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Reflection on Indolent Non-Hodgkin Lymphomas

By Rebecca Connor, MD  

An internet search for synonyms of the word indolent produces many terms relaying a desire to avoid activity or exertion, including lazy, idle, slothful, and my personal favorite, lackadaisical. These terms are in stark contrast to the industrious and stimulating research presented at the 2018 ASH Annual Meeting in the sessions on indolent non-Hodgkin lymphoma (NHL). I will highlight a few, but many more can be found online in the ASH web program.

Earlier in 2018, a flurry of excitement regarding “chemotherapy-free” treatment of symptomatic, advanced-stage follicular lymphoma (FL) came after early results from the phase III RELEVANCE trial, which suggested that lenalidomide plus rituximab (R2) results in similar progression-free survival (PFS) as that seen with chemoimmunotherapy, but with a different toxicity profile. At the 2018 meeting, the AUGMENT phase III, multicenter, randomized trial provided additional data regarding R2, suggesting that when compared with rituximab plus placebo, R2 improves PFS in patients with relapsed FL or marginal zone lymphoma not refractory to rituximab (abstract #445). Longer follow-up is needed from both trials to evaluate long-term toxicity and overall survival.

While anti-CD20 monoclonal antibodies are instrumental in the initial treatment of indolent NHL, we are still learning about their value in rituximab-refractory disease. Earlier, the randomized GADOLIN trial reported improved PFS with bendamustine plus obinutuzumab followed by obinutuzumab maintenance, when compared with bendamustine alone in rituximab-refractory indolent NHL. In contrast, in the Complement A+B randomized trial presented at this meeting, the addition of a finite course of ofatumumab to bendamustine did not significantly impact PFS in rituximab refractory indolent NHL (abstract #450). Additional trials are needed to guide the incorporation of antibodies (which ones, for how long) in this setting.

While most patients with FL treated with modern regimens will enjoy survival times that mirror the general population, approximately 20 percent of patients will have an aggressive course with brief remissions, frequent relapses, and shortened survival. Recent reports have highlighted the prognostic value of early treatment failure (e.g., progression within 24 months of chemoimmunotherapy) as a marker of aggressive disease. At this meeting, analysis of an international database confirmed that early treatment failure was associated with inferior survival in patients with marginal zone lymphoma (abstract #393). In an analysis of the GALLIUM trial (abstract #396), detection of minimal residual disease at the end of induction was associated with a high risk of early progression or death, perhaps offering an opportunity to identify this aggressive subset prior to relapse.

There is hope that novel agents may improve outcomes for patients with early treatment failure. In an analysis of the CHRONOS-1 study, the PI3K inhibitor copanlisib seemed to be equally effective in individuals with early treatment failure and in those with late relapse (abstract #395). Several single-arm trials demonstrated the feasibility of new combinations such as obinutuzumab plus lenalidomide (abstract #446) and avadomide (a cereblon modulating agent) plus obinutuzumab (abstract #449). Further study is needed to assess the efficacy of these regimens.

Together, we are making great strides toward a better understanding of these complicated lymphomas, illustrating that this research arena is far from indolent.

Dr. Connor indicated no relevant conflicts of  interest.

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