Targeted agents for patients with follicular lymphoma

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? 

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.

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.

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

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

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 setting—axi-cel and umbralisib—and 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!