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 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, nearly one-third of patients relapse after achieving a complete response (CR), and approximately 10 percent are refractory to initial therapy (ie, do not achieve CR).

Relapsed or refractory (r/r) DLBCL can be cured in some patients with intensive treatments, such as chimeric antigen receptor (CAR)-T cell therapy or hematopoietic cell transplantation (HCT), but some patients do not respond adequately or subsequently relapse. Other patients are not candidates for intensive treatment because of limited medical fitness. Various treatments are used for patients with second or later relapse of DLBCL and patients with limited medical fitness; we encourage participation in a clinical trial for all.

This topic discusses treatment of medically fit patients who have a second or later relapse of DLBCL and 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.

Neurologic examination should be performed. Patients with abnormal findings on 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 (CBC) with leukocyte differential count

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

•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 r/r DLBCL and exclude other diagnoses.

●Suspected first relapse – For patients with an apparent relapse after previously achieving a complete response (CR; based on positron emission tomography [PET]/computed tomography [CT] (table 1)), a biopsy should be performed to confirm the diagnosis, exclude other conditions (eg, other types of lymphoma, carcinoma, sarcoidosis, tuberculosis, fungal infection), and to assess for disease transformation or acquisition of new mutations.

●Second or later relapse – For patients with a second or later relapse, a repeat biopsy may not be required if other diagnoses can be excluded clinically. However, a biopsy should be performed to confirm a second relapse if it occurs following a CR to 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 may not be required if there was clear progression in the size and metabolic activity of a disease site. If a biopsy is not performed, morphology, immunophenotype, and cytogenetic/molecular features of the initial biopsy specimen should be reviewed to ensure that DLBCL was correctly diagnosed.

Medical fitness — Assessment of 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 2)

•Physiologic fitness – Physiologic fitness (eg, comorbid conditions, activities of daily living, physical performance tests, cognition) as measured by the Charlson comorbidity index (CCI) (table 3) or the HCT-specific comorbidity index (table 4)

●Fitness categories – We categorize patients with r/r DLBCL according to fitness for treatment, based on performance status (PS) 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, and in some cases, treatment may alleviate disease consequences/complications and enhance the patient's ability to tolerate and benefit from subsequent treatment.

There are no clear distinctions among fitness categories, and some measures of PS or physiologic fitness can apply to different categories. In selecting a category of fitness, we seek to protect frail patients from treatment that they are unlikely to tolerate, while not depriving others from 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 2)

-CCI: 0 to 2 (table 4)

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".)

•Medically unfit, but not frail – Patients who are medically unfit 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 function; 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 medically unfit but not frail if either of the following applies:

-ECOG: 3 (table 2)

-CCI: 3 (table 4)

•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 2)

-CCI: ≥3 (table 4)

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'.)

Other approaches for assessing fitness have been described. As an example, the Elderly Prognostic Index (EPI) integrates age with a simplified comprehensive geriatric assessment of functional activities and comorbidities; in this model, by definition, all patients ≥80 years are classified as unfit or frail [1]. The three categories of fitness in the EPI have been validated as independent prognostic factors for survival [2,3]. Clinician-administered or patient-completed instruments can be useful to assess 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 [4].

Geriatric assessment may be useful for judging medical fitness of some patients in this setting [4]. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

Other considerations for 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 5) is based on clinical evaluation and PET/CT, according to the Lugano criteria (table 6). 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 1).

●Bone marrow – Bone marrow examination is preferred, but it is not required for restaging all patients with r/r DLBCL.

PET is generally a good predictor for marrow involvement by DLBCL. However, if autologous HCT is a consideration, bone marrow examination is usually performed prior to transplantation to assess possible myelodysplasia or acute myeloid leukemia, 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'.)

Bone marrow should be analyzed by microscopy, cytogenetics (using fluorescence in situ hybridization or Giemsa-stained chromosomes), and molecular studies, as described separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Pathology'.)

Prognosis — A modification of International Prognostic Index (IPI) that categorizes patients according to age cohort should be applied in this setting; this modified index has greater discriminatory power for older adults than the original IPI [5].

Outcomes are generally poor for patients who relapse following autologous HCT and for those who are not eligible for transplantation or other intensive therapies [6-8]. 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 [9]. 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 central nervous system (CNS) involvement, 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) rather than other approaches, based on successful outcomes with CAR-T cell therapy as second-line therapy for patients with primary refractory disease or first relapse <12 months after initial treatment, as 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'.)

For patients who require bridging therapy to control disease prior to CAR-T cell therapy, we generally avoid CD19-directed therapies (eg, tafasitamab, loncastuximab); these treatments are 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'.)

Randomized trials of patients with first relapse or primary refractory DLBCL reported that axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) achieved superior survival compared with autologous hematopoietic cell transplantation (HCT) [10,11]; a third randomized trial reported that tisagenlecleucel (tisa-cel) was not superior to autologous HCT [12].

The various CD19-directed CAR-T cell products have not been compared head-to-head, but all are associated with an objective response in at least half of patients with relapsed or refractory (r/r) DLBCL. However, all CAR-T cell products can cause potentially life-threatening adverse events (AEs), including cytokine release syndrome (CRS) and neurologic toxicity. Preliminary reports suggest that liso-cel may be associated with less toxicity than axi-cel or tisa-cel. The choice of CAR-T cell agent may be influenced by availability, manufacturing time, and institutional preference.

Axi-cel, liso-cel, and tisa-cel are approved by the US Food and Drug Administration (FDA) for treatment of r/r DLBCL after ≥2 prior treatments.

Toxicity and indications for individual CAR-T cell products are described below. (See 'Chimeric antigen receptor T cell therapy' below.)

If necessary, treatment with a bispecific antibody, polatuzumab (if not previously administered), or low-dose chemotherapy may be used as bridging therapy. (See 'Bispecific antibody therapy' below and 'Polatuzumab/bendamustine/rituximab' below and 'Lower-intensity chemotherapy' below.)

Detailed discussion of outcomes with individual CD19-directed CAR-T cell agents 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 'Relapse <12 months or primary refractory DLBCL'.)

Prior chimeric antigen receptor T cell therapy — For a medically fit patient who relapses after receiving CAR-T cell therapy, we suggest bispecific antibody therapy (also called bispecific T cell engager therapy) rather than HCT or other approaches (algorithm 1). This suggestion is based on the more favorable balance of efficacy and toxicity with bispecific antibody therapy.

No randomized trials have directly compared treatments in this setting, and no approach has proven to be clearly superior. Prognosis generally worsens with increasing episodes of relapse, but some patients achieve long-term disease control using bispecific antibody therapy.

Management of relapse after CAR-T cell therapy is challenging, and treatment must be individualized. The approach is informed by prior treatments, comorbid conditions, institutional experience, and patient preference. Other acceptable options include antibody-based therapies (eg, tafasitamab, polatuzumab vedotin, loncastuximab) or allogeneic HCT; for patients who seek symptom relief without an expectation of longer-term disease control, lower-intensity chemotherapy or palliative approaches are appropriate.

Bispecific antibody therapy is discussed below. (See 'Bispecific antibody therapy' below.)

Other antibody-based treatments are discussed below. (See 'Other antibody-based therapies' below.)

Allogeneic HCT should only be offered to fit patients who achieve a complete response (CR) or near-CR after salvage therapy. (See 'Allogeneic hematopoietic cell transplantation' below.)

Lower-intensity chemotherapy and palliative treatments are discussed below. (See 'Lower-intensity chemotherapy' below and 'Palliative treatments' below.)

MEDICALLY UNFIT, BUT NOT FRAIL — Treatment of relapsed or refractory (r/r) DLBCL in patients who are medically unfit 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 first relapse or primary refractory DLBCL versus second or later relapse.

First relapse or primary refractory DLBCL — For first relapse or primary refractory DLBCL in patients who are medically unfit but not frail, we suggest treatment with lisocabtagene maraleucel (liso-cel) rather than other CD19-directed chimeric antigen receptor (CAR)-T cell products, bispecific antibody therapy, other antibody-based treatments, or lower-intensity chemotherapy.

Where liso-cel is not available, we generally favor bispecific antibody therapy or another antibody-based treatment (eg, tafasitamab, polatuzumab vedotin, loncastuximab). Selection of an alternative approach is acceptable based on product availability, manufacturing time, comorbid conditions, performance status, and patient preference.

A trial of liso-cel versus autologous hematopoietic cell transplantation (HCT) for r/r DLBCL suggested that liso-cel has similar efficacy but less toxicity than other commercially available, CD19-directed CAR-T cell products [10-12]. Liso-cel is also associated with improved patient-reported quality of life, cognitive function, fatigue, and pain [13]. 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), median duration of response (DOR) of 17 months, and modest toxicity [14]; these outcomes are at least as good as those 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 or relapse <12 months after first-line systemic therapy in patients who are not eligible for HCT and for r/r DLBCL after ≥2 lines of systemic therapy.

Treatment with bispecific antibody therapy and other antibody-based approaches are discussed below. (See 'Bispecific antibody therapy' below and 'Other antibody-based therapies' below.)

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

There is no preferred approach, and no studies have directly compared outcomes and toxicity of various treatment options. Selection of therapy is guided by availability, comorbid conditions, toxicity, and patient preference/convenience. Some patients may choose to receive palliative or supportive care because they place greater value on avoidance of toxicity than on disease response. (See 'Palliative treatments' below.)

Options include:

●Bispecific antibody therapy – Glofitamab and epcoritamab are CD20 x CD3 bispecific antibodies that are associated with CR in approximately 40 percent of patients. Glofitamab is administered intravenously for 12 cycles (fixed duration), while epcoritamab is given subcutaneously until disease progression. (See 'Glofitamab' below and 'Epcoritamab' below.)

Treatment with bispecific antibodies may be associated with severe or life-threatening cytokine release syndrome (CRS) and/or rare cases of immune effector cell-associated neurotoxicity syndrome (ICANS), as described separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

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

●Polatuzumab vedotin/bendamustine/rituximab – Anti-CD79b antibody-drug conjugate that, when administered with bendamustine and rituximab, is associated with CR in up to 40 percent of patients; treatment is associated with serious 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 administered by infusion once per three-week cycle. It can achieve substantial responses, and treatment is associated with moderate cytopenias and edema/effusions. (See 'Loncastuximab' below.)

●Selinexor – An orally available selective inhibitor of nuclear export that can achieve a response (mostly partial responses) in one-quarter of patients with r/r DLBCL, but it is associated with substantial toxicity. (See 'Selinexor' below.)

●Chemotherapy – Treatment with lower-intensity chemotherapy can provide transient responses with modest adverse events. (See 'Lower-intensity chemotherapy' below.)

FRAIL PATIENTS — We provide palliative and supportive care for patients whose frailty precludes other treatments. It is important to carefully discuss the goals of care, likely outcomes, and available resources for personal and medical assistance.

Transfusion support, antibiotics, palliative radiation therapy, single-agent chemotherapy, or rituximab can be provided to relieve symptoms. (See 'Lower-intensity chemotherapy' below.)

Other patients will select end-of-life care rather than the possibility of treatment-related adverse events. (See 'Palliative treatments' below.)

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, using 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 therapy [15].

●Comparison of CD19-directed chimeric antigen receptor T cell products – No prospective studies have directly compared the various CAR-T cell products. All achieved similar outcomes with r/r DLBCL, and all are associated with serious adverse events (AEs), including potentially fatal complications.

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

•Axicabtagene ciloleucel

•Lisocabtagene maraleucel

•Tisagenlecleucel

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 adverse events – 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 – Axicabtagene ciloleucel and lisocabtagene maraleucel 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 medically unfit, but not frail patients – Lisocabtagene maraleucel 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 – Axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel are acceptable for treatment after ≥2 lines of systemic therapy for DLBCL.

Axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel are approved by the FDA for treatment of adults with r/r DLBCL after ≥2 lines of systemic therapy; in addition, axicabtagene ciloleucel is approved for treatment of adults with primary refractory DLBCL or relapse <12 months after initial therapy.

Bispecific antibody therapy — Bispecific antibodies link a CD3 antibody with another monoclonal antibody (eg, CD20) that targets the malignant B cells.

Glofitamab — Glofitamab is a CD20 x CD3 bispecific antibody with a 2:1 tumor-to-T cell-binding configuration.

●Administration – Glofitamab is administered intravenously for a fixed duration of 12 cycles. Treatment begins with stepped-up doses of 2.5 and 10 mg, followed by 30 mg on day 1 of cycles 2 through 12. Patients in a phase 2 study (described below) received pretreatment with obinutuzumab to mitigate CRS [16].

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

●Outcomes – In a phase 2 study of 154 patients with r/r aggressive B cell lymphoma (71 percent with DLBCL, not otherwise specified), glofitamab was associated with 52 percent overall response rate (ORR; including 39 percent complete response [CR]) and 37 percent 12-month progression-free survival (PFS) [16]. Most responses were observed within six weeks and were durable; three-quarters of patients with CR maintained that response at 12 months. The study enrolled patients (≥18 years) with Eastern Cooperative Oncology Group performance status 0 to 1, including one-third who had previously received CAR-T cell therapy. Response rates were similar regardless of age (<65 years versus ≥65 years) and among patients who had or had not received previous 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 treatment of adults with r/r DLBCL who received ≥2 lines of systemic therapy and are not eligible to receive or previously received CAR-T cell therapy [17].

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. Treatment begins with a phase of dose escalation and must be accompanied by prophylaxis for CRS.

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 [18].

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).

•Diphenhydramine – 50 mg orally or intravenously (or equivalent).

•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, and cytopenias.

●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 [19]. 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.

Epcoritamab is approved by the FDA for adult patients with r/r DLBCL and high-grade B cell lymphoma after ≥2 lines of systemic therapy [18].

Other antibody-based therapies — Treatments using monoclonal antibodies directed against antigens expressed by DLBCL (eg, CD19, CD79b) are effective against r/r DLBCL. The choice of treatment 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.

We generally avoid use of CD19-directed monoclonal antibodies as bridging therapy prior to administration of CD19-directed CAR-T cell therapy, as discussed above. (See 'No prior chimeric antigen receptor T cell therapy' above.)

Tafasitamab — Tafasitamab is a humanized anti-CD19 monoclonal antibody [20]. Tafasitamab should be administered with lenalidomide.

●Administration – Tafasitamab is given 12 mg/kg by intravenous infusion according to the following schedule in 28-day cycles [21]:

•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 can then be continued as monotherapy until disease progression or unacceptable toxicity. Many patients will require dose reduction of lenalidomide.

●Toxicity – Grade ≥3 AEs occurred in 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) [22]. 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) [22]. 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 [23]. During the monotherapy phase of the study, grade ≥3 AEs were neutropenia (49 percent), thrombocytopenia (17 percent), and febrile neutropenia (12 percent).

It is uncertain at present if tafasitamab should be avoided in patients who may later receive anti-CD19 CAR-T cell therapy.

Tafasitamab is approved by the FDA in combination with lenalidomide for the treatment of adults with r/r DLBCL who are not eligible for autologous hematopoietic cell transplantation (HCT) [21].

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]. Prescribing information includes warnings for peripheral neuropathy, infusion reactions, myelosuppression, serious and opportunistic infections, progressive multifocal leukoencephalopathy (PML), 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 FDA in combination with bendamustine and rituximab for r/r DLBCL after ≥2 prior therapies [24].

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

●Administration – Loncastuximab 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 day -1 (ie, the day before treatment).

It is presently uncertain if loncastuximab should be avoided in patients who may later receive anti-CD19 CAR-T cell therapy.

●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].

Loncastuximab is approved by the FDA for r/r DLBCL after ≥2 prior systemic therapies [29].

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 [30]. Selinexor was associated with an objective response in approximately one-quarter of highly selected patients, but it is associated with significant toxicity [31].

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 [31]. 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 treatment of adults with r/r DLBCL after ≥2 lines of systemic therapy [32].

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.

To lessen toxicity, we favor sequential, single-agent chemotherapy, with or without rituximab. There is no consensus, but options include:

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

●Lenalidomide – This oral agent is generally combined with rituximab [33-38]. AEs include cytopenias, infections, and increased risk for thrombosis. Lenalidomide may be more efficacious in r/r DLBCL with non-germinal center B cell (GCB)-like features than with GCB histology, according to a systematic review and meta-analysis [39].

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 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 "Determining eligibility for allogeneic hematopoietic cell transplantation".)

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 [40]. Compared with autologous HCT, allogeneic HCT is associated with considerably higher rates of transplant-related morbidity and mortality [41]. 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 [42]. Other retrospective studies reported that outcomes with NMA and RIC were comparable [43,44].

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 concerns of the clinician and patient. For patients who achieve a complete response, we generally schedule routine clinical and laboratory evaluation 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 [45].

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 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 first relapse but may not be required for second or later relapse or primary refractory DLBCL, as discussed above. (See 'Diagnosis' above.)

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

•Fitness – Based on performance status (table 2) and comorbid conditions (table 4). Age, per se, 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

-Medically unfit but not frail

-Frail

•Restaging – Positron emission tomography/CT (table 1), according to Lugano criteria (table 6). (See 'Restaging' above.)

•Prognosis – Assessed by 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 patients who did not previously receive chimeric antigen receptor (CAR)-T cell therapy, we suggest CD19-directed CAR-T cell therapy rather than other treatments (Grade 2C). (See 'No prior chimeric antigen receptor T cell therapy' above.)

•Prior chimeric antigen receptor T cell therapy – For a medically fit patient who relapses after receiving CAR-T cell therapy, we suggest bispecific antibody therapy rather than hematopoietic cell transplantation (HCT) or other approaches (Grade 2C). (See 'Prior chimeric antigen receptor T cell therapy' above.)

●Medically unfit, but not frail – Stratified as follows:

•First relapse or primary refractory disease – For first relapse or primary refractory DLBCL in patients who are medically unfit, but not frail, we suggest lisocabtagene maraleucel (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 second or later relapse, management varies with availability of agents, comorbid conditions, toxicity, and patient preference/convenience. Options include:

-CD19-directed chimeric antigen receptor T cell therapy (see 'Chimeric antigen receptor T cell therapy' above)

-Bispecific antibody therapy (see 'Bispecific antibody therapy' above)

-Antibody-based treatments (see 'Other antibody-based therapies' above)

-Other treatments (see 'Other treatments' above)

-Palliative treatment (see 'Palliative treatments' above)

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

●Treatments – Include (see 'Treatments' above):

•Chimeric antigen receptor T cell therapy – (see 'Chimeric antigen receptor T cell therapy' above)

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

-Glofitamab (see 'Glofitamab' above)

-Epcoritamab (see 'Epcoritamab' above)

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

-Tafasitamab (see 'Tafasitamab' above)

-Polatuzumab/bendamustine/rituximab (see 'Polatuzumab/bendamustine/rituximab' above)

-Loncastuximab (see 'Loncastuximab' above)

•Other approaches – Include:

-Selinexor (see 'Selinexor' above)

-Lower-intensity chemotherapy (see 'Lower-intensity chemotherapy' above)

-Palliative treatments (see 'Palliative treatments' above)