Gene-Based Risk Model Improves Prognosis for Follicular Lymphoma

By combining clinical risk factors with mutation status from seven genes, researchers were able to improve prognostication for patients with follicular lymphoma who are undergoing first-line immunochemotherapy, according to the results of a retrospective study published in Lancet Oncology.

The seven genes included in the clinicogenetic risk model, named m7-FLIPI, were EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

“By adding the mutational status for seven genes to established clinical risk factors, we developed an improved prognostic algorithm to help clarify which patients are likely to have poor outcome after standard immunochemotherapy,” wrote Alessandro Pastore, MD, from the University Hospital of the Ludwig-Maximilians University Munich, and colleagues. “If the m7-FLIPI is further validated in subsequent studies, it could serve as a valuable biomarker to select patients for trials of risk-adapted treatment strategies.”

To establish this model, the researchers conducted DNA deep sequencing of 74 genes from 151 follicular lymphoma tissue samples. The samples were all taken from patients within 1 year of initiating immunochemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The established model included mutational status of the seven genes, the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status.

With a median follow-up of 7.7 years, the 5-year failure-free survival of the cohort was 66.22% and the 5-year overall survival was 83.25%.

The m7-FLIPI model showed that patients in the high-risk group had fourfold worse 5-year failure-free survival compared with patients classified as low-risk (38.29% vs 77.21%; hazard ratio [HR] = 4.14 [95% confidence interval (CI), 2.47–6.93]; P < .0001). Overall survival was also significantly worse in patients classified as high-risk by the model compared with low-risk patients (65.25% vs 89.98%; P = .00031).

In addition, the multifaceted m7-FLIPI model outperformed a prognostic model of only gene mutations (HR = 3.76 [95% CI, 2.10–6.74]; P < .0001).

Overall, the new model had a positive predictive value of 64% for 5-year failure-free survival and the negative predictive value was 78%.

“In both cohorts, about half the patients classified as high-risk using FLIPI were classified as low-risk using m7-FLIPI and these patients had outcomes indistinguishable from those with low-risk FLIPI,” the researchers wrote. “This reclassification of risk category using the m7-FLIPI score primarily results from gene mutations, in particular mutation of EZH2, that lower the risk of a failure-free survival event after immunochemotherapy.”

The researchers then validated the model in a group of 107 patients with symptomatic follicular lymphoma who were considered ineligible for curative irradiation. This group had more patients aged older than 60 years and more with a ECOG performance status greater than 1.

In this group, the high-risk patients had a 5-year failure-free survival of 25% compared with 68.24% for low-risk patients (HR = 3.58 [95% CI, 2.00–6.42]; P < .0001). The overall survival for high-risk patients was 41.67% compared with 84.01% for low-risk patients (P < .0001). The positive predictive value in this cohort was 72% and the negative predictive value was 68%.

“Our cohorts span two continents and include both a clinical trial population (German Low-Grade Lymphoma Study Group 2000) and a population-based registry (BC Cancer Agency),” the researchers wrote. “We believe that the fact that the validation cohort received a different immunochemotherapy and maintenance regimen and gave virtually the same results supports the broad applicability of the m7-FLIPI.”