Targeted therapies transforming treatment of indolent non-Hodgkin lymphoma
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Targeted therapies have rapidly changed the treatment landscape of indolent non-Hodgkin lymphoma, a heterogenous group of diseases for which individualized care is crucial, according to a speaker at Chemotherapy Foundation Symposium.
“As we enter the targeted therapy era, we’re understanding there are really different responses to various indolent lymphomas, so it’s important to consider each subtype individually,” Lori Leslie, MD, of the lymphoma division at John Theurer Cancer Center and assistant professor of medicine at Hackensack Meridian School of Medicine, said during a presentation.
For these lymphomas — with the exception of mantle cell lymphoma — watch and wait is still an appropriate strategy for asymptomatic individuals and general indications remain similar, Leslie said. But as the treatment landscape evolves and understanding of the molecular drivers of lymphoma improves, several barriers must be overcome, she said. “When you see just a few cases of follicular or marginal zone lymphoma a year, it’s easier to stick with what’s familiar,” she said. “It’s easy to confuse the indications because, again, they’re so variable and becoming divergent.”
In B-cell NHL, the immunomodulatory agent lenalidomide (Revlimid, Bristol Myers Squibb) has demonstrated direct cytotoxicity, angiogenesis inhibition, significant immunostimulatory effects with enhanced T-cell and natural killer cell effects, and microenvironmental effects. Some data suggest lenalidomide can resensitize cells to rituximab (Rituxan; Genentech, Biogen), which has given rise to the R-squared (R2) regimen combining the agents, Leslie said.
Lenalidomide toxicities include teratogenicity, venous and arterial thromboembolism, and cytopenias. However, Leslie said in her experience with a 1-year course of treatment for patients with follicular and marginal zone lymphoma, the R2 regimen has been relatively easy to manage.
“So, if we have this regimen, should we move away from chemoimmunotherapy in the front-line setting for follicular lymphoma? For most, probably no,” she said.
The regimen did not meet the primary endpoint of complete response rate at 120 weeks vs. rituximab plus chemotherapy in the phase 3 RELEVANCE study, Leslie said, although response rates were similar and R2 had a slightly more favorable toxicity profile.
R2 has not been approved by the FDA in the front-line setting for patients with follicular lymphoma; however, National Comprehensive Cancer Network recommends consideration of the regimen for patients with treatment-naive disease. R2 has been approved by the FDA for relapsed or refractory follicular and marginal zone lymphoma based on results of the phase 3 AUGMENT and MAGNIFY studies.
When discussing B-cell receptor pathway inhibitors, the treatment landscape becomes much more divergent, Leslie said.
Three covalent Bruton tyrosine kinase inhibitors have been FDA approved for indolent NHL: ibrutinib (Imbruvica; Pharmacyclics, Janssen), acalabrutinib (Calquence, AstraZeneca) and zanubrutinib (Brukinsa, BeiGene). None is designed to overcome resistance. The same is true of the PI3 kinase inhibitors idelalisib (Zydelig, Gilead), duvelisib (Copiktra, Secura Bio), copanlisib (Aliqopa, Bayer) and umbralisib (Ukoniq, TG Therapeutics), all of which have been FDA approved for relapsed or refractory follicular lymphoma. Phase 2 study data has shown these drugs confer response rates in the 40% to 60% range among these patients, with PFS of about 1 year, Leslie said. Umbralisib, which specifically inhibits CK1 epsilon, received FDA approval for marginal zone lymphoma earlier this year based on study data that showed an overall response rate of 49% with median follow-up of 27.8 months, and responses appeared durable.
In contrast, BTK inhibitors have produced disappointing results in follicular lymphoma but are still being investigated as part of combination therapy, Leslie said. BTK inhibitors have shown much more promise in marginal zone lymphoma, with ibrutinib and zanubrutinib approved by the FDA for use as early as in the second-line setting.
About 20% of patients with follicular lymphoma have activating mutations in EZH2, which is also critical in the pathogenesis of patients with wild-type EZH2, Leslie said.
Tazemetostat (Tazverik, Epizyme), an EZH2 inhibitor, has been FDA approved for certain patients with relapsed or refractory follicular lymphoma. Trial results showed the agent induced responses in patients with EZH2-mutant and wild-type with a low rate of grade 3 or higher toxicities.
Leslie also touched upon CD19-directed CAR T-cell therapy, including axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead), which received FDA approval in March for treatment of relapsed or refractory follicular lymphoma.
“This is kind of an upfront investment for a long-term, potentially treatment-free period,” she said. “I kind of explain it to patients as a one-and-done type of approach,” she said.
Further data on axicabtagene ciloleucel in follicular lymphoma and marginal zone lymphoma will be presented in the near future, Leslie said.
References:
Fowler NH, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03433.
Leslie L. Targeting indolent B-cell NHL: Not all subtypes are created equally. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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Leslie L. Targeting indolent B-cell NHL: Not all subtypes are created equally. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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