Relapsed/Refractory Follicular Lymphoma Has a Bounty of Options in the Third Line

Oncology Live®Vol. 23/ No. 4
Volume 23
Issue 04

Caron A. Jacobson, MD, MMSc, and a panel of experts, talk about the evolving landscape for patients with relapsed or refractory follicular lymphoma, plus data on PI3K inhibitors and CAR T-cell therapies.

Caron A. Jacobson, MD, MMSc

Caron A. Jacobson, MD, MMSc

Slow disease progression is often associated with low-grade follicular lymphoma. Despite the use of watch-and-wait approaches for the disease in early, low-grade stages, patients may eventually require treatment. “Patients live with this disease for generally 20 to 30 years and sometimes they need therapy,” Caron A. Jacobson, MD, MMSc, said in a recent OncLive Peer Exchange®.

Standard first-line treatment options for this population include front-line chemoimmunotherapy with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab and bendamustine.1 However, data for some chemotherapy-free regimens, such as rituximab and lenalidomide (Revlimid), have demonstrated impressive results, and obinutuzumab (Gazyva) and lenalidomide demonstrated a 2-year progression-free survival (PFS) rate of 96%.2

“Therapy is often very effective at causing the lymphoma to go into remission, but given enough time [the disease] is bound to relapse and patients will need subsequent therapies,” Jacobson said. “It has generally a very long natural history and because most people are 68 or 70 and older when [they receive their diagnosis], it’s a disease they’ll die with, not necessarily a disease they’ll die from.”

In the Peer Exchange discussion, Jacobson and a panel of hematologic experts talked about the evolving landscape for patients with relapsed or refractory follicular lymphoma. They highlighted updated findings presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, during which data on PI3K inhibitors and chimeric antigen receptor (CAR) T-cell therapies provided new insights for sequencing therapies in this population.

Inhibitors in the Third Line and Beyond

The National Comprehensive Cancer Network guidelines indicate that patients may benefit from a period of observation following disease progression after first-line therapy.1 Preferred regimens for those patients are similar to those offered in the first line and include chemoimmunotherapy with anti-CD20 monoclonal antibodies, and either single-agent rituximab or rituximab in combination with lenalidomide.

For patients with more advanced relapsed or refractory disease, options in the third or later line of therapy are expanding, including several approved PI3K inhibitors.3,4 “We have duvelisib [Copiktra], idelalisib [Zydelig], copanlisib [Aliqopa], and umbralisib [Ukoniq],” Jacobson said. “What’s been remarkable is that the PI3 kinases seem very consistent in terms of response rate, complete response rate, and durable remission rate. But the durable remission rate does tend to be just approximately 1 year.”

Despite the agents’ efficacy, confirmatory trials for both duvelisib and idelalisib have failed to support the continued approval for the treatment of patients with follicular lymphoma. In December 2021, Secura Bio, Inc, voluntarily withdrew duvalisib’s indication for use in patients with relapsed or refractory follicular lymphoma following at least 2 previous systemic therapies, stating that the competitive landscape for this population no longer merited the postmarketing requirements for the agent’s continued approval. Duvelisib had received accelerated approval in 2018.5

Idelalisib met a similar end in January 2022, when Gilead Sciences, Inc, announced its decision to remove the indications for patients with treat relapsed follicular lymphoma and relapsed small lymphocytic leukemia, both of which had been accelerated approvals.6 The company also cited the competitive landscape as playing a part in difficulties experienced during recruitment for the confirmatory trial.

In terms of distinguishing between the available options, toxicities may play a role in the decision. “The data with copanlisib are a little bit distinct,” Brian T. Hill, MD, PhD, said. “It has some other unique toxicities—it can cause hyperglycemia and hypertension during the infusion—and does require weekly doses.” Hill added that this information and the availability of other PI3K inhibitors have increased investigators’ knowledge base. “New dosing strategies are being explored with some of the newer agents [regarding] intermittent dosing, which likely are going to lead to better tolerability. One of the things that we’ve seen over the development of these agents is that most investigators and clinicians have [become] better at managing and being on the lookout for the toxicities, so that may be part of why we see lower grades with some of the newer agents.”

That awareness fueled the decision to evaluate the efficacy of the PI3K inhibitor in combination with the well-established rituximab. The combination demonstrated superior efficacy to rituximab alone across patients with indolent non-Hodgkin lymphoma (NHL) in the phase 3 CHRONOS-3 study (NCT02367040). Investigators of the study compared copanlisib in combination with rituximab with placebo plus rituximab in patients with relapsed, advanced indolent NHL, including those with follicular lymphoma grades 1-3a, lymphoplasmacytic lymphoma/ Waldenström macroglobulinemia, marginal zone lymphoma, and small lymphocytic lymphoma.7,8

Patients randomized to the copanlisib arm (n = 307) received the agent at 60 mg intravenously (IV) on days 1, 8, and 15 of a 28-day cycle. Patients in the copanlisib arm and those in the placebo arm (n = 151) received rituximab at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1, and on day 1 of cycles 3, 5, 7, and 9. The primary end point was PFS by central review. Select secondary end points included objective response rate (ORR), duration of response (DOR), and overall survival (OS). A majority of patients in both arms had follicular lymphoma histology at 59.9% and 60.3%, respectively.

In the overall population, the median PFS for patients in the copanlisib arm was 21.5 months (95% CI, 17.8-33.0) vs 13.8 months (95% CI, 10.2-17.5) in the placebo arm (HR, 0.52; 95% CI, 0.39-0.69; P < .001).8 In the subgroup of patients with follicular lymphoma, the median PFS was 22.2 months (95% CI, 17.8-33.1) among patients treated with copanlisib (n = 184) vs 18.7 months (95% CI, 10.2-21.1) among the 91 patients who received placebo (HR, 0.58; 95% CI, 0.400.83; P = .001).

The ORRs in the overall population were 81% vs 48% in the copanlisib and placebo arms, respectively, with complete response (CR) rates of 34% and 15%, respectively. Among patients with follicular lymphoma the ORR was 85% with copanlisib compared with 54% with placebo. The CR rates were 37% and 21%, respectively. Investigators noted safety signals were consistent with the known adverse effects for each agent and no new ones were observed.8

“This is really so far a very positive trial, showing that with the rituximab/copanlisib combination, there is a high response rate, a longer duration of response,” Michael Wang, MD, said. “I hope that the overall survival will also be improved, [demonstrating] that rituximab with copanlisib is a very effective therapy.” In June 2021, Bayer submitted a supplementary new drug application to the FDA for the investigational combination.9

Moderator Bijal Shah, MD, MS, asked the panel about the use of next-generation sequencing to guide treatment decisions.

Hill pointed out that although it is not routinely done in the front line, sequencing to determine EZH2 mutations or p53 in the relapsed setting is information worth pursuing. “I do think that it’s worth knowing the EZH2 status of any [patient with] relapsed follicular lymphoma, and that’s something that is routinely available or can be sent out [as] EZH2 is included on some of the panels that are available from Foundation Medicine and other groups,” Hill said. “You may sometimes get other information—p53 or other things—from those panels that, again, might sort of sway you in one direction or the other.”

EZH2 mutations represent an actionable mutation in relapsed or refractory disease. Specifically, patients may be eligible for treatment with tazemetostat (Tazverik) approved in the third-line setting for the treatment of patients with relapsed or refractory follicular lymphoma. Supporting the decision were data from the 2 single cohorts of a multicenter trial (NCT01897571). Among 42 patients the ORR was 69% (95% CI, 53%-82%), with a 12% CR rate and a 57% partial response rate.10

CAR T-Cell Therapies Push Remission Rates Higher

In addition to the expanded offerings for patients afforded by the advent of several PI3K inhibitors, the approved cellular therapy axicabtagene ciloleucel (axi-cel; Yescarta) has continued to demonstrate promise for patients with relapsed or refractory follicular lymphoma. “I certainly think transplant is a reasonable approach, [but] I haven’t been doing as many autologous transplants in follicular lymphoma as I used to,” Ian W. Flinn, MD, PhD, said. “I’m much more excited about the potential for CAR T cells in this setting.”

Long-term follow-up data from the single-arm, phase 2 ZUMA-5 trial (NCT03105336) were presented at the 2021 ASH meeting.11 In the trial, patients with indolent NHL who had previously received 2 or more lines of systemic therapy, including treatment with an anti-CD20 monoclonal antibody and an alkylating agent, received axi-cel at 2 × 106 CAR T cells/kg. The primary end point was ORR per central review. Key secondary end points included duration of response, PFS, OS, and safety.

Data for 86 patients with follicular lymphoma who received axi-cel showed that at a median follow-up of 30.9 months (range, 24.7-44.3) the ORR was 94.2%, including a 79% CR rate.11 Updated survival data showed that the median OS was not reached (NR) among patients with follicular lymphoma and the 24-month OS rate was 81.2% (95% CI, 71.2%-88.1%). The median PFS was 39.6 months (95% CI, 25.7–not estimable) in the follicular lymphoma group, with a 24-month PFS of 63.4% (95% CI, 51.6%-73.0%).

“For patients who achieve a CR, we saw in the data presented at ASH that with follow-up now of close to 24 months, over 70% of those patients are still in response,” Jacobson said. “Just like in patients with mantle cell lymphoma, we don’t know if this is going to be a curative therapy for any patients with follicular lymphoma or a subset of patients with follicular lymphoma, but this is clearly the longest remission duration we’re getting in this advanced line of therapy.”

To compare expectations across therapies, Jacobson and colleagues conducted an analysis comparing the outcomes from ZUMA-5 with those from other agents that patients with follicular lymphoma may have received in a similar setting, using a weighted sample from the international SCHOLAR-5 external control cohort.12

“SCHOLAR-5 was a combination of retrospective reviews of modern thirdline approaches for follicular lymphoma at a number of international sites in Europe and in the United States,” Jacobson explained. “It also included data from the DELTA trial [NCT01282424] of idelalisib in this line of therapy. Investigators performed propensity score weighting to match the patients enrolled in ZUMA-5,” she said, adding that patients were very closely matched in terms of the known risk observed in this histology.

In total, 85 patients were included in the SCHOLAR-5 cohort. The ORR among these patients was 49.9% vs 94.2% for those treated with axi-cel in ZUMA-5 (odds ratio, 16.2; 95% CI, 5.6-46.9). The median OS was 59.8 months (95% CI, 29.1-NR) vs NR (95% CI, 39.6-NR) in the SCHOLAR-5 and ZUMA-5 cohorts, respectively (HR, 0.52; 95% CI, 0.28-0.95; P = .033). The median PFS was 12.7 months (95% CI, 6.2-14.7) vs 39.6 months (95% CI, 25.7-NR) in the SCHOLAR-5 and ZUMA-5 cohorts, respectively (HR, 0.28; 95% CI, 0.17-0.45; P < .001). The benefit was more pronounced among a subgroup of patients who had received 4 or more prior lines of therapy.

“ZUMA-5 was superior to other available therapies that were used in this setting from SCHOLAR-5 in terms of response rate, complete response rate, time to next treatment, and time to treatment failure,” Jacobson said. “But most importantly the data were statistically significantly superior in terms of 3-year OS, which was a shock. No one thought that you could see an OS benefit in follicular lymphoma.”

Jacobson noted that she would add an asterisk to the data because they are not from a randomized trial. However, she added, “these are probably the best data we have that supports using CAR T-cell therapy for patients in this advanced line of therapy.”


  1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 5.2021. Accessed February 2, 2022.
  2. Nastoupil LJ, Westin JR, Hagemeister FB, et al. Results of a phase II study of obinutuzumab in combination with lenalidomide in previously untreated, high tumor burden follicular lymphoma (FL). Blood. 2019;134(suppl 1):125. doi:10.1182/blood-2019-129422
  3. Aliqopa. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2021. Accessed February 2, 2022.
  4. Ukoniq. Prescribing information. TG Therapeutics; 2021. Accessed February 2, 2022.
  5. Secura Bio announces Copiktra (duvelisib) strategic focus on T-cell lymphoma and voluntary U.S. withdrawal of the relapsed or refractory follicular lymphoma indication. News release. Secure Bio, Inc. December 3, 2021. Accessed February 2, 2022.
  6. Gilead statement on Zydelig U.S. indication for follicular lymphoma and small lymphocytic leukemia. News release. Gilead Sciences, Inc. January 14, 2022. Accessed February 2, 2022.
  7. Matasar MJ, Capra M, Özcan M, et al. Duration of objective responses for patients with indolent non-Hodgkin lymphoma discontinuing treatment before progression: analysis from the phase III Chronos-3 trial comparing copanlisib plus rituximab with placebo plus rituximab. Blood. 2021;138(suppl 1):3538. doi:10.1182/ blood-2021-150873
  8. Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(5):678-689. doi:10.1016/S1470-2045(21)00145-5
  9. Bayer submits regulatory applications for oncology treatment investigational combination of Aliqopa (copanlisib) and rituximab in the US and EU. News release. Bayer. June 21, 2021. Accessed February 2, 2022.
  10. FDA granted accelerated approval to tazemetostat for follicular lymphoma. FDA. June 18, 2020. Accessed February 2, 2022.
  11. Neelapu SS, Chavez JC, Sehgal AR, et al. Long-term follow-up analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2021;138(suppl 1):93. doi:10.1182/blood-2021-148473
  12. Palomba ML, Ghione P, Patel AR, et al. A comparison of clinical outcomes from updated Zuma-5 (axicabtagene ciloleucel) and the international Scholar-5 external control cohort in relapsed/ refractory follicular lymphoma (R/R FL). Blood. 2021;138(suppl 1):3543. doi:10.1182/blood-2021-147608
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