Diffuse Large B-Cell Lymphoma (DLBCL)


Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL).)1 Even though a large fraction of patients with DLBCL respond to first-line treatment, 30% to 40% cannot achieve remission or experience relapse, which leads to a poor prognosis. These groups require second-line or even more experimental therapies.1 The median survival of patients with primary or secondary refractory DLBCL is 5 to 7 months, highlighting the need for new therapeutic strategies.1

In addition to the currently available therapeutic options for DLBCL, research has focused on the development of a variety of experimental therapies, including immune checkpoint inhibitors, BCL-2 inhibitors, antibody-drug conjugates (ADC) and monoclonal antibodies, bispecific T-cell engager antibodies, and chimeric antigen receptor (CAR) T-cell therapies.

CAR T-Cell Therapies

Treatment with CAR T cells has achieved significant clinical outcomes; however, the toxicities associated with this treatment and the time required to manufacture the therapeutic product are important obstacles that industry is trying to overcome.2 

Relapse after CAR T-cell therapy can be related to a loss of CD19 or an upregulation of programmed death ligand 1 (PD-L1). Therefore, CAR T cells that secrete human anti-PD-L1 antibodies are being explored and have been shown to prevent T-cell exhaustion3; overall response rates (ORRs) of 62% and 81% have been observed with CD19 plus anti-CD22 and anti-CD19 plus anti-CD20 CAR T cells, respectively, in patients with relapsed or refractory DLBCL.4,5 The combination of CAR T cells with immune checkpoint inhibitors is also being explored, such as the bicistronic anti-CD19 and anti-CD22 CAR T-cell therapy AUTO3 in combination with Keytruda® (pembrolizumab).1,2 

Bispecific T-Cell Engager Therapy 

Bispecific T-cell engager (BiTE) antibodies are a new class of immunotherapeutics.2 BiTE antibodies have 2 single-chain variable fragments, one of which binds a tumor antigen and the other mainly CD3 T cells, thus targeting both tumor and T cells.6,7 These antibodies stimulate the release of cytokines, interfere with the tumor microenvironment, and potentiate cell death through T cells.6 

Mosunetuzumab is a humanized immunoglobulin G1 anti-CD20/CD3 BiTE that has been tested in older and unfit patients with DLBCL. An ORR of 58% was achieved when this experimental drug was given as a single agent; when combined with CHOP (M-CHOP), it achieved an ORR of 96%.8

Blincyto® (blinatumomab), an anti-CD19/CD3 BiTE with activity against B-cell acute lymphoblastic leukemia, has shown therapeutic potential in patients with newly diagnosed high-risk DLBCL.9 It is also under study in combination with pembrolizumab and with Revlimid® (lenalidomide).2 However, neurotoxicity is associated with this BiTE, and administration as a continuous infusion is challenging.7

Glofitamab is a BiTE with 2 CD20-binding molecules and 1 CD-3 binding molecule that is currently being evaluated as a single agent and in combination with Gazyva® (obinutuzumab) in patients with NHL. The safety profile of glofitamab is manageable and mostly ≤ grade 2 cytokine release syndrome (CRS). In addition to obinituzumab pre-treatment, step-up dosing of glofitamab can be used as a CRS mitigation strategy for administration of a high target dose of up to 30mg.6

Epcoritamab is an anti-CD20/CD30 BiTE developed for subcutaneous administration. In a phase 1/2 study of patients with relapsed or refractory NHL, the ORR with epcoritamab was 66.7%, and the complete response (CR) rate was 33.3%.6

Immune Checkpoint Inhibitors

As immune evasion is characteristic of DLBCL, trials have taken place on the inhibition of known immune checkpoints, including the use of pembrolizumab and Opdivo® (nivolumab) for PD-1 and the use of Imfinzi® (durvalumab), Bavencio® (avelumab), and Tecentriq® atezolizumab for PD-L1. However, the results have not been satisfactory, with only avelumab reaching phase 3 in clinical trials.2,6 

Other targets in addition to PD-1 and PD-L1 have been identified (VISTA, TIM-3, LAG-3, TIGIT); however, no studies are currently being conducted that focus on DLBCL. Higher expression of PD-L1 correlates with improved progression-free survival (PFS) as it can be used as a biomarker to identify patients who benefit from this first-line treatment strategy.2 

Monoclonal Antibodies and Antibody-Drug Conjugates

Epratuzumab is a CD22-directed monoclonal antibody with reported efficacy in relapsed and untreated DLBCL.10 A combination of this antibody with Rituxan® (rituximab) has achieved an ORR of 67% and a CR rate of 50% in a few patients with relapsed or refractory DLBCL.11

MT-3724 is an ADC against CD20 in which a single-chain variable fragment is linked to Shiga-like toxin 1a. A phase 1 clinical trial of MT-3724 given as monotherapy to patients with previously treated DLBCL reported an ORR of 30%.2 A phase 2 trial with MT-3724 was initiated; however, this study was terminated by sponsor decision.12

Coltuximab ravtansine (SAR3419, huB4-DM4) is an anti-CD19 ADC conjugated to a maytansinoid-derivate antimitotic payload DM4 via a disulfide linker.2 This ADC has been evaluated in a phase 2 trial that enrolled patients with relapsed or refractory DLBCL who had previously received rituximab; an ORR of 43.9% was reported.13 

BCL-2 Inhibitors

Research has discovered that overexpression of B-cell lymphoma 2 (BCL-2) maintains the viability of tumor cells by inhibiting apoptosis and promoting resistance to the R-CHOP regimen.2 Venclexta® (venetoclax) is an oral BCL-2 inhibitor that has been under clinical study.2 A first-in-human phase 1 trial reported an ORR of 18% in patients with relapsed or refractory DLBCL.14 The phase 2 CAVALLI trial (NCT02055820) also evaluated the use of venetoclax in combination with R-CHOP, reporting improved progression-free survival in patients treated with the experimental drug.8

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References

1. Harris LJ, Patel K, Martin M. Novel therapies for relapsed or refractory diffuse large B-cell lymphoma. Int J Mol Sci. 2020;21(22):8553. doi:10.3390/ijms21228553

2. Wang L, Li LR, Young KH. New agents and regimens for diffuse large B cell lymphoma. J Hematol Oncol. 2020;13(1):175. doi:10.1186/s13045-020-01011-z

3. Suarez ER, Chang de K, Sun J, S et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget. 2016;7(23):34341-34355. doi:10.18632/oncotarget.9114

4. Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med.2021;27(8):1419-1431. doi:10.1038/s41591-021-01436-0

5. Sang W, Shi M, Yang J, et al. Combination of anti-CD19 and anti-CD20 chimeric antigen receptor T cells for relapsed and refractory diffuse larger B cell lymphoma: an open-label, single-arm, phase Ⅰ/Ⅱ trial. Blood. 2019;134(Suppl 1):1590. doi:10.1182/blood-2019-127640

6. Susanibar-Adaniya S, Barta SK. 2021 update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol. 2021;96(5):617-629. doi:10.1002/ajh.26151

7. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612

8. Spinner MA, Advani RH. Current frontline treatment of diffuse large B-cell lymphoma. Oncology (Williston Park). 2022;36(1):51-58. doi:10.46883/2022.25920940

9. Katz DA, Chu MP, David KA, et al. Open-label, phase 2 study of blinatumomab after first-line rituximab-chemotherapy in adults with newly diagnosed, high-risk diffuse large B-cell lymphoma. Blood. 2019;134(Suppl 1):4077. doi:10.1182/blood-2019-121708

10. Leonard JP, Coleman M, Ketas JC, et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin’s lymphoma: phase I/II clinical trial results. Clin Cancer Res. 2004;10(16):5327-5334. doi:10.1158/1078-0432.CCR-04-0294

11. Leonard JP, Coleman M, Ketas J, et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(22):5044-5051. doi:10.1200/JCO.2005.13.821

12. Safety, PD & efficacy of MT-3724 for the treatment of patients with relapsed or refractory DLBCL (MT-3724NHL001). ClinicalTrials.gov. February 11, 2015. Updated September 5, 2021. Accessed August 10, 2022.

13. Trnĕný M, Verhoef G, Dyer MJ, et al. A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine (SAR3419) in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy. Haematologica. 2018;103(8):1351-1358. doi:10.3324/haematol.2017.168401

14. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320

Reviewed by Debjyoti Talukdar, MD, on 8/30/2022.

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