Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy

Abstract

• The posttreatment end point progression of FL within 24 months (POD24) is strongly associated with OS.• A pretreatment clinicogenetic risk model (m7-FLIPI) predicts POD24 and OS and identifies the smallest subgroup with highest unmet need.Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P < .0001) and 26% (vs 86%, P < .0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P 5 .00031) and 4.76 in BCCA patients (P 5 .0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL. (Blood. 2016; 128(8):1112-1120

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium

“…Of all previously published numerical alterations in FL, only gain of chromosome 18 stood out as an independent prognostic marker. Our results confirm EZH2 as a strong prognostic marker in FL, with wild-type gene status associated with poor disease outcome (EF), 31,32 but other markers, such as EP300 and TNFRSF14, which have been implicated to have a significant, though minor, impact on prognosis, were not substantiated in our study. 31,54 This is likely due to selection bias and relative underrepresentation of poor prognosis patients in previous series for which our study design was specifically optimized.…”

“…Statistically significant differences after multiple testing correction were only found for gain of chromosomal region 18p11. 32 …”

“…31 This method may also be valuable for very high-risk FL cohorts, as reported by the same group. 32 The objective of the study herein by the LLBC consortium was to critically assess, in a homogeneously treated patient cohort, whether the previously implicated microenvironmental and molecular markers of the tumor have clinically relevant prognostic value. We hypothesized that the microenvironmental and molecular markers would be most prominent when we compared tissue samples of patients with an extremely poor prognosis (i.e., progression or death within 2 years, a well-established criterion for poor prognosis in FL) 33 with those with a very favorable prognosis (a response to first-line treatment lasting >5 years).…”

Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy

“…1 Several studies identified a high-risk population of patients, comprising ;20% of all patients with NHL, who had FL that progressed within 24 months from initiation of the first-line chemoimmunotherapy and were at increased risk of death. [2][3][4] Idelalisib, a highly selective, orally bioavailable inhibitor of the d isoform of phosphoinositide 3-kinase d, is indicated in the United States and Europe as monotherapy for relapsed FL. 5,6 A phase 2, multicenter, open-label, single-arm study evaluated the efficacy and safety of idelalisib in 125 patients previously treated with first-line chemoimmunotherapy who had relapsed indolent NHL that was refractory to both alkylators and rituximab (NCT01282424).…”

Can histologic transformation of follicular lymphoma be predicted and prevented?

“…Early progression, most commonly defined as progression within 2 years after starting rituximabchemotherapy, occurs in ;20% of patients and has recently been associated with poor outcome. [6][7][8][9] Similarly, transformation to aggressive lymphoma, occurring in 2% to 3% of patients per year, has repeatedly been linked to adverse prognosis when compared with patients not experiencing transformation. [10][11][12][13][14][15] There is an association between early progression and transformation.…”