only worthwhile in the highest-risk patients if performed soon after treatment failure, intensive chemotherapy is not a viable option for the vast majority of patients.
Radioimmunotherapy-a radiation-emitting radionuclide combined with an antibody targeting CD20-is an effective therapy in follicular lymphoma as consolidation following frontline chemotherapy or in the relapsed setting.[27,28] Myelosuppression is the primary toxicity, and secondary MDS and AML rates appear similar to those observed with chemotherapy. The most favorable outcomes are observed in patients with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. With one-dose administration, this may be an attractive approach for a select group of patients.
Targeting the B-cell receptor (BCR) signaling pathway has been an attractive approach for refractory follicular lymphoma. There are currently two phosphatidylinositol 3-kinase (PI3K) inhibitors approved by the US Food and Drug Administration for the treatment of relapsed/refractory follicular lymphoma patients in whom two prior lines of therapy have failed-idelalisib (PI3KÎ´ inhibitor) and copanlisib (pan-PI3K inhibitor). Idelalisib was associated with an overall response rate of 57% in relapsed/refractory indolent non-Hodgkin lymphoma, with a median PFS of 11 months. The most common grade 3 or higher adverse events were neutropenia (27%), transaminitis (13%), diarrhea (13%), and pneumonia (7%). A post hoc analysis of this study revealed similar outcomes among high-risk follicular lymphoma patients (early relapse), suggesting that targeted therapy may overcome chemotherapy resistance. Similarly, copanlisib was associated with a favorable efficacy profile in relapsed/refractory follicular lymphoma, with a different safety profile: less gastrointestinal toxicity, and higher rates of hyperglycemia and hypertension. The toxicity profile associated with PI3K inhibitors may have curbed enthusiasm for these agents; however, recognition and early intervention may be the key to avoiding significant morbidity. In contrast, ibrutinib, a proximal BCR signaling pathway inhibitor with a predictable safety profile, has only modest activity in follicular lymphoma (overall response rate, 20.9%; median PFS, 4.6 months).
Tazemetostat, an EZH2 inhibitor, has been associated with promising results in early-phase studies, with high response rates particularly in those with the EZH2 mutation, and a favorable toxicity profile, and may provide another non-chemotherapy option targeting one of the most common mutations in follicular lymphoma. The existence of effective targeted options for chemo-refractory disease highlights the progress made with rational biologic targeting in relapsed follicular lymphoma.
A personalized approach to follicular lymphoma is warranted to minimize acute and late toxicity associated with chemotherapy. Improved risk stratification and predictive biomarkers are needed. Until these become reality, balancing the goal of obtaining a durable remission and that of avoiding a negative impact on quality of life argues against the routine use of chemotherapy in follicular lymphoma.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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