Over the last few years, researchers have identified a subset of follicular lymphoma patients who are in need of more effective treatment options: individuals who experience progression within the first 2 years following standard therapy.
“Approximately 20 percent of patients with follicular lymphoma experience disease progression within 2 years of chemoimmunotherapy,” noted study author Jonathan W. Friedberg, MD, MMSc, Director of the Wilmot Cancer Institute, and Professor in the Department of Medicine at the University of Rochester, N.Y. “Several datasets have demonstrated that these patients have very short overall survival—less than 50 percent at 5 years—strikingly different from the remainder of patients with follicular lymphoma who have an outstanding overall survival rate. Ten-year overall survival typically exceeds 90 percent.
“Therefore, it is clear this subgroup represents probably the greatest unmet need in the follicular lymphoma patient population,” he continued. “Very little is known about how to treat these patients and the majority of previous studies have enrolled patients with relapsed follicular lymphoma without separating the patients out who experienced early progression versus those who have later disease progression.”
Recognizing a gap in available treatments, Friedberg and his team sought to better understand the needs of this subset of follicular lymphoma patients. “We thought it would be useful to look at recent studies that had been conducted with novel agents of follicular lymphoma to shed light on this patient population and associated treatment challenges.”
Researchers performed a retrospective post hoc analysis to determine the effect of idelalisib on clinical outcomes among follicular lymphoma patients experiencing early progressive disease after initial chemoimmunotherapy (Blood 2017;129:3037-3039).
Idelalisib, a phosphoinositide 3-kinase (PI3K) inhibitor, is currently indicated in the U.S. and Europe as a monotherapy for relapsed follicular lymphoma.
The study included grades 1, 2, and 3A (with specific exclusion of grade 3B), according to researchers. Of the patients included in the study, 46 received first-line chemoimmunotherapy. Late progressive disease occurred in nine of these patients after 24 months of initial treatment. Thirty-seven had early progression within 24 months from the beginning of treatment.
Among the enrolled patients, 19 (51.4%) were male and 18 (48.6%) were female. Grade 1 or 2 follicular lymphoma was present in 89.2 percent of included patients, and 56.8 percent had high-risk Follicular Lymphoma International Prognostic Index scores, study authors reported.
“This high-risk population was well represented in the trial (37/125 [30%]), and all 37 patients received idelalisib treatment,” according to investigators. The majority of these high-risk patients (21/37) received R-CHOP as a first-line therapy and were heavily pretreated with an average number of three prior therapies. The time from start of first-line therapy to the beginning of idelalisib treatment was 30.3 months.
Efficacy results of this retrospective analysis supported the benefit of idelalisib therapy for this high-risk subset of follicular lymphoma patients.
Findings show antitumor activity in patients who relapsed within 24 months of standard treatment. According to researchers, the objective response rate was 56.8 percent (21 out of 37 patients); additionally, there were five complete responses (13.5%) and 16 partial responses (43.2%).
Study authors reported that there was not a significant difference in response rates between patients who experienced progressive disease within 12 months after initial treatment (12 out of 17) and those who progressed between 12 and 24 months following chemoimmunotherapy (nine out of 20). Among all 37 patients with early progression, the median duration of response was 11.8 months.
Researchers reported an overall median progression-free survival (PFS) of 11.1 months; PFS was 8 months for patients who experienced progressive disease within 12 months compared to 13.6 months for those who progressed between 12 and 24 months.
“Our results suggested that even the group of patients who had the highest risk—patients who relapsed very quickly after their initial induction treatment—still had a reasonable response rate with idelalisib,” explained Friedberg.
“Progression-free survival was, understandably, somewhat shorter than what would be expected if you didn't limit it to the high-risk group, but the overall outcomes were rather similar to what was seen in previous studies that did not separate the time to initial relapse.
“Therefore, the takeaway from this research is that we demonstrated that idelalisib is an active drug in this patient population,” he continued. “And, there is a subset of patients who derive significant benefit.”
Friedberg acknowledged the limitations of the study, including its retrospective design. “This was not a prospective study specifically initiated to look at early progressing patients, so it is possible there may have been some selection bias where the highest risk patients could have been shunted towards other treatments,” he noted.
“I think the other point to make is that, since these trials have been conducted, we have learned there may be increased toxicity to idelalisib, particularly when used a little earlier in the course of the disease of follicular lymphoma,” Friedberg continued.
“And, we have learned that you need to be vigilant if you use this drug and try to prevent and monitor for such toxicity, but with those caveats, I do believe it is an approved option that should be considered for this patient population.
“Additionally, these positive results have built the foundation for additional study of PI3K inhibitors and the role this type of treatment could play among early progressing patients.”
This study is only the first step in better understanding and treating this subset of high-risk follicular lymphoma patients.
“Our previous research has established that PI3K is a good target, especially in this subset of follicular lymphoma,” noted Friedberg. “Therefore, a prospective trial is now underway to continue our work with this particular patient population.”
The primary objective of this intergroup, randomized trial, the “Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma” (NCT03269669) is to compare complete remission rate following “six cycles of two targeted therapeutic regimens (obinutuzumab + TGR-1202 and obinutuzumab + lenalidomide) with obinutuzumab-CHOP in early progressing or refractory follicular lymphoma.”
Eligible patients include those with grade 1, 2, or 3a follicular lymphoma who have not achieved complete remission or relapse within 2 years following first-line chemoimmunotherapy.
“This trial also aims to determine biomarkers of response, so we can better understand the subset of patients who particularly benefit from this drug,” Friedberg noted. “This study, as well as future trials, will continue to enhance our knowledge of this patient population and allow clinicians to provide the best therapeutic options.”
Looking to the future, Friedberg recognizes a need for a deeper understanding of the disease biology of follicular lymphoma.
“While our study in Blood gives physicians a treatment option today, I believe it also suggests that patients who are intrinsically resistant to chemotherapy and antibody treatment may respond to PI3K inhibition and that is an important message,” he explained. “What we need to be able to do moving forward is to really understand biologically why and whether we can better define which patients who receive this treatment are going to have long responses versus those with more modest responses.”
Additionally, Friedberg pointed out another important role idelalisib could play in treatment. “There are evolving data that suggests autologous stem cell transplantation (ASCT) may be a good option for patients with early progressing follicular lymphoma, particularly those who are young,” he concluded. “Idelalisib could also be considered a bridge to other treatment options, including ASCT.”
Catlin Nalley is associate editor.