The key factors when selecting treatment for smoldering lymphoma for patients with relapsed or refractory disease are histological transformation and whether or not the patient has early disease progression after chemoimmunotherapy, and that is especially true for follicular lymphoma (FL), according to Brad S. Kahl, MARYLAND.1
During a virtual presentation at 26th Annual International Congress on Hematological Malignancies, organized by Physician’s Education Resource®, Kahl, professor of medicine in the division of oncology at Washington University School of Medicine and medical oncologist at the Siteman Cancer Center, explained that with histological transformation, the LF should be treated as diffuse large B-cell lymphoma. In the case of early progression, it is important to keep in mind that early progression is associated with a poor prognosis and that there is an unmet medical need. pleased to develop new options for these patients.
Patients with relapsed or refractory FL can have multiple relapses, Kahl explained, and after the first relapse, the median progression-free survival (PFS) decreases.
Research shows that the median PFS in first-line treated patients 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 this data, Kahl said, “It shows how remission times aren’t as durable as you might think when you start getting into 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 first-line treatment is. And then it really drops dramatically with the second line, third line, fourth line with median progression free survivals, often, just about a year, and so you can really start to burn through your treatments pretty quickly when you get into the frame of multiple relapses.”
Despite the challenge of treating these tumors, treatment options include conventional therapies such as chemoimmunotherapy with or without maintenance, rituximab (Rituxan) with or without maintenance, radioimmunotherapy, and autologous/allogeneic transplantation. New FDA-approved strategies for treating patients with relapsed/refractory FL include lenalidomide therapy (Revlimid), PI3 kinase inhibitor (PI3K), tazemetostat (Tazverik), and T-cell therapy chimeric antigen receptor (CAR). Additionally, new agents being investigated for relapsed/refractory FL include bispecific antibodies and agents targeting CD47.
Regimens containing lenalidomide
A lenalidomide 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 days 1 through 21 of a 28-day cycle (the R2 treatment) is supported by data from the phase 3 randomized double-blind AUGMENT study (NCT01938001). Data show that adding lenalidomide to rituximab improves 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 who were not refractory to rituximab.
“The R2 or the lenalidomide/rituximab regimen probably has the most impressive data in the relapse setting, with response rates just north of 80% and a reasonably high complete response [CR] immediate progression-free survival rate that is in the 2-3 year range in the AUGMENT trial,” Kahl said.
R2 was also found to improve survival compared to rituximab monotherapy. At a median follow-up of 28.3 months, the median PFS by independent review board 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 (RR, 0.45; 95% CI, 0.34-0.62; P 2 versus 87% with rituximab/placebo.
In the safety-evaluable population, adverse events (AEs) leading to drug discontinuation were observed in 8% of R2 versus 4% of the rituximab/placebo arm. Kahl noted that the majority of patients (55%) treated with R2 were able to continue taking the 20 mg lenalidomide dose throughout the year. Overall, 30% of R patients2 versus 39% in the rituximab/placebo arm discontinued treatment, and there were 2 deaths in the R2 arms.
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 2021.1
Umbralisib was evaluated in patients with relapsed/refractory indolent lymphoma who received at least 2 prior lines of treatment with anti-CD20 monoclonal antibody therapy and an alkylating agent in the UNITY-NHL trial (NCT02793583) .1.4
Kahl highlighted the results of the FL cohort which 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, colitis resolved in all but 1 patient. Additionally, discontinuation of therapy due to increased aspartate aminotransferase, increased alanine aminotransferase, or diarrhea was observed in 2.9% of patients each.1.4
The parsaclisib data from the CITADEL-203 study (NCT03126019) provides another PI3K inhibitor option after copanlisib (Aliqopa) and duvelisib (Copiktra) were withdrawn from the market, Kahl explained.1 In the study, parsaclisib achieved a high rate of both rapid and durable responses in patients with relapsed/refractory FL who had received at least 2 prior systemic treatments. 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. Discontinuation of study treatment occurred in 24% of cases, due to common AEs of diarrhea in 8% of cases and colitis in 5% of cases.1
EZH2 inhibitor therapy
EZH2 inhibition is rather new in FL, according to Kahl, but 20% of FL patients have a EZH2 mutation that makes it an important therapeutic option. Currently, the 1 FDA-approved EZH2 inhibitor for the treatment of relapsed/refractory FL is tazemetostat.
The accelerated approval of tazemetostat was based on data from the EZH2-FL mutated and EZH2 wild-type LF cohorts from study E7438-G000-101 (NCT01897571)6. EZH2– in the mutated population, tazemetostat achieved an ORR of 69% (95% CI, 53% to 82%), and the median PFS was 13.8 months (95% CI, 10.7 to 22, 0). In the EZH2 wild-type population, the ORR was 35% (95% CI, 23% to 49%), and the median PFS was 11.1 months (95% CI, 3.7 to 14.6).7
Safety data showed that tazemetostat was well tolerated. The most common AEs of all grades 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 clinical trial (NCT03105336), axi-cel achieved an ORR of 94% with a CR rate of 79%. Tisa-cel showed similar results in ELARA (NCT03568461) with an ORR of 86% and a CR rate of 69%. Based on that data, Kahl said, “It’s hard to know just how good it is. I don’t think we have the full picture of the risk-benefit profile. This may turn out to be a very good option for some patients. So I’m really interested to know more about the current recovery, and I’m really interested to see what the curves look like at 3, 4 and 5 years.
A pivotal phase 2 study of mosunetuzumab (RG7828) is ongoing, evaluating its efficacy and safety in patients with relapsed/refractory FL (NCT02500407).1
“Mosunetuzumab, a bispecific monoclonal antibody that targets CD20 and CD3, is another agent we are very excited about in relapsed follicular lymphoma. And we saw updated data at the ASH meeting last year for this agent and relapsed follicular lymphoma… What we saw were very good response rates, [an] 80% overall response rate, 60% complete response rate, and median progression-free survival is reported to be approximately 18 months,” Kahl said.
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. CRS aside, Kahl says the treatment appears to be well tolerated.
Overall, the list of targeted agents is long for the treatment of indolent lymphomas, but only 3 of the agents are FDA approved to treat relapsed/refractory FL. New drugs that are currently being studied in clinical trials will further improve the field, Kahl explained.
“It’s an exciting time with all the development of a new agent in relapsed indolent lymphoma,” Kahl said.
1. Kahl B. Indolent Lymphoma – Treatment Options for R/R Disease. Presented at: 2022 International Congress on Hematological Malignancies: Focus on Leukaemias, Lymphomas and Myeloma; February 23-25, 2022; Miami, Florida.
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 National LymphoCare Observational Study. Br J Haematol. 2019;184(4):660-663. doi:10.1111/bjh.15149.
3. Leonard JP, Trneny M, Izutsu K, et al; INCREASE Trial Investigators. AUGMENTATION: A Phase 3 study comparing lenalidomide and rituximab to placebo and 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(supplement 1):36-38. doi:10.1182/blood-2020-134869
6. The FDA granted accelerated approval to tazemetostat for follicular lymphoma. Press release. FDA. June 18, 2020. Accessed February 26, 2022. https://bit.ly/3tdAWJC
7. Morchhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicenter, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1