Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit

INTRODUCTION — Most patients with diffuse large B cell lymphoma (DLBCL) are cured with initial treatment using rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [1]. However, 10 percent of patients do not respond adequately to initial treatment (primary refractory disease), and nearly one-third of patients will later relapse after achieving a complete response. Prognosis and treatment vary according to whether disease was refractory to initial systemic therapy and with the interval from initial treatment until relapse.

This topic will discuss evaluation and management of fit patients with primary refractory disease and first relapse of DLBCL.

Management of patients with second or later relapse of DLBCL and patients who are not medically fit is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit".)

DIAGNOSIS — Diagnosis of relapsed or refractory (r/r) DLBCL requires biopsy confirmation in most cases.

Initial evaluation and diagnosis of DLBCL are described separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)

Refractory DLBCL — Primary refractory DLBCL is disease that did not respond adequately to initial systemic therapy.

●Description – Refractory DLBCL refers to disease that did not achieve a complete response (CR) with initial therapy, based on positron emission tomography (PET)/computed tomography (CT) (table 1) according to Lugano criteria (table 2).

●Clinical setting – Refractory disease should be suspected in a patient with persistent PET activity (ie, PET score 4 or 5) or clinical evidence of persistent or progressive disease, such as B symptoms (unexplained fevers, sweats, or weight loss), incomplete nodal response, or a new site of disease during or soon after initial systemic therapy for DLBCL.

●Confirmatory biopsy – A repeat biopsy is generally performed to confirm the diagnosis and to exclude a reactive, post-treatment inflammatory response.

A repeat biopsy may not be required if PET/CT revealed clear progression of the size and metabolic activity of a disease site. If a biopsy is not performed for suspected primary refractory disease, the morphology, immunophenotype, and cytogenetic/molecular features of the initial biopsy specimen should be reviewed to ensure that DLBCL was correctly diagnosed. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)

Relapsed DLBCL — Relapsed DLBCL refers to disease that recurs after a CR was documented by PET/CT.

●Clinical setting – Relapsed DLBCL should be suspected in a patient with B symptoms, progressive lymphadenopathy, organomegaly, organ dysfunction, development of an extranodal mass, or unexplained cytopenias after achieving a CR.

Most relapses occur in the first two years after completing treatment, but up to one-fifth of cases occur more than five years after treatment [2,3]. Relapse is usually suspected by history or physical examination; only rarely is relapse identified solely on the basis of routine follow-up imaging [4,5]. Clinical manifestations of DLBCL are discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Clinical presentation'.)

●Confirmatory biopsy – A biopsy is required to confirm the diagnosis of relapsed DLBCL, exclude other conditions (eg, other types of lymphoma, carcinoma, sarcoidosis, tuberculosis, fungal infection, Epstein-Barr virus infection), and assess acquisition of new cytogenetic or molecular features.

Selection of a biopsy site, the importance of an adequate specimen, and analysis of the specimen are described separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy' and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)

PRETREATMENT EVALUATION — Pretreatment evaluation should assess medical fitness, restage the disease, and determine prognosis.

Clinical/laboratory/pathology

●History and physical examination – The presence of B symptoms and lymph node, organ involvement, or other extranodal disease should be documented by history and physical examination. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Pretreatment evaluation'.)

●Neurologic abnormalities – Patients with neurologic symptoms or abnormalities on neurologic examination should undergo neuroimaging and lumbar puncture, as described separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

Lymphomatous involvement of the central nervous system (CNS) influences the choice of salvage chemotherapy, as described below. (See 'Central nervous system involvement' below.)

●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 – Testing for human immunodeficiency virus (HIV) and hepatitis B.

●Clinical tests

•Cardiac – Echocardiogram or radionuclide ventriculogram (RVG) should be performed, if clinically indicated. If the patient will undergo hematopoietic cell transplantation (HCT), assessment of cardiac function is required prior to transplantation.

•Pregnancy testing – If appropriate.

Medical fitness — We assess and classify fitness for treatment according to functional status and comorbid conditions.

Age is not a measure of fitness, but some institutions limit autologous HCT to patients ≤75 years.

●Assessment – Assessment of fitness should include:

•Performance status – Eastern Cooperative Oncology Group (ECOG) performance status (table 3).

•Comorbidity score – Charlson comorbidity index (CCI) or the HCT-specific comorbidity index scoring systems (table 4) are helpful for assessing fitness in some patients.

●Medical fitness – Patients who can tolerate intensive treatments, such as chimeric antigen receptor (CAR)-T cell therapy, intensive salvage chemotherapy, and autologous HCT, generally have both of the following:

•ECOG: 0 to 2 (table 3)

•CCI: 0 to 2 (table 4)

●Transplant eligibility – Patients (except frail individuals) should be evaluated for transplantation eligibility soon after the diagnosis of relapsed or refractory (r/r) DLBCL.

Although no specific age excludes autologous HCT, many institutions limit transplantation to patients ≤75 years with adequate heart, kidney, and liver function and performance status, as discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Geriatric assessment may be useful for judging medical fitness of some patients in this setting [6]. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Pretreatment evaluation'.)

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

●Imaging – PET/CT is scored using the five-point (Deauville) scale (table 1).

●Bone marrow examination – Bone marrow aspirate and biopsy are generally not required for restaging r/r DLBCL because PET is a good predictor for marrow involvement.

However, bone marrow examination may be useful in patients with cytopenias (especially in older patients) who may later undergo HCT or CAR-T cell therapy, as they may experience prolonged postprocedure cytopenias. The choice of CAR-T cell therapy versus autologous HCT may be influenced by detection of marrow "packed" with lymphoma, myelodysplasia, or profound hypoplasia.

If bone marrow examination is performed, it 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 'Diagnosis'.)

Prognosis — We apply the International Prognostic Index (IPI) (table 6) at the time of diagnosis of r/r DLBCL. The IPI has been validated as a prognostic tool in this setting [7,8].

In the CORAL trial, event-free survival (EFS) at three years was lower in patients with age-adjusted IPI score 2 to 3 compared with patients with IPI score 0 to 1 (18 versus 40 percent, respectively) [9]. The prognostic value of the IPI score for relapsed disease was also validated in the Parma trial [10].

Other factors that have been associated with outcomes in r/r DLBCL include:

●Duration of remission – Longer duration of initial complete response is generally associated with a more favorable response to salvage chemotherapy.

For patients who relapsed <12 versus >12 months after initial diagnosis in the Parma trial, which was conducted prior to the rituximab era, overall response rates to salvage chemotherapy were 40 and 69 percent, respectively; it is uncertain if such differences would be seen in the rituximab era [11]. In a retrospective analysis of 162 patients with relapsed DLBCL, overall survival (OS) did not differ between those whose initial duration of remission was ≥5 versus <5 years [12].

●Pathologic features – In the CORAL trial, compared with patients whose tumors did not have MYC rearrangement, those with a MYC rearrangement had inferior rates of four-year progression-free survival (18 versus 42 percent, respectively) and four-year OS (29 versus 62 percent, respectively) [13].

OVERVIEW OF MANAGEMENT — The preferred approach for medically fit patients varies with the clinical setting (algorithm 1), as follows:

●Early relapse – Relapse <12 months after completing initial therapy or primary refractory DLBCL (see 'Relapse <12 months or primary refractory DLBCL' below)

●Later relapse – Relapse ≥12 months after initial therapy (see 'Relapse ≥12 months after treatment' below)

For patients with documented central nervous system (CNS) involvement, CNS disease should be controlled before or at the time when systemic therapy begins. Management of CNS involvement by DLBCL is described separately. (See "Secondary central nervous system lymphoma: Treatment and prognosis", section on 'Diffuse large B cell lymphoma'.)

RELAPSE <12 MONTHS OR PRIMARY REFRACTORY DLBCL — For patients with early first relapse (<12 months) or primary refractory DLBCL, we recommend CD19-directed chimeric antigen receptor (CAR)-T cell therapy using axicabtagene ciloleucel or lisocabtagene maraleucel, rather than autologous hematopoietic cell transplantation (HCT) or tisagenlecleucel (algorithm 1). This recommendation is based on superior survival using axicabtagene ciloleucel or lisocabtagene maraleucel compared with autologous HCT in randomized trials [14,15]; tisagenlecleucel did not achieve better outcomes than autologous HCT in a separate randomized trial [16].

●Administration – CAR-T cell therapy is a form of immunotherapy in which the patient's own T lymphocytes are transfected ex vivo with a gene that encodes a CAR to direct the patient's immune system against the lymphoma. Manufacturing is complex and expensive, administration is limited to qualified institutions, and the preferred product varies among institutions. Treatment with CD19-directed CAR-T cell therapy is discussed below. (See 'CD19-directed chimeric antigen receptor-T cell therapy' below.)

●Bridging therapy prior to chimeric antigen receptor-T cell infusion – Treatment may be required to control progressive disease after T cell collection but prior to CAR-T infusion.

We generally avoid using CD19-directed treatments (eg, tafasitamab, loncastuximab) as bridging therapy prior to CD19-directed CAR-T cell therapy. Options for bridging therapy include polatuzumab, chemotherapy, radiation therapy, and other approaches, as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Treatments'.)

●Toxicity – All CAR-T cell products are associated with potentially fatal complications, but the spectrum and severity of adverse effects (AEs) may vary among the individual products. At present, it appears that lisocabtagene maraleucel is associated with less toxicity than the other commercially available CAR-T cell products.

The most severe complications of CAR-T cell therapy are:

•Cytokine release syndrome – A severe systemic response to the activation and proliferation of CAR-T cells typically manifests as high fever, flu-like symptoms, hypotension, and mental status changes. Some degree of cytokine release syndrome (CRS) is observed in nearly all treated patients and may be life threatening for some, but it 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 – This neurotoxicity can be severe or life threatening, as described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

•T cell lymphomas – Reports are emerging of T cell malignancies in patients who received CD19- or BCMA (B cell maturation antigen)-directed CAR-T cell therapy; malignant cells in some of these lymphomas are CAR positive [17]. Although rare, the actual incidence of secondary T cell lymphomas is not well defined, and it is uncertain if these tumors are associated with all CAR-T cell products.

The potential risk of secondary malignancies is a class warning in prescribing information for all US Food and Drug Administration (FDA)-approved CD19- and BCMA-directed autologous T cell immunotherapies. At present, no products have been recalled, and no regulatory action has been taken.

If a new malignancy occurs following CAR-T cell therapy, the event should be reported to the manufacturer and to the FDA AE Reporting System (FAERS) [18]. Patients receiving any CAR-T cell product should be monitored life-long for development of new malignancies.

●Chimeric antigen receptor-T cell therapy versus autologous hematopoietic cell transplantation for early relapse or refractory DLBCL

•Axicabtagene ciloleucel – Axicabtagene ciloleucel comprises a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3 zeta costimulatory domains. Axicabtagene ciloleucel is approved by the FDA for adults with primary refractory DLBCL, relapse <12 months, and relapsed or refractory (r/r) DLBCL after ≥2 lines of systemic therapy.

In the phase 3 ZUMA-7 trial, axicabtagene ciloleucel achieved superior outcomes in 359 patients with r/r DLBCL who were randomly assigned to axicabtagene ciloleucel versus standard care (salvage chemotherapy followed by autologous HCT) [19]. High-risk features were common; three-quarters of patients had primary refractory DLBCL, nearly one-third were ≥65 years, and one-fifth had adverse pathologic features. With a median follow-up of 47 months, axicabtagene ciloleucel achieved superior, four-year overall survival (OS; 55 versus 46 percent; hazard ratio [HR] 0.73 [95% CI 0.54-0.98]) and progression-free survival (PFS; 42 versus 24 percent; HR 0.51 [95% CI 0.38-0.67]). Grade ≥3 CRS was reported in 6 percent of patients and grade ≥3 neurologic events in 21 percent; there were no deaths attributed to CRS or neurologic events [14]. In a separate report, axicabtagene ciloleucel was associated with improved quality of life compared with standard care, including patients ≥65 years [20].

•Lisocabtagene maraleucel – Lisocabtagene maraleucel is an anti-CD19 CAR-T cell product with a 4-1BB (CD137) costimulatory domain that is administered as sequential infusions of two components (CD8-positive and CD4-positive CAR-T cells, which are selected from the leukapheresis material and independently activated, transduced, and expanded) [21]. Lisocabtagene maraleucel is approved by the 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.

Lisocabtagene maraleucel achieved better outcomes than autologous HCT according to interim analysis of the phase 3 TRANSFORM trial [15]. With a median follow-up of six months, lisocabtagene maraleucel achieved superior median OS (not reached versus 16 months [95% CI 0.26-1]), event-free survival (EFS; 10 versus 2 months; HR 0.35 [95% CI 0.23-0.53]), PFS (14 versus 6 months; HR 0.41 [95% CI 0.25-0.66]), overall response rate (ORR; 79 versus 48 percent), complete response (CR; 61 versus 36 percent), and had an acceptable safety profile among 184 patients with early relapse or primary refractory DLBCL [15]. In another study, lisocabtagene maraleucel was associated with improved, patient-reported quality of life, cognitive function, fatigue, and pain compared with standard care [22]. In the multicenter TRANSCEND NHL001 study, lisocabtagene maraleucel was associated with a 73 percent ORR, 53 percent CR, 17-month median duration of response (DOR), and 55 percent one-year DOR among 256 evaluable patients with r/r DLBCL [21]. Grade ≥3 CRS was reported in 2 percent and grade ≥3 neurologic events in 10 percent of treated patients; 3 percent of patients died with treatment-associated AEs.

•Tisagenlecleucel – Tisagenlecleucel comprises a murine anti-CD19 scFv linked to a CD8 hinge and a transmembrane region fused to intracellular signaling domains for 4-1BB and CD3 zeta [23]. Tisagenlecleucel is approved by the FDA after ≥2 lines of systemic therapy for adults with r/r DLBCL, high-grade B cell lymphoma, and DLBCL arising from follicular lymphoma.

In a phase 3 trial of tisagenlecleucel versus autologous HCT, the median EFS was three months for both groups, and the ORR was similar (46 percent for tisagenlecleucel versus 43 percent for standard care) among 322 patients with early relapse or primary refractory DLBCL [16]. Deaths from treatment-related AEs were reported in 10 of 161 patients treated with tisagenlecleucel.

RELAPSE ≥12 MONTHS AFTER TREATMENT — For patients with a late first relapse of DLBCL (eg, ≥12 months after completing therapy), we suggest salvage chemotherapy followed by autologous hematopoietic cell transplantation (HCT) rather than salvage chemotherapy alone or chimeric antigen receptor (CAR)-T cell therapy (algorithm 1).

Autologous HCT following a complete response (CR) or near-CR after salvage chemotherapy has long been standard care for transplant-eligible patients. No randomized trials have directly compared autologous HCT with CAR-T cell therapy for late relapse of DLBCL, but autologous transplantation is associated with long-term survival in at least one-half of patients with first relapse of DLBCL and better survival than salvage chemotherapy alone.

Autologous HCT involves the following:

●Intensive salvage chemotherapy – Two or three cycles of intensive salvage therapy are given to reduce the burden of disease and determine if the relapsed DLBCL is sensitive to chemotherapy based on positron emission tomography (PET)/CT. Choice of a salvage chemotherapy regimen is discussed below. (See 'Selection of salvage chemotherapy' below.)

●Response to salvage chemotherapy – Subsequent care is guided by PET/CT response (algorithm 1), using the five-point scale (Deauville score) (table 1), according to Lugano criteria (table 2). (See 'Response to salvage therapy' below.)

●Autologous hematopoietic cell transplantation – Graft source and conditioning regimen are discussed below. (See 'Autologous hematopoietic cell transplantation' below.)

In the phase 3 Parma trial, autologous HCT achieved superior overall survival (OS) compared with salvage therapy alone [24]. Among 109 patients with chemotherapy-sensitive lymphoma (most of whom had DLBCL), patients randomly assigned to transplantation had a superior OS (53 versus 32 percent), overall response rate (ORR; 84 versus 44 percent), and event-free survival (EFS; 46 versus 12 percent), compared with four additional cycles of R-DHAP chemotherapy (rituximab, dexamethasone, high-dose cytarabine, cisplatin). However, transplantation was more toxic than chemotherapy; 4 of 49 patients died with transplant-related effects (three infections, one cardiac toxicity), while none of the chemotherapy-only patients died from treatment. However, this trial was performed prior to the use of mobilized peripheral blood stem and progenitor cells (PBSPCs) as a stem cell source; contemporary approaches, which also feature improved supportive care, are associated with lower risk of mortality (eg, 1 to 2 percent) [25].

Outcomes with autologous HCT from phase 3 trials of CAR-T cell therapy versus transplantation for primary refractory DLBCL and early relapse are discussed above. (See 'Relapse <12 months or primary refractory DLBCL' above.)

Our approach to autologous HCT for relapsed DLBCL is consistent with guidelines of the United States National Comprehensive Cancer Network [26], the European Society of Medical Oncology [27], and the American Society for Blood and Marrow Transplantation [28].

TREATMENTS

CD19-directed chimeric antigen receptor-T cell therapy — Chimeric antigen receptor (CAR)-T cell therapy is a form of immunotherapy that directs the patient’s own T lymphocytes against the lymphoma. The manufacturing process is complex and expensive, administration is limited to qualified institutions, and the preferred product differs among institutions. CAR-T cell therapy can cause potentially fatal cytokine release syndrome (CRS) and neurologic toxicity.

Three commercially available, anti-CD19 CAR-T cell products are currently available: axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel.

●Manufacture – CAR-T cells are generated from the patient's own T lymphocytes, which are genetically modified (transfected) ex vivo with a gene that encodes a CAR to direct the patient's immune system against the lymphoma. The T cells are expanded in a production facility and then infused back into the patient as therapy.

●Products – Commercially available, CD19-directed CAR-T cell products differ modestly in molecular design, but they also differ regarding manufacturing time, preferred bridging therapy, and adverse effects (AEs) [29].

●Toxicity – All CAR-T cell products are associated with serious and potentially fatal complications, but the rates and spectrum of AEs vary with the individual products. Presently, it appears that lisocabtagene maraleucel is associated with less toxicity than the other products.

The most severe complications of treatment 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, hypotension, and mental status changes. Some degree of CRS is observed in nearly all treated patients and may be life threatening for some, but it 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 – This neurotoxicity can be severe or life threatening, as described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

•Other adverse effects – Other AEs include hypersensitivity reactions; serious infections; prolonged cytopenias; prolonged hypogammaglobulinemia; and second malignancies, including treatment-related myeloid neoplasms (eg, myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML]).

●Mitigation strategy – The US Food and Drug Administration (FDA) labels carry a boxed warning for CRS and neurologic events. In the United States, CAR-T cell products are only available through a risk evaluation and mitigation strategy (REMS). 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) must be available for immediate administration.

Autologous transplantation — Autologous hematopoietic cell transplantation (HCT) is generally reserved for medically fit patients with late first relapse of DLBCL who achieve a complete response (CR) or near-CR with salvage chemotherapy, as discussed above. (See 'Relapse ≥12 months after treatment' above.)

Note that in treating relapsed or refractory (r/r) DLBCL, we distinguish between:

●Salvage therapy – Intensive treatment that reduces the burden of disease while determining if it is sensitive to chemotherapy (and thus amenable to transplantation).

●Conditioning therapy – High-dose chemotherapy (and occasionally immunotherapy or radiation therapy) administered immediately prior to HCT.

Selection of salvage chemotherapy — For patients with r/r DLBCL who are candidates for autologous HCT, we suggest intensive salvage therapy rather than lower-intensity therapy because intensive treatment is more likely to achieve a robust response that enables transplantation [9,30-32]. No studies have directly compared intensive salvage regimens with lower-intensity regimens, and comparisons across studies are difficult because of different inclusion criteria, pathologic features, patient composition, and outcome measures.

Salvage regimens are presented below. (See 'Salvage regimens' below.)

Prophylaxis for tumor lysis syndrome (TLS) should be considered for patients who have a high tumor burden (eg, large tumor masses or markedly elevated lactate dehydrogenase [LDH]). Prophylaxis for TLS is described separately. (See "Tumor lysis syndrome: Prevention and treatment".)

●Central nervous system involvement or higher risk for central nervous system involvement – We stratify selection of a salvage regimen according to the presence or higher risk for central nervous system (CNS) involvement. There is no consensus, but for patients who presented with DLBCL, features associated with higher risk for CNS involvement include ≥2 of the following (see "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Central nervous system (CNS) evaluation'):

•Age >60 years

•Elevated LDH

•Eastern Cooperative Oncology Group (ECOG) performance status >1

•Extranodal involvement at >1 site

•Kidney or adrenal involvement

Salvage therapy for patients with CNS involvement or higher risk for CNS involvement is discussed below. (See 'Central nervous system involvement' below.)

●No central nervous system involvement – For patients who do not have CNS involvement or higher risk for CNS involvement, selection of a salvage regimen is discussed below. (See 'No central nervous system involvement' below.)

No central nervous system involvement — For patients with no CNS involvement or higher-risk features for CNS disease, we select an intensive salvage regimen based on comorbidities, toxicity, pathologic features, clinician experience, and convenience (ie, outpatient administration). Higher risk for CNS involvement is discussed above. (See 'Selection of salvage chemotherapy' above.)

The following regimens have similar efficacy and potential for proceeding to HCT, but AEs and the preferred regimen vary among institutions:

●R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) – (See 'R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin)' below.)

●R-ICE (rituximab, ifosfamide, carboplatin, etoposide) – (See 'R-ICE (rituximab, ifosfamide, carboplatin, etoposide)' below.)

●R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin) – (See 'R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin)' below.)

●R-GemOx (rituximab, gemcitabine, oxaliplatin) – (See 'R-GemOx (rituximab, gemcitabine, oxaliplatin)' below.)

Factors that may influence the choice of a salvage regimen are:

●Outpatient administration – R-GDP and R-ICE can be administered in the outpatient setting.

●Prior etoposide therapy – We generally avoid R-ICE for patients who previously received R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) or other etoposide-containing regimens.

●Kidney function – For patients with limited kidney function, carboplatin-based salvage therapy may be preferred over cisplatin-based therapy. Some experts treat with oxaliplatin, although it is not FDA approved in this setting.

Central nervous system involvement — For patients with documented CNS involvement and for selected patients at higher risk for CNS involvement, we suggest a high-dose cytarabine-based salvage regimen, rather than other regimens. No studies have directly compared high-dose cytarabine-based salvage therapy with other regimens for r/r DLBCL; this suggestion is based on activity of such regimens against primary and secondary CNS lymphoma. (See "Secondary central nervous system lymphoma: Treatment and prognosis", section on 'Relapsed DLBCL, secondary CNS disease'.)

Higher risk for CNS involvement is described above. (See 'Selection of salvage chemotherapy' above.)

High-dose cytarabine-based salvage regimens include:

●R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin) – (See 'R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin)' below.)

●R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) – (See 'R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin)' below.)

Some experts consider methotrexate-containing regimens (eg, MATRix-RICE) acceptable based on treatment of patients with secondary CNS lymphoma involvement. (See "Secondary central nervous system lymphoma: Treatment and prognosis", section on 'Relapsed DLBCL, secondary CNS disease'.)

Salvage regimens — Common intensive salvage regimens for r/r DLBCL follow.

R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin)

●Administration – R-GDP includes rituximab 375 mg/m² intravenously on day -1, gemcitabine 1000 mg/m² per day on days 1 and 8, dexamethasone 40 mg by mouth daily on days 1 through 4, and cisplatin 75 mg/m² on day 1, administered at 21-day intervals [30,33,34].

●Adverse effects – Hematologic toxicity is universal, and febrile neutropenia is seen in approximately 15 percent of patients.

●Outcomes – R-GDP was less toxic but had comparable efficacy compared with R-DHAP in the phase 3 LY.12 trial [30]. R-GDP has not been compared head-to-head with other salvage regimens.

In the LY.12 trial, 619 patients (69 percent had r/r DLBCL) were randomly assigned to R-GDP versus R-DHAP [30]. There was no difference in the overall survival (OS), event-free survival (EFS), overall response rate (ORR; 45 versus 44 percent), or ability to proceed to autologous HCT (52 versus 49 percent), but R-GDP was associated with fewer episodes of grade ≥3 toxicity (47 versus 61 percent), less hospitalization (47 versus 99 percent), and better, patient-reported quality of life. There were eight treatment-related deaths (two patients receiving R-GDP, six with R-DHAP). However, some experts favor R-DHAP in patients with germinal center B cell (GCB) features based on a retrospective study [35], as described below. (See 'R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin)' below.)

R-ICE (rituximab, ifosfamide, carboplatin, etoposide)

●Administration – R-ICE includes rituximab 375 mg/m² on day -1; ifosfamide 5000 mg/m² continuous infusion for 24 hours on day 2; mesna 100 mg/m² on days 1, 2, and 3; carboplatin (area under the curve 5 [maximum dose 800 mg] on day 2); and etoposide 100 mg/m² per day on days 1, 2, and 3 (table 7) and is generally given every 21 days [9,36,37].

●Adverse effects – Hematologic toxicity is universal, with one-third of patients requiring transfusions, and grade ≥3 nonhematologic AEs include infection (in up to one-quarter of patients) and occasional nephrotoxicity.

●Outcomes – In the phase 3 CORAL trial, there was no difference in outcomes among 396 patients who were randomly assigned to three cycles of salvage therapy using R-ICE versus three cycles of R-DHAP, but R-DHAP caused more kidney toxicity [9]. R-DHAP and R-ICE achieved comparable ORR (64 versus 63 percent), three-year EFS (26 and 35 percent), and three-year OS (47 and 51 percent). In both arms, 16 percent of patients had febrile neutropenia, but R-DHAP was associated with grade 4 renal toxicity in 11 patients, and more patients needed platelet transfusions (57 versus 35 percent).

R-GemOx (rituximab, gemcitabine, oxaliplatin)

●Administration – R-GemOx includes rituximab 375 mg/m² on day -1, gemcitabine 1000 mg/m² on day 2, and oxaliplatin 100 mg/m² on day 2 [38,39].

●Adverse effects – Severe hematologic toxicity occurs in one-half of patients, and neuropathy can occur.

●Outcomes – R-GemOx is associated with ORR in up to one-half of patients and complete response (CR) in up to one-third of patients with r/r DLBCL [31,38-41].

Oxaliplatin has not been approved by the FDA for treatment of r/r DLBCL.

R-DHAP (rituximab, dexamethasone, high-dose cytarabine, plus a platin)

●Administration – R-DHAP includes rituximab 375 mg/m² on day -1, dexamethasone 40 mg/day on days 1 to 4, cisplatin 100 mg/m² on day 1 by continuous infusion, and cytarabine 2 g/m² in a three-hour infusion on day 2 every three weeks [9]. Some experts use carboplatin [42] or oxaliplatin [43] to avoid the nephrotoxicity of cisplatin.

For patients with pre-existent kidney insufficiency, some experts replace cisplatin with carboplatin or oxaliplatin to lessen nephrotoxicity, but there are limited outcomes data with these regimens [44].

●Adverse effects – Hematologic toxicity is universal, with one-third of patients requiring transfusions, and grade ≥3 nonhematologic AEs include infection (in up to one-quarter of patients) and occasional nephrotoxicity.

●Outcomes – In the phase 3 CORAL trial, outcomes were similar among 396 patients who were randomly assigned to three cycles of salvage therapy using R-DHAP versus R-ICE, but R-DHAP caused more kidney toxicity [9]. The two trial arms achieved a comparable ORR (64 versus 63 percent), three-year EFS (26 and 35 percent), and three-year OS (47 and 51 percent). In both arms, 16 percent of the patients had febrile neutropenia, but R-DHAP was associated with grade 4 renal toxicity in 11 patients, and more patients needed platelet transfusions (57 versus 35 percent). The LY.12 and ORCHARRD phase 3 trials reported similar outcomes with R-DHAP for r/r DLBCL [30,45].

Retrospective analysis of the CORAL study reported that outcomes varied according to cell-of-origin status and that for patients with GCB-like DLBCL, treatment with R-DHAP was associated with better outcomes than patients treated with R-ICE (three-year progression-free survival [PFS] 100 versus 27 percent) [35].

R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin)

●Administration – R-ESHAP refers to rituximab 375 mg/m² on day 1, etoposide 40 mg/m²/day as a one-hour infusion on days 1 to 4, methylprednisolone 250 to 500 mg/day as a 15-minute infusion on days 1 to 5, cisplatin 25 mg/m²/day as a continuous infusion from day 1 to 4, and cytarabine 2 g/m² as a two-hour infusion on day 5, every three or four weeks [32].

●Adverse effects – Hematologic toxicity is universal, with significant rates of neutropenic fever (30 percent) if growth factors are not used. Other AEs (eg, nausea, vomiting, diarrhea, nephrotoxicity, electrolyte disturbances) are generally mild.

●Outcomes – A retrospective study of 163 patients reported that R-ESHAP for relapsed DLBCL was associated with a 75 to 86 percent ORR and 41 to 50 percent CR, while for primary refractory DLBCL, ORR was 33 percent and CR was 8 percent [32].

Response to salvage therapy — Positron emission tomography (PET) is repeated after completing salvage therapy.

Response criteria — Chemosensitivity (ie, response to salvage therapy) is judged by PET response on the five-point (Deauville) scale (table 1) according to Lugano criteria (table 5).

●Complete response – PET score 1, 2, or 3 and no residual mediastinal mass.

●Partial response – PET score 4 or 5 with reduced uptake compared with baseline and no new progressive lesions.

●Stable or progressive disease – PET score 4 or 5 with no significant change or increased intensity.

Post-salvage therapy management — Post-salvage therapy management is guided by the PET response (algorithm 1). (See 'Response criteria' above.)

●Complete response – For patients with CR after salvage therapy, we suggest proceeding to autologous HCT. (See 'Autologous hematopoietic cell transplantation' below.)

More than one-half of the patients who undergo autologous HCT for r/r DLBCL and achieve CR by PET with salvage therapy are alive five years later [46-48].

•In the phase 3 Parma trial, autologous HCT achieved superior survival compared with salvage therapy alone; however, this trial was conducted prior to routine use of rituximab [24]. Further details of the Parma trial are presented above. (See 'Relapse ≥12 months after treatment' above.)

•In a population-based study, four-year OS was 51 percent with autologous HCT compared with 28 percent four-year OS for the entire population of 239 patients with relapsed DLBCL [49]. A registry study reported 63 percent five-year OS and 48 percent five-year disease-free survival (DFS) after autologous HCT in 470 patients [50].

●Partial response – For patients with partial response (PR) after salvage therapy, some experts favor switching to CAR-T cell therapy, while others proceed to autologous HCT.

Those who favor switching to CAR-T cell therapy base that choice on extrapolation from phase 3 trials that demonstrated superior outcomes with CAR-T cell therapy in patients with adverse features (ie, early relapse or primary refractory disease), as discussed above. (See 'Relapse <12 months or primary refractory DLBCL' above.)

Experts who favor proceeding to autologous HCT in patients with a PR after salvage therapy may base that decision on a retrospective review from the CIBMTR (Center for International Blood and Marrow Transplant Research) registry [50]. For patients with PR after salvage therapy for r/r DLBCL, autologous HCT was associated with better two-year OS (69 versus 47 percent; hazard ratio [HR] 1.63 [95% CI 1.14-2.33]) and lower relapse rate (HR 1.49 [95% CI 1.08-2.05]) compared with switching to CAR-T cell therapy. There was no difference in PFS or nonrelapse mortality (NRM). Other CIBMTR analyses reported 41 percent five-year PFS in patients with PR who then underwent autologous HCT [46,47].

●Stable or progressive disease – Proceed to management for second or later relapse. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Medically fit with second or later relapse'.)

A systematic review and meta-analysis of 12 studies of autologous HCT, which included 313 patients with relapsed DLBCL, examined the predictive value of PET after salvage therapy [51]. Compared with chemotherapy-sensitive disease, patients with chemotherapy-resistant disease (ie, positive PET after salvage therapy) had shorter PFS (HR 4.3 [95% CI 3.1-6.0]). Other prospective and retrospective studies also reported more favorable outcomes after autologous HCT in patients with chemotherapy-sensitive disease [46,48,51-54]. Patients with PR prior to transplantation have a 30 to 60 percent probability of DFS at three to five years; by comparison, patients with DLBCL that is resistant to salvage chemotherapy have a DFS probability of <10 to 20 percent [7,55]. Other studies also reported the prognostic importance of negative PET after salvage therapy [56-58].

Autologous hematopoietic cell transplantation — Autologous HCT consists of myeloablative conditioning chemotherapy followed by infusion of autologous hematopoietic stem/progenitor cells in patients with chemosensitive DLBCL. Results from trials that directly compared autologous HCT versus CAR-T cell therapy are described above. (See 'Relapse <12 months or primary refractory DLBCL' above.)

Transplantation is generally reserved for medically fit patients with relapsed DLBCL who have chemosensitive disease with salvage therapy. There is no age above which the benefits of autologous HCT are clearly outweighed by toxicity [28], but some institutions reserve transplantation for patients ≤75 years.

A bone marrow examination should be performed prior to transplantation to exclude involvement of the graft with MDS/neoplasm or AML. Some experts consider evaluation of peripheral blood to exclude features of MDS and AML as an acceptable alternative to bone marrow examination in this setting. Suitability for autologous HCT is discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Most relapses occur during the first two years after transplantation; NRM surpasses relapse as the main cause of death beginning eight years after transplantation [59]. The most common causes of NRM in the first two years are respiratory failure (31 percent), infection (13 percent), cardiac toxicity (15 percent), and secondary malignancy (15 percent). After two years, secondary malignancies, including MDS, acute leukemia, and solid tumors, are the most common cause of NRM. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

Older age (≥50 years), response less than CR, and primary refractory disease were associated with inferior survival in a registry study of patients with DLBCL undergoing autologous HCT [60]. The International Prognostic Index (IPI) identified groups with different OS and PFS among 80 patients undergoing autologous HCT for r/r DLBCL [8]. An analysis of 150 patients from three separate studies also reported that the IPI distinguished groups with different outcomes in this setting [7].

Graft source — Peripheral blood stem/progenitor cells (PBSPCs) are generally the preferred graft source for autologous HCT.

Compared with bone marrow grafts, PBSPCs yield faster engraftment, less potential for contamination with tumor cells, improved quality of life, lower transplantation-associated costs, and do not require general anesthesia for collection. Sources and collection of autologous grafts are discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Conditioning regimen — Patients who undergo autologous HCT for r/r DLBCL should receive myeloablative conditioning therapy. No myeloablative conditioning regimen has proven superior, and the preferred protocol varies among institutions. The most common conditioning regimens used for r/r DLBCL are:

●BEAM (carmustine [BCNU], etoposide, cytarabine, melphalan) [61]

●CBV (cyclophosphamide/BCNU/etoposide) [62]

●Thiotepa-based (thiotepa/BCNU or thiotepa/busulfan, cyclophosphamide) [63]

BEAM is generally associated with more gastrointestinal toxicity, while CBV has more pulmonary toxicity [62,64]. Other conditioning regimens have been used less commonly in this setting [62,65,66], but bendamustine-containing conditioning regimens [67] should be avoided because they may impair the collection of T cells, if CAR-T cell therapy is a future consideration.

There is no clear benefit to including rituximab in the conditioning regimen based on a large registry analysis and retrospective studies [60,68,69].

Myeloablative conditioning regimens are discussed in greater detail separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Myeloablative regimens'.)

Post-hematopoietic cell transplantation maintenance therapy — We suggest not administering rituximab maintenance therapy after autologous HCT because it has no demonstrated benefit [28].

The multicenter CORAL trial that randomly assigned patients to R-ICE versus R-DHAP also included a second randomization to no maintenance therapy versus maintenance rituximab 375 mg/m² every two months for a year after autologous HCT [70]. Compared with no maintenance therapy, rituximab maintenance resulted in similar rates of estimated four-year EFS (52 versus 53 percent), PFS (52 versus 56 percent), and OS (61 versus 65 percent), but it was associated with more adverse events after day 100 (mostly infections).

MONITORING — Patients should be monitored for relapse and for treatment-related toxicities.

●After chimeric antigen receptor-T cell therapy – We generally repeat positron emission tomography (PET)/CT at day 30 and, if positive, repeat it at day 100; after that, we only repeat PET/CT for symptoms.

We monitor immunoglobulin G (IgG) levels and CD4 counts for at least one year. We provide acyclovir prophylaxis for one year and trimethoprim-sulfamethoxazole prophylaxis until CD4 counts are >200/microL.

●After autologous hematopoietic cell transplantation – We schedule a follow-up three to six months after transplantation, but there is no consensus for the protocol and schedule of further follow-up, and practices vary among institutions. To limit radiation exposure and because the likelihood of detecting an asymptomatic relapse is small, we limit routine CTs, and we do not perform regularly scheduled PETs. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Autologous HCT'.)

CLINICAL TRIALS — We suggest participation in a clinical trial for patients with relapsed or refractory DLBCL. 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 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)" and "Patient education: Autologous bone marrow transplant (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (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 recurred after achieving a complete response (CR; relapsed DLBCL) carries an adverse prognosis.

●Diagnosis – Repeat biopsy is needed to diagnose relapsed DLBCL and for most cases of refractory disease. (See 'Diagnosis' above.)

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

•Medical fitness – Based on performance status (table 3) and comorbid conditions (table 4). (See 'Medical fitness' above.)

•Restaging – Includes positron emission tomography (PET)/CT. (See 'Restaging' above.)

•Prognosis – Assessed by the International Prognostic Index (table 6). (See 'Prognosis' above.)

●Management – The preferred approach for medically fit patients varies with the clinical presentation (algorithm 1).

•Refractory or early relapse of DLBCL – For refractory disease or early relapse (<12 months after initial therapy), we recommend CD19-directed chimeric antigen receptor (CAR)-T cell therapy using lisocabtagene maraleucel or axicabtagene ciloleucel, rather than autologous hematopoietic cell transplantation (HCT) or tisagenlecleucel (Grade 1B). (See 'Relapse <12 months or primary refractory DLBCL' above.)

If bridging therapy is required for rapidly progressive disease prior to CAR-T cell therapy, we generally avoid CD19-directed therapy (eg, tafasitamab, loncastuximab) prior to CD19-directed CAR-T cell therapy.

•Late first relapse – For first relapse ≥12 months after initial therapy, we suggest autologous HCT (for patients who achieve complete response [CR] or near-CR to salvage chemotherapy) rather than CAR-T cell therapy (Grade 2C). (See 'Relapse ≥12 months after treatment' above.)

Management of less-fit patients and those with second or later relapse is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit".)

●Chimeric antigen receptor-T cell therapy – CD19-directed CAR-T cell products are generated from the patient's own genetically modified T lymphocytes.

Severe adverse effects include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and rare cases of secondary T cell lymphoma. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

●Autologous hematopoietic cell transplantation – Comprises intensive salvage chemotherapy and response assessment, followed by myeloablative transplantation for patients with chemosensitive disease (table 2).

•Choice of salvage therapy – For relapsed or refractory DLBCL, we suggest intensive salvage therapy rather than lower-intensity salvage therapy to assess chemosensitivity of the tumor (Grade 2C). (See 'Salvage regimens' above.)

-No central nervous system involvement – For no central nervous system (CNS) involvement or higher-risk features for CNS disease, salvage therapy is selected according to prior therapy, toxicity, comorbidities, institutional preference, and convenience. (See 'No central nervous system involvement' above.)

-Central nervous system involvement – For CNS involvement or higher risk for CNS involvement, we suggest high-dose cytarabine-based salvage therapy, rather than other intensive salvage regimens (Grade 2C). (See 'Central nervous system involvement' above.)

Salvage regimens are described above. (See 'Salvage regimens' above.)

•Response to salvage therapy – Chemosensitivity is judged by PET response (see 'Response to salvage therapy' above):

-Complete response – For CR or near-CR after salvage therapy, we suggest proceeding to autologous HCT (Grade 2C).

-Partial response – For partial response after salvage therapy, some UpToDate experts favor switching to CAR-T cell therapy, while others proceed to autologous HCT. (See 'Post-salvage therapy management' above.)

-Stable or progressive disease – Treat for second or later relapse. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit".)

•Autologous hematopoietic cell transplantation – (See 'Autologous hematopoietic cell transplantation' above.)

-Stem cell source – Peripheral blood stem/progenitor cells are generally the preferred graft source in this setting. (See 'Graft source' above.)

-Conditioning – Myeloablative conditioning therapy is used for autologous HCT. (See 'Conditioning regimen' above.)

-No maintenance therapy – We suggest no rituximab maintenance therapy after autologous HCT (Grade 2B). (See 'Post-hematopoietic cell transplantation maintenance therapy' above.)