INTRODUCTION — Nearly one-third of patients relapse after achieving a complete response of diffuse large B cell lymphoma (DLBCL) using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 10 percent are refractory to initial therapy. Management is influenced by whether the patient has primary refractory disease, first relapse, or second or later relapse; prior treatments; and the level of medical fitness.
This topic discusses treatment of medically-fit patients who have a second or later relapse of DLBCL and management of relapsed or refractory DLBCL in patients who are not medically-fit for intensive treatments.
Evaluation and management of medically-fit patients with suspected first relapse of DLBCL or primary refractory DLBCL are discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Autologous HCT'.)
PRETREATMENT EVALUATION — Pretreatment evaluation 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 (LP), as described separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)
●Laboratory
•Complete blood count (CBC) with differential.
•Serum electrolytes, glucose, blood urea nitrogen (BUN) and creatinine, calcium, uric acid, and liver function tests, including lactate dehydrogenase (LDH).
•HIV and hepatitis B testing.
•Pregnancy testing, if appropriate.
●Pathology – A biopsy should be performed to confirm the diagnosis of relapsed or refractory DLBCL.
For patients with suspected refractory DLBCL, the biopsy is important to exclude post-treatment inflammatory changes and other conditions (eg, tuberculosis, sarcoidosis, fungal infection, carcinoma). For patients with suspected first relapse of DLBCL, the purpose of the biopsy is to determine if there is histologic transformation or new mutations. For a patient with a second or later relapse, a repeat biopsy may not be required if other diagnoses can be excluded clinically.
Medical fitness — Assessment and categorization of medical fitness affects treatment decisions for relapsed and refractory (r/r) DLBCL.
●Assessment – Medical fitness is assessed with the following instruments:
•Performance status – Eastern Cooperative Oncology Group (ECOG) performance scale (table 1).
•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 hematopoietic cell transplantation (HCT)-specific comorbidity index (HCT-CI) (table 3).
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 were validated in two studies 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].
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'.)
●Fitness categories – We categorize patients with r/r DLBCL according to their fitness for treatment, based on performance status (PS) and physiologic fitness. 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. Chronic comorbid conditions should be weighted more heavily than transient medical complications of the lymphoma itself (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.
It should be recognized that there are no clear distinctions between categories of medical fitness. Furthermore, some measures of PS or physiologic fitness can apply to different fitness 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 1)
-CCI: 0 to 2 (table 3)
•Medically-unfit, but not frail – Patients who are medically-unfit, but not frail cannot tolerate autologous HCT, but they may be able to tolerate treatments such as chimeric antigen receptor (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 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'.)
Restaging — Restaging (table 4) is based on clinical evaluation and positron emission tomography/computed tomography (PET/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 scale (also called the Deauville scale) (table 6).
●Bone marrow examination is not required for pretreatment staging in this setting, because PET is a good predictor for marrow involvement. If a bone marrow examination is performed as a component of pretreatment staging, it should be examined by microscopy, cytogenetics (using fluorescence in situ hybridization [FISH] 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 the 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 complete response, and 6 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, 2 cycles of subsequent therapy, or relapse ≤12 months from autologous HCT; outcomes were especially poor for patients with refractory DLBCL [9].
MEDICALLY-FIT WITH SECOND OR LATER RELAPSE — Treatment for medically-fit patients with second or later relapse depends on whether the patient previously received CD19-directed chimeric antigen receptor (CAR)-T cell therapy (algorithm 1).
Management of first relapse in medically-fit patients is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Choice of treatment'.)
For patients with a relapse of DLBCL that includes secondary central nervous system (CNS) involvement, management is discussed separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis" and "Secondary central nervous system lymphoma: Treatment and prognosis".)
No prior CAR-T cell therapy — For medically-fit patients with second relapse who did not previously receive CAR-T cell therapy, we suggest CD19-directed CAR-T cell therapy, rather than other treatments. No trials have directly compared CAR-T cell therapy with other treatments (eg, antibody-based treatments, chemotherapy, repeat autologous transplantation, or allogeneic hematopoietic cell transplantation [HCT]) or compared available CAR-T cell products head-to-head in this setting.
All commercially available CAR-T cell products are associated with an objective response in at least half of patients, but they can cause potentially life-threatening adverse events (AEs), including cytokine release syndrome (CRS) and neurologic toxicity. Outcomes and AEs vary and the choice of agent is influenced by institutional preference. Preliminary reports suggest that lisocabtagene maraleucel (liso-cel) may be associated with less toxicity than axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Each of these products has been approved by the US Food and Drug Administration (FDA) for treatment of relapsed or refractory DLBCL after ≥2 prior treatments. Management, toxicity, and outcomes with the individual CAR-T cell products are described below. (See 'CAR-T cell therapy' below.)
Prior CAR-T cell therapy — For patients who relapse after CAR-T cell therapy, the goal of treatment is to prolong survival, alleviate symptoms, and maintain the quality of life.
Treatment options include antibody-based therapies, chemotherapy, and palliative therapy (algorithm 1). The choice of therapy is informed by prior treatments, comorbid conditions, institutional experience, and patient preference and convenience. Administration and outcomes with these and other approaches are described below. (See 'Antibody-based therapies' below and 'Other treatments' below.)
Autologous HCT may be an option for a medically-fit patient who received CAR-T cell therapy for first relapse or refractory DLBCL (ie, for a patient who did not previously undergo autologous HCT). There is no evidence to support a second autologous HCT or a second CD19-directed CAR-T cell therapy. For highly selected, medically-fit patients, long-term survival is possible with allogeneic HCT, but this option must be weighed against the risk of substantial short-term and long-term toxicity. (See 'Allogeneic HCT' below.)
MEDICALLY UNFIT, BUT NOT FRAIL — For patients who are medically-unfit but not frail, treatment of relapsed or refractory DLBCL must be individualized, as this category includes patients with a wide range of general fitness, comorbid conditions, and performance status. Factors to consider include whether this is the first relapse versus a second or later relapse, prior treatments, toxicity, availability, clinician experience, and patient preferences.
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, antibody-based treatments, chemotherapy, or other approaches. No studies have directly compared CAR-T cell therapy with other treatments and the commercially-available CAR-T cell products have not been compared head-to-head. Liso-cel is suggested in this setting because, compared with other CAR-T cell products, it appears to at least as efficacious and is associated with less toxicity. (See 'Lisocabtagene maraleucel' below.)
None of the CD19-directed CAR-T cell therapies is currently approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for first relapse of DLBCL or primary refractory disease.
Where liso-cel is not available, acceptable options include antibody-based treatments (eg, tafasitamab plus lenalidomide, polatuzumab vedotin/bendamustine/rituximab, loncastuximab tesirine), moderate- or lower-intensity chemotherapy, or other approaches. Available treatments, institutional experience, and patient preference influence the choice of therapy. Administration and outcomes with these approaches are discussed below. (See 'Antibody-based therapies' below and 'Other treatments' below.)
For the patient who received an abbreviated course of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) as initial therapy for early stage DLBCL, R-CHOP can be considered for treatment of first relapse. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Treatment'.)
Second or later relapse — The goals of management in this setting are to relieve symptoms, prolong survival, and control the disease, while limiting treatment-related toxicity. Cure is not a realistic goal for most patients and the likelihood of a robust and prolonged response generally decreases with successive relapses. We encourage participation in a clinical trial.
There is no preferred approach in this setting and no studies have directly compared outcomes and toxicity of the various treatment options. Each of the treatments described below can provide a substantial response, but the toxicities vary and duration of response are not well-defined. Selection of therapy should consider comorbidities, toxicity, prior therapy, and availability; patient preference and convenience are especially important in this setting. (See 'Antibody-based therapies' below and 'Other treatments' below.)
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.)
Other options include:
●Tafasitamab plus lenalidomide – Tafasitamab is a humanized CD19-directed antibody that, together with lenalidomide, can achieve a 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 is an anti-CD79b antibody-drug conjugate that when administered with bendamustine and rituximab, achieves a complete response in up to 40 percent of patients; treatment is associated with serious cytopenias and moderate neuropathy. (See 'Polatuzumab/bendamustine/rituximab' below.)
●Loncastuximab tesirine is 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.)
●Chemotherapy – Treatment with single-agent chemotherapy or other lower-intensity chemotherapy regimens can provide transient responses with modest adverse events. (See 'Chemotherapy' below.)
●Selinexor is an orally available selective inhibitor of nuclear export (SINE) that can achieve a response in one-quarter of patients, but it is associated with substantial toxicity. (See 'Selinexor' below.)
Bispecific antibodies that engage the lymphoma cells (eg, via CD19 or CD20) and T cells (via CD3) are under investigation in this setting.
FRAIL PATIENTS — For patients whose frailty precludes the treatments described above, we generally provide palliative/supportive care. 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 if they may relieve symptoms. (See 'Lower-intensity' below.)
Other patients will select end-of-life care rather than the possibility of treatment-related adverse events. (See 'Palliative treatments' below.)
TREATMENTS
CAR-T cell therapy — Chimeric antigen receptor (CAR)-T cell therapy refers to genetically-modified autologous T lymphocytes that are transfected with a CAR, expanded ex vivo, and then infused into the patient. Each CAR-T cell product has substantial activity against relapsed or refractory (r/r) DLBCL, but treatment can be associated with substantial toxicity and the manufacturing process is complex, expensive, and may be prolonged. Availability of CAR-T therapy is limited to qualified institutions and the preferred product differs between institutions. Age, alone, does not appear to be a barrier to treatment with CAR-T therapy [10].
Efficacy and toxicity vary, and no prospective studies have directly compared the commercially available anti-CD19 CAR-T products. Preferred CD19-directed CAR-T cell products vary according to the clinical setting, including whether the patient has primary refractory DLBCL, first relapse versus second or later relapse, and the level of medical fitness. We generally favor axicabtagene ciloleucel for young, fit patients and lisocabtagene maraleucel for older or less-fit patients, based on clinical trials for first relapse or refractory DLBCL, as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Anti-CD19 CAR-T cell therapy'.)
All CAR-T cell products are associated with serious and potentially fatal complications, but the rates and spectrum of adverse events (AE) vary. Facilities that dispense these agents require special certification, staff must be trained to recognize and manage adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor [IL-6R]) must be available for immediate administration. The most severe complications of treatment include:
●Cytokine release syndrome (CRS) is a severe systemic response to the activation and proliferation of CAR-T cells that is typically manifest as high fever, flu-like symptoms, hypotension, and mental status changes. Some degree of 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 (ICANS) can be severe or life-threatening, as described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
●Other adverse events include hypersensitivity reactions, serious infections, prolonged cytopenias, prolonged hypogammaglobulinemia, and second malignancies, including treatment-related myeloid neoplasms (eg, myelodysplastic syndrome or acute myeloid leukemia).
The US Food and Drug Administration (FDA) labels carry a boxed warning for CRS and neurologic events and in the United States, CAR-T cell products are only available through a risk evaluation and mitigation strategy (REMS).
Outcomes and toxicity of the individual CAR-T cell products follow.
Lisocabtagene maraleucel — Lisocabtagene maraleucel (liso-cel) is generally favored for treatment of older or less-fit patients, as it appears to be better-tolerated than the other commercially available anti-CD19 CAR-T cell products, although efficacy and toxicity of the individual CAR-T cell products have not been compared head-to-head.
Liso-cel is a CD19-directed CAR-T cell with a 4-1BB co-stimulatory domain that is administered as sequential infusions of two components (CD8+ and CD4+ CAR-T cells); CD8+ and CD4+ T cells are selected from leukapheresis material and they are independently activated, transduced, and expanded [11].
In the multicenter TRANSCEND NHL001 study, liso-cel was administered to 256 evaluable patients, half of whom had r/r DLBCL [11]. Patients received a median of three lines of prior systemic therapy (including transplantation in one-third), the median age was 63 years, and patients with moderate kidney or cardiac dysfunction were included in the study. Liso-cel was associated with 73 percent objective response rate (ORR), including 53 percent complete response (CR); median duration of response (DoR) was 17 months and one-year DoR was 55 percent. The predominant grade ≥3 AEs were cytopenias. Importantly, grade ≥3 CRS was reported in only 2 percent and grade ≥3 neurological events in 10 percent of treated patients; 3 percent of patients died with treatment-associated AEs.
Axicabtagene ciloleucel — The multicenter ZUMA-1 study gave axicabtagene ciloleucel (axi-cel) to 101 patients with refractory disease or relapse within one year after autologous transplantation [12]. ORR was 82 percent and 18-month overall survival (OS) was 52 percent [12]. CRS and neurologic events occurred in 13 and 28 percent of patients, respectively, and three patients died during treatment; other grade ≥3 AEs included neutropenia (78 percent), anemia (43 percent), and thrombocytopenia (38 percent). Longer follow-up (median 27 months) reported >2 year median OS, 11 month median DoR, 6 month median progression-free survival (PFS), and no additional treatment-related deaths or toxicity [13].
Subgroup analysis of ZUMA-1 reported that CAR-T cell expansion, pharmacokinetics, and efficacy were independent of patient age [10]. Compared with patients <65 years, more of the patients aged ≥65 years had CR (75 percent versus 53 percent), but other outcomes did not differ, including 24-month OS (54 versus 49 percent), median DoR (12 versus 8 months), and PFS (13 versus 6 months). The incidence of grade ≥3 CRS was similar (7 versus 12 percent), but the older cohort had more grade ≥3 neurologic toxicities (44 versus 28 percent).
Tisagenlecleucel — The multicenter JULIET study reported 40 percent CR and 12 percent partial response (PR) among 93 evaluable patients treated with tisagenlecleucel (tisa-cel) for r/r DLBCL [14]. The rate of relapse-free survival (RFS) at 12 months after initial response was 65 percent (79 percent among those with a CR). The most common grade ≥3 AEs were CRS (22 percent); neurologic events (12 percent); and cytopenias lasting >28 days, infections, and febrile neutropenia (in 32, 20, and 14 percent, respectively). Three patients died from disease progression within 30 days after infusion, but no deaths were attributed to tisagenlecleucel, CRS, or cerebral edema.
Antibody-based therapies
Tafasitamab — Tafasitamab is a humanized anti-CD19 monoclonal antibody [15]. Tafasitamab should be administered with lenalidomide.
●Administration – Tafasitamab is given by intravenous infusion (12 mg/kg) according to the following schedule in 28-day cycles [16]:
•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
Tafasitamab should be given in combination with lenalidomide (25 mg by mouth on days 1 to 21 of each cycle) 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); fatal AEs occurred in 5 percent of patients, including cerebrovascular accident, respiratory failure, progressive multifocal leukoencephalopathy, and sudden death [17].
●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 DoR [17]. 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 OS was 34 months, median DoR was nearly 44 months, and for patients who achieved CR, three-year OS was >80 percent [18]. During the monotherapy phase of the study, grade ≥3 AEs were neutropenia (49 percent), thrombocytopenia (17 percent), and febrile neutropenia (12 percent).
It is presently uncertain if tafasitamab should be avoided in patients who may later receive anti-CD19 CAR-T cell therapy.
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) [16].
Polatuzumab/bendamustine/rituximab — Polatuzumab vedotin (Pola) 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.
●Administration – Pola is given by intravenous infusion (1.8 mg/kg over 90 minutes) every 21 days for six cycles, in combination with bendamustine and rituximab [19]. If the previous infusion is tolerated, subsequent infusions may be administered over 30 minutes. Dose reduction 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 [20]. 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 [19].
●Outcomes – A trial that randomly assigned 80 transplant-ineligible patients to bendamustine plus rituximab (BR) versus BR plus pola (PBR) reported that PBR achieved superior outcomes but was associated with more grade ≥3 cytopenias and neuropathy (generally grade ≤2 and reversible) [20]. 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, pola plus rituximab (without bendamustine) was administered as bridging therapy to 41 patients who were to receive CAR-T cell; half of patients successfully underwent CAR-T cell treatment and six-month OS was 78 percent [21].
Pola is approved by the US FDA in combination with bendamustine and rituximab for r/r DLBCL, after ≥2 prior therapies [19].
Loncastuximab — Loncastuximab tesirine (Lonca) is a CD19-directed antibody-drug conjugate.
●Administration – Lonca is given as an intravenous infusion over 30 minutes on day 1 of each three-week cycle:
•0.15 mg/kg every for two cycles
•0.075 mg/kg every for subsequent cycles
Dexamethasone prophylaxis should be given for three days, beginning day -1 (ie, the day before treatment with lonca).
It is presently uncertain if lonca 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) [22].
●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) [22]. 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 5 month DoR in patients with DLBCL [23].
Lonca is approved by the US FDA for r/r DLBCL after ≥2 prior systemic therapies [24].
Other treatments
Chemotherapy — Moderate-intensity or lower-intensity chemotherapy can reduce the burden of disease, relieve symptoms, and prolong survival, but it is not associated with long-term disease control/cure for r/r DLBCL. The likelihood of a substantial and prolonged response diminishes with successive treatments. Selection of a chemotherapy regimen is guided by medical fitness, comorbid conditions, toxicity, prior treatments, and patient preference.
There is no consensus regarding preferred protocols and no strict divisions between what are considered lower-intensity, moderate-intensity, and intensive chemotherapy regimens.
Moderate-intensity — Moderate-intensity chemotherapy may be given in certain circumstances to medically-fit patients with second or later relapse (eg, as salvage therapy prior to transplantation), but treatment is associated with substantial toxicity. These regimens may be considered for medically-unfit patients, but they are not suitable for frail patients.
Examples of regimens include R-GemOx (rituximab, gemcitabine, oxaliplatin) [25-27], R-CEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine) [28], and R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) [29].
R-GemOx can achieve a response in up to one-half of patients, but it is associated with substantial hematologic toxicity and may cause neuropathy [25-27]. Administration and toxicity of R-GemOx are described separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Selection of salvage chemotherapy'.)
Lower-intensity — For patients who choose lower-intensity chemotherapy, we favor sequential single-agent chemotherapy plus rituximab to limit toxicity. There is no consensus regarding a preferred agent or regimen; options include:
●Cytarabine (1500 to 2000 mg/m2 intravenously every two weeks) combined with rituximab.
●Lenalidomide is an oral agent that is generally combined with rituximab [30-35]. 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 [36].
Selinexor — Selinexor is an orally available selective inhibitor of nuclear export (SINE); the mechanism of action appears to be inhibition of nucleo-cytoplasmic shuttling proteins that functionally inactivate p53 and other tumor suppressor proteins [37]. Selinexor was associated with an objective response in approximately one-quarter of highly-selected patients, but it is associated with significant toxicity [38].
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 selected for patients with less aggressive disease [38]. 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 US FDA for the treatment of adults with r/r DLBCL after ≥2 lines of systemic therapy [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 HCT — Allogeneic hematopoietic cell transplantation (HCT) is only rarely used for relapsed or refractory (r/r) DLBCL because of substantial treatment-related mortality and toxicity. However, if chimeric antigen receptor (CAR)-T cell therapy and antibody-based treatments are not available or were previously administered, allogeneic HCT may be considered for selected medically-fit patients who relapse after autologous HCT and achieve a complete response (CR) or near-CR to salvage chemotherapy. 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 (MUD) 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. Overall survival (OS) and progression-free survival (PFS) are similar after myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) or non-myeloablative (NMA) conditioning; MAC is generally associated with lower rates of relapse, but higher rates of non-relapse mortality (NRM) [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 — Patients should be followed longitudinally for relapse and for treatment-related toxicities.
There is no optimal schedule for follow-up examinations after relapsed/refractory DLBCL and few data to support the choice of protocol. 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 (PET) or other imaging, as the likelihood of detecting asymptomatic relapse is small.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
CLINICAL TRIALS — 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 (www.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 5th to 6th 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 10th to 12th 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
●Diffuse large B cell lymphoma (DLBCL) is refractory to initial therapy in 10 percent and relapses in up to one-third of patients.
●Pretreatment evaluation includes:
•Medical fitness is classified according to performance status (table 1) and comorbid conditions (table 3) as one of the following (see 'Medical fitness' above):
-Medically-fit
-Medically-unfit, but not frail
-Frail
•Restaging is performed by clinical evaluation and positron emission tomography (PET)/computed tomography (CT), according to Lugano criteria (table 5). (See 'Restaging' above.)
•Prognosis – (See 'Prognosis' above.)
●Management varies as follows:
•Medically fit, second or later relapse, with prior transplant (algorithm 1):
-No prior chimeric antigen receptor (CAR)-T cell therapy – For medically-fit patients who relapse after autologous hematopoietic cell transplantation (HCT), we suggest CD19-directed CAR-T cell therapy, rather than other treatments (Grade 2C). (See 'No prior CAR-T cell therapy' above.)
-Prior CAR-T cell therapy – For medically-fit patients who relapse after both autologous HCT and CAR-T cell therapy, treatment options include antibody-based therapy, chemotherapy, and palliative therapy. (See 'Prior CAR-T cell therapy' above.)
•Medically-unfit, but not frail – For patients with relapsed or refractory DLBCL who are medically-unfit but not frail, we suggest lisocabtagene maraleucel (liso-cel), rather than other CD19-directed CAR-T cell therapy, antibody-based treatments, chemotherapy, or other approaches (Grade 2B). (See 'First relapse or primary refractory DLBCL' above.)
For second or later relapse, the choice of treatment is guided by patient preference, convenience, comorbidities, toxicity, prior therapy, availability, and clinician experience, as described above (see 'Second or later relapse' above):
-CAR-T cell therapy (see 'CAR-T cell therapy' above)
-Tafasitamab plus lenalidomide (see 'Tafasitamab' above)
-Polatuzumab vedotin (see 'Polatuzumab/bendamustine/rituximab' above)
-Loncastuximab tesirine (see 'Loncastuximab' above)
-Chemotherapy using either lower-intensity combination chemotherapy or sequential single-agent treatment (see 'Chemotherapy' above)
-Selinexor (see 'Selinexor' above)
-Palliative therapy – Palliative care may be chosen by patients who place greater value in avoidance of toxicity than disease response. Palliative care may include transfusion support. (See 'Palliative treatments' above.)
•Frail patients – For frail patients, we favor management of symptoms with supportive care or end-of-life care. (See 'Frail patients' above.)
