Refractoriness to immunochemotherapy in follicular lymphoma: Predictive factors and outcome

Abstract

Follicular lymphoma is characterized by a good response to immunochemotherapy (ICT). However, a small percentage of patients responds poorly to treatment and seems to have a worse outcome. This study attempted to identify the predictive factors and outcome of refractoriness to first-line ICT. All patients diagnosed with stage II to IV follicular lymphoma between 2002 and 2014 and treated with first-line ICT in 4 Spanish institutions were analyzed. Those with no response or progression or relapse within 6 months of first-line response assessment were considered ICT refractory. Three hundred forty-three patients were included (median age 58 years, 48% male), of whom 53 (15%) were ICT refractory. On multivariate analysis, high-risk follicular lymphoma international prognostic index (FLIPI) score, B symptoms, and elevated β2-microglobulin were correlated with refractoriness, and refractoriness, high-risk FLIPI score, and β2-microglobulin were correlated with overall survival (OS). Compared with ICT-sensitive, ICT-refractory patients had a higher incidence of histological transformation (5-year cumulative incidence 25% [14%-39%] vs. 6% [3%-10%], P < .001), a higher rate of refractoriness to second-line therapy (16/33 [48%] vs. 13/57 [23%], P = .01), and a lower OS (5-year OS probability 38% [95% CI 23%-53%] vs. 87% [82%-92%%], P < .001). In conclusion, refractoriness to ICT was seen in 15% of patients and was predicted by high-FLIPI scores, B symptoms, and elevated serum β2-micrglobulin. Immunochemotherapy-refractory patients had a worse prognosis than ICT-sensitive patients, and current treatment options for this subgroup are not satisfactory.

Treatment of localized‐stage follicular lymphoma

“…Finally, genetic studies in localized-stage FL may help better understand the clinical heterogeneity of FL, including patients with noted bad outcome, that is with early progression of disease and HT. 37,78,79 It is conceivable that localized-stage FL could have a better prognosis not only derived from the lower tumour burden and its curability, but by being particularly slow-growing (which, in turn, would aid in being diagnosed at a localized stage) or sensitive to therapy. In line with that possibility, in a series of stage II-IV ICT-treated patients with FL, none of the patients with stage II showed either HT or refractoriness to treatment 78 although this subgroup was small.…”

The case for lymphoma-specific survival

“…At present, it has become clear that FL is a very heterogeneous disease, and that the different prognostic subgroups can largely be drawn based on response to first-line immunochemotherapy (ICT). Thus, patients with poor response to frontline ICT have a poorer response to subsequent lines of therapy as well as a shorter overall survival (OS) [6][7][8], and they also seem to have notably higher rates of histological transformation (HT). Although it is unclear whether there is a late plateau in the HT curves [9]; HT is more frequent [7,8] and aggressive [10,11] shortly after diagnosis.…”

“…Thus, patients with poor response to frontline ICT have a poorer response to subsequent lines of therapy as well as a shorter overall survival (OS) [6][7][8], and they also seem to have notably higher rates of histological transformation (HT). Although it is unclear whether there is a late plateau in the HT curves [9]; HT is more frequent [7,8] and aggressive [10,11] shortly after diagnosis. Conversely, patients with remission persisting 2 years after diagnosis (or perhaps as early as 1 year) can expect to live as long as the general population [12], which seems to indicate that their risk of death from either the disease or toxicity is lower.…”

“…Conversely, patients with remission persisting 2 years after diagnosis (or perhaps as early as 1 year) can expect to live as long as the general population [12], which seems to indicate that their risk of death from either the disease or toxicity is lower. In a recent study analyzing the outcome of FL patients based on their response to front-line ICT [7], we found that most patients with ICT-refractory disease were dead at the time of analysis (31/53, 58%), mostly due to lymphoma (27/31, 87%) while only a minority of ICT-sensitive patients had died (35/290, 12%), 14 (40%) due to lymphoma and 10 (29%) due to toxicity (unpublished data). Importantly, however, a majority of patients remained alive.…”

Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure who reach complete response after rescue treatment

“…Anti‐CD20 maintenance therapy prolongs remission and probably survival and has become a standard of care after first‐line therapy . Nevertheless, several studies have shown that approximately 15% to 20% of patients with FL will not respond to first‐line immunochemotherapy based on rituximab (refractoriness) or will experience early therapy failure (ETF), defined as relapse or progression within 2 years of commencing first‐line immunochemotherapy . The outcome for this subgroup of high‐risk FL patients is much worse than that of those who respond well to first‐line treatment, with reported 5‐year OS of approximately 50% versus 90% in the latter …”