Progress in Advanced-Stage Follicular Lymphoma

The past two decades have seen tremendous progress in the treatment of advanced-stage follicular lymphoma.1 Two articles published earlier this year in Journal of Clinical Oncology underscore the excellent long-term outcomes of this disease after chemoimmunotherapy-based induction strategies. The S0016 trial, which randomly assigned patients to either rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or CHOP with 131I tositumomab demonstrated a 10-year progression-free survival (PFS) of 49% and overall survival of 78%; neither arm included maintenance.2 Similarly, in the FOLL05 study, for patients treated with R-CHOP (without maintenance), the 8-year PFS was 49%, and overall survival was 83%.3 Preliminary long-term follow-up of the Study Group Indolent Lymphomas (STiL) trial, which randomly assigned patients to either R-CHOP or bendamustine and rituximab (BR), again without maintenance, demonstrates improved time to next treatment (not reached v 56 months) favoring BR and 10-year overall survival of 71% (BR) and 66% (R-CHOP).4 Indeed, a recently published analysis from the Iowa/Mayo Clinic group and the French Lymphoma Study Association suggests that the majority of patients with follicular lymphoma who do not have a progression event within the first 12 months of diagnosis seem to enjoy survival equivalent to age-matched healthy controls.5 There are few situations in medicine where half of patients remain in remission after 10 years of follow-up from first therapy, and we are still hesitant to use the word cure. However, I suspect that a significant proportion of these patients with follicular lymphoma will not require additional antilymphoma therapy for the remainder of their lifetime. It is important to note these outstanding outcomes are occurring with empirically derived (nonprecision) chemoimmunotherapy approaches.

Despite these favorable outcomes for the majority of patients with follicular lymphoma, subsets of patients can be identified with much shorter survivals. The M7 Follicular Lymphoma–International Prognostic Index combines several clinical factors at diagnosis with mutation status of seven genes and can identify approximately 25% of patients who have a 5-year PFS after standard chemoimmunotherapy of only 25%.6 Twenty percent of patients with follicular lymphoma reliably experience disease progression within 2 years after chemoimmunotherapy, and these patients have poor overall survival, with a median of ≤ 5 years in several data sets.7-9 Although several clinical and laboratory factors correlating with early progression of follicular lymphoma have been identified,10-12 these still require validation and are not ready for widespread therapeutic application. Early progression is almost certainly a surrogate for unique lymphoma biology conferring relative resistance to standard treatment. Major efforts are underway to better understand the underlying mechanisms of this resistance to therapy,13 complicated by substantial clonal heterogeneity in this disease.14 A recently published 23-gene expression score could identify approximately 35% of patients with inferior outcomes after induction chemoimmunotherapy, including increased risk of progression within 2 years.15 Genes predicting poor outcome in this signature had characteristics of Burkitt-like cells and immature pre-B cells, suggesting that some follicular lymphoma cells have the potential to acquire an aggressively behaving germinal center expression program. Microenvironment gene signatures also contributed to inferior PFS, in keeping with prior reports(....)

Journal of Clinical Oncology , éditorial en libre accès, 2017

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