Christopher R. D’Angelo, MD, assistant professor, Division of Hematology & Oncology, The University of Nebraska Medical Center, discusses emerging therapies in diffuse large B-cell lymphoma (DLBCL).

In the genomic landscape of DLBCL, some pathways have been identified as attractive and hyperactive targets, D’Angelo says. For instance, proteolysis targeting chimeras (PROTACs), an evolving therapy in DLBCL, were presented in a discussion of a phase 1 study (NCT04830137) at the 2022 ASCO Annual Meeting, D’Angelo notes.

PROTACs work by linking a target to a cell’s E3 ubiquitin ligase recruiting ligand, a proteasome degradation system, which causes a more thorough degradation of the target than binding agents do, D’Angelo explains. PROTACs have been used to target and degrade BTK, offering a potential advantage over covalent and noncovalent BTK inhibitors, D’Angelo says.

The phase 1 trial is currently recruiting patients with a variety of B-cell non-Hodgkin lymphomas, including DLBCL, D’Angelo notes. PROTACs have displayed preliminary efficacy in non-germinal center B-cell–like DLBCL, and further findings in that population and others are awaited, D’Angelo concludes.

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Christopher R. D’Angelo, MD, discusses emerging therapies in diffuse large B-cell lymphoma. 

Dr. D’Angelo on Emerging Therapies in DLBCL

Christopher R. D’Angelo, MD, an assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology at the University of Nebraska Medical Center, discusses factors that determine whether CAR T-cell therapy or autologous stem cell transplant should be used in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

For some patients, there may be some concern about potential responses to salvage chemotherapy, D’Angelo says. If a patient demonstrates a mixed response with some tumor shrinkage but stability in other lesions, that may raise the question of how durable that treatment is and how chemotherapy sensitive the patient is, D’Angelo explains. That may serve as the rationale for utilizing CAR T-cell therapy over salvage chemotherapy, D’Angelo notes.

At the same time, it is important to recognize that there is a patient population where questions remain regarding how well transplant will work, as well as whether it is worth the associated toxicities if they are going to relapse. It is difficult to begin selecting the next line of therapy while patients are still recovering from autologous stem cell transplant, D’Angelo concludes.

Christopher R. D’Angelo, MD, discusses factors that determine whether CAR T-cell therapy or autologous stem cell transplant should be used in patients with relapsed/refractory diffuse large B-cell lymphoma.


Dr. D’Angelo on Selecting CAR T-Cell Therapy or Transplantation in DLBCL

Christopher R. D’Angelo, MD, an assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology at the University of Nebraska Medical Center, discusses the potential drawbacks of 5-drug combinations in B-cell lymphoma.

The 5-drug ViPOR combination of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid) is being evaluated in a phase 1b/2 trial (NCT03223610) in patients with relapsed/refractory B-cell lymphoma.

Adding more agents to a traditional doublet regimen confers potential drawbacks, including the risk of significant toxicity, says D’Angelo. Moreover, when multiple agents are added to a single regimen, patients are left with less options should they relapse, D’Angelo explains. Additionally, some novel treatment strategies are utilizing oral agents, which are often dosed indefinitely or until a patient progresses or relapses, D’Angelo explains.

Time-limited combinations that are not associated with significant up-front toxicity and can prolong survival are intriguing, D’Angelo says. However, multiple-drug combinations that induce responses but do not prolong life may not be optimal for this patient population, concludes D’Angelo.

Christopher R. D’Angelo, MD, discusses the potential drawbacks of 5-drug combinations in B-cell lymphoma.  



Dr. D’Angelo on the Potential Drawbacks of 5-Drug Combinations in B-Cell Lymphoma 

Christopher R. D’Angelo, MD, an assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology at the University of Nebraska Medical Center, discusses novel therapeutics under investigation in patients with diffuse large B-cell lymphoma (DLBCL).

Emerging bispecific T-cell engager therapies are showing promise within the relapsed/refractory setting, says D'Angelo. Next-generation BTK inhibitors have also been shown to induce responses in patients who have progressed following treatment with ibrutinib (Imbruvica), D’Angelo adds. Moreover, it has been suggested that resistance mechanisms may potentially be overcome with some of these effective, novel therapies, D'Angelo concludes.

Christopher R. D’Angelo, MD, discusses novel therapeutics under investigation in patients with diffuse large B-cell lymphoma.



Dr. D'Angelo on Novel Therapeutics Under Exploration in DLBCL

Christopher R. D’Angelo, MD, an assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology at the University of Nebraska Medical Center, discusses sequencing therapies for patients with lymphoma.

It is best to start an agent in the relapse setting to see whether there is activity, as it can often be difficult to achieve a response in this patient population, according to D'Angelo. Many drugs have been approved for use in the relapsed/refractory setting and are often moved through the pipeline, D'Angelo says.

Additionally, many agents start off being utilized as a monotherapy before eventually being incorporated into a combination regimen; the approach moves forward depending on the reported responses, explains D’Angelo. CAR T-cell therapy is an example of this strategy, and the modality is currently being studied as the next best option following relapse vs stem cell transplantation and salvage chemotherapy.

It is important to thoroughly test these combinations and consider end points that might be important to patients, such as overall survival and progression-free survival (PFS), adds D’Angelo. PFS can be particuarly important to patients, especially when it could be indicative of time off therapy, D'Angelo concludes.

Christopher R. D’Angelo, MD, discusses sequencing therapies for patients with lymphoma.

Dr. D'Angelo on Sequencing Therapies in Lymphoma

Christopher R. D’Angelo, MD, an assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology at the University of Nebraska Medical Center, discusses advances made with CAR T-cell therapy in lymphoma.

Recently, it has been possible to achieve durable remissions and complete responses with CAR T-cell therapy in this patient population, D’Angelo says. This could indicate that this modality may represent a potential curable approach for a refractory population, according to D’Angelo.

Safer CAR T-cell products with increased efficacy and complete, durable responses, are anticipated, D'Angelo notes.

Additionally, the emergence of novel CAR T-cell therapy combinations with agents such as lenalidomide (Revlimid) and ibrutinib (Imbruvica), possess potential, D’Angelo concludes. 

Christopher R. D’Angelo, MD, discusses advances made with CAR T-cell therapy in lymphoma.


Christopher R. D’Angelo, MD

Articles

Dr. D’Angelo on Emerging Therapies in DLBCL

Dr. D’Angelo on Selecting CAR T-Cell Therapy or Transplantation in DLBCL

Dr. D’Angelo on the Potential Drawbacks of 5-Drug Combinations in B-Cell Lymphoma

Dr. D'Angelo on Novel Therapeutics Under Exploration in DLBCL

Dr. D'Angelo on Sequencing Therapies in Lymphoma

Dr. D’Angelo on Future Directions With CAR T-Cell Therapy in Lymphoma