patient care perspectives

“Off-the-Shelf” Treatment Options in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

by Brad Kahl, MD

Overview

Patients with relapsed diffuse large B-cell lymphoma (DLBCL) are often highly symptomatic and need immediate relief with “off-the-shelf” therapies that can alleviate their symptoms while they are awaiting treatment with chimeric antigen receptor (CAR) T-cell therapy. Several new treatment options are now available.

Expert Commentary

Brad Kahl, MD

Professor of Medicine, Division of Oncology
Washington University School of Medicine
Director, Lymphoma Program
Alvin J. Siteman Cancer Center
Saint Louis, MO

While CAR T-cell therapies are a fantastic addition to the management of DLBCL, the commercially available products are not off the shelf. There is a gap in time from the point at which a clinician might want to give the patient a CAR T-cell product to when the patient is actually going to receive the agent and experience benefits from it. . . .” 

Brad Kahl, MD

When you see a patient with relapsed disease and they are very symptomatic (eg, they are experiencing extreme pain), their disease requires immediate treatment. You cannot leave them in that condition for days or weeks, so you need to use something off the shelf immediately. While CAR T-cell therapies are a fantastic addition to the management of DLBCL, the commercially available products are not off the shelf. There is a gap in time from the point at which a clinician might want to give the patient a CAR T-cell product to when the patient is actually going to receive the agent and experience benefits from it, and this can take weeks in many instances. What are the treatment options for these patients?

The traditional immunochemotherapy regimens include rituximab, ifosfamide, carboplatin, and etoposide phosphate (R-ICE); rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP); and rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP). These combinations are fairly aggressive, and we will utilize these regimens if we are envisioning the patient moving forward with autologous stem cell transplantation. If the patient is older, more frail, and not a candidate for autologous stem cell transplantation, we might choose something gentler, such as the gemcitabine and oxaliplatin (GemOx) regimen. Response rates for these regimens are in the 40% to 60% range, with approximately half of those being complete responses, although there is much room for improvement.

In the last few years, several newer therapies have been US Food and Drug Administration (FDA) approved, and they have become good options for our patients. The polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) regimen has demonstrated good activity and is fairly well tolerated. Pola-BR is an option for getting older and frail patients into remission and relieving their symptoms, but it is used for palliative—not curative—intent. One caveat is that, since bendamustine is hard on T cells, we try to avoid it if the patient may be moving on to CAR T-cell therapy.

Tafasitamab plus lenalidomide is a really interesting combination. Tafasitamab is an anti-CD19 monoclonal antibody with modest activity as a single agent, but it has fairly impressive activity when used with lenalidomide, with objective and complete response rates of 60% and 43%, respectively, in the L-MIND trial. The majority of the responses were durable.

Most recently, loncastuximab tesirine, a CD19-based antibody-drug conjugate, was granted accelerated approval by the FDA based on the results of the LOTIS-2 trial, where the overall response rate in the refractory DLBCL setting was close to 50%, with approximately half of those being complete responders. The median duration of response with single-agent loncastuximab tesirine for patients with complete response was approximately 13 months, which is a fairly durable response in a very high-risk population. Loncastuximab tesirine is a good off-the-shelf option, as you could administer it to your patients that day or the following day. It works very quickly. It is a 30-minute infusion, and it is given every 3 weeks. Patients in the LOTIS-2 trial received loncastuximab tesirine for up to 1 year. Until we have more data on the optimal sequencing of therapy, most of us right now are generally trying to avoid loncastuximab tesirine and tafasitamab prior to CAR T-cell therapy.

There are also several bispecific antibodies that are under investigation and appear to be highly promising in this setting. The agents that are furthest along in development include mosunetuzumab, glofitamab, and epcoritamab. All of these therapies have the potential for FDA approval as single agents in DLBCL, although we do not yet have long-term follow-up to assess the durability of remission.

References

Caimi P, Ai WZ, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2. J Clin Oncol. 2021;39(15):7546. doi:10.1200/JCO.2021.39.15_suppl.7546 

Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific T-cell engager) platform: development and future potential of a targeted immune-oncology therapy across tumor types. Cancer. 2020;126(14):3192-3201. doi:10.1002/cncr.32909

Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4

Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

Smith SD, Lopedote P, Samara Y, et al. Polatuzumab vedotin for relapsed/refractory aggressive B-cell lymphoma: a multicenter post-marketing analysis. Clin Lymphoma Myeloma Leuk. 2021;21(3):170-175. doi:10.1016/j.clml.2020.12.013

Wang L, Li L-R, 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

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