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Targeted agents for patients with follicular lymphoma

Jun 4, 2021
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The virtual Lymphoma Hub Satellite Symposium will take place on Friday, June 18, 2021, at the 16th International Conference on Malignant Lymphoma (ICML). Hosted by Lymphoma Hub Chair Gilles Salles, the symposium will focus on the sequencing of therapies in high-risk relapsed/refractory (R/R) lymphoma and chronic lymphocytic leukemia (CLL). The Lymphoma Hub is proud to introduce the panel of international experts who will be participating: Francesc Bosch, Andrew Davies, Loretta Nastoupil, and Steven Le Gouill.

This article sets the scene for a talk by Loretta Nastoupil outlining the approaches to early-relapsing follicular lymphoma (FL). Why not start by watching the Lymphoma Hub video with Emmanuel Bachy, Hospices Civils de Lyon, Lyon, FR, who outlines how to better treat patients with early-relapsing FL? 

How can we better treat patients with early-relapsing follicular lymphoma?

FL is associated with recurrent relapse, necessitating prolonged, intermittent treatment throughout a patient’s lifetime. Established mechanisms behind follicular lymphomagenesis include the B cell receptor (BCR), phosphoinositide 3-kinase (PI3K), and B-cell lymphoma 2 (BCL2) pathways, as well as perturbed epigenetic regulation and antitumor immune response.1 Greater understanding of the driving mechanisms of FL has resulted in the design and approval of a number of targeted agents, which promise to one day replace conventional chemotherapy.

Can we avoid chemotherapy entirely in follicular lymphoma?

Figure 1 highlights the major targeted agents either approved or under evaluation for the treatment of patients with FL. With the exception of lenalidomide, which has demonstrated encouraging response rates as a frontline treatment in combination with anti-CD20 therapy, most agents are reserved for single-agent use as a third-line treatment for FL. Results from clinical trials suggest that PI3K inhibitors and epigenetic regulators are among the most efficacious monotherapies for FL.

Figure 1. Targeted agents for FL.1,2,3* 

Axi-cel; axicabtagene ciloleucel; CD, cluster of differentiation; CXCL12, C-X-C motif chemokine ligand 12; CXCR4, C-X-C chemokine receptor type 4; EZH2, enhancer of zeste homolog 2; FDA, U.S. Food and Drug Administration; HDAC, histone deacetylase; mAb, monoclonal antibody; PD-1, programmed death receptor 1; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C; Tisa-cel, tisagenlecleucel.
*Bold font indicates agents approved by the FDA.
Figure adapted from Cheah, Fowler, and Wang.2

 Combination therapies

Although therapy with single targeted agents has demonstrated encouraging efficacy in the FL setting, this approach can give rise to drug resistance. Therefore, emerging therapies for FL also include regimens including two or more targeted agents, with the hope to overcome resistance and improve patient outcomes further.1 Data from clinical trials suggest that combination regimens typically achieve deeper, more durable response rates.1 Examples of innovative combinations under evaluation for the treatment of FL are shown in Table 1.

Despite promising response rates, combination regimens have been associated with increased toxicity, and so clinical studies evaluating drug combinations for FL are of utmost importance.

Table 1. Combination regimens under investigation for the treatment of FL.1,4–7

Regimen

Trial

N

Indication

ORR, %

O-Pola-Len3

NCT02600897; GO29834

46

R/R

76

O-Pola-Ven1

NCT02611323

71

R/R

87

R-Benda-Ven1

NCT02187861

51

R/R

84

R-Benda1

NCT02187861

51

R/R

84

R-Ven1

NCT02187861

52

R/R

35

R-Len1,5

NCT01938001; AUGMENT
NCT01650701; RELEVANCE

147
513

R/R
TN

78
84

O-Len1

NCT01582776; (GALEN)

86

R/R

79

O-Pola6

NCT01691898

23

R/R

78

Ublituximab, umbralisib, ibrutinib1

NCT02006485

7

R/R

71

R-acalabrutinib7

NCT02180711

13
13

R/R
TN

39
92

Benda, bendamustine; Len, lenalidomide; O, obinutuzumab; ORR, overall response rate; Pola, polatuzumab; R, rituximab; R/R, relapsed/refractory; TN, treatment naïve; Ven; venetoclax.

Conclusion

The treatment landscape for FL has progressed significantly in recent years due to an increased understanding of disease pathology. So far in 2021, two targeted agents have been approved by the U.S. Food and Drug Administration (FDA) in the FL settingaxi-cel and umbralisiband investigation into novel targeted drug combinations promises to further improve response rates in patients with FL.

Be sure to tune in to the Lymphoma Hub Satellite Symposium for more information on these agents and ongoing trials evaluating novel combinations for the treatment of FL!

  1. Batlevi CL, Morschhauser F. Novel targeted agents for follicular lymphoma. Ann Lymphoma. 2021;5:3. DOI: 21037/aol-20-45
  2. Cheah C, Fowler N, Wang M. Breakthrough therapies in B-cell non-Hodgkin lymphoma. Ann Oncol. 2016;27(5):778-787. DOI: 1093/annonc/mdw029
  3. Lynch RC. Phase II study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma (CITADEL-203). Oral abstract #2935. 62nd ASH Annual Meeting & Exposition; Dec 7, 2020; Virtual.
  4. Diefenbach C, Kahl BS, Banerjee L, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed/refractory follicular lymphoma: primary analysis of the full efficacy population in a phase Ib/II Trial. Blood. 2019;134 (Supplement_1):126. DOI: 1182/blood-2019-123669
  5. Damaj G. et al. The RELEVANCE study: Lenalidomide and rituximab vs chemotherapy and rituximab in untreated follicular lymphoma. 1st Annual Meeting of the International Academy for Clinical Hematology(2018 IACH), Paris, FR.
  6. Phillips T, Brunvand M, Chen A, et al. Polatuzumab vedotin combined with obinutuzumab for patients with relapsed or refractory non-Hodgkin lymphoma: preliminary safety and clinical activity of a phase Ib/II study. Blood. 2016;128:622.
  7. Fowler N, Coleman M, Stevens DA, et al. Acalabrutinib alone or in combination with rituximab (R) in follicular lymphoma (FL). J Clin Oncol. 2018;36(no. 15_suppl):7549-7549. DOI: 1200/JCO.2018.36.15_suppl.7549

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