New Sequencing Approaches Shape Follicular Lymphoma Landscape

OncologyLive, Vol. 20/No. 21, Volume 20, Issue 21

With a variety of available agents in follicular lymphoma, determining which treatments to choose and how best to sequence them can be challenging.

Ian W. Flinn, MD, PhD

Follicular lymphoma is an indolent non-Hodgkin lymphoma that often requires multiple lines of treatment after it relapses or becomes refractory to standard therapies. With a variety of available agents, including the more recently approved R2 regimen of lenalidomide (Revlimid) plus rituximab (Rituxan) as well as the PI3K inhibitor duvelisib (Copiktra), determining which treatments to choose and how best to sequence them can be challenging.

During a recent OncLive Peer Exchange® program, a panel of lymphoma experts discussed their approach to selecting and sequencing follicular lymphoma treatments. Overall, based on the recent FDA approvals, the panelists favored using R2 in the second line and PI3K inhibitors in the third line, and they discussed the differences between the PI3K inhibitors currently approved for follicular lymphoma.

“For the first time in a long time, we’re starting to get a more unified approach to the treatment of follicular lymphoma,” Ian W. Flinn, MD, PhD, said. The panelists also examined several emerging treatments, including immunotherapies, chimeric antigen receptor (CAR) T-cell therapy, and the EZH2 inhibitor tazemetostat, some of which have the potential to shake up the treatment landscape if approved.

R2 in the Second Line

In May, the FDA approved R2 for patients with previously treated follicular lymphoma or marginal zone lymphoma (MZL).1 “[For] the first time, there is a chemotherapy-free regimen with an immunomodulator, lenalidomide, and an anti-CD20 monoclonal, rituximab,” Pier Luigi Zinzani, MD, PhD, said, adding later that he thinks it will become the best second-line treatment for patients with follicular lymphoma.

R2 was approved based on 2 clinical trials, AUGMENT (NCT01938001) and MAGNIFY (NCT01996865).1-3 AUGMENT randomly assigned 358 patients with relapsed/refractory follicular lymphoma (n = 295) or MZL (n = 63) to R2 (n = 178) or rituximab/placebo (n = 180).2 In patients with follicular lymphoma, the overall response rate (ORR) by independent review committee (IRC) assessment was 80.0% (118 of 147 patients; 95% CI, 73%-86%) in the R2 arm versus 55.4% (82 of 148 patients; 95% CI, 47%-64%) in the placebo arm.1

Progression-free survival (PFS) was also significantly improved in the R2 arm versus the placebo arm, with an HR of 0.46 (95% CI, 0.34-0.62; P <.001) and a median duration of response (DOR) of 39.4 months (95% CI, 22.9—not reached) versus 14.1 months (95% CI, 11.4-16.7), respectively.2

MAGNIFY was designed to determine the optimal duration of lenalidomide.3 It randomly assigned 370 patients with follicular lymphoma or MZL and stable disease or better (N = 370) who were previously treated with ≥1 prior therapy to continued R2 versus rituximab maintenance.3 In those with follicular lymphoma, the ORR by investigator assessment was 59% (104 of 177; 95% CI, 51%-66%).1 At a median follow-up of 16.7 months, the median DOR was 36.8 months and the median PFS was 36.0 months.3

Although R2 showed a good clinical response and had an acceptable safety profile, the panelists noted that some challenges with toxicity can exist. Across AUGMENT and MAGNIFY, the most common adverse events (AEs) were neutropenia, fatigue, diarrhea, constipation, nausea, and cough.1

However, lenalidomide is also associated with hematologic toxicity and venous and arterial thromboembolism, which can become life-threatening or fatal.1 The panelists noted that dose modifications can help mitigate these risks. “I think you have to be on guard for dose reductions and dose holds. The cytopenias are very responsive to growth factor and dosing holds, but respect those and don’t press the envelope in a disease where the goal is quality of life for as long as possible,” Matthew Lunning, DO, said.

John M. Pagel, MD, PhD, concurred, adding, “A lot of these people will do very well with great efficacy at lower doses, so I have a very low threshold to dose-reduce.” He indicated that he also often starts patients at lower doses and that he would use this regimen for patients with more aggressive disease that is likely to relapse more quickly (eg, relapse <1 year after frontline treatment). “[Although these patients] are going to end up doing worse than somebody who has longer remissions from up-front therapy, I like the idea of doing something that’s not the same type of chemoimmunotherapy or close to [what] they got before,” he said. “I think R2 is really going to become the standard of care in second-line treatment even for more aggressive [disease].”

PI3K Inhibitors in the Third Line

Currently, 3 PI3K inhibitors are approved to treat follicular lymphoma: idelalisib (Zydelig), copanlisib (Aliqopa), and, more recently, duvelisib (Table).4-6

Duvelisib received accelerated approval in September 2018 for adult patients with relapsed or refractory follicular lymphoma after ≥2 prior systemic therapies based on data from the DYNAMO + R trial (NCT02204982).7 The study included 129 patients, 83 patients with follicular lymphoma, who were refractory to rituximab and to either chemotherapy or radioimmunotherapy.

The ORR by IRC in the follicular lymphoma arm was 42% (95% CI, 31%-54%). Thirty-four patients (41%) with follicular lymphoma had a partial response and 1 patient (1%) had a complete response. Among these 35 responders, 15 (43%) maintained responses for ≥6 months and 6 (17%) maintained responses for ≥12 months.7,8 The estimated median DOR among all 129 patients was 10 months, and the estimated median PFS was 9.5 months.8 “The label is not exactly the patients who were on the trial. It’s for [patients with 2 prior therapies], not just [those with] double refractory [disease], which I think is helpful in everyday practice,” Flinn said.

The panelists discussed the challenge of determining which PI3K inhibitor to choose. They noted that each inhibitor targets different PI3K isoforms, with idelalisib targeting the δ isoforms, copanlisib targeting the δ and α isoforms, and duvelisib targeting the δ and y isoforms.

Pagel said that although he finds duvelisib’s dual isoform action scientifically exciting, the clinical relevance of this mechanism in follicular lymphoma remains unclear. “The idea [is] that maybe it’s causing some changes in the tumor microenvironment that would be important for inhibiting cell growth or proliferation—so it’s through interactions with myeloid cells or even T cells in the microenvironment…[but] from a clinical translation, I’m not sure they necessarily make a difference that we’ve seen,” he said, adding that the results from ongoing T-cell studies will provide more information.

One such ongoing study is PRIMO (NCT03372057), which is assessing the safety and efficacy of duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma.9 The panelists also agreed that it is unclear whether a benefit exists in targeting the α isoform in patients with follicular lymphoma. They indicated that thus far, the benefit has been shown in mantle cell lymphoma only, with no data available in follicular lymphoma.

Another difference between PI3K inhibitors that the panelists discussed is their administration. Although duvelisib and idelalisib are taken orally twice daily, copanlisib requires intravenous (IV) administration. “Copanlisib has been limited in its use and exposure in the United States simply because of that IV administration that’s weekly for 3 weeks out of 4...that’s a lot of infusion time in the treatment center. Eventually there’s fatigue with that from a patient standpoint,” Pagel said. Subsequently, patients on a copanlisib regimen may be more likely to be placed on a drug holiday, he said.

The panelists suggested that both the isoform action and dosing schedule of the available PI3K inhibitors may affect their toxicity profiles. “The initial hypothesis with idelalisib was that by hitting the specific isoform, the δ isoform, you would not get the off-target toxicity or the toxicity associated with hitting the other isoforms. Of course, there’s another potential corollary to that: By hitting only the δ isoform, you’re going to open yourself up to some of the immunologic toxicities that were predicted in a mouse model prior to that,” Flinn said.

Currently, copanlisib is the only approved PI3K inhibitor in follicular lymphoma that does not have a boxed warning, and it is generally associated with milder and more easily managed AEs, such as hyperglycemia and hypertension.5 In contrast, idelalisib and duvelisib have boxed warnings regarding a variety of serious and potentially fatal toxicities, including infections, diarrhea/colitis, skin reactions, and pneumonitis.4,6

Flinn and Zinzani suggested this difference in toxicity profile may stem from the different dosing schedules. Although copanlisib requires IV administration, it is given over 1 hour on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule of 3 weeks on and 1 week off, unlike the daily treatment required with duvelisib and idelalisib.4-6 Consequently, alternative dosing schedules are being examined for duvelisib, such as drug holidays, decreased dosing, and induction to see whether such modifications might improve its AE profile, Flinn said.

Table. PI3K Inhibitors Approved for Relapsed/Refractory Follicular Lymphoma4-6,a

Although no head-to-head comparisons exist to guide selection between the available PI3K inhibitors, the panelists emphasized the importance of remembering these agents in the treatment armamentarium for follicular lymphoma. “This class of drugs should not be forgotten in this disease. I have had patients on a PI3K inhibitor with relapsed follicular lymphoma who have had really quite striking turnaround of their disease and done extremely well for a long period,” Pagel said.

Emerging Treatments

Several emerging therapies, including various immunotherapy regimens, are currently in clinical trials, have the potential to change the treatment landscape. One such agent is polatuzumab vedotinpiiq (Polivy), an anti-CD79b antibody-drug conjugate. It was studied in combination with bendamustine and rituximab in patients with either relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL).10 Although it did not show benefit in follicular lymphoma, it did show benefit in DLBCL, resulting in FDA approval in June 2019 as a combination regimen with bendamustine and rituximab for adult patients with relapsed/refractory DLBCL, not otherwise specified, after ≥2 prior therapies.10

However, the panelists noted that another study that combined polatuzumab with obinutuzumab (Gazyva) and lenalidomide has shown promise in follicular lymphoma.11 “It was a phase I study in which they were dose-escalating the polatuzumab and the lenalidomide...and when they figured out the recommended phase II dose, it had a pretty good ORR—I think about a 50% complete remission [CR] rate,” Lunning said.

Although checkpoint inhibitors have revolutionized the treatment of many solid tumors, the panelists noted that this has not necessarily been the case with lymphomas. However, they discussed a small study that appears to deviate from that trend. The study combined pembrolizumab (Keytruda) with rituximab in 27 patients with follicular lymphoma.12

“The CR rate was 50% in relapsed and refractory patients with follicular lymphoma, and the overall response rate was 65%,” Zinzani said. The treatment was well tolerated, with most AEs being mild (grade ≤2).12 Grade 3 events included nausea, infusion reactions, aseptic meningitis, and pneumonia.12

The panelists said more studies are needed before checkpoint inhibitors can be comfortably used in follicular lymphoma. “They can be extremely toxic and if we don’t really understand how to use them in follicular lymphoma, we have to be very cautious,” Pagel emphasized.

CAR T-cell therapy has been a significant breakthrough in cancer treatment, showing favorable impact in patients with hematologic malignancies associated with poor outcomes; however, its role in treating an indolent disease such as follicular lymphoma remains unclear, the panelists noted.

“At the end of the day, there is a small subset of patients potentially eligible for CAR T-cells,” Zinzani said. He suggested CAR T-cell therapy could potentially be considered as a consolidation therapy instead of autologous or allogeneic transplantation, whereas Lunning said another use may be in patients with transformed follicular lymphoma, which is another area of unmet medical need. More studies are needed to better delineate the role of CAR T-cell therapy.

An agent that the panelists found particularly exciting is tazemetostat, an EZH2 inhibitor. “It is the first epigenetic agent that we have in follicular lymphoma,” Pagel said.

In an open-label, multicenter, phase II study that enrolled patients with mutant and wild-type EZH2 relapsed/refractory DLBCL or follicular lymphoma, the interim data for 92 evaluable patients with follicular lymphoma showed an ORR of 74% in the group with mutated disease (n = 39) and 34% in the group with wildtype disease (n = 53).13

“I think it’s an exciting drug, not just because of [the efficacy data] but because it’s extremely well tolerated. The AE profile is almost nonexistent,” Pagel said, adding that the drug has not been shown to cause significant myelosuppression, gastrointestinal toxicity, or rash and that no major safety signals have been observed.

Pagel said the next step will be evaluating tazemetostat in various combination regimens. “The company that’s sponsoring [tazemetostat] is now going to be looking at it in combination with R2 as an obvious partner, so there will be a randomized trial of R2 versus R2 and tazemetostat. And that’s maybe where the field is evolving,” he said.

In addition to assessing tazemetostat with R2, Epizyme, the company developing the agent, announced it also has plans to launch trials of tazemetostat in combination with rituximab for patients with relapsed/refractory follicular lymphoma and in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone as a frontline treatment for high-risk patients with follicular lymphoma.14

Watch online:


  1. FDA approves lenalidomide for follicular and marginal zone lymphoma. FDA website. Published May 28, 2019. Accessed October 16, 2019.
  2. Leonard JP, Trneny M, Izutsu K, et al; AUGMENT Trial Investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi: 10.1200/JCO.19.00010.
  3. Andorsky DJ, Coleman M, Yacoub A, et al. MAGNIFY: phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(suppl 15; abstr 7513). doi: 10.1200/JCO.2019.37.
  4. Zydelig [prescribing information]. Foster City, CA: Gilead Sciences Inc; 2014. Accessed October 21, 2019.
  5. Aliqopa [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015. Accessed October 21, 2019.
  6. Copiktra [prescribing information]. Needham, MA: Verastem Inc; 2018. Accessed October 21, 2019.
  7. Duvelisib (Copiktra, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). FDA website. Published September 24, 2018. Accessed October 16, 2019.
  8. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi: 10.1200/JCO.18.00915.
  9. Horwitz SM, Soto J, Youssoufian H, et al. The PRIMO study: a phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL). J Clin Oncol. 2018;36(suppl 15; abstr TPS7590). doi: 10.1200/JCO.2018.36.15_suppl.TPS7590.
  10. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA website. Published June 10, 2019. Accessed October 18, 2019.
  11. Diefenback C, Kahl B, Banerjee L, et al. Polatuzumab vedotin (Pola) + obinutuzumab (G) and lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL): interim analysis of a phase Ib/II trial. J Clin Oncol. 2019;37(suppl 15; abstr 7505). doi: 10.1200/JCO.2019.37.15_suppl.7505.
  12. Nastoupil LJ, Westin JR, Fowler NH, et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. J Clin Oncol. 2017;35(suppl 15; abstr 7519). doi: 10.1200/JCO.2019.37.15_suppl.7505.
  13. Morschhauser 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(S2):154-156. doi: 10.1002/hon.111_2629.
  14. Epizyme provides business update and reports fourth quarter and full year 2018 financial results [news release]. Cambridge, MA: Epizyme Inc; February 26, 2019. Accessed October 19, 2019.