Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit

INTRODUCTION — 

Most patients with diffuse large B cell lymphoma (DLBCL) are cured after initial treatment using either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-polaCHP (rituximab, polatuzumab vedotin, cyclophosphamide, vincristine, prednisone). However, nearly one-third of patients relapse after achieving a complete response (CR), and approximately 10 percent are refractory to initial therapy (ie, they do not achieve a CR).

Relapsed or refractory (r/r) DLBCL can be cured in some patients with chimeric antigen receptor T cell therapy or hematopoietic cell transplantation, but some patients do not respond adequately or subsequently relapse. Other patients are not candidates for such intensive treatments because of limited medical fitness.

This topic discusses the treatment of medically fit patients who have a second or later relapse of DLBCL and the management of r/r DLBCL in patients who are not medically fit for intensive treatments.

Management of medically fit patients with a first relapse or primary refractory DLBCL is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Autologous hematopoietic cell transplantation'.)

PRETREATMENT EVALUATION — 

Pretreatment evaluation of a patient with relapsed or refractory (r/r) DLBCL includes assessment of medical fitness, restaging, and estimation of prognosis.

Clinical and laboratory evaluation

●History and physical examination – The presence of B symptoms (ie, fever, sweats, weight loss) and lymph node and/or organ involvement should be documented by history and physical examination.

A neurologic examination should be performed. Patients with abnormal findings on a neurologic examination should undergo neuroimaging and lumbar puncture, as described separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

●Laboratory

•Hematology – Complete blood count with leukocyte differential count.

•Chemistries – Serum electrolytes, glucose, blood urea nitrogen and creatinine, calcium, uric acid, and liver function tests, including lactate dehydrogenase.

•Infectious diseases – Human immunodeficiency virus (HIV) and hepatitis B testing.

•Pregnancy testing – If appropriate.

Diagnosis — A biopsy is generally performed to confirm the diagnosis of DLBCL and exclude other diagnoses.

●Suspected first relapse – For patients with a suspected relapse after a previous complete response (CR), a biopsy should be performed to confirm the diagnosis of DLBCL and exclude other conditions.

Other causes to be excluded include carcinoma, sarcoidosis, tuberculosis, and fungal infection. The biopsy can also identify the acquisition of new mutations or the transformation of another type of lymphoma to DLBCL. For patients with a late relapse, the biopsy might identify an indolent lymphoma.

●Second or later relapse – For patients with a second or later relapse, a repeat biopsy may not be required if other diagnoses can be clinically excluded. However, a biopsy should be performed to confirm a suspected relapse if it occurs after achieving a CR with hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR)-T cell therapy.

●Suspected primary refractory disease – For patients who did not achieve a CR with initial therapy, a repeat biopsy is encouraged, but it may not be required if there is clear progression in the size and metabolic activity of a disease site. If a biopsy is not performed, the morphology, immunophenotype, and cytogenetic/molecular features of the initial biopsy specimen should be reviewed to ensure that DLBCL was correctly diagnosed.

Medical fitness — Medical fitness affects treatment decisions for r/r DLBCL. Age, per se, does not determine the level of medical fitness, but caution should be used when considering intensive therapy for patients ≥75 years old because comorbidities increase with age.

Some patients are not fit for intensive treatment of primary refractory disease or first relapse because of comorbid conditions, while others who were previously fit may experience a functional decline after prior treatments or subsequent relapses.

●Assessment – Medical fitness is assessed with the following instruments:

•Performance status – Eastern Cooperative Oncology Group (ECOG) performance scale (table 1).

•Physiologic fitness – Physiologic fitness (eg, comorbid conditions, activities of daily living, physical performance tests, cognition) as measured by the Charlson comorbidity index (CCI) (table 2) or the HCT-specific comorbidity index (table 3).

●Fitness categories – We categorize fitness using the clinical evaluation and instruments to assess performance status and physiologic fitness.

Chronic comorbid conditions should be weighted more heavily than transient medical complications of the lymphoma (eg, infection, heart failure exacerbated by anemia). The burden of r/r DLBCL can contribute to a lack of fitness. In some cases, the planned treatment (or pretreatment with rituximab and a steroid) may alleviate disease consequences/complications, enhance the patient's ability to tolerate and benefit from subsequent treatment, and enable more intensive therapy.

There are no clear distinctions among fitness categories, and some measures of performance status or physiologic fitness can apply to different categories. In selecting a fitness category, we seek to protect frail patients from treatment that they are unlikely to tolerate, while not depriving others of the opportunity to achieve a meaningful response and prolonged survival.

•Medically fit – Medically fit patients are judged to be able to tolerate intensive treatment, including HCT, based on both of the following:

-ECOG: 0 to 2 (table 1)

-CCI: 0 to 2 (table 3)

Management of medically fit individuals with first relapse or primary refractory DLBCL is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

•Less fit but not frail – Patients who are less fit but not frail cannot tolerate autologous HCT, but they may be able to tolerate CAR-T cell therapy or antibody-based treatments. This category includes a broad range of physical functions. Some patients have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that can affect their ability to tolerate treatment.

We judge patients to be less fit but not frail if either of the following applies:

-ECOG: 3 (table 1)

-CCI: 3 (table 3)

•Frail – Frail patients are those whose debility or comorbid conditions would not permit treatment aimed at modifying the disease course, as reflected by both the following:

-ECOG: ≥3 (table 1)

-CCI: ≥3 (table 3)

Note that our use of the term "frail" for managing patients with hematologic malignancies may differ from other definitions of frailty. (See "Frailty", section on 'Concepts and definitions'.)

For patients ≥65 years with DLBCL, the Elderly Prognostic Index (EPI) [1] can be used to assess fitness status using an online calculator. The EPI uses activities of daily living (ADL), instrumental ADL (IADL), and Cumulative Illness Rating Scale for Geriatrics (CIRS-G) to categorize patient fitness. Applying the EPI to 1163 patients (median age 76 years) classified 23 percent as low risk, 48 percent as intermediate risk, and 29 percent as high risk, with significantly different three-year overall survival (87, 69, and 42 percent, respectively). The EPI was validated using an external series of 328 patients.

Clinician-administered or patient-completed instruments can be useful in assessing the risk for falls, cognitive deficits, depression, functional decline, and death; these tools can also complement a formal geriatric assessment for judging medical fitness in older patients who may have a range of frailties [2].

Geriatric assessment may be useful for judging the medical fitness of some patients in this setting [2]. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

Other considerations for the treatment of older or frail patients are described separately. (See "Initial treatment of advanced-stage diffuse large B cell lymphoma", section on 'Older adults'.)

Restaging — Restaging (table 4) is based on clinical evaluation and positron emission tomography (PET)/computed tomography (CT), according to the Lugano criteria (table 5). Disease stage at relapse should be designated by subscript R (_R).

●Imaging – PET/CT should be scored according to the five-point (Deauville) scale (table 6).

●Bone marrow examination – PET is a good predictor for marrow involvement by DLBCL, and a bone marrow examination is not routinely used for staging. A bone marrow examination is generally needed only to assess unexplained cytopenias.

However, if autologous HCT is a consideration, a bone marrow examination should be performed to assess possible myelodysplasia or acute myeloid leukemia prior to transplantation, as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Autologous hematopoietic cell transplantation'.)

Prognosis — A modification of the International Prognostic Index (IPI) that categorizes patients according to age cohort should be applied for assessing prognosis in this setting. As an example, National Cancer Center Network IPI (NCCN-IPI) has greater discriminatory power for older adults than the original IPI [3].

These indices predate the availability of CAR-T cell therapy and bispecific antibodies, and they may not accurately estimate outcomes with these treatments.

Outcomes are generally poor for patients who relapse following autologous HCT and for patients who are not eligible for transplantation or other intensive therapies [4-6]. A multicenter retrospective study (SCHOLAR-1) of 636 patients from the pre-CAR-T era reported 26 percent overall response rate, 7 percent CR, and six-month median overall survival among patients who did not achieve at least a partial response after one of the following: >4 cycles of initial therapy, two cycles of subsequent therapy, or relapse ≤12 months from autologous HCT [7]. Outcomes were especially poor for patients with refractory DLBCL.

MEDICALLY FIT WITH SECOND OR LATER RELAPSE — 

Treatment for medically fit patients with second or later relapse is stratified according to whether the patient previously received CD19-directed chimeric antigen receptor (CAR)-T cell therapy (algorithm 1).

For patients with documented involvement of the central nervous system (CNS), the CNS disease should be controlled before or at the time of systemic treatment. Management of CNS involvement by DLBCL is described separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis" and "Secondary central nervous system lymphoma: Treatment and prognosis".)

No prior chimeric antigen receptor T cell therapy — For medically fit patients with second or later relapse of DLBCL who did not previously receive CAR-T cell therapy, we suggest CD19-directed CAR-T cell therapy (algorithm 1). Axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel) is preferred in this setting, with the choice influenced by availability, manufacturing time, and institutional preference.

The suggestion for axi-cel or liso-cel is extrapolated from phase 3 trials that reported superior survival with either agent compared with autologous hematopoietic cell transplantation (HCT) for primary refractory disease or first relapse <12 months after initial treatment [8,9]. By contrast, tisagenlecleucel (tisa-cel) was not superior to autologous HCT in another phase 3 trial [10].

Axi-cel and liso-cel are approved by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory (r/r) DLBCL after ≥2 prior treatments. The administration, toxicity, and outcomes with individual CAR-T cell products are described below. (See 'Chimeric antigen receptor T cell therapy' below.)

●Outcomes – CD19-directed CAR-T cell products are associated with a response in at least one-half of patients with r/r DLBCL. All can cause potentially life-threatening adverse effects (AEs), including cytokine release syndrome (CRS) and neurologic toxicity, but liso-cel appears to cause less toxicity than the others. CD19-directed CAR-T cell therapy for DLBCL at first relapse or for those refractory to frontline therapy is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Relapse <12 months or primary refractory DLBCL'.)

One study reported that 50 patients treated with axi-cel had similar progression-free survival (PFS) compared with 37 patients treated with liso-cel [11]. However, the patients treated with liso-cel had more favorable prognostic features, and when the analysis included the propensity score, axi-cel was associated with superior PFS (hazard ratio [HR] 2.95 [95% CI 1.14-7.60]). Axi-cel was associated with more CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged neutropenia. The more favorable prognostic features among those treated with liso-cel may reflect the longer wait times for that product than for axi-cel (41 versus 30 days).

●Bridging therapy – If bridging therapy is needed before CAR-T cell therapy, options include polatuzumab vedotin (CD79b-directed immunoconjugate), CD20 x CD3 bispecific antibodies (eg, glofitamab, epcoritamab), salvage chemotherapy, or radiation therapy (RT).

We avoid CD19-directed treatments (eg, tafasitamab, loncastuximab tesirine) as bridging therapy prior to CD19-directed CAR-T cell therapy; polatuzumab vedotin should be avoided in patients previously treated with the agent (eg, in R-pola-CHP [rituximab, polatuzumab vedotin, cyclophosphamide, vincristine, prednisone]), and we avoid bendamustine. A steroid pulse plus either rituximab or obinutuzumab, or lenalidomide plus either rituximab or obinutuzumab may be considered in this setting.

Salvage chemotherapy regimens are discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Salvage regimens'.)

Bispecific antibodies and polatuzumab vedotin are discussed below. (See 'Bispecific antibody therapy' below and 'Polatuzumab/bendamustine/rituximab' below.)

Prior chimeric antigen receptor T cell therapy — For medically fit patients who relapse after CAR-T cell therapy, we suggest CD20 x CD3 bispecific T cell engager (eg, glofitamab or epcoritamab-based therapy) (algorithm 1) because of the favorable balance of efficacy and toxicity.

Epcoritamab and glofitamab are discussed below. (See 'Glofitamab' below and 'Epcoritamab' below.)

While we favor either glofitamab or epcoritamab in this setting, other antibody-based therapies are acceptable, including tafasitamab/lenalidomide, polatuzumab vedotin/bendamustine/rituximab, loncastuximab tesirine, and brentuximab vedotin/lenalidomide, as described below. (See 'Other antibody-based therapies' below.)

In settings where these agents are not available, allogeneic HCT is an acceptable option for fit patients who achieve a complete response (CR) or near CR after salvage therapy. (See 'Allogeneic hematopoietic cell transplantation' below.)

No randomized trials have either directly compared glofitamab with epcoritamab or compared either agent with the other antibody-based treatments in this setting. Treatment and outcomes with glofitamab and epcoritamab are presented below. (See 'Bispecific antibody therapy' below.)

Selected medically fit patients may choose allogeneic HCT when antibody-based agents are not available.

LESS FIT BUT NOT FRAIL — 

Treatment of relapsed or refractory (r/r) DLBCL in patients who are less fit but not frail must be individualized, as this category includes patients with a wide range of general fitness, comorbid conditions, and performance status.

Treatment is stratified according to whether this is the first relapse or primary refractory DLBCL versus the second or later relapse.

First relapse or primary refractory DLBCL — For the first relapse or primary refractory DLBCL in less-fit patients, we suggest lisocabtagene maraleucel (liso-cel) based on the balance of efficacy and acceptable toxicity.

Liso-cel is less toxic than other CD19-directed chimeric antigen receptor (CAR)-T agents, and it is generally suitable for less-fit patients. Where liso-cel is not available or suitable, we manage as discussed below. (See 'Second or later relapse' below.)

A trial of liso-cel versus autologous hematopoietic cell transplantation (HCT) for r/r DLBCL suggested that liso-cel has good efficacy but less toxicity than other commercially available CD19-directed CAR-T cell products [8-10]. Liso-cel is also associated with improved quality of life, cognitive function, fatigue, and pain [12]. No studies have directly compared liso-cel with other treatments in this setting, but in the TRANSCEND NHL001 study, liso-cel was associated with a 73 percent overall response rate (ORR), 53 percent complete response (CR), 17-month median duration of response (DOR), and modest toxicity [13]. These outcomes are at least as good as responses with various antibody-based or chemotherapy treatments. (See 'Other antibody-based therapies' below and 'Lower-intensity chemotherapy' below.)

Liso-cel is approved by the US Food and Drug Administration (FDA) for primary refractory DLBCL, relapse <12 months after first-line systemic therapy in patients who are not eligible for HCT, and r/r DLBCL after ≥2 lines of systemic therapy.

Second or later relapse — For the second or later relapse of DLBCL in less-fit patients, we suggest CD20 x CD3 bispecific antibody-based treatment based on the balance of efficacy and toxicity.

Glofitamab and epcoritamab are CD20 x CD3 bispecific T cell engager antibodies that are associated with a CR in approximately 40 percent of patients. No randomized trials have directly compared glofitamab with epcoritamab, nor compared either agent with other antibody-based treatments in this setting.

Glofitamab is administered intravenously for a fixed duration of 12 cycles, or it can be given with gemcitabine plus oxaliplatin (Glofit-GemOx), as discussed below. (See 'Glofitamab' below.)

Epcoritamab is given subcutaneously and can be given until disease progression or intolerance. (See 'Bispecific antibody therapy' below.)

There is no consensus approach when a bispecific antibody is not available or suitable, and treatment is individualized according to product availability, comorbidities, performance status, and patient preference. Acceptable alternatives include:

●Other antibody-based treatments

•Tafasitamab/lenalidomide – Tafasitamab is a humanized CD19-directed antibody that, when given with lenalidomide, is associated with response in more than one-half of patients, but treatment requires frequent outpatient infusions and is associated with significant cytopenias in most patients. (See 'Tafasitamab/lenalidomide' below.)

•Polatuzumab/bendamustine/rituximab – Polatuzumab vedotin is a CD79b antibody-drug conjugate that is associated with up to 40 percent CR when it is given with bendamustine and rituximab. Treatment can cause significant cytopenias and moderate neuropathy. Bendamustine should be held or dose reduced in heavily pretreated patients, those with cytopenias, or for planned bispecific antibody therapy. (See 'Polatuzumab/bendamustine/rituximab' below.)

•Loncastuximab tesirine – A CD19-directed antibody-drug conjugate that is infused once per three-week cycle. It can achieve substantial responses, and treatment is associated with moderate cytopenias and edema/effusions. (See 'Loncastuximab' below.)

•Brentuximab vedotin/rituximab/lenalidomide – When given with rituximab and lenalidomide, brentuximab vedotin (a CD30-directed immunoconjugate) was associated with a response in more than one-half of patients, but progression-free survival was short (approximately four months). Treatment with this regimen may cause neuropathy and cytopenias. (See 'Brentuximab vedotin/lenalidomide/rituximab' below.)

●Other approaches – Some patients may choose lower-intensity treatments or palliative or supportive care because they place greater value on avoiding toxicity than on disease response. (See 'Other treatments' below and 'Palliative treatments' below.)

The likelihood of a robust and prolonged response generally decreases with successive relapses, and a cure is not a realistic expectation in this setting. The goals are to relieve symptoms, control the disease, and prolong survival while limiting treatment-related toxicity.

FRAIL PATIENTS — 

For patients whose frailty precludes more intensive treatments, we focus on relieving symptoms and prolonging survival.

There is no consensus treatment in this setting, but single-agent chemotherapy and/or rituximab, palliative radiation therapy, or glucocorticoids can provide symptom relief with little toxicity. Patients can also receive transfusion support and antibiotics, if needed.

It is important to carefully discuss the goals of care, likely outcomes, and available resources for personal and medical assistance.

TREATMENTS

Chimeric antigen receptor T cell therapy — Chimeric antigen receptor (CAR)-T cell therapy is a form of immunotherapy that directs T cells against the lymphoma by ex vivo transfection of the patient's own T lymphocytes with a gene that encodes a CAR. The manufacturing process is complex and expensive, administration is limited to qualified institutions, and the preferred product varies among institutions.

CD19-directed CAR-T cell therapy has substantial activity against relapsed or refractory (r/r) DLBCL but can be associated with substantial toxicity. Age alone does not appear to be a barrier to treatment with CAR-T cell therapy [14].

●Comparison of CD19-directed CAR-T cell products – CD19-directed CAR-T cell products are associated with similar outcomes with r/r DLBCL, and all can cause serious adverse effects (AEs), including potentially fatal complications. A study that reported that axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) were associated with comparable progression-free survival (PFS) [11] is discussed above. (See 'No prior chimeric antigen receptor T cell therapy' above.)

Commercially available CD19-directed CAR-T cell agents are:

•Axi-cel

•Liso-cel

•Tisagenlecleucel (tisa-cel)

Details of outcomes with these agents in randomized trials for r/r DLBCL are presented separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Autologous hematopoietic cell transplantation'.)

●Toxicity – Serious AEs associated with CAR-T cell therapy include:

•Cytokine release syndrome – A severe systemic response to the activation and proliferation of CAR-T cells that typically manifests as high fever, flu-like symptoms, and hypotension. Some degree of cytokine release syndrome (CRS) is observed in nearly all treated patients, and it can be life-threatening for some, but CRS typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids, as described separately. (See "Cytokine release syndrome (CRS)".)

•Immune effector cell-associated neurotoxicity syndrome – Immune effector cell-associated neurotoxicity syndrome (ICANS) can be severe or life-threatening, as described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

•Other AEs – Other AEs include hypersensitivity reactions, serious infections, prolonged cytopenias, hypogammaglobulinemia, rare cases of hemophagocytic lymphohistiocytosis, and second malignancies, including treatment-related myeloid neoplasms (eg, myelodysplastic syndrome or acute myeloid leukemia).

Facilities that dispense these agents require special certification, staff must be trained to recognize and manage AEs, and tocilizumab (a humanized monoclonal antibody against the interleukin 6 receptor [IL-6R]) must be available for immediate administration. The US Food and Drug Administration (FDA) labels carry a boxed warning for CRS and neurologic events. CAR-T cell products are only available in the United States through a risk evaluation and mitigation strategy (REMS).

●Preferred agents – The preferred CAR-T cell product varies according to the clinical setting and availability:

•Second or later relapse in medically fit patients – Axi-cel and liso-cel are preferred for second or later relapse in medically fit patients who did not previously receive CAR-T cell therapy, as described above. (See 'No prior chimeric antigen receptor T cell therapy' above.)

•First relapse or primary refractory DLBCL in less fit but not frail patients – Liso-cel is the preferred agent for first relapse or primary refractory DLBCL in patients who are medically unfit but not frail. (See 'First relapse or primary refractory DLBCL' above.)

•Relapse after ≥2 lines of systemic therapy – Axi-cel and liso-cel are acceptable for treatment after ≥2 lines of systemic therapy for DLBCL.

Axi-cel and liso-cel are approved by the FDA for treatment of adults with primary refractory DLBCL, relapse <12 months after initial therapy, and r/r DLBCL after ≥2 lines of systemic therapy.

Bispecific antibody therapy — Bispecific antibodies link a CD20-directed antibody that targets malignant B cells with a T cell-engaging anti-CD3 antibody.

Bispecific antibodies can cause severe or life-threatening CRS and/or rare cases of ICANS, as described separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Glofitamab — Glofitamab is a CD20 x CD3 bispecific antibody with a 2:1 tumor-to-T cell-binding configuration. Glofitamab can be given as a single agent, or it can be combined with chemotherapy (which causes more toxicity in heavily pretreated patients).

●Administration

•Single agent – Glofitamab is administered intravenously every 21 days, for a fixed duration of 12 cycles.

Treatment begins with stepped-up doses of 2.5 mg on day 8 and 10 mg on day 15 of cycle 1, followed by 30 mg on day 1 of cycles 2 through 12.

A single dose of obinutuzumab 1000 mg is given intravenously on day 1 of cycle 1 (7 days before the first dose of glofitamab) to mitigate the risk of CRS.

•Glofitamab with gemcitabine plus oxaliplatin (Glofit-GemOx) – Glofitamab using stepped-up dosing to 30 mg (described above), gemcitabine 1000 mg/m², and oxaliplatin 100 mg/m² every 21 days for 8 cycles, followed by 4 additional cycles of glofitamab monotherapy.

●Toxicity – Glofitamab is associated with modest CRS, ICANS, tumor lysis syndrome, and infections.

●Outcomes

•Glofit-GemOx was superior to rituximab plus GemOx (R-GemOx) for r/r DLBCL in transplant-ineligible patients (≥18 years) in the phase 3 STARGLO trial [15]. Patients randomly assigned to glofit-GemOx (eight cycles of glofit-GemOx, followed by four cycles of glofitamab monotherapy) achieved superior median survival (25.5 versus 12.9 months; hazard ratio [HR] 0.62 [95% CI 0.43-0.88]) and superior progression-free survival (PFS; 13.8 versus 3.6 months; HR 0.40 [95% CI 0.28-0.57]) compared with R-GemOx. Glofit-GemOx was more toxic, including more grade ≥3 AEs (78 versus 41 percent) and more grade ≥3 AEs related to glofitamab or rituximab (47 versus 23 percent). Grade ≥2 neurologic AEs were more common with glofit-GemOx (31 versus 13 percent), and CRS was reported in 44 percent of patients receiving glofit-GemOx, but only 2 percent had grade ≥3 CRS.

•In a phase 2 study of 154 patients with r/r aggressive B cell lymphoma (71 percent with DLBCL, not otherwise specified), glofitamab monotherapy was associated with 52 percent overall response rate (ORR; including 39 percent complete response [CR]) and 37 percent 12-month PFS [16]. One-third of patients previously received CAR-T cell therapy. Most responses were observed within six weeks and were durable; three-quarters of patients with a CR maintained that response at 12 months. Response rates were similar regardless of age or prior CAR-T cell therapy. Grade ≥3 AEs occurred in 62 percent, including 5 percent fatal AEs and 9 percent who discontinued treatment due to AEs. Grade ≥3 AEs included CRS in 4 percent, ICANS in 3 percent, and febrile neutropenia in 3 percent.

Glofitamab is approved in the United States and Canada for the treatment of adults with r/r DLBCL after ≥2 lines of systemic therapy and who are not eligible to receive or have previously received CAR-T cell therapy.

Epcoritamab — Epcoritamab is a subcutaneously administered CD20 x CD3 bispecific antibody.

●Administration – Epcoritamab is given in 28-day cycles until disease progression or unacceptable toxicity.

Epcoritamab is administered once weekly as stepped-up doses in weeks 1 to 3 of cycle 1 (a 0.16 mg priming dose once on day 1, followed by a 0.8 mg intermediate dose once on day 8), then as full doses once weekly through cycle 3, once every two weeks in cycles 4 to 9, and then once every four weeks in cycle 10 and thereafter [17].

Prophylaxis for CRS is given before each dose of epcoritamab in cycle 1, as follows:

•Prednisolone – 100 mg orally (or an intravenous equivalent) is administered 30 to 120 minutes before each epcoritamab dose (once daily on days 1 to 4 for the priming dose, once daily on days 8 to 11 for the intermediate dose, once daily on days 15 to 18 for the first full dose, and once daily on days 22 to 25 for the second full dose).

•Antihistamine – Premedication strategies vary among clinicians. Diphenhydramine 50 mg (orally or intravenously) is effective but may be poorly tolerated in some patients. The nonsedating antihistamine, cetirizine, is also effective. (See "Infusion-related reactions to monoclonal antibodies for cancer therapy", section on 'Preventing infusion reactions'.)

•Acetaminophen – 650 to 1000 mg orally, once daily on days 1, 8, 15, and 22 of cycle 1.

If grade ≥2 CRS occurs after the fourth epcoritamab dose in cycle 1, corticosteroids are given with epcoritamab for four days or until resolution of CRS.

●Toxicity – Treatment is associated with CRS, ICANS, cytopenias, and infections.

Immunoglobulin levels should be checked in patients with infections because hypogammaglobulinemia is common.

●Outcomes – A multicenter study of 157 adults with r/r CD20-positive large B cell lymphoma and ≥2 prior lines of therapy (including anti-CD20 therapies) reported a 4.4-month median PFS and 63 percent ORR (including 39 percent CR); among patients with CR, the median PFS was not reached after >11 months [18]. Treatment was associated with grade ≥3 CRS in 3 percent (grade 1 or 2 CRS in 50 percent), ICANS (one patient had grade ≥3, which resulted in death; grade 1 or 2 ICANS in 50 percent), grade ≥3 neutropenia in 15 percent, and anemia in 10 percent.

The US FDA approved epcoritamab for adults with r/r DLBCL and high-grade B cell lymphoma after ≥2 lines of systemic therapy.

Other antibody-based therapies — Monoclonal antibodies directed against CD19 (tafasitamab, loncastuximab), CD79 (polatuzumab), or CD30 (brentuximab vedotin) can be effective against r/r DLBCL.

The choice varies with availability, toxicity, prior therapies, institutional experience, and patient preference/convenience. No prospective studies have directly compared these agents for r/r DLBCL, and no regimen has demonstrated a superior balance of efficacy and toxicity.

Tafasitamab/lenalidomide — Tafasitamab is a humanized anti-CD19 monoclonal antibody that is administered with lenalidomide.

●Administration – Tafasitamab is given 12 mg/kg by intravenous infusion according to the following schedule in 28-day cycles [19]:

•Cycle 1: Days 1, 4, 8, 15, and 22

•Cycles 2 and 3: Days 1, 8, 15, and 22

•Cycle 4 and beyond: Days 1 and 15

Lenalidomide 25 mg by mouth on days 1 to 21 of each cycle is taken in combination with tafasitamab for a maximum of 12 cycles.

Tafasitamab is then continued as monotherapy until disease progression or unacceptable toxicity. Many patients will require dose reduction of lenalidomide.

●Toxicity – Grade ≥3 AEs occurred in one-half of patients, including infusion reactions (mostly in the first two cycles), neutropenia (49 percent), infections (26 percent), pneumonia (7 percent), and febrile neutropenia (6 percent) [20]. Fatal AEs occurred in 5 percent of patients, including cerebrovascular accident, respiratory failure, progressive multifocal leukoencephalopathy, and sudden death.

●Outcomes – The phase 2 L-MIND study reported that among 80 patients with r/r DLBCL treated with tafasitamab plus lenalidomide, ORR was 60 percent (43 percent CR) with 22-month duration of response (DOR) [20]. This study excluded patients with primary refractory disease and those with "double-hit" lymphoma. After completing 12 months of combination therapy, tafasitamab monotherapy was continued; median overall survival (OS) was 34 months, median DOR was nearly 44 months, and for patients who achieved CR, three-year OS was >80 percent [21]. During the monotherapy phase of the study, grade ≥3 AEs were neutropenia (49 percent), thrombocytopenia (17 percent), and febrile neutropenia (12 percent).

A real-world study of tafasitamab plus lenalidomide reported less favorable outcomes [22]. This multicenter study that included 178 patients reported a 6.5-month median OS, 1.9-month median PFS, 31 percent ORR, and 19 percent CR. Comparable results were reported in another real-world study of tafasitamab [23].

Tafasitamab is approved by the US FDA in combination with lenalidomide for the treatment of adults with r/r DLBCL who are not eligible for autologous hematopoietic cell transplantation (HCT).

Polatuzumab/bendamustine/rituximab — Polatuzumab vedotin is an anti-CD79b antibody-drug conjugate that is approved for administration with bendamustine and rituximab. However, bendamustine may be avoided in patients who received prior bendamustine, those with baseline cytopenias, and those who may later receive CAR-T cell therapy or bispecific antibody therapy.

●Administration – Polatuzumab vedotin 1.8 mg/kg over 90 minutes is given by intravenous infusion every 21 days for six cycles, in combination with bendamustine and rituximab [24]. If the previous infusion was tolerated, subsequent infusions may be administered over 30 minutes. Dose reduction or discontinuation of bendamustine or growth factor support may be needed.

●Toxicity – Grade ≥3 AEs occurred in two-thirds of patients (mostly cytopenias and infections) and were fatal in 7 percent [25]. The prescribing information includes warnings for peripheral neuropathy, infusion reactions, myelosuppression, serious and opportunistic infections, progressive multifocal leukoencephalopathy, tumor lysis syndrome, hepatotoxicity, and fetal toxicity [24].

●Outcomes – A trial that randomly assigned 80 transplant-ineligible patients to bendamustine plus rituximab versus bendamustine plus rituximab plus polatuzumab vedotin (PBR) reported that PBR achieved superior outcomes but was associated with more grade ≥3 cytopenias and neuropathy (generally grade ≤2 and reversible) [25]. Outcomes with PBR included superior rates of CR (40 versus 18 percent, respectively), median PFS (10 versus 4 months), and median OS (12 versus 5 months).

In another study, polatuzumab vedotin plus rituximab (without bendamustine) was administered as bridging therapy to 41 patients who were to receive CAR-T cell treatment [26]. One-half of the patients successfully underwent CAR-T cell treatment, and the six-month OS was 78 percent.

Polatuzumab vedotin is approved by the US FDA in combination with bendamustine and rituximab for r/r DLBCL after ≥2 prior therapies.

Loncastuximab — Loncastuximab tesirine is a CD19-directed antibody-drug conjugate.

●Administration – Loncastuximab tesirine is given as an intravenous infusion over 30 minutes on day 1 of each three-week cycle:

•0.15 mg/kg for two cycles

•0.075 mg/kg for subsequent cycles

Dexamethasone prophylaxis should be given for three days, beginning on day -1 (ie, the day before treatment).

●Toxicity – Grade ≥3 neutropenia occurred in 32 percent and thrombocytopenia in 20 percent; less common grade ≥3 AEs included edema (3 percent), pleural effusion (3 percent), and pericardial effusion (1 percent) [27].

●Outcomes – A multicenter study (LOTIS-2) reported 48 percent ORR (24 percent CR) among 145 patients with refractory DLBCL or higher-risk disease (eg, double-hit, triple-hit, or transformed DLBCL) [27]. Grade ≥3 AEs included neutropenia (26 percent), thrombocytopenia (18 percent), and liver enzyme abnormalities (17 percent); no fatal events were considered related to treatment. A phase 1 study reported 42 percent ORR and five-month DOR in patients with DLBCL [28].

A real-world study of 118 patients who received loncastuximab monotherapy after progressing on CAR-T cell therapy reported 73 percent ORR, including 34 percent CR [29]. At 12 months, OS and PFS were 84 and 77 percent, respectively.

Loncastuximab is approved by the US FDA for r/r DLBCL after ≥2 prior systemic therapies.

Brentuximab vedotin/lenalidomide/rituximab — Brentuximab vedotin (BV) is a CD30-directed immunoconjugate.

BV/rituximab/lenalidomide was superior to rituximab/lenalidomide in a phase 3 trial, but the median PFS was less than other available treatment options in this setting [30]. BV was effective even in some cases of r/r DLBCL that do not express CD30.

●Administration – BV 1.2 mg/kg is given intravenously on day 1 of each three-week cycle.

If BV/rituximab/lenalidomide is given, rituximab 375 mg/m² is infused on day 1 of each cycle, and lenalidomide 20 mg is taken orally each day.

●Toxicity – BV is associated with peripheral neuropathy and cytopenias.

●Outcomes – BV/rituximab/lenalidomide achieved superior survival compared with placebo/rituximab/lenalidomide in the phase 3 ECHELON-3 trial for 230 patients with r/r DLBCL [30]. Compared with rituximab/lenalidomide, BV/rituximab/lenalidomide achieved longer median OS (13.8 versus 8.5 months; HR for death 0.63 [95% CI 0.45-0.89]), PFS (4.2 versus 2.6 months), and DOR (8.3 versus 3 months). BV/rituximab/lenalidomide also achieved a better ORR (64 versus 42 percent) and CR (40 versus 19 percent). The patient population included prior CAR-T cell therapy in 29 percent, previous bispecific antibody therapy in 15 percent, and prior HCT in 12 percent. The survival benefit was observed across high-risk subgroups, including age ≥65 years, International Prognostic Index (IPI) score ≥3, and prior CAR-T cell therapy.

BV is approved by the US FDA in combination with lenalidomide and rituximab for r/r DLBCL after ≥2 lines of systemic therapy for patients who are ineligible for autologous HCT or CAR-T cell therapy.

Other treatments

Selinexor — Selinexor is an orally available selective inhibitor of nuclear export; the mechanism of action appears to be inhibition of nucleocytoplasmic shuttling proteins that functionally inactivate p53 and other tumor suppressor proteins [31].

Selinexor was associated with an objective response in approximately one-quarter of highly selected patients, which is lower than most other treatment options in this setting, and it is associated with significant toxicity [32].

In a multicenter study, 127 heavily pretreated patients received selinexor 60 mg by mouth on days 1 and 3 each week and achieved 28 percent ORR, including 12 percent CR; importantly, ≥60 days were required to elapse prior to enrollment in the study, which may have been selected for patients with less aggressive disease [32]. Overall, the median DOR was 9 months, but it was 23 months in those with CR. The most common grade ≥3 AEs were thrombocytopenia (46 percent), neutropenia (24 percent), anemia (22 percent), fatigue (11 percent), hyponatremia (8 percent), and nausea (6 percent). There were no treatment-related deaths, and AEs were generally reversible and manageable with dose modifications and supportive care.

Selinexor is approved by the FDA for adults with r/r DLBCL after ≥2 lines of systemic therapy.

Lower-intensity chemotherapy — Lower-intensity chemotherapy can reduce the burden of disease, relieve symptoms, and prolong survival, but it is not associated with long-term disease control or cure for r/r DLBCL. The likelihood of a substantial or prolonged response diminishes with successive treatments.

Treatment can be given with or without rituximab, but there is no consensus regimen. Options include:

●Cytarabine – 1500 to 2000 mg/m² intravenously every two weeks combined with rituximab.

●R-GemOx – Rituximab, gemcitabine, and oxaliplatin are discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'R-GemOx (rituximab, gemcitabine, oxaliplatin)'.)

Palliative treatments — For patients who seek symptom relief with limited toxicity, palliative treatments for r/r DLBCL may include:

●Palliative radiation therapy – To one or a few disease sites.

●Dexamethasone – Up to 40 mg daily for two to four days can lessen symptoms for patients with end-stage DLBCL.

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION — 

Allogeneic hematopoietic cell transplantation (HCT) is used only infrequently for relapsed or refractory (r/r) DLBCL due to the substantial treatment-related toxicity and availability of alternative approaches. Nevertheless, allogeneic HCT may be acceptable for selected medically fit patients who achieve a complete response (CR) or near CR after relapse following autologous HCT and chimeric antigen receptor (CAR)-T cell therapy, when antibody-based agents are not available. (See 'Prior chimeric antigen receptor T cell therapy' above.)

Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Human leukocyte antigen (HLA)-matched related donors are preferred, but an HLA-matched unrelated donor or alternate donor sources (eg, haploidentical or umbilical cord blood) may provide acceptable grafts. (See "Donor selection for hematopoietic cell transplantation".)

There is no consensus conditioning regimen for allogeneic HCT. Overall survival (OS) and progression-free survival (PFS) are similar after myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning; MAC is generally associated with lower rates of relapse but higher rates of nonrelapse mortality [33]. Compared with autologous HCT, allogeneic HCT is associated with considerably higher rates of transplant-related morbidity and mortality [34]. Retrospective analysis of 101 patients who underwent allogeneic HCT for DLBCL after prior autologous HCT reported that relapse rate, PFS, and OS at three years were 30, 42, and 54 percent, respectively [35]. Other retrospective studies reported that outcomes with NMA conditioning and RIC were comparable [36,37].

MONITORING — 

There is no consensus for monitoring the patient with relapsed or refractory DLBCL for relapse and treatment-related toxicities. The schedule should be individualized according to the concerns of the clinician and patient. For patients who achieve a complete response, we generally schedule routine clinical and laboratory evaluations every three months for the first two years and extend the interval to four or six months for the next three years.

We do not perform regularly scheduled positron emission tomography or other surveillance imaging. Most relapses are suspected by history or physical examination, and only rarely is relapse identified solely on the basis of routine follow-up imaging [38].

CLINICAL TRIALS — 

We strongly encourage participation in a clinical trial for patients with relapsed or refractory DLBCL.

Often, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of diffuse large B cell lymphoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Diffuse large B cell lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Diffuse large B cell lymphoma (DLBCL) that did not respond adequately to initial therapy (primary refractory DLBCL) or that recurred after achieving a complete response (CR; relapsed DLBCL) carries an adverse prognosis. Management varies with the clinical setting and medical fitness.

●Diagnosis – Repeat biopsy is generally required to confirm the first relapse, but a biopsy may not be required for the second or later relapse or primary refractory DLBCL, as discussed above. (See 'Diagnosis' above.)

●Pretreatment evaluation – Includes (see 'Pretreatment evaluation' above):

•Fitness – Based on clinical evaluation, performance status (table 1), and comorbid conditions (table 3). Age does not determine medical fitness, but caution is urged with intensive therapy for patients ≥75 years. (See 'Medical fitness' above.)

There are no clear distinctions among categories, and classification may vary with intercurrent disease or effects of treatment.

-Medically fit

-Less fit but not frail

-Frail

•Restaging – Based on positron emission tomography/CT (table 6), according to Lugano criteria (table 5). (See 'Restaging' above.)

•Prognosis – Assessed by the International Prognostic Index (table 7). (See 'Prognosis' above.)

●Medically fit, with second or later relapse – Management varies with prior treatments (algorithm 1):

•No prior chimeric antigen receptor T cell therapy – For second or later relapse in fit patients who did not previously receive chimeric antigen receptor (CAR)-T cell therapy, we suggest either axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel) rather than tisagenlecleucel or a bispecific antibody (Grade 2C). (See 'No prior chimeric antigen receptor T cell therapy' above.)

•Prior CAR-T cell therapy – For a medically fit patient who relapses after CAR-T cell therapy, we suggest a bispecific antibody (eg, glofitamab, epcoritamab) rather than other antibody-based therapies (Grade 2C). (See 'Prior chimeric antigen receptor T cell therapy' above.)

●Less fit but not frail – Stratified as follows:

•First relapse or primary refractory disease – For the first relapse or primary refractory DLBCL in less-fit patients, we suggest liso-cel rather than other CAR-T cell products or other approaches (Grade 2C). (See 'First relapse or primary refractory DLBCL' above.)

•Second or later relapse – For the second or later relapse, we suggest a bispecific antibody (eg, glofitamab, epcoritamab) rather than other antibody-based treatments (Grade 2C). (See 'Second or later relapse' above.)

When a bispecific antibody is not available or suitable, treatment is individualized according to product availability, comorbidities, performance status, and patient preference. Acceptable options include other antibody-based treatments (eg, tafasitamab/lenalidomide, bendamustine/rituximab/polatuzumab vedotin, loncastuximab teserine, brentuximab vedotin/lenalidomide/rituximab) or lower-intensity treatments. (See 'Other antibody-based therapies' above and 'Other treatments' above.)

Some patients may favor palliative or supportive care alone in this setting. (See 'Palliative treatments' above.)

●Frail – We offer palliation and supportive care. (See 'Frail patients' above.)

●Treatments

•CAR-T cell therapy (See 'Chimeric antigen receptor T cell therapy' above.)

•Bispecific antibody therapy – CD20 x CD3 bispecific monoclonal antibodies:

-(See 'Glofitamab' above.)

-(See 'Epcoritamab' above.)

•Other antibody-based treatments – The choice varies with availability, toxicity, comorbidities, and patient preference/convenience (see 'Other antibody-based therapies' above):

-(See 'Tafasitamab/lenalidomide' above.)

-(See 'Polatuzumab/bendamustine/rituximab' above.)

-(See 'Loncastuximab' above.)

-(See 'Brentuximab vedotin/lenalidomide/rituximab' above.)

•Other approaches – Include:

-(See 'Selinexor' above.)

-(See 'Lower-intensity chemotherapy' above.)

-(See 'Palliative treatments' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.