For a presentation at ASCO 2021, John Seymour, PhD, Professor at the Peter MacCallum Cancer Centre of the Royal Melbourne Hospital and University of Melbourne in Australia, discussed six FDA-approved agents or drug classes—Phosphoinositide 3-kinase inhibitors (P13K), Bruton tyrosine kinase (BTK) inhibitors, lenalidomide, tazemetostat, axicabtagene ciloleucel, and venetoclax—and the data supporting their application in relapsed/refractory follicular lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia.

“An important overarching comment is that previously, with non-targeted actions such as cytotoxic chemotherapy, activity was generally shared and broadly similar across the spectrum of the indolent lymphoma proliferative disorders, so that extrapolation was possible,” he noted. “That is no longer true with the targeted agents, and thus, their efficacy must be considered on a disease-by-disease basis.”

Evidence-Based Decisions

Dr. Seymour framed the discussion around an illustrative case of a woman aged 71 with follicular lymphoma who was thought to achieve complete remission with six cycles of bendamustine and rituximab but presented 3 years later with symptomatic disseminated recurrent disease and a dominant mesenteric nodal mass. He noted the importance of openly discussing with patients their own priorities and values and considering these in selecting therapies.

Standard of care options included repeating chemo-immunotherapy or lenalidomide and rituximab. Although chemotherapy-free, the latter option had a serious adverse event rate of 26% in the AUGMENT study, with a 50% occurrence rate for grade 3-4 neutropenia and 36% of patients requiring growth factor. “Specific toxicities to be aware of with [this combination] are rash and transient tumor flare, both occurring in about 10% of patients” said Dr. Seymour. With a preference to minimize in-hospital time and avoid potentially severe toxicities couple with the patient’s cardiovascular risk profile, she received lenalidomide and rituximab, completing treatment—with the requirement for a dose reduction due to a ration neutropenia—and achieved complete remission. The patient experienced another relapse 2 years later, with symptomatic adenopathy and fatigue. Repeat biopsy showed follicular histology. The FDA-approved standard of care options then included BTK inhibitors, tazemetostat, and several P13K inhibitors. Dr. Seymour didn’t discuss the option chosen for the illustrative patient, but instead hinted at the choice in an explanation of his personal algorithm for an approach to sequencing the available approved targeted therapies in relapsed follicular lymphoma.

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A Personal Algorithm
“Chemo-immunotherapy remains the recommended frontline treatment, with the choice between obinutuzumab or rituximab,” Dr. Seymour said. “I prefer obinutuzumab.”

Histologic transformation should be considered and excluded at first relapse, he noted, adding that the prognostically adverse early relapses should be considered and managed differently. “For the more common late relapses of follicular histology, [lenalidomide plus rituximab] has the strongest supporting data, with either tazemetostat or the PI3K inhibitors used third line, with my preference for tazemetostat if the [enhancer of zeste homolog 2] mutation is present,” continued Dr. Seymour. “When selecting a PI3K inhibitor, convenience of delivery and adverse event profile are guiding factors, and I personally prefer umbrilisib. I’m not yet sure of the true place of [axicabtagene ciloleucel] in follicular lymphoma, given its expense, logistic complexities, and my concern regarding neurologic toxicity. The [complete response] rate is high, and most responses so far appear durable. If these are sustained, it raises the potential for long-term disease control in this otherwise incurable disease context. Then its use would move earlier in the treatment algorithm.”