Precise Selection of Treatment for Follicular Lymphoma

In the indolent lymphoma subgroup of follicular lymphoma (FL), multiple regimens have activity. When choosing between chemotherapy-based regimens, rituximab combinations, a PI3K inhibitor, an EZH2 inhibitor, or chimeric antigen receptor T-cell therapy, an individualized approach is necessary, according to Loretta J. Nastoupil, MD.¹

During Session IX: Indolent B-cell Lymphoma at the 10th Annual Meeting of the Society of Hematologic Oncology, Nastoupil, associate professor, deputy chair, and section chief in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, as well as the director, Lymphoma Outcomes Database, Department of Lymphoma/Myeloma, Division of Cancer Medicine both at The University of Texas MD Anderson Cancer Center, Houston, Texas, , gave a presentation with suggestions on how to approach individualized treatment for patients with FL in the frontline, relapsed/refractory, and maintenance settings.

“Follicular lymphoma is an indolent process with favorable outcomes and prolonged natural history for the majority of patients. However, it is important to recognize poor-risk groups that are currently defined as those that progress within 24 months of chemoimmunotherapy and those that become refractory to CD20-targeting and alkylator therapies. Therefore, the unmet need currently is identifying optimal strategies to minimize the risk of early relapse or bring novel, effective, well-tolerated therapies to the third-line or later setting, Nastoupil told The SOHO Daily News.

Choosing Frontline Treatment

In the first-line setting, Nastoupil explained that most therapies of the available therapies are appropriate to use, but hematologists/oncologists should take the patient’s fitness into consideration.

R-CHOP

One available regimen is the combination of rituximab (Rituxan®; Genentech, Biogen) plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), which has been available for over decade. Newer evidence supports its use specifically for patients with transformation. These patients can be identified by a low threshold for PET (standard uptake value > 13-15) and should be re-biopsied to confirm the findings.

Patients with FL who receive R-CHOP can have a 2-year overall survival (OS) rate of 71% (95% CI, 61.5%-78.0%) or a 5-year OS of 50% (95% CI, 40.3%-58.8%), according to data from 588 patients with FL.²

Nastoupil noted that there is a subset of patients with FL who cannot tolerate anthracyclines such as the doxorubicin that is a component of the R-CHOP regimen. For such patients, Nastoupil recommends bendamustine (Bendeka®; Teva) plus rituximab (BR) or lenalidomide (Revlimid®; Bristol Myers Squibb) plus rituximab (R2).

BR Regimen

In a phase 3 study of 549 patients with FL (NCT00991211), BR was found to be non-inferior to R-CHOP and showed a favored survival outcome vs R-CHOP.

At a median follow-up 69.5 months in the BR arm and 31.2 months in the R-CHOP arm, the 5-years OS rate was 80% vs 78%, respectively (HR, 0.58; 95% CI, 0.44-0.74; stratified log-rank P =0.0000148).

R2 Regimen

Data supporting the use of R2 in patients with FL in the frontline setting who cannot tolerate anthracyclines comes from the RELEVANCE protocols (NCT01476787 and NCT01650701). A total of 1030 patients were evaluated in the study, and it was determined that the efficacy of R2 was like that of any chemotherapy. The safety profile of R2 and chemotherapy differed.⁴

The 3-year progression-free survival (PFS) was 77% (95% CI, 72%-80%) in the R2 arm vs 78% (95% CI, 74%-81%) in the chemotherapy arm (HR, 0.94; 95% CI, 0.73-1.22; P =0.63). Objective responses were also assessed in RELEVANCE, and the objective response rate (ORR) observed with R2 was 84% compared with 89% in the chemotherapy arm. The median duration of response (DOR) was 77% with R2 vs 74% with chemotherapy.

Nastoupil explained that there is ongoing research looking at how the tumor microenvironment and genotype can guide the clinical decision between R2 and chemotherapy with rituximab.

Selecting Treatment for Relapsed/Refractory Disease

In the relapsed or refractory setting of FL, therapies are more targeted. When selecting therapy for a patient in this setting, Nastoupil says that doctors should consider prior therapies, remission duration with last therapy, number of lines of therapy, EZH2 status, and other important characteristics.

The available options include PI3K inhibitors, EZH2 inhibitors, and CAR T-cell therapy. All the options have efficacy and treatment decision choices come down to safety and tolerability.

PI3K Inhibitors

The approved PI3K inhibitors include idelalisib (Zydelig®; Gilead), copanlisib (Aliqupa®; Bayer), duvelisib (Copiktra®; Secura Bio), an umbralisib (Ukoniq®; TG Therapeutics).

Results from the DELTA study (NCT01282424), CHRONOS-1 (NCT01660451), DYNAMO (NCT01882803), and UNITY (NCT02793583) support the use of PI3K inhibitors in this patient population. Data displayed during Nastoupil’s presentation shows that the median PFS for these agents range from 9.5 months to 11.2 months, and the ORRs range from 42% to 59%. The median DOR for PI3K inhibitors ranges from 10 months to 12.5 months.¹

PI3K inhibitors are associated with grade 3 or higher adverse events like alanine aminotransferase and aspartate aminotransferase increases, diarrhea/colitis, pneumonia, hyperglycemia, and hypertension. In addition, serous AEs occur with these agents and have caused concern from the FDA.¹

EZH2 Inhibitors

The EZH2 inhibitor used in the relapsed/refractory setting is tazemetostat (Tazverik, Epizyme, Inc.). In a phase 2 study, tazemetostat demonstrated durable anti-tumor activity in patients. The ORR observed with the agent was 77% with complete responses in 7%. The responses were also considerable in the wild-type EZH2 subgroup, with an ORR of 34%.⁵

Tazemetostat was well-tolerated in the study. Only 5% of patients discontinued treatment due to a treatment-related AE, and 9% required a dose reduction.

CAR T-Cell Therapy

Both axicabtagene ciloleucel (axi-cel; Yescarta®; Gilead) and tisagenlecleucel (tisa-cel; Kymriah®; Novartis) are effective CAR T-cell therapies for relapsed/refractory. These drugs offer CRs of 81% and 66%, respectively.

In terms of PFS, the median observed with axicabtagene ciloleucel was 23.5 months (95% CI, 22.8-NE), and with tisagenlecleucel, the median PFs was 29.5 months (95% CI, 17.9-NE).¹

CAR T-cell therapies are associated with cytokine release syndrome and neurologic events. These AEs are important to consider before selecting this therapy for a patient with relapsed/refractory FL, according to Nastoupil.

“The other unmet need in follicular lymphoma is identifying optimal sequencing of therapy given there are several heterogeneous approaches to this disease, and most patients will undergo several courses of therapy over their lifetime,” Nastoupil told the SOHO Daily News. “Balancing the goals of therapy from the vantage point of patients and our desire to extend life is important. In the absence of predictive biomarkers, we generally approach sequencing based on patient specific characteristics including fitness and comorbidities, with disease specific characteristics including type and duration of response to prior therapy, EZH2 status, and features suggestive of transformation. What is desirable is a clinical tool that can help in identifying the proper sequence of therapy to reduce the heterogeneity that currently exists.”

_REFERENCES:

_{1. Nastoupil L. Follicular lymphoma treatment choices. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.}

_{2. Casulo C, Bytrek 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. doi: 10.1200/JCO.2014.59.7534}

_{3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi: 10.1016/S0140-6736(12)61763-2.}

_{4. Morschauser F, Fowler NH, Feugier P. et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi: 10.1056/NEJMoa1805104.}

_{5. Morchhauser F, Tilly H, Chaidos A, et al. Interim update from a phase 2 multicenter study of tazemetostat, an ezh2 inhibitor, in patients with relapsed or refractory follicular lymphoma. Hematol Oncol.2019;37:154-156. https://doi.org/10.1002/hon.111_2629}