Update on Follicular Lymphoma

Abstract

The past two decades have seen remarkable progress in both biological understanding and optimizing treatment of follicular lymphoma. Historically considered an incurable disease, long-term follow-up of several induction approaches demonstrates that up to 40% of patients enjoy remission durations of 10 or more years, and risk of dying of lymphoma continues to fall. This update will focus on progress in follicular lymphoma over the past three years, which has included refinements in staging and prognosis, novel immunotherapy treatment approaches for relapsed and refractory disease, and long-term follow-up of pivotal trials. Ongoing trials will define the optimal sequence for these novel treatments, including whether earlier incorporation of these approaches may result in definitive cure of this disease. Through ongoing and planned correlative studies, we are poised to ultimately achieve the goal of a precision management approach to follicular lymphoma.

Introduction

Follicular lymphoma is the second most common incident lymphoma in the Western hemisphere.¹ The etiology of the disease in most patients is poorly understood, although several risk factors are currently under investigation.² The past two decades have seen remarkable progress in our understanding the biology of follicular lymphoma. Recurrent mutations in histones, JAK-STAT and NF-kappB signaling are often present, with early driver mutations in chromatin regulatory genes including CREBBP, EZH2 and KMT2D.³ This understanding has directly led to modest clinical progress; for example, tazemetostat, an EZH2 inhibitor, has been approved for patients with relapsed follicular lymphoma based upon high durable response rates observed particularly in EZH2-mutated disease.⁴ A heterogeneous tumor microenvironment with differential representation of T-cell subsets and variable MHC expression on follicular lymphoma cells adds significant complexity to tumor behavior,⁵ and gene expression from the follicular lymphoma microenvironment is more predictive of outcome than tumor genomic signatures.⁶ Moreover, multiple clones with differential mutational changes may be present in the same patient.⁷ The constellation of both genetic/molecular and clonal heterogeneity as well as microenvironmental contributions renders precision medicine a significant challenge in this disease.⁸

Although historically considered incurable, the median overall survival of patients diagnosed with follicular lymphoma has improved significantly over the past two decades.^9,10 Most patients diagnosed with follicular lymphoma will now die from other causes. However, despite this success, there is widespread variability to management of both newly diagnosed and relapsed disease.^11–13 The initial treatment approach remains clinically-driven: uncommon patients with early stage disease are treated with radiation therapy, patients with low tumor burden are either observed or treated with rituximab, and patients with high tumor burden are treated with chemoimmunotherapy.¹⁴

This review will focus on progress in follicular lymphoma over the past three years, which has included refinements in staging and prognosis, novel treatment approaches for relapsed and refractory disease, and long-term follow-up of pivotal trials.

Bone marrow biopsies not necessary for most patients with follicular lymphoma

Historically, standard staging evaluations for patients with newly diagnosed follicular lymphoma have included performance of bone marrow biopsy, where the majority of patients with advanced stage disease may have a positive result. Practice guidelines, including the European Society for Medical Oncology and the National Comprehensive Cancer Network guidelines have endorsed bone marrow aspiration and biopsy, particularly to confirm early-stage presentations or to evaluate etiology of cytopenias. However, several recently published datasets have questioned the value of this approach. An analysis of the GALLIUM trial which enrolled over 1000 patients with newly diagnosed follicular lymphoma and randomized them to chemotherapy with either obinutuzumab or rituximab showed that bone marrow biopsy impacted response assessment in less than 1% of patients.¹⁵ Similar results were shown in a single institution study from Cornell in 100 patients with follicular lymphoma treated on clinical trials.¹⁶

These preliminary findings led to a large analysis from the National Clinical Trials Network published this year in Journal of Clinical Oncology.¹⁷ Seven trials (N=580 patients) were included, and only 5 patients had positive bone marrow biopsy at baseline who subsequently achieved a complete response on imaging with persistently positive bone marrow biopsy. As validation, a similar observation was made based upon an ECOG trial, published in the same manuscript.¹⁷ These results suggest that bone marrow biopsy can be eliminated as part of routine staging for patients with follicular lymphoma, as it does not contribute to prognosis or response assessment in 99% of patients.

There are multiple reasons why bone marrow biopsy is no longer prognostic in this disease. FDG/PET imaging is a much more accurate staging modality than conventional CT scans, and the incremental value of bone marrow assessment in patients staged with PET/CT is limited; this has been also demonstrated in other lymphoma histologies.^18,19 Additionally, monoclonal antibody therapy is very efficient at clearing bone marrow disease compared to historical approaches of chemotherapy alone. Future studies will need to determine whether “liquid biopsies” evaluating circulating tumor DNA may provide additional information beyond imaging.²⁰ For now, however, based upon the aforementioned recent NCTN analysis, bone marrow biopsy should no longer be routinely included in diagnostic or response assessment guidelines for patients with advanced stage follicular lymphoma. There still may be a role for marrow assessment in patients with early stage presentations who are being considered for definitive involved site radiation therapy.²¹

Validation of POD24 prognosis

The observation that 20% of patients treated with chemoimmunotherapy progress within 24 months of treatment (POD24) and experience a poor outcome was first demonstrated in 2015 by National LymphoCare Study investigators.²² Last year, a pooled analysis of 13 clinical trials was performed to identify clinical factors associated with POD 24 and the impact on overall survival.²³ This study demonstrated that known poor prognostic factors including male sex, poor performance status, elevated beta-2 microglobulin and high FL-IPI score²⁴ all were associated with POD24. As expected, a multivariable Cox model adjusted for sex and stratified by performance status and FLIPI showed that POD24 was associated with poor subsequent overall survival in this dataset, the largest ever published confirming this observation (N=5225 patients). Unfortunately, validated biomarkers are not yet available to reliably identify patients at diagnosis who will experience early disease progression.

The POD24 patient population has been designated as a priority for novel therapy development by the National Clinical Trials Network and others.^25,26 The S1608 trial (NCT03269669), currently open to accrual in the United States, randomizes patients who experience POD24 to either lenalidomide/obinutuzumab or chemoimmunotherapy as part of second line treatment. The primary endpoint is complete response, and responding patients may proceed to high dose therapy and autologous transplantation²⁷ or CAR-T cell therapy. A major secondary endpoint includes genome sequencing at initial diagnosis and relapse to validate previous molecular prognostic scores²⁸, and ultimately identify new targets for treatment.

Long-term follow-up of RELEVANCE trial confirms initial favorable results

The RELEVANCE trial randomized patients with advanced stage, newly diagnosed follicular lymphoma to either chemoimmunotherapy or the rituximab/lenalidomide combination. Initial results of this study were published five years ago, and showed similar response rates and progression-free survival between the two arms.²⁹ Long-term follow-up results (median follow-up, 72 months) on over 1000 patients enrolled on this trial were recently published.³⁰ Six year PFS rates were 60% for rituximab/lenalidomide, and 59% for chemoimmunotherapy. Overall survival was estimated at 89% for both arms. There were slightly more histological transformation events (4.4% vs. 3.3%) in the rituximab/lenalidomide arm. Similar to other studies, patients who experienced early disease progression (within 24 months of completion of therapy) had markedly inferior five-year overall survival.

The initial publication of RELEVANCE did not significantly change the treatment paradigm, as guidelines and expert opinion still favor chemoimmunotherapy as the optimal initial approach for patients who present with high tumor burden advanced stage disease.³¹ Long-term follow-up of chemoimmunotherapy with or without rituximab maintenance has shown that approximately 40% of patients remain disease-free 10 years or more after initial therapy.^10,32 It is likely that a subset of these patients are at least functionally cured.^8,33 Given the favorable outcome of the RELEVANCE trial at 6 years, showing durability of the lenalidomide/rituximab arm, the combination of lenalidomide and rituximab should now be viewed as a viable non-chemotherapy option for upfront treatment of follicular lymphoma, with a different toxicity profile from chemotherapy.

No benefit to a response-adapted approach to rituximab maintenance treatment

The FOLL12 study randomized patients with newly diagnosed, advanced stage, high tumor burden follicular lymphoma to rituximab maintenance, or a response-adapted maintenance approach based upon PET/CT and minimal residual disease assessment.³⁴ For the response-adapted arm, patients with a complete metabolic response on PET who were minimal residual disease (MRD) undetected were observed; those with detectable MRD received rituximab x 4 and then were reassessed. Patients without complete metabolic response received radioimmunotherapy³⁵ prior to rituximab maintenance. Randomization of over 800 patients occurred after six cycles of either RCHOP or BR induction therapy. With a median follow-up of 53 months, the 3-year PFS was inferior in the response-adapted arm of the study compared with the maintenance arm. These results of the FOLL12 trial do not support a response-adapted treatment paradigm in FL.

This study reveals the heterogeneous nature of follicular lymphoma, and limitations of MRD assessment at the present time. Minimal residual disease detection in follicular lymphoma is complicated by the aforementioned divergent evolutionary pattern of this disease, and the frequent presence of multiple neoplastic clones.³⁶ Moreover, blood and bone marrow may not be adequate surrogates for lymph node compartment disease frequently seen in follicular lymphoma. The various MRD platforms need further longitudinal validation in patient with follicular lymphoma before being incorporated as an integral biomarker in future trials or clinical practice.

Mosunetuzumab is highly active and now approved for treatment of relapsed/refractory follicular lymphoma

Mosunetuzumab is a monoclonal antibody targeting both CD20 and CD3, facilitating T-cell engagement and elimination of malignant B-cells. A recently published phase 1 single-agent trial of mosunetuzumab included over 200 patients with various lymphoma histologies.³⁷ Common adverse events included neutropenia and cytokine release syndrome with fever; only 7% of patients required hospitalization. Neurologic adverse events were uncommon. In patients with follicular lymphoma, complete response rates exceeded 50% for patients who were “double refractory” (to alkylating agent and monoclonal antibody) as well as patients who progressed within 24 months of initial therapy, the high-risk group in need of novel therapy approaches.^22,38

These promising results led to an international, pivotal phase 2 trial enrolling 90 patients with follicular lymphoma either relapsed or refractory to two or more lines of previous treatment including an alkylating agent and monoclonal antibody therapy.³⁹ With a median follow-up of over 18 months, 60% of patients achieved complete response. The median progression free survival was 21 months and median duration of response was 22 months. Similar to the phase 1 trial, cytokine release syndrome occurred in 44% of patients but almost all episodes were of low grade. Only one patient each had grade 3 and 4 cytokine release syndrome respectively. These promising results led to approvals of mosunetuzumab in this setting by the United States Food and Drug Administration, as well as European regulatory authorities in 2022. Other bispecific antibodies dual targeting CD20/CD3 currently in development have demonstrated similar efficacy in follicular lymphoma, with some differential toxicitiy.^40,41

Future trials will need to define the optimal sequencing the bispecific antibodies in the management of patients with follicular lymphoma. The United States National Clinical Trials Network is developing a trial utilizing mosunetuzumab as upfront monotherapy in patients with low tumor burden follicular lymphoma to determine whether this approach could cure (or functionally cure) of this disease.

CAR-T cell therapy

Chimeric antigen receptor (CAR-T) cell therapy has had a profound impact on the outcome of patients with highly refractory diffuse large B-cell lymphoma and mantle cell lymphoma, curing patients who otherwise have limited or no therapeutic options.^39,42–45 Mature results from the ZUMA-5 trial which enrolled 127 with follicular lymphoma and used axicabtagene ciloleucel (a commercially available CD19 CAR-T construct) as the treatment were published last year.⁴⁶ Of 84 patients with follicular lymphoma included in the primary analysis, the complete response rate was 79%. These responses were durable, with estimated PFS at 18 months of 66%. Adverse events were similar to what has been reported previously with CAR-T therapy, with some decrease in severity of cytokine release syndrome and neurological toxicity compared with more aggressive lymphoma histologies. These results were retrospectively compared with a matched cohort balancing patients through propensity scoring on known prognostic factors.⁴⁷ The median progression-free survival in the matched cohort was 12 months compared to not reached in the CAR-T cohort. Response rates and overall survival were also dramatically different, favoring CAR-T therapy. Based on this study, axicabtagene ciloleucel is approved in the United States for use in patients with relapsed or refractory follicular lymphoma.

Similar results were recently published using tisagenlecleucel, an alternative CD19 CAR-T construct.⁴⁸ This study included 97 patients with follicular lymphoma who received a CAR-T cell infusion. The complete response rate was 69%, and the progression-free survival rate for the overall population at 12 months was 67%. The overall safety profile was in keeping with previous experience with this agent; almost 20% of patients in this trial were able to be treated as outpatient. Based on this trial, tisagenlecleucel was also approved by the United States Food and Drug Administration for use in follicular lymphoma.

Further studies are needed to define the optimal setting to utilize CAR-T cell therapy in patients with follicular lymphoma, and further follow-up of these and other studies is needed to determine whether or not this represents a curative approach, as preliminary long-term follow-up data suggest.⁴⁹ At present, CAR-T cell treatment is generally reserved for patients with disease refractory to monoclonal antibody therapy and alkylating agents, or other high risk situations such as selected patients who experience POD24. The optimal sequence of using bispecific antibodies and CAR-T cells to treat follicular lymphoma is unknown; responses to bispecific antibodies have clearly been documented after CAR-T cell therapy, but data are lacking evaluating CAR-T cell responses after bispecific antibodies.

Conclusion: continued progress

The past three years have seen refinements in our staging and prognosis assessments of follicular lymphoma, and have confirmed durable outcomes of highly active induction regimens. The biggest clinical advances have been around immunotherapy, with the approvals of two CD19 CAR-T cell constructs and a CD3/CD20 bispecific antibody. Ongoing trials will define the optimal sequence of these and other novel agents, including whether earlier incorporation of these approaches may result in definitive cure of this disease. Through ongoing and planned correlative studies, we are poised to ultimately achieve the goal of a precision management approach to follicular lymphoma.⁵⁰