Growing Indications in Follicular Lymphoma Signal an Exciting Moment in Indolent Lymphoma Treatment


“It's an exciting time with all the novel agent development in relapsed indolent lymphoma,” according to Brad S. Kahl, MD.

Brad S. Kahl, MD

Brad S. Kahl, MD

Key factors when selecting indolent lymphoma treatment for patients with relapsed or refractory disease are histologic transformation and whether or not the patient had early progression of disease following chemoimmunotherapy, and this is particularly true for follicular lymphoma (FL), according to Brad S. Kahl, MD.1

During a virtual presentation at the 26th Annual International Congress on Hematologic Malignancies, hosted by Physician’s Education Resource®, Kahl, a professor of medicine in the Division of Oncology at Washington University School of Medicine and a medical oncologist at Siteman Cancer Center, explained that with histologic transformation, FL should be treated like diffuse large B-cell lymphoma. In the case of early progression, it is important to bear in mind that early progression is associated with poor prognosis and there is an unmet medical need to develop novel options for these patients.

Patients with relapsed or refractory FL may have multiple relapses, explained Kahl, and after the first relapse, the median progression-free survival (PFS) decreases.

Research shows that the median PFS in patients treated in the frontline setting is 6.62 years (95% CI, 6.10-7.20). In the second line, the median PFS decreases to 1.50 years (95% CI, 1.35-1.70). Beyond the second-line setting, the median PFS in patients with relapsed/refractory FL is less than 1 year.1,2

Regarding these data, Kahl stated: “It shows how the remission durations are not as durable as one might think when you start getting into the second line, third line, fourth line in follicular lymphoma. These patients tend to have a pattern of multiple relapses, and you can see how durable the first-line treatment is. And then it really diminishes dramatically with second line, third line, fourth line with median progression-free survivals, often, just around a year, and so you can really start to burn through your treatments rather quickly when you get into the multiple relapse setting.”

Despite the challenge of treating these tumors, treatment options include conventional therapies like chemoimmunotherapy with or without maintenance, rituximab (Rituxan) with or without maintenance, radioimmunotherapy, and autologous/allogeneic transplant. Newer FDA-approved strategies for the treatment of patients with relapsed/refractory FL include a lenalidomide (Revlimid)-based therapy, a PI3 kinase (PI3K) inhibitor, tazemetostat (Tazverik), and chimeric antigen receptor (CAR) T-cell therapy. Additionally, novel agents being investigated for relapsed/refractory FL include bispecific antibodies and CD47-targeted agents.

FDA-Approved Agents

Lenalidomide-containing Regimens

A lenalidomide-based regimen consisting of rituximab 375 mg/m2 administered on days 1, 8, 15, and 22 of cycle 1 and on days 2-5 of cycle 2 in combination with lenalidomide 20 mg/m2 on days 1-21 of a 28-day cycle (the R2 regimen) is supported by data from the phase 3, double-blind, randomized AUGMENT study (NCT01938001). The data show that the addition of lenalidomide to rituximab improved efficacy in patients with recurrent indolent lymphoma and with a tolerable safety profile.1,3

The AUGMENT population consisted of patients who had at least 1 prior chemotherapy, immunotherapy, or chemoimmunotherapy and 2 prior doses of rituximab but were not refractory to rituximab.

“The R2 or lenalidomide/rituximab regimen has probably the most impressive data in the relapse setting, with response rates just north of 80% and a reasonably high complete response [CR] rate and immediate progression-free survival that is in the 2- to 3-year range in the AUGMENT trial,” Kahl said.

R2 was also found to improve survival in comparison with rituximab monotherapy. At a median follow-up of 28.3 months, the median PFS per independent review committee was 39.4 months (95% CI, 22.9 to not evaluable [NE]) with R2 versus 14.1 months (95% CI, 11.4-16.7) with rituximab/placebo (HR, 0.45; 95% CI, 0.34-0.62; P < .0001). The 2-year overall survival (OS) rate was 93% with R2 compared with 87% with rituximab/placebo.

In the safety-evaluable population, adverse events (AEs) leading to drug discontinuation were observed in 8% of the R2 arm compared with 4% of the rituximab/placebo arm. Kahl noted that the majority of the patients (55%) treated with R2 were able to remain on the 20-mg dose of lenalidomide for the full year. Overall, 30% of patients in the R2 arm versus 39% in the rituximab/placebo arm discontinued treatment, and there were 2 deaths in the R2 arm.

PI3K Inhibitors

One PI3K inhibitor approved for the treatment of relapsed/refractory FL is umbralisib (Ukoniq), and a new drug application for parsaclisib was accepted by the FDA in November of 2021.1

Umbralisib was evaluated in patients with relapsed/refractory indolent lymphoma who had 2 or more prior lines of treatment with an anti-CD20 monoclonal antibody therapy and an alkylating agent in the UNITY-NHL trial (NCT02793583).1,4

Kahl highlighted findings from the FL cohort who had an objective response rate (ORR) of 45.3% with complete responses in 5%, and a median PFS of 10.6 months (95% CI, 7.2-13.7).1

A notable AE with umbralisib was non-infectious colitis occurring in 4 patients. Notably, the colitis was resolved in all but 1 patient. Also, discontinuation of treatment as a result of aspartate aminotransferase increase, alanine aminotransferase increase, or diarrhea was observed in 2.9% of patients each.1,4

Data on parsaclisib from the CITADEL-203 study (NCT03126019) offer another PI3K inhibitor option after both copanlisib (Aliqopa) and duvelisib (Copiktra) were withdrawn from the market, explained Kahl.1 In the study, parsaclisib achieved a high rate of responses that were both rapidly occurring and durable in patients with relapsed/refractory FL who had received at least 2 prior systemic therapies. The agent also demonstrated an acceptable safety profile in the study.5

According to Kahl, the ORR observed with parsaclisib was 75% with a CR rate of 18%. The median PFS was 14 months. Treatment discontinuation in the study occurred in 24%, due to common AEs of diarrhea in 8% and colitis in 5%.1

EZH2 Inhibitor Therapy

EZH2 inhibition is rather new in FL, according to Kahl, but 20% of patients with FL have a EZH2 mutation making it an important therapeutic option. Currently, the 1 EZH2 inhibitor approved by the FDA for the treatment of relapsed/refractory FL is tazemetostat.

The accelerated approval of tazemetostat was based upon data from the EZH2-mutated FL and EZH2 wild-type FL cohorts of Study E7438-G000-101 (NCT01897571).6 In the EZH2-mutated population, tazemetostat achieved an ORR of 69% (95% CI, 53%-82%), and the median PFS was 13.8 months (95% CI, 10.7-22.0). In the EZH2 wild-type population, the ORR was 35% (95% CI, 23%-49%), and the median PFS was 11.1 months (95% CI, 3.7-14.6).7

Safety data showed that tazemetostat was well tolerated. The most common AEs of any grade were nausea (23%), asthenia (18%), and diarrhea (18%).

CAR T-Cell Therapy

Axicabtagene ciloleucel (axi-cel; Yescarta) is an FDA-approved treatment for relapsed/refractory FL and tisagenlecleucel (tisa-cel; Kymriah) is currently under investigation. According to Kahl, both therapies have very high response rates, good durability of response, but toxicity including cytokine release syndrome (CRS) and cytopenia remains a concern.1

In the ZUMA-5 (NCT03105336) clinical trial, axi-cel achieved an ORR of 94% with a 79% CR rate. Tisa-cel showed similar findings in ELARA (NCT03568461) with an ORR of 86% and a CR rate of 69%. Based on these data, Kahl stated: “It's hard to know right now how good this is. I don't think we have a full picture of the risk-benefit profile. This may turn out to be a very good option for selected patients. So, I'm really interested to learn more about current recovery, and I'm really interested to see how the curves look at 3, 4, and 5 years.”

Encouraging Investigational Agents

A pivotal phase 2 study of mosunetuzumab (RG7828) is underway, evaluating its efficacy and safety in patients with relapsed/refractory FL (NCT02500407).1

“Another agent that we're very excited about in relapsed follicular lymphoma is mosunetuzumab, which is a bispecific monoclonal antibody that targets CD20 and CD3. And we saw updated data at the ASH meeting this past year for this agent and relapsed follicular lymphoma.... What we saw were very nice response rates, [an] overall response rate of 80%, a complete response rate of 60%, and the median progression-free survival is reported at right around 18 months,” said Kahl.

Like other therapies for the treatment of relapsed/refractory FL, there is a risk of CRS with mosunetuzumab, but most cases appear to be grade 1 or 2 in severity. Aside from CRS, Kahl says that the treatment appears to be well tolerated.

Overall, the list of targeted agents is extensive for the treatment of indolent lymphomas, but only 3 of the agents are FDA-approved to treat relapsed/refractory FL. Novel drugs that are currently being investigated in clinical trials will improve the field even further, Kahl explained.

“It's an exciting time with all the with all the novel agent development in relapsed indolent lymphoma,” Kahl stated.


1. Kahl B. Indolent lymphoma – Treatment options for R/R disease. Presented at: 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma; February 23-25, 2022; Miami, FL.

2. Link BK, Day B, Zhou X, et al. Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br J Haematol. 2019;184(4):660-663. doi:10.1111/bjh.15149.

3. Leonard JP, Trneny M, Izutsu K, et al; AUGMENT Trial Investigators. AUGMENT: A phase 3 study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010

4. Fowler NH, Samaniego F, Jurczak, W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39(15):1609-1618. doi:10.1200/JCO.20.03433

5. Lynch RC, Paneesha S, Avigdor A, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma (CITADEL-203). Blood. 2020;136(suppl 1):36-38. doi:10.1182/blood-2020-134869

6. FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed February 26, 2022.

7. Morchhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1

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