High-Risk Follicular Lymphoma Subgroup Identified

Carla Casulo, MD

Patients with follicular lymphoma progressing within 2 years on first-line R-CHOP have a 5-year overall survival (OS) rate of only 50%, compared with 90% in longer responders, according to an analysis published in the Journal of Clinical Oncology. Researchers are now focused on immunotherapeutic, targeted, and other approaches to improving outcomes in this high-risk, early relapse population.

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator,” wrote Carla Casulo, MD, assistant professor of Medicine at the University of Rochester Medical Center, and fellow researchers. “Understanding the mechanisms responsible for this by means of targeted sequencing or gene expression profiling would be important to improving the outcome of this group…Moreover, we propose that 2-year PFS may be a practical and meaningful clinical endpoint for trials involving a chemoimmunotherapy backbone in FL.”

Outcomes across several studies have shown that one in five patients with follicular lymphoma (FL) progresses within 24 months of first-line chemoimmunotherapy, regardless of whether maintenance therapy is used. To assess the clinical significance of this early progression, Casulo et al examined outcomes with first-line R-CHOP among 588 patients with stage II-IV FL enrolled in the National LymphoCare Study (NLCS).

At a median follow-up of 7 years, the researchers observed that 110 (19%) of the 588 patients had progressed within 2 years, 420 (71%) had response durations >2 years, 46 (8%) were lost to follow-up, and 12 (2%) died within 2 years of diagnosis but did not have disease progression.

Among the cohort of 110 patients with early progression, 66% had grade 1 or 2 disease, 65% were male, and the median age was 58 years (range, 31-88 years).

Fifty-seven of the patients who progressed early died during the study follow-up. The 2-year OS rate was 68% among patients who relapsed within 2 years compared with 97% in the longer responders. Five-year OS rates were 50% and 90%, respectively. After adjusting for the FL International Prognostic Index (FLIPI), the trend in poorer outcomes among early relapse patients was maintained (HR, 6.44; 95% CI, 4.33-9.58).

OS outcomes were also evaluated from the time patients experienced disease progression. In this analysis, OS results were again inferior among patients who relapsed early compared with those who progressed >2 years postdiagnosis (HR, 1.89; 95% CI, 1.18-3.03; P = .008).

To corroborate their results, Casulo et al also assessed outcomes in an independent validation cohort of 147 patients with stage II-IV follicular lymphoma who received first-line R-CHOP at the University of Iowa and Mayo Clinic Molecular Epidemiology Resource.

Patient characteristics were similar between the validation cohort and the primary NLCS analysis; however, there were more patients with grade 3 disease in the validation cohort (54% vs 38%; P <.001). At a median of 5.5 years’ follow-up, 26% of patients had relapsed within 24 months of diagnosis, 71% did not progress early, 3% had a follow-up of <24 months, and all patients who died within 2 years of diagnosis had disease progression.

Two-year and 5-year OS rates in the validation cohort were similar to the primary analysis at 64% and 34% versus 98% and 94% in the early relapse group versus the longer responders, respectively. The results remained consistent after adjusting for FLIPI score (HR, 19.8; 95% CI, 6.7-58.8).

An editorial published simultaneously with Casulo et al’s research noted that little is known about the biologic and genetic makeup of these more aggressive FLs of early relapse patients, as compared with the FLs of patients who experience longer response and survival durations.

“Analyzing these lymphomas for various immunologic and inflammatory markers, both in the blood as well as in the lymphoma itself, and with deep-sequencing techniques, has the potential to define additional biologic and genetic markers to annotate clinical prognostic tools,” wrote colleagues Caron A. Jacobson, MD, and Arnold S. Freedman, MD, from the Dana-Farber Cancer Institute.

Researchers could then potentially use these prognostic tools to vary treatment and improve outcomes in the high-risk patients, Jacobson and Freedman noted. The analyses could identify patients who would benefit from more intensive chemotherapy approaches upfront, or those who would have chemorefractory disease and have improved outcomes with more targeted/immunotherapeutic approaches.

Commenting on the latter, Jacobson and Freedman described novel approaches that have shown promise in patients with FL, including checkpoint inhibition, inhibiting PI3K delta, chimeric antigen receptor (CAR) T-cell therapy, and HDAC inhibition:

The PD-1 inhibitor nivolumab (opdivo) has induced a response rate of 40% in relapsed/refractory FL; the PI3K delta inhibitor idelalisib (Zydelig) is FDA-approved for the treatment of relapsed FL; responses have been reported in a few FL patients with an anti-CD19—directed CAR T-cell therapy, and there are larger, ongoing and planned trials with this treatment; and the HDAC inhibitor vorinostat had an overall response rate of 49% and a median progression-free survival of 20 months in a phase II study of relapsed patients with indolent lymphomas that including 39 patients with FL.

“Combining any of these strategies with a BCL2 antagonist like ABT-199 (venetoclax), which targets the hallmark t(11;14) genetic lesion involving the BCL2 locus in these lymphomas, may result in additive benefit,” Jacobson and Freedman wrote, adding, “How such agents can be combined with chemotherapy for the treatment of both previously untreated and relapsed disease also remains to be determined.”

1. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522.
2. Jacobson CA, Freedman AS. Rethinking prognosis and therapy for follicular lymphoma. J Clin Oncol. 2015;33(23):2489-2491.