A Changing Treatment Landscape for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

The progression from chemotherapy to therapies that use antibody technology has led to important advancements in treatment precision and efficacy in cancer care. Immunotherapies paved the way for utilizing the specificity of the body’s own immune system to target and eradicate cancer cells, which in turn led to advances in antibody engineering. There have been promising improvements in overall and progression-free survival in the treatment of several types of cancer, including certain types of lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, comprising of 30% to 40% of B-cell non-Hodgkin lymphomas.1 Thanks to treatment advancements, R-CHOP chemoimmunotherapy presents a 60% to 70% chance of DLBCL curability.1

An Unmet Need for Patients with R/R DLBCL

Despite historical advancements, for those with relapsed or refractory (R/R) disease, the prognosis is less promising. Some patients are eligible for autologous stem cell transplantation (ASCT) or chimeric antigen receptor T (CAR T) cell therapy, and up to 20% to 25% of those cases may be cured.2,3 Among R/R patients and those who are ineligible for ASCT, the median overall survival (OS) can be less than 12 months.3,4 Every year, more than 3,500 patients in the U.S. with DLBCL experience a second line treatment failure or a second relapse.5

Another Option in R/R DLBCL Care

ADCETRIS® (brentuximab vedotin) was approved in February 2025 by the U.S. Food and Drug Administration (FDA) 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 two or more lines of systemic therapy who are not eligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or CAR T-cell therapy, in combination with lenalidomide and a rituximab product.6 Patients treated with ADCETRIS can have a serious brain infection called progressive multifocal leukoencephalopathy that can lead to death.6 Additional Important Safety Information and full Prescribing Information, including Boxed Warning, are below.6 

The approval was supported by the positive results of the randomized, double-blind, placebo-controlled, multicenter, Phase 3 ECHELON-3 trial, which demonstrated a significant and clinically meaningful improvement in its primary endpoint, OS, in patients with R/R DLBCL who received ADCETRIS plus lenalidomide and rituximab (n = 112) compared to placebo plus lenalidomide and rituximab (n = 118).6,7 Key secondary endpoints included investigator-assessed progression-free survival (PFS) and objective response rate (ORR).7 To enroll in the trial, patients must have received ≥2 previous lines of systemic therapy, be either biologically or socially ineligible for hematopoietic stem-cell transplant or CAR T-cell therapy, and have an Eastern Cooperative Oncology Group performance status of ≤2.7

Data published in January showed after a median follow-up of 16.4 months, the addition of ADCETRIS to lenalidomide and rituximab reduced the risk of death by 37% (HR 0.63 [95% CI: 0.45-0.89; P = .009]) compared to the placebo-lenalidomide-rituximab combination, resulting in a median OS of 13.8 months (95% CI: 10.3-18.8) vs 8.5 months (95% CI: 5.4-11.7), regardless of CD30 expression.7 The ORR for patients treated with the ADCETRIS regimen was 64% (95% CI: 55-73) vs 42% (95% CI: 33-51) with the placebo combination (two-sided P < .001).7

No new safety signals were identified for the ADCETRIS regimen.6,7 Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 88% of patients treated with the ADCETRIS regimen vs 77% in the placebo group.7 The most common (≥25% in either arm) TEAEs of any grade were neutropenia (46% vs 32%), thrombocytopenia (32% vs 22%), diarrhea (31% vs 23%) and anemia (29% vs 27%).7 Additional Important Safety Information and full Prescribing Information, including Boxed Warning, are below.6

Antibody-Drug Conjugate Technology

ADCETRIS is not like traditional chemotherapy. It is an antibody drug conjugate (ADC) made up of three parts: a CD30-directed monoclonal antibody, a drug (monomethyl auristatin E [MMAE]), and a protease-cleavable linker. The linker system is designed to be stable in the bloodstream but to release MMAE upon internalization. CD30 is expressed on the surface of sALCL cells and on Hodgkin Reed-Sternberg (HRS) cells in cHL and some T, B, and natural killer (NK) cells. It is also expressed in limited quantities on healthy tissues and cells.

Looking Ahead

The approval in R/R DLBCL marks the eighth FDA-approved indication for ADCETRIS and reinforces its legacy for certain types of lymphomas. Learn more about ADCETRIS at adcetrispro.com.

At Pfizer, we are committed to advancing cancer care even further and our researchers will continue to explore how to help improve outcomes for cancer patients. For more on Pfizer’s commitment to accelerating breakthroughs in cancer, visit www.pfizer.com.

Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML, and death can occur in ADCETRIS-treated patients.

CONTRAINDICATION

Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

WARNINGS AND PRECAUTIONS

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.

Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL or relapsed or refractory LBCL and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment. Avoid use in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with pre-existing GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in adult patients are peripheral neuropathy, nausea, fatigue, musculoskeletal pain, constipation, diarrhea, vomiting, pyrexia, upper respiratory tract infection, mucositis, abdominal pain, and rash. The most common laboratory abnormalities (≥20%) in adult patients are decreased neutrophils, increased creatinine, decreased hemoglobin, decreased lymphocytes, increased glucose, increased ALT, and increased AST.

The most common Grade ≥3 adverse reactions (≥5%) in combination with AVEPC in pediatric patients were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.

DRUG INTERACTIONS

Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

Lactation: Breastfeeding is not recommended during ADCETRIS treatment.

Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.

ADCETRIS Indications

ADCETRIS is indicated for the treatment of:

• Previously untreated Stage III/IV cHL
  • Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine.
• Previously untreated high risk cHL
  • Pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.
• cHL post-auto-HSCT consolidation
  • Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.
• Relapsed cHL
  • Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.
• Previously untreated sALCL or other CD30-expressing PTCL
  • Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.
• Relapsed sALCL
  • Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.
• Relapsed pcALCL or CD30-expressing MF
  • Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.
• Relapsed and Refractory Large B-Cell Lymphoma (LBCL)
  • Adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) NOS, DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy who are not eligible for autoHSCT or chimeric antigen receptor (CAR) T-cell therapy, in combination with lenalidomide and a rituximab product.

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References:

1. Vodicka P, Klener P, Trneny M. Diffuse Large B-Cell Lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options. Onco Targets Ther. 2022;15:1481-1501. doi:10.2147/OTT.S326632
2. Varma G, Goldstein J, Advani RH. Novel agents in relapsed/refractory diffuse large B-cell lymphoma. Hematological Oncology. 2023;41(S1):92-106. doi:10.1002/hon.3143
3. Rojek AE, Ahmed N, Gomez Llobell M, et al. CAR T cell therapy in early relapsed/refractory large B-cell lymphoma: real world analysis from the cell therapy consortium. Abstract #4503. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.
4. Ernst M, Oeser A, Besiroglu B, et al. Chimeric antigen receptor (CAR) T‐cell therapy for people with relapsed or refractory diffuse large B‐cell lymphoma. Cochrane Database Syst Rev. 2021;2021(9):CD013365. doi:10.1002/14651858.CD013365.pub2
5. American Cancer Society. Cancer Facts & Figures 2025. Atlanta: American Cancer Society; 2025.
6. ADCETRIS®- brentuximab vedotin injection, powder, lyophilized, for solution SEAGEN INC.; February 26, 2025.https://labeling.pfizer.com/ShowLabeling.aspx?id=20629
7. Bartlett NL, Hahn U, Kim WS, et al. Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma. J Clin Oncol. Published online January 7, 2025. doi:10.1200/JCO-24-02242