Introduction to a review series: the paradox of indolent B-cell lymphoma

Laurie H. Sehn

The paradox of indolent non-Hodgkin lymphoma (NHL) is that while the protracted nature of the disease and treatment responsiveness allow for extended survival, advanced-stage disease remains incurable, which requires patients to be managed over a lifetime. In addition, although outcome is favorable for the majority of patients, a subset of patients present with more rapidly evolving disease that exhibits treatment resistance which will greatly impact their longevity. Even when the disease seems to be quiescent, there remains a constant risk of transformation to a more aggressive histology that ultimately poses the greatest threat.

The World Health Organization classification of lymphoma recognizes a variety of NHL subtypes that can be categorized as indolent. The most common of these is follicular lymphoma (FL), which represents ∼25% of all newly diagnosed cases of NHL and 70% of indolent lymphomas. Thus, clinical trials that evaluate treatment strategies in indolent NHL include a predominance of patients with FL (sometimes exclusively), which requires results to then be extrapolated in practice to less common histologic subtypes. As greater insight into the molecular differences between lymphoma subtypes emerges, it has become clear that this practice is suboptimal.

Over the last two decades, an increasing number of treatment options have become available that improve overall outcome but increase the complexity of management. More recently, biological advances have led to a plethora of novel targeted agents that are currently under evaluation. It is now understood that disease behavior is influenced by an interplay between tumor cells and cells of the microenvironment and is mediated by host genetic factors. Despite a greater understanding of the oncogenic mechanisms of indolent NHL, there remains a need for reliable validated tools that will enable better prognostication and guide treatment choice.

The articles in this review series explore the unique biology and management aspects of a selection of indolent lymphoma subtypes and will evaluate the role of transplantation strategies. The articles in this review series, “Indolent B-cell lymphoma,” include the following:

Outcomes in FL have dramatically improved, such that median survival is estimated to be greater than 12 to 15 years. The introduction of rituximab has been associated with improved response rates, improved duration of response, and improved overall survival, which has established immunochemotherapy as the standard of care. However, not all patients have a favorable outcome. The 20% of patients who experience disease progression within 2 years of diagnosis have a 5-year survival rate of ∼50%, compared with a 5-year survival rate of 90% for the remaining patients. This poor-risk subgroup represents the patients with FL who have the greatest need. Improved prognostication is paramount for identifying these patients at diagnosis, such that alternate treatment strategies can be explored. The recently developed m7-FLIPI, a risk model that combines clinical risk factors [the Follicular Lymphoma International Prognostic Index] and the mutational status of 7 genes, represents a first step toward incorporating biological risk into prognostic stratification. Beyond prognostication, predictive markers that can guide the use of novel targeted therapies for subgroups of patients who are most likely to benefit will be essential for making progress.

Collectively, marginal zone lymphomas (MZLs) represent the second most common subtype of indolent NHL, although individually the three variants—nodal MZL (NMZL), splenic MZL (SMZL), and extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma)—are relatively rare. NMZL exhibits a clinical presentation and disease course that are similar to those of FL. However, gene expression profiling studies have revealed markers that are differentially expressed in NMZL compared with FL. Whereas NMZL exhibits morphologic and immunophenotypic similarities to the other MZL subtypes (SMZL and MALT), unique clinical and molecular features allow distinction. Because of the paucity of clinical trials specifically addressing NMZL, there are no standard treatment recommendations. Patients are typically treated according to management algorithms developed for FL, with an apparent improvement in outcome over recent years. However, a comparison of outcomes with those seen in FL or the other MZL subtypes is difficult on the basis of available data. Recent genomic studies have characterized multiple deregulated pathways in NMZL, with combinations that seem to be specific for this entity. As a consequence, trials of novel targeted therapies exploiting these unique aspects are logical and are being initiated.

Patients with SMZL typically present with the clinical constellation of spleen-dominant disease, bone marrow involvement, and peripheral blood lymphocytosis. In addition to establishing the diagnosis, splenectomy can be an effective therapeutic maneuver, resulting in disease debulking and correction of cytopenias. Because the disease course is typically indolent, many patients can be observed without a need for therapy, whereas a subset of patients exhibit disease with more aggressive behavior requiring systemic intervention. As with NMZL, subtype-specific clinical trials are rare, and thus there is no consensus on treatment. Therapeutic options include those typically used for other indolent lymphomas, which rely on immunochemotherapy. An epidemiologic association with hepatitis C virus in some cases raises the possibility of treatment with antiviral therapies. Although the pathogenesis is not fully elucidated, a critical role for an antigenic driver has been postulated. Genomic studies have identified several key pathways that are recurrently deregulated, including nuclear factor κB signaling, NOTCH pathway genes, and KLF2, as well as the presence of subtype-specific abnormalities (7q deletion and NOTCH2 mutations). Advances in biological understanding will inevitably translate into novel targeted approaches.

MALT lymphoma is believed to arise as a result of chronic inflammation within extranodal sites, which yields clinically diverse presentations, depending on the site of origin. In many cases, an etiologic pathogen has been postulated, although the strongest evidence relates to the development of gastric MALT lymphoma in the presence of chronic gastritis resulting from Helicobacter pylori. In this circumstance, eradication of H. pylori with antibiotics can be curative in a substantial proportion of patients. In addition to external pathogens, autoimmune disorders have also been shown to increase risk. Genomic studies of MALT lymphoma have revealed recurring abnormalities, including the presence of recurrent chromosomal translocations, the frequency of which varies according to anatomic localization. Because of the clinical and genetic diversity of MALT lymphoma, outcome comparisons according to site of presentation are difficult to perform. Many patients present with localized disease, enabling the use of localized therapy such as involved field radiotherapy with curative intent. Disseminated disease can frequently be observed, whereas symptomatic presentations typically respond well to standard immunochemotherapy. Ultimately, optimization of site-specific therapy guided by biologic differences is an important goal.

Because of improved outcomes and an increasing number of available therapeutic options, the role of intensive strategies including autologous and allogeneic stem cell transplantation in the management of indolent lymphoma warrants consideration. The majority of patients can be effectively treated with standard approaches, but a proportion of patients prove resistant to standard therapies and inevitably succumb to their disease. Therefore, stem cell transplantation may offer some patients an essential treatment alternative. However, the identification of high-risk patients who may benefit from transplantation is limited with available prognostic tools. Although the age limit of transplantation has increased and morbidities have diminished, only a small proportion of patients are amenable to such intense therapy. Importantly, because of recent advances in standard therapies, historical trials that evaluate transplantation are no longer clinically relevant. Further delineation of the optimal timing of transplantation and appropriate patient selection will require prospective evaluation. Until then, the decision to undergo transplantation will need to be carefully individualized, taking into account patient characteristics, disease biology, and treatment responsiveness as well as patient preferences.

This is indeed an exciting and complicated time in the treatment of indolent lymphoma. The articles in this series highlight the unique biology between and within individual histologic subtypes that must be recognized in order to achieve a tailored-therapy approach. Because the majority of patients with indolent lymphoma have a favorable outcome, performing trials with unselected previously untreated patients is becoming unfeasible. Validated tools to allow the appropriate selection of higher-risk patients and the identification of surrogate end points will be crucial for enabling trials to be performed within a reasonable time frame. Although this will expedite progress, it will further accentuate the problem with many trials: they evaluate only short-term end points and do not allow for the assessment of sequencing of agents. Given that the care of indolent lymphoma is a marathon and not a sprint, this is where the art of medicine will lie. Management strategies must account for disease biology, the risk-benefit ratio of available therapies, and patient comorbidities and preferences. Ultimately, agents should be optimally combined or sequenced to ensure that both duration and quality of life are maximized. Because of the rarity of these entities, well-designed clinical trials and greater collaboration will be essential to ensure timely completion.

  • Submitted March 14, 2016.
  • Accepted March 15, 2016.