Armand Reviews Novel Therapeutics in Relapsed/Refractory Follicular Lymphoma

Although it is too soon to tell whether the addition of a CD20-directed antibody to novel agents in relapsed/refractory follicular lymphoma should become standard practice, it is clear that immunotherapy could represent the next paradigm shift.

A CD20-directed monoclonal antibody should be always be added to chemotherapy and lenalidomide (Revlimid) in the sequence of therapy for patients with follicular lymphoma, explained Philippe Armand, MD, PhD, who added that although it is too soon to tell whether the addition of a CD20-directed antibody to novel agents in the relapsed/refractory setting should also become standard practice, it is clear that immunotherapy could represent the next paradigm shift.

“For PI3 kinase [PI3K] inhibitors and EZH2 inhibitors, don’t add a CD20[-directed] antibody to therapy yet because the trials haven’t done it,” said Armand, chief in the Division of Lymphoma and the Harold and Virginia Lash Endowed Chair in Lymphoma Research at Dana-Farber Cancer Institute, in a virtual presentation during the 25th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, an event hosted by Physician’s Education Resource®, LCC.

“All the drugs that are approved [received indications] based on single-agent activity,” said Armand, who is also a senior physician and an associate professor of medicine at Harvard Medical School. “My guess is that when the trials are done with rituximab [Rituxan], [the data] will look better [with the addition of the CD20-directed antibody], because it has for every other drug.”

In addition to rituximab, ublituximab is under study as another potential CD20-directed antibody that could be used in combination with novel agents in the relapsed/refractory setting.

On February 5, 2021, the FDA granted an accelerated approval to the PI3K inhibitor umbralisib (Ukoniq) for the treatment of select patients with relapsed/refractory marginal zone lymphoma and relapsed/refractory follicular lymphoma.1 In follicular lymphoma, the agent is approved for use in patients who have previously received at least 3 lines of systemic treatment.

The regulatory decision was based on data from 2 single-arm cohorts of the ongoing, open-label, multicenter, multicohort UTX-TGR-205 trial (NCT02793583), in which umbralisib led to an objective response rate (ORR) of 43% (95% CI, 33.6%-52.2%) and a complete response (CR) rate of 3%. The median duration of response (DOR) was 11.1 months (95% CI, 8.3-16.4).

Although still early, Armand highlighted data from a phase 1 trial (NCT02006485), in which the addition of ublituximab to umbralisib “looked better...than single-agent [umbralisib] in the phase 2 study.”

The results of the phase 1 study showed an ORR of 44%, a CR rate of 22%, and a median DOR of 20.3 months in patients with follicular lymphoma (n = 18).2

Bispecific antibodies represent another novel therapeutic class in follicular lymphoma for which data are beginning to emerge, added Armand.

“We now have data on 4 bispecific [antibodies]. They all have high response rates in pretty heavily pretreated patients. They have a pretty favorable safety profile, though they’re not devoid of toxicity, and [they] are drugs that really seem to be begging to be combined and to be used earlier in lines of therapy,” said Armand.

These agents include odronextamab (REGN1979), epcoritamab, mosunetuzumab, and glofitamab (RG6026), which showed ORRs ranging from 67% to 93%, CR rates ranging from 54% to 75% and a median DOR ranging from 8 months to 20 months.3-6

“Potentially even more exciting in the near [future] is CAR T-cell therapy,” added Armand. Currently, data have been presented on 2 products: axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah), both having shown very high ORRs and CR rates in heavily pretreated patients.

With axi-cel, patients with follicular lymphoma enrolled in the phase 2 ZUMA-5 trial experienced an ORR of 94% and a CR rate of 80%; the 2-year DOR was 64%.7 With tisagenlecleucel, patients enrolled in the phase 2 ELARA trial experienced an ORR of 83% and a CR rate of 65%; the 6-month DOR was 80%.8

“At 1 year, there was 1 progression-free survival event [with axi-cel], suggesting that those drugs may be curative in at least a large subset of patients with follicular lymphoma, and if that’s true, that’s really a game changer,” said Armand.

“The treatment of relapsed/refractory follicular lymphoma is a transformed field, with more transformation ahead,” Armand concluded.


  1. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA. February 5, 2021. Accessed March 2, 2021.
  2. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118
  3. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136659
  4. Hutchins M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-133820
  5. Assouline SE, Kim WS, Sehn LH, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. Blood. 2020;136(suppl 1):42-44. doi:10.1182/blood-2020-135839
  6. Hutchins M, Carlo-Stella C, Bachy E, et al. Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-Hodgkin lymphoma. Blood. 2020;136(suppl 1):46-48. doi:10.1182/blood-2020-136044
  7. Jacobson C, Chavez JC, Sehgal AR, et al. Primary 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. 2020;136(suppl 1):40-41. doi:10.1182/blood-2020-136834
  8. Fowler NH, Dickinson M, Dreyling M, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: interim analysis of the phase 2 Elara trial. Blood. 2020;136(suppl 1):1-3. doi:10.1182/blood-2020-138983