Key Takeaways Successful integration of ADCs for R/R DLBCL requires proactive patient selection and toxicity monitoring/management to prevent treatment-limiting adverse events. Optimizing R/R DLBCL outcomes depends on sequencing and dynamic reassessment of disease biology, such as repeat biomarker testing after prior targeted therapies to ensure continued target expression and biologic rationale for ADC use. Antibody–drug conjugates (ADCs) are an important component of the therapeutic armamentarium in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) , particularly for patients who are not candidates for or have progressed after CAR T-cell therapy or bispecific antibodies (BsAbs). As the treatment landscape evolves and becomes more complex, ADCs will likely play an expanding role as both combination partners and in earlier lines of therapy, driven by advances in biomarker-guided care and drug design. In this commentary, Brad Kahl, MD, reviews the role of ADCs in R/R DLBCL, highlighting patient selection, clinical integration, key challenges, and future directions. Clinical Context and Current Positioning of ADCs DLBCL remains a potentially curable hematologic malignancy for many patients. However, outcomes for those with primary refractory disease or early relapse remain poor, and therapeutic decision-making in the R/R setting is increasingly complex. The advent of CAR T-cell therapy and BsAbs has reshaped the treatment paradigm, with ADCs now playing a complementary but critical role, particularly in later lines or for patients ineligible for stem cell transplant or CAR T-cell therapy. ADCs provide targeted cytotoxic delivery via antigen-specific antibodies linked to potent payloads (eg, monomethyl auristatin E or pyrrolobenzodiazepines), enabling tumor-directed therapy while limiting systemic exposure. In R/R DLBCL, currently available ADCs include polatuzumab vedotin, loncastuximab tesirine, and brentuximab vedotin. Their optimal use depends on previous therapies, biomarker expression, and evolving sequencing strategies. Determining Patient Eligibility for Currently Available ADCs Polatuzumab vedotin targets CD79b, which is broadly expressed by DLBCL cells. It is approved by the FDA in combination with bendamustine/rituximab (BR) for adults with R/R DLBCL after at least 2 prior therapies based on the phase Ib/II GO29365 study. It is also approved in combination with R-CHP for adults with previously untreated DLBCL (not otherwise specified) and an International Prognostic Index score of ≥2, based on statistically significant and meaningful improvements in progression-free survival vs R-CHOP in the phase III POLARIX trial . Loncastuximab tesirine is an ADC targeting CD19, which is widely expressed in B-cell malignancies. However, prior CD19-directed therapies, such as CAR T-cell therapy or the monoclonal antibody tafasitamab, can lead to antigen loss. Thus, retesting for CD19 expression is recommended before initiating another anti-CD19 treatment. Loncastuximab tesirine is currently approved for adults with R/R DLBCL after at least 2 prior lines of systemic therapy based on the phase II LOTIS-2 trial , which demonstrated an overall response rate of 48.3%. Patients with preserved CD19 expression and limited alternative options are the ideal candidates. Brentuximab vedotin is indicated in combination with lenalidomide/rituximab for adults who have received at least 2 prior lines of systemic therapy and are ineligible for transplant or CAR T-cell therapy. This is based on the statistically significant improvement in overall survival demonstrated in the phase III ECHELON-3 study . Although its regulatory approval in LBCL does not mandate CD30 expression, clinical practice typically favors and National Comprehensive Cancer Network guidelines recommend its use in CD30-positive disease. Common Clinical Challenges With ADCs Using ADCs in clinical practice can present challenges beyond treatment selection. Educational gaps remain significant for care teams with limited ADC experience, requiring efforts to understand their mechanisms, toxicities, and monitoring strategies. Fortunately, resources such as communication checklists and mechanism of action summaries are available. Regarding toxicities, there is a need for standardized guidance on management , as many ADCs are delivered in outpatient settings. Operational considerations, including infrastructure, staffing models, and defined team roles, are critical for safe care delivery. Transitions of care require coordination to maintain safety. In addition, financial pressures and variable access to support resources complicate the implementation of ADC therapies. Frequently Asked Questions How does biomarker status guide ADC selection? If considering brentuximab vedotin, I test for CD30 expression; higher expression increases confidence in this option. For loncastuximab tesirine, if patients have never received CD19-directed therapy, it is safe to assume they express CD19. If they have had prior anti-CD19 CAR T-cell therapy or tafasitamab, they may have lost CD19 expression, so rebiopsy and retesting are worthwhile. If polatuzumab vedotin is being considered for frontline (with R-CHP) or R/R disease (with BR), I do not believe it is necessary to test for CD79b. However, if a patient has previously received polatuzumab vedotin plus R-CHP, I would not use it again with BR for later-line therapy. When should BsAbs be favored over ADCs? I consider BsAbs for most patients because complete response rates are high and BsAbs are reasonably well tolerated. The preferred consensus is usually to use BsAbs first, followed by available ADCs. Is the cell population in which ADCs are effective known? There are no data suggesting differential activity for loncastuximab tesirine or brentuximab vedotin based on tumor cell of origin. However, polatuzumab vedotin appears more active in the activated B-cell (ABC) subtype. This is likely because of its activity in high-risk patients with co-occurring MYD88 and CD79b mutations (the MCD subtype), which is embedded within the ABC subtype. Although there is currently no molecular test for the MCD subtype, it could eventually help determine which patients will benefit most from polatuzumab vedotin. What is your treatment strategy in the third-line setting and beyond (ie, use of ADCs) in the context of CAR T-cell therapy? ADCs are effective as bridging therapy or for holding treatment in patients who have not received CAR T-cell therapy. Polatuzumab vedotin is useful for bridging to CAR T-cell therapy, but I would not use loncastuximab tesirine for this purpose, as a CD19-directed therapy might not be appropriate before CAR T-cell treatment. Future Directions for ADCs in R/R DLBCL The role of ADCs in DLBCL is rapidly expanding. One key direction is earlier integration, as seen with polatuzumab vedotin in the frontline setting. This suggests that ADCs may shift from salvage therapy to components of curative regimens. Another direction is combination strategies; pairing ADCs with immunomodulatory agents or BsAbs may enhance efficacy, although overlapping toxicities like neuropathy will require careful management. Refined biomarkers and a deeper understanding of resistance mechanisms will also allow for more precise patient selection. Finally, next-generation ADCs with novel payloads and improved linkers may offer enhanced potency with fewer off-target effects, enabling use in more vulnerable populations. Your Thoughts What are your thoughts on the best use and sequencing of ADCs, BsAbs, and CAR T-cell therapies for patients with R/R DLBCL? Join the conversation by answering the polling question and posting a comment. 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. -->
Key Takeaways
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Successful integration of ADCs for R/R DLBCL requires proactive patient selection and toxicity monitoring/management to prevent treatment-limiting adverse events.
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Optimizing R/R DLBCL outcomes depends on sequencing and dynamic reassessment of disease biology, such as repeat biomarker testing after prior targeted therapies to ensure continued target expression and biologic rationale for ADC use.
Antibody–drug conjugates (ADCs) are an important component of the therapeutic armamentarium in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) , particularly for patients who are not candidates for or have progressed after CAR T-cell therapy or bispecific antibodies (BsAbs). As the treatment landscape evolves and becomes more complex, ADCs will likely play an expanding role as both combination partners and in earlier lines of therapy, driven by advances in biomarker-guided care and drug design. In this commentary, Brad Kahl, MD, reviews the role of ADCs in R/R DLBCL, highlighting patient selection, clinical integration, key challenges, and future directions.
Clinical Context and Current Positioning of ADCs
DLBCL remains a potentially curable hematologic malignancy for many patients. However, outcomes for those with primary refractory disease or early relapse remain poor, and therapeutic decision-making in the R/R setting is increasingly complex. The advent of CAR T-cell therapy and BsAbs has reshaped the treatment paradigm, with ADCs now playing a complementary but critical role, particularly in later lines or for patients ineligible for stem cell transplant or CAR T-cell therapy. ADCs provide targeted cytotoxic delivery via antigen-specific antibodies linked to potent payloads (eg, monomethyl auristatin E or pyrrolobenzodiazepines), enabling tumor-directed therapy while limiting systemic exposure. In R/R DLBCL, currently available ADCs include polatuzumab vedotin, loncastuximab tesirine, and brentuximab vedotin. Their optimal use depends on previous therapies, biomarker expression, and evolving sequencing strategies.