Expert Calls Attention to Treatment-Emergent AEs in Follicular Lymphoma

Lawrence D. Kaplan, MD, discusses standard frontline treatment in follicular lymphoma, toxicities of some of the newer agents, and preliminary data with bispecific antibodies.

Lawrence D. Kaplan, MD

Immunomodulatory drugs and PI3K inhibitors have shown activity in frontline and relapsed/refractory follicular lymphoma, respectively, and according to Lawrence D. Kaplan, MD, their unique toxicity profiles can help inform treatment decisions.

In the frontline setting, investigators evaluated the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R2) versus the historical standard of rituximab and chemotherapy in the phase III RELEVANCE trial. However, the chemotherapy-free regimen failed to demonstrate a significant advantage over rituximab and chemotherapy, and it failed to meet its primary end point as a superiority trial. After 120 weeks, the complete remission (CR) or unconfirmed CR rate was 48% in the R2 arm versus 53% in the rituximab and chemotherapy arm (P = .13) per independent review.1

The rate of grade ≥3 treatment-emergent adverse events (AEs) was higher in the rituximab/chemotherapy arm versus the R2 arm, at approximately 70% and 60%, respectively. The incidence of neutropenia, febrile neutropenia, growth factor usage, gastrointestinal upset, and neuropathy was more common in the rituximab/chemotherapy arm; however, the incidence of cutaneous reactions, tumor flare, and diarrhea was more common with R2.

“R2 is clearly an active regimen in the frontline setting, and there are certainly instances where it might be a good choice,” said Kaplan. “It's not unusual for a patient to say that they don’t want bendamustine or another chemotherapy-based regimen. In that situation, my first choice would probably be R2.”

In the relapsed/refractory setting, 3 PI3K inhibitors—idelalisib (Zydelig), duvelisib (Copiktra), and copanlisib (Aliqopa)—are approved for use in patients who have received ≥2 prior systemic therapies.

“They are all active drugs with response rates in the 50% range,” said Kaplan. “However, they do have significant toxicities.” Notably, idelalisib and duvelisib come with boxed warnings for associated toxicities, such as hepatotoxicity, noninfectious pneumonitis, diarrhea, and colitis.2,3

To address the need for more tolerable options, several additional treatment strategies are under investigation. One such effort is examining the use of bispecific antibodies, which have shown preliminary efficacy and reduced toxicity, said Kaplan.

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Kaplan, a clinical professor of medicine and director of the Adult Lymphoma Program in the Division of Hematology-Oncology at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed standard frontline treatment in follicular lymphoma, toxicities of some of the newer agents, and preliminary data with bispecific antibodies.

OncLive: How do you approach treatment for a patient with newly diagnosed follicular lymphoma?

Kaplan: The standard of care is rituximab chemotherapy, and attempts have been made to [improve upon that]. However, the RELEVANCE trial, which compared R2 with rituximab and chemotherapy followed by rituximab maintenance, failed to demonstrate the superiority of R2. As a result, it's difficult to [say that R2 is a preferred] frontline therapy.

What other factors do you consider when selecting frontline treatment?

Mostly, it’s [patient preference]. I can't think of another instance where R2 would be the better choice. The decision may depend on underlying medical issues. Lenalidomide still has toxicities, although it’s not chemotherapy. [Patients on lenalidomide may] experience issues with their blood counts. Cytopenias can be a real problem; diarrhea can sometimes be a problem. You have to take some of those things into account.

Could you shed light on some of the agents that are being used in later lines of treatment?

The PI3K inhibitors have worked their way into later lines of therapy. Three agents are approved for use as monotherapy in the third-line setting. The 2 oral drugs, idelalisib and duvelisib, are particularly toxic. They both have black box warnings on the FDA prescribing information that mostly pertain to autoimmune toxicities, such as hepatotoxicity, noninfectious pneumonitis, diarrhea, and colitis. A significant number of patients will experience these toxicities, and grade ≥3 autoimmune toxicities are seen in at least 25% of the those who receive these drugs. One has to be prepared to intervene, if necessary, to control those toxicities.

Copanlisib is the third drug, and it is the only 1 of the 3 drugs that is administered intravenously. The fact that [this agent is] dosed intermittently may be why we’re seeing a lower incidence of some of these toxicities, particularly the autoimmune events. One of the downsides of the drug is that it can’t be taken at home. At UCSF, copanlisib has become our preferred PI3K inhibitor.

Were any exciting studies presented at the 2019 ASH Annual Meeting in follicular lymphoma?

Yes. The 2019 ASH Annual Meeting was a good meeting for lymphoma; there was a big focus on the [bispecific] monoclonal antibodies, most of which target CD3 and CD20. Not only were these active agents in aggressive B-cell lymphomas, but they appear to have significant response rates in indolent B-cell lymphomas as well, including in patients with recurrence after CAR T-cell therapy. Many of these studies [have limited follow-up]. However, these agents are likely going to be a lot easier to administer in the outpatient setting with somewhat less toxicity than CAR T-cell therapy. Moreover, that may make these agents more widely available to the patient populations who need them.


  1. Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36(suppl 15; abstr 7500). doi: 10.1200/JCO.2018.36.15_suppl.7500.
  2. Zydelig (idelalisib) [prescribing information]. Foster City, CA: Gilead Sciences, Inc; July 2014. Accessed January 16, 2020.
  3. Copiktra (duvelisib) [prescribing information]. Needham, MA: Verastem, Inc; September 2018. Accessed January 16, 2020.