Dr Amengual on the Efficacy of Tazemetostat Plus Lenalidomide/Rituximab in Follicular Lymphoma

"I was encouraged by the real-world data [regarding] the use of glofitamab for DLBCL in the relapsed setting. There was a slight reduction in overall response rate and overall survival [compared with clinical trial populations,] but [these outcomes] still closely mirrored what we see in the clinical trials for those who are less sick and receiving glofitamab in earlier lines of treatment"

Jennifer Amengual, MD, Herbert Irving Assistant Professor of Medicine, Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, discusses the efficacy of tazemetostat (Tazverik) vs placebo in combination with lenalidomide (Revlimid) and rituximab (Rituxan) for patients with relapsed/refractory follicular lymphoma (FL), according to data from the phase 3 SYMPHONY-1 study (NCT04224493).

In this dose-finding study, patients received rituximab for the first 5 cycles, lenalidomide for the first 12 cycles, and continuous tazemetostat, Amengual begins. The regimen demonstrated no unexpected toxicities, and response rates were notable across molecular subgroups, she states.

The overall response rate (ORR) was 90.9% across the intention-to-treat population (n = 44), including 88.9% in EZH2 wild-type disease, despite prior assumptions that tazemetostat would have enhanced activity in EZH2-mutated tumors, Amengual reports. Among patients refractory to rituximab, the ORR was 93.3%, and those with POD24 follicular lymphoma—historically associated with poor outcomes—had an ORR of 92%, she notes. At a median follow-up of 22.5 months, median progression-free survival and duration of response were not reached, Amengual adds.

These findings were contextualized alongside data from the phase 2 TRANSCEND FL study (NCT04245839) evaluating lisocabtagene maraleucel (liso-cel; Breyanzi) in relapsed/refractory follicular lymphoma, Amengual continues. Liso-cel demonstrated an ORR of 96%, all of which were complete responses, she details. Notably, the CAR T-cell therapy cohort included younger patients, whereas SYMPHONY-1 enrolled an older population, she says.

The results underscore the expanding treatment landscape for follicular lymphoma, highlighting the potential for durable responses with an effective, predominantly oral regimen, as an alternative to intensive cellular therapies, Amengual concludes.

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Jennifer Amengual, MD, discusses the efficacy of tazemetostat plus lenalidomide and rituximab in relapsed/refractory follicular lymphoma.

Jennifer Effie Amengual, MD, Herbert Irving Assistant Professor of Medicine, Division of Hematology and Oncology, Center for Lymphoid Malignancies and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, discusses considerations for community oncologists looking to refer patients with relapsed/refractory follicular lymphoma (FL) to the ongoing second-line, phase 3 SYMPHONY-1 trial (NCT04224493).

The 3-stage SYMPHONY-1 trial is investigating the combination of tazemetostat (Tazverik), lenalidomide (Revlimid), and rituximab (Rituxan) in patients with relapsed/refractory FL. Stage 1 was a phase 1b safety run-in portion in which all patients received the triplet to determine the recommended phase 3 dose (RP3D) of tazemetostat. Stage 2 is a phase 3 portion that will randomly assign patients to receive lenalidomide and rituximab plus either tazemetostat at the RP3D of 800 mg twice daily, or placebo. Stage 3 is an optional portion in which patients will receive tazemetostat at the RP3D plus rituximab and lenalidomide in 28-day cycles.

Tazemetostat is an effective treatment option for patients with FL who can delay more intensive regimens, Amengual says. Since both tazemetostat and lenalidomide are oral agents, this triplet regimen can also be administered as a mostly outpatient treatment, Amengual notes. In SYMPHONY-1, patients receive intravenous rituximab for the first 5, 28-day cycles before receiving an entirely oral regimen, so they only need to visit the clinic for a few months at the start of treatment, Amengual explains.

So far, most patients enrolled in SYMPHONY-1 who were refractory to rituximab in their previous line of therapy have responded to tazemetostat plus lenalidomide and rituximab, Amengual emphasizes. Additionally, all patients who relapsed within 24 months of their first line of therapy, who are classified as having POD24 and comprise approximately one-third of the phase 1 patient population, have responded to the triplet, according to Amengual. This tolerable, easy-to-administer regimen may overcome common barriers to treatment experienced by patients with rituximab-resistant, rituximab-refractory, or POD24 disease, Amengual concludes.

Jennifer Effie Amengual, MD, discusses considerations for community oncologists looking to refer patients with relapsed/refractory follicular lymphoma (FL) to the ongoing second-line, phase 3 SYMPHONY-1 trial (NCT04224493).

Dr Amengual on Tazemetostat, Lenalidomide, and Rituximab in Relapsed/Refractory FL

Jennifer E. Amengual, MD, assistant professor of medicine and developmental therapeutics, member, Center for Lymphoid Malignancies, Columbia University, discusses the development of novel agents for subtypes of diffuse large b-cell lymphoma.

The understanding of molecular pathogenesis of diffuse large b-cell lymphoma has lead to the identification of three main subtypes: the germinal center subtype, the ABC subtype, and type 3 or primary mediastinal, Amengual says.

Amengual says most of the work lately has focused on developing novel therapeutics for the ABC subtype, which has a worse prognosis than the germinal center subtype. Because ibrutinib and lenalidomide have started to change the treatment of ABC subtype lymphoma, the focus has now shifted to develop novel agents for the germinal center subtype of diffuse large b-cell lymphoma.

It’s been shown that BCL6, which drives the subtype, can be modulated through acetylation, Amengual says. Treatment with HDAC inhibitors can shift the balance between suppressing the oncogene BCL6 and by activating a tumor suppressor such as P53.

In preclinical models of diffuse large b-cell lymphoma, Amengual says, physicians were able to enforce acetylation of BCL6 and P53, which leads to induction of apoptosis. This was validated in mouse models and was then translated to a clinical trial of patients with relapsed/refractory lymphoma. It was found that in a heavily pretreated cohort of patients, there was a 24% overall response rate with the treatment with HDAC inhibitors vorinostat and niacinamide, Amengual says.

Jennifer E. Amengual, MD, discusses the development of novel agents for subtypes of diffuse large b-cell lymphoma.

Dr. Amengual on Novel Therapeutics in Lymphoma

Jennifer E. Amengual, MD, assistant professor of medicine and developmental therapeutics, member, Center for Lymphoid Malignancies, Columbia University, discusses the potential of the combination of vorinostat and niacinamide as treatment for patients with diffuse large B-cell lymphoma.

Vorinostat, a pan-class histone deacetylase (HDAC) inhibitor, has little effect in patients with diffuse large b-cell lymphoma on its own, Amengual explains, and has more of an effect in T-cell subtype lymphomas.

Niocinamide is a class III HDAC inhibitor, which is also known as a sirtuin inhibitor. When sirtuins are activated, Amengual says, cell survival is prolonged during times of genotoxic stress. But inhibiting sirtuins in certain diseases, like lymphoma, may prove to be beneficial.

Amengual says it has been observed that combining sirtuin inhibitors with pan-HDAC inhibitors is synergistic and has potential as a treatment for lymphoma.

Jennifer E. Amengual, MD

Articles

Dr Amengual on the Efficacy of Tazemetostat Plus Lenalidomide/Rituximab in Follicular Lymphoma

Dr Amengual on Tazemetostat, Lenalidomide, and Rituximab in Relapsed/Refractory FL

Dr. Amengual on Novel Therapeutics in Lymphoma

Dr. Amengual on Vorinostat and Niacinamide in Lymphoma