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Relapsed/Refractory Diffuse Large B-Cell Lymphoma With ADCs
Managing Relapsed/Refractory Diffuse Large B-Cell Lymphoma With ADCs: Answers to Frequently Asked Questions

Released: October 30, 2025

Jeremy S. Abramson
Jeremy S. Abramson, MD, MMSc
Michael R. Bishop
Michael R. Bishop, MD
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Key Takeaways
  • There are several treatment options available for patients with relapsed or refractory DLBCL including emerging antibody–drug conjugates (ADCs) targeting CD19, CD30, and CD79b found on the surface of lymphoma cells, bispecific antibodies, and CAR T-cell therapies.
  • Tailoring ADC therapy to patients with relapsed or refractory DLBCL is crucial for optimal management of the disease and mitigating potential side effects of treatment.
  • Key ADC-related toxicities to monitor for vary with the specific drug and include peripheral neuropathy, pleural effusion, and skin-related events, which can often be managed with dose holds and dose reductions.

In this commentary, Jeremy S. Abramson, MD, MMSc, and Michael R. Bishop, MD, answer frequently asked questions from healthcare professionals related to considering antibody–drug conjugates (ADCs) in the context of CAR T-cell therapies and bispecific antibody treatment options for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

What are the current indications and what resources are required for using ADCs when compared with CAR T-cell therapies and bispecific antibodies for R/R DLBCL?

Jeremy S. Abramson, MD, MMSc:
How we incorporate multiple new classes of drugs into the management of DLBCL is rapidly evolving. ADCs are distinguished from both CAR T-cells and bispecific antibodies in that you do not require special resources or infrastructure to treat with an ADC—unlike therapies that require management of cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome such as bispecific antibodies and CAR T-cell therapy.

Brentuximab vedotin is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with R/R large B-cell lymphoma (LBCL), including DLBCL not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), after 2 or more lines of systemic therapy, and who are not eligible for autologous hematopoietic stem cell transplant or CAR T-cell therapy.

Brentuximab vedotin is a CD30-directed ADC with a monomethyl auristatin E (MMAE) payload. Brentuximab vedotin was evaluated in combination with lenalidomide and rituximab vs placebo plus lenalidomide and rituximab in the multicenter, randomized, phase III ECHELON-3 study. Patients in that study had R/R DLBCL after 2 or more previous systemic therapies and were not eligible for stem cell transplant or CAR T-cell therapy. Patients were excluded if they had cerebral/meningeal disease and/or grade ≥2 peripheral neuropathy—which is an adverse event (AE) of interest with brentuximab vedotin. In ECHELON-3, addition of brentuximab vedotin to lenalidomide and rituximab was shown to improve median overall survival (OS) by 5.3 months (13.8 vs 8.5 months) (HR: 0.63; P = .0085) in the overall population and across patient subgroups, including across CD30 expression levels, previous receipt of CAR T-cell therapy, or cell of origin. The most common AE was neutropenia (46%; grade ≥3: 43%) and patients also experienced peripheral sensory neuropathy (20%; grade ≥3: 4%), which can be particularly burdensome for patients when performing activities of daily living.

Loncastuximab tesirine, a CD19–directed ADC with a pyrrolobenzodiazepine dimer toxin (PBD) payload, has a distinctive toxicity profile and is the only ADC that targets CD19. Loncastuximab tesirine is indicated after 2 or more lines of systemic therapy for DLBCL NOS, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The phase II LOTIS-2 study evaluated loncastuximab tesirine in 145 patients with R/R DLBCL that was refractory to previous treatment, including patients who had previous CAR T-cell therapy (9%). In that study, the overall response rate was 48% and median duration of response was 10.3 months. In an update conducted after a median follow-up of 7.8 months, median OS was 9.5 months, and median progression-free survival (PFS) was 4.9 months. Notable grade ≥3 AEs were neutropenia (26%), thrombocytopenia (18%), and edema/effusions (5%).

Polatuzumab vedotin, an anti-CD79b ADC with an MMAE payload, is indicated in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for previously untreated DLBCL NOS or high-grade B-cell lymphoma with an international prognostic index score of ≥2, as well as in combination with bendamustine and rituximab (BR) for the treatment of adults with R/R DLBCL after at least 2 previous therapies. In the R/R DLBCL setting, data from the randomized phase II study of polatuzumab vedotin plus BR  vs placebo plus BR showed improved outcomes for patients with R/R DLBCL who were not eligible for transplant. The investigator-assessed overall response rate was 70% with polatuzumab vedotin plus BR and was 33% in the arm receiving placebo plus BR; the median duration of response was 8.8 vs 3.7 months, respectively. Median PFS (6.7 vs 2.0 months; HR: 0.31 P <.0001) and median OS (11.8 vs 4.7 months; HR: 0.35; P = .0008) were both improved with polatuzumab vedotin with BR vs BR alone. Regarding safety, the most common all grade AEs included diarrhea (44% vs 21%), infections (39% vs 41%), and nausea (26 vs 28%). Similar to brentuximab vedotin, peripheral neuropathy can be expected with polatuzumab vedotin, and any grade peripheral neuropathy was observed in 39% (grade 2: 18%) of patients receiving polatuzumab vedotin plus BR compared with 3% of patients receiving BR (grade 2: 3%). Moreover, the in the phase III POLARIX trial, polatuzumab plus R-CHP vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) showed comparable response rates (86.6% vs 82.7%) and improved 24-month PFS rates (76.7% vs 70.2%), and at the 5-year analysis the hazard ratio for OS was 0.85 (95% CI: 0.3-1.15). There were no new safety signals in this study.

How do you choose among the treatment options available for patients with R/R DLBCL and 2 previous therapies? Specifically, between ADC or cell-based therapy? 

Jeremy S. Abramson, MD, MMSc:
The problem of having multiple treatment choices for R/R DLBCL is a good one to have. I would first think about what is available in my clinical practice and how quickly I can get access to it. For third-line or later treatments, either CAR T-cells or bispecific antibodies can be excellent options if the patient is eligible. These are also available for transplant-eligible patients. Bispecific antibody options for R/R DLBCL include glofitamab with or without gemcitabine/oxaliplatin based on the results from the STARGLO trial. I would also use glofitamab with gemcitabine/oxaliplatin in a second-line non–transplant eligible patient who did not have access to CAR T-cell therapy.

In the third-line and later setting I also consider loncastuximab tesirine and polatuzumab vedotin ADCs as they are both available. I might also use polatuzumab vedotin plus R-CHP in the first-line setting which might limit its use in the relapse setting but in a patient who had a lengthy initial remission, I would potentially use it again in the relapsed setting. Another consideration is that the use of bendamustine may deplete T-cells in patients we would like to consider for CAR T-cell therapy as an option later. For this reason, I may choose to use polatuzumab plus rituximab first and often use it as either bridging therapy to get patients to a CAR T-cell therapy or if they relapse post CAR T-cell therapy. Brentuximab vedotin plus lenalidomide/rituximab is also an option as a third-line or later treatment.

Michael R. Bishop, MD:
The ADC I would choose for a patient with R/R DLBCL will depend on the previous therapy the patient has received. I also look at the antigen expression, particularly for brentuximab vedotin, because of the variability of CD30 expression in large B cell lymphoma.  CD19 and CD79a are almost universally expressed in DLBCL, but CD19 needs to be checked in patient who have received prior anti-CD19 therapy, particularly CAR T cell therapy.

In your practice, what AEs need close monitoring with ADC-based therapy?

Jeremy S. Abramson, MD, MMSc:
The PBD payload on loncastuximab tesirine is associated with a unique toxicity profile. It can potentially cause “vascular leaks” with edema and/or pleural effusions. To prevent and manage this, we often use 4 mg of dexamethasone (oral or IV) for 3 days, starting the day before first dosing, which helps improve the side effects. Patients may also become sensitive to sunlight and develop a sun exposure–related rash and may experience gamma glutamyl transferase of unclear clinical significance.

Michael R. Bishop, MD:
An ADC-related AE that I monitor closely with brentuximab vedotin is peripheral neuropathy, which can become a challenge for patients. I educate patients about this AE before starting therapy and at every visit I ask them whether they have experienced any new or worsening tingling sensation in their hands and whether it affects their ability to put on clothes, button up their shirts, zip up their pants, or hold a fork or knife. I also instruct them to let me know as soon as possible if they experience any of these symptoms so that we may consider holding or lowering their next dose to help them recover before we resume treatment.

I also monitor patients receiving loncastuximab tesirine for shortness of breath and peripheral edema, which are potential life-threating AEs often caused by drug toxicity on the heart and lungs. Signs and symptoms of this AE may include fluid accumulation in the lungs (pleural effusion), abdomen (ascites), and body (edema), and may require immediate medical attention. ADC treatment might be temporarily stopped or dose reduced if the side effects are severe. Patients should notify their care team for new or worsening swelling or puffiness, weight gain, chest pain, shortness of breath, or trouble breathing.

Jeremy S. Abramson, MD, MMSc:
Patients with peripheral neuropathy may ask me about gabapentin or duloxetine, but the reality is that those drugs can mostly be helpful for painful neuropathy (ie, shooting or burning pain) but do not alleviate the numbness or the pins and needles sensation. I often recommend dose holds or dose reductions if the neuropathy is clinically significant, and will discontinue the drug entirely if neuropathy is severe or functionally limiting.

In a patient with HIV-associated DLBCL, what is your experience with treating those patients? Would they  be a suitable candidate for CAR T-cell therapy?

Jeremy S. Abramson, MD, MMSc:
In a patient with well-controlled HIV, which are most patients today, I would treat as I would any other patient with R/R DLBCL. However, a patient with DLBCL who has HIV and CD4 count around 50/mm3 is not somebody you want to give fludarabine/cyclophosphamide let alone a CAR T-cell therapy. A patient with poorly controlled HIV is going to be challenging to manage. I am comfortable with bispecific antibodies in this population because they do not go after their T-cells and it does not involve lymphodepleting chemotherapy. You can always stop it in the event of toxicity. I may also consider ADCs, but it depends on baseline toxicity and comorbidities. For instance, if they already have hepatic irritation from their HIV I would avoid loncastuximab tesirine. If they have neuropathy from their medications for HIV-related neuropathy, I will avoid polatuzumab vedotin or brentuximab vedotin.

Do you repeat lymph node biopsy every time you have R/R DLBCL disease?

Jeremy S. Abramson, MD, MMSc:
I typically try and do a biopsy at every relapse except in a situation where I give a patient a treatment and they are clearly primary refractory and are progressing on it. It is not likely they went into remission and then relapsed. If I had a biopsy and then give them R-CHOP and they are progressing on it, I am comfortable taking them right to CAR T-cell therapy without biopsy, assuming I had a good biopsy to begin with. Part of me wants to make sure they do not have a new primary malignancy, I suppose.

Michael R. Bishop, MD:
In the relapse setting, I like to document what the expression is for CD19 before I decide on which ADC to use, particularly if they had received anti-CD19–directed therapy. My patients are often highly educated about the therapies available to them, but ADCs are not often on their radar. When I do discuss ADCs as options for them, I use a trojan horse analogy and tell them the medication uses an antibody that improves targeting to cancer cells and that when internalized by the cancer cells releases a potent chemotherapy. I also mention to patients that this internalization of the drug helps mitigate the side effects due to lower systemic exposure of these cytotoxic agents.

Your Thoughts
Have you provided care for patients with R/R DLBCL who might be eligible for ADC-based therapy? What has your experience been so far in your practice? Visit the program page to explore more content on this topic including a downloadable patient communication resource and a link to register for an upcoming live webinar. Join the conversation by answering the polling question and posting a comment.

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Which of the 3 approved ADCs do you use in your practice for patients with R/R DLBCL?

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