Pursuing Optimal Therapy Remains a Challenge in Indolent B-Cell Lymphoma

Christopher Flowers, MD, MS

Follicular lymphoma (FL) and other forms of indolent non-Hodgkin lymphoma (iNHL) are commonly considered incurable diseases with continual risk of relapse over time, shorter durations of response with each subsequent line of therapy, and a risk of transformation to a more aggressive B-cell lymphoma. Although these lymphomas are characterized as indolent, one of the most common causes of death for these patients is lymphoma.¹ On the other hand, a significant proportion of patients worldwide live disease-free for a decade or longer following first-line therapy, with various approaches suggesting that there may be pathways to develop approaches for a cure for at least a subset of patients.^1-5 In the “Indolent B-Cell Lymphoma” session during the Society of Hematologic Oncology 2021 Annual Meeting, 4 presentations were explored: “Molecular Pathogenesis of Follicular Lymphoma and Its Relevance to Clinical Practice,” “Sequencing Therapy in Follicular Lymphoma,” “Novel Therapies in Indolent Lymphoma,” and “CAR T-Cell Therapy in Indolent Lymphoma” in lectures by world-class experts Jessica Okosun, MA, MB BChir, MRCP, FRCPath, PhD, Peter Martin, MD, Loretta Nastoupil, MD, and Caron Jacobson, MD, MMSc.

Next-generation sequencing studies, led by Michael R. Green, PhD, Dr Okosun, and others, have described the panoply of genomic events involved in FL and have aided in identifying candidate genetic drivers^.6-9 This work clarified the diverse genomic landscape and the temporal clonal dynamics of FL. Common genomic events that occur with t(14;18) include high frequencies of mutations affecting epigenetic regulation, disruptions in pathways such as those involved in immune recognition (eg, TNFRSF14), NF-KB (eg, CARD11), and JAK/STAT signaling (eg, STAT6).9,10 Next-generation sequencing also has been used to examine factors associated with progression of FL, transformation of iNHL to more aggressive lymphomas, and spatial heterogeneity in FL. Recent studies have explored the subclonal diversity and spatial heterogeneity observed among patients with FL that have potential clinical implications for the development of prognostic and predictive biomarkers and targeted treatment strategies. For instance, exome sequencing of FL tumors and paired germline have identified nonsynonymous somatic variants corresponding to missense (81%), indels (10%), nonsense (7%), and splice site (2%) changes.⁶ This work revealed spatially discordant mutations in genes such as EZH2 and EP300. One attractive treatment paradigm emerging from this work involves specifically targeting highly recurrent and truncal gene mutations that have roles in FL pathogenesis. Other studies did not identify a single compelling genetic event responsible for transformation, but instead suggest that the acquisition of certain genetic alterations may result in aggressive transformation.^7,9,11 Exploration of the FL genomics in this session can clarify stratified treatment approaches targeting specific early genetic lesions identified in FL and may eventually provide strategies to eradicate these cell populations and provide pathways to cure FL.

In the past decade, many new agents have been introduced for the management of FL, and therapeutic strategies have evolved over time. Recently, my co-chair in this session, Nathan Fowler, MD, and I reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory FL.¹² However, since that review other agents have received FDA approval for patients with relapsed FL. There is considerable variation in response rates for recently approved therapies ranging from objective response rates of 40% to 60% for PI3K inhibitors, 35% to 65% for EZH2 inhibitors, and greater than 70% for autologous stem cell transplantation, and CD19-directed chimeric antigen receptor (CAR) T-cell therapy.^13-18 Recently approved therapies in relapsed FL have commonly been based on response rate and duration of response (DOR) demonstrated in phase 2 studies. However, despite numerous trials performed in the field, there is no single standard of care for patients with iNHL who are undergoing second-line treatment or beyond.

As a result of the patterns of relapse and transformation associated with iNHL, the clinical treatment of patients with FL and other iNHLs often requires multiple lines of therapy using various regimens with different mechanisms of action.^19-22 The clinical benefits and adverse effects associated with the treatments available at relapse vary and are influenced by patient and disease characteristics at the time of progression, the duration of the interval from last treatment, and the toxicity and responses associated with the treatments previously administered. This results in a marked heterogeneity of clinical situations encountered during the treatment of these patients. Some patients with iNHL will remain well treated using available treatments, whereas others will develop disease refractory to conventional approaches and become candidates for novel treatments and clinical trials. Additional real-world data regarding patient characteristics at relapse, patterns of care, expectations of response rates and duration, and survival outcomes are lacking in the setting of relapsed and refractory iNHL. To help inform treatment decisions by health care providers treating patients with iNHL in this complex and evolving treatment landscape, Dr Martin will describe approaches for sequencing therapies. To optimally individualize treatment strategies for patients with previously untreated and relapsed iNHL, the risks and benefits of the available options should be well known. This lecture will enable providers to effectively discuss the goals of therapy with the patient at each intervention, which is also critical in providing an optimal sequence of therapy.

Although many patients with FL experience long or possibly near-normal life expectancies, there remains persistent variability in patient outcomes.^19-22 Patients who relapse within 2 years of first-line chemoimmunotherapy or with histologic transformation are at risk for early mortality and are high-priority candidates for novel treatment strategies evaluated in clinical trials.^23-25 Prior studies have demonstrated diminishing DOR by line of therapy.^26,27

However, variability of iNHL disease biology, treatment options, and treatment patterns complicate outcome assessments based on line of therapy alone. Several novel and targeted therapies are being developed and evaluated in patients with relapsed iNHL, including cereblon inhibitors, anti–CD20-CD3 bispecific antibodies, and additional anti-CD19 CAR T-cell therapies. Dr Nastoupil will provide key insights on the novel therapies available for patients in clinical trials and those that are establishing pathways toward applications in clinical settings.

CAR therapy targeting CD19 is one promising treatment for patients with relapsed or refractory FL and CD19+ iNHLs. Patients who are candidates for CAR T-cell therapy often have symptomatic disease that could be fatal if left untreated. Dr Jacobson will discuss strategies for bridging therapy, which may include chemotherapy, targeted therapy, or radiation therapy; approved and experimental CAR T-cell approaches for FL and iNHLs; and describe traditional and novel adverse events and outcomes from clinical trials involving CAR T-cell therapy.

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