Diffuse Large B-Cell Lymphoma (DLBCL)

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Practice Essentials

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, representing approximately 30% of non-Hodgkin lymphomas (NHLs),[1] and it is rapidly fatal if untreated. See the image below. Most cases respond to standard immunochemotherapy. For nonresponders, who have traditionally had a poor prognosis, alternative therapeutic approaches are increasingly available.



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Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture ....

Signs and symptoms

DLBCLs have a rapid growth rate and present as masses infiltrating tissues or obstructing organs. Signs and symptoms include the following:

The following are common findings on physical examination:

See Presentation for more detail.

Diagnosis

Lab studies

Lab studies used in the diagnosis and assessment of diffuse large cell lymphoma include the following:

Imaging studies

Imaging studies used in the diagnosis and assessment of diffuse large cell lymphoma include the following:

Biopsy and lumbar puncture

Bone marrow aspiration and biopsy are performed as part of the staging process to help rule out involvement with lymphoma. Lymph node biopsy is required to establish a definitive diagnosis of NHL. The diagnosis of DLBCL is usually confirmed after positive findings are obtained from a lymph node biopsy specimen.

In patients with advanced-stage disease, a lumbar puncture for cytologic and chemical analysis of the CSF may be necessary.

See Workup for more detail.

Management

R-CHOP (rituximab plus cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) is the standard chemotherapy regimen for DLBCL; R-CHOP may be followed by radiation therapy (RT). Second-line chemotherapy regimens vary, depending on whether hematopoietic stem cell transplantation (HSCT) is being considered.

Options for relapsed or refractory disease include the following:

See Treatment and Medication for more detail.

Background

Historical classification of NHLs

Considerable progress has been made in NHL classification. In 1982, the National Cancer Institute introduced the International Working Formulation, a translation system for other, older classifications, including the Rappaport and the immunologically oriented Lukes-Collins and Kiel systems. The International Working Formulation provided a conceptual framework that groups lymphomas as low grade (indolent), intermediate grade, or high grade, with respect to their natural histories.[2]  Of intermediate-grade diffuse large cell lymphomas, approximately 79% were of B-cell origin; 16%, of T-cell origin; and 5%, unclassifiable. Exceptional cases expressed both B-cell and T-cell markers. 

In 1994, the International Lymphoma Study Group proposed the Revised European-American Lymphoma (REAL) classification schema.[3] It classifies NHLs as being derived from B or T/natural killer (NK) cells, and it includes disease entities that were not part of the International Working Formulation.

In addition to morphologic descriptions, the REAL schema included immunologic, cytogenetic, and molecular information to define distinct lymphoma entities. The REAL classification combined the large cell and the immunoblastic categories of diffuse large cell lymphoma. DLBCL is designated under the REAL classification as classic diffuse large cell lymphoma of B-cell origin. Lymphomas of T-cell or NK-cell origin exhibit biologic and clinical features distinct from DLBCLs. (See Workup.)

Currently, the World Health Organization schema is used to classify DLBCLs (see Pathophysiology).

Pathophysiology

B-cell lymphomas arise at various stages of B-cell development. Under normal circumstances, a pro-B cell undergoes various stages of maturation that include the following:

  1. The recombination of the V, D, and J gene segments necessary for assembling of the immunoglobulins’ heavy and light chains
  2. Somatic hypermutation
  3. Immunoglobulin-class switching

During the process of V(D)J recombination (regulated by the recombination activating genes 1 [RAG1] and 2 [RAG2] enzymes) and somatic hypermutation/immunoglobulin-class switching (regulated by the activation-induced cytidine deaminase [AID] enzyme) phases, multiple DNA alterations occur. Consequently, normal B cells are susceptible to the development of undesirable chromosomal translocations or gene mutations, leading to the selective growth advantage of a malignant clone and the development of B-cell lymphoma.[4]

The type of mutation(s) and the stage of lymphoid maturation at the time of genetic aberration(s) play a role in the type of lymphoma that may develop in a given patient.[5]  Subtypes of diffuse large B-cell lymphoma (DLBCL) arise from genetic alterations occurring during the process of B-cell differentiation/maturation and, in general, are characterized by a blockage of the programmed cell death process (ie, up-regulation of Bcl-2, loss of Bcl-6 function, p53 deletion/mutation), an increase in cell proliferation (eg. increase in nuclear factor kappa B [NFkB], up-regulation of c-Myc), or impaired terminal differentiation (ie, defective Blimp-1 function). Specific genetic alteration(s) or protein expression/function deregulation varies depending on the subtype of DLBCL.

Several oncogenic pathways have been identified in DLBCL (B-cell receptor [BCR] signaling pathway, constitutive activation of NFkB activity pathways, and deregulation of the Bcl-6/apoptosis pathway); however, only one pathway appears to play a pivotal role in the biology of distinct types of DLBCL (ie, germinal center B-cell [GCB] versus activated B-cell [ABC] DLBCL).[4]

On DNA microarray studies, most DLBCLs exhibit gene expression patterns indicative of either of two different stages of B-cell differentiation, which allows classification by cell of origin.[6]  GCB DLBCL expresses genes characteristic of germinal center B-cells, while ABC DLBCL expresses genes normally induced during in vitro activation of peripheral blood B-cells.[7]  A third heterogeneous subtype of DLBCL does not express genes characteristic of either ABC- or GCB-type cells and is labeled unclassifiable.

GCB DLBCL is associated with recurrent gene translocations involving BCL-2 and C-REL amplification, whereas the ABC subtype has frequent amplifications of the oncogene SPIB, recurrent trisomy for chromosome 3, and activation of the antiapoptotic nuclear factor (NF)-κB signaling pathway.[6]

Constitutive NF kappa-B signaling

Lymphoid malignancies usually avoid cell death by constitutive activation of the NFkB pathway. It is a transcription factor regulating the expression of the immunoglobulin kappa light chain.[8]  In B cells, NFkB activation occurs transiently downstream of numerous receptors, including the BCR, CD40, the B-cell–activating factor (BAFF) receptor, and various Toll-like receptors (TLRs).[9]  Alternatively, activation of NFkB results from the proteasome degradation of its inhibitor (inhibitor of kappa B [IkB]).

The hallmark of ABC-DLBCL is the activation of NFkB through the classic pathway. Many of the NFkB target genes are expressed in ABC-DLBCL compared with GCB-DLBCL, and this explains how genetic inhibition of this pathway is lethal to ABC-DLBCL but not GCB-DLBCL lines.[10]  Clinically, it has been observed that ABC-DLBCL is more refractory to standard immunochemotherapy than other DLBCL subtypes. This could be explained by the ability of NFkB to antagonize the antitumor activity of chemotherapy agents.[11]  Moreover, pharmacologic inhibitors of NFkB activity (ie, lenalidomide or bortezomib) appear to have selective activity in non–GCB-DLBCL.[12, 13]

Additional mechanisms leading to an increase in NFkB activity have been described in ABC-DLBCL, particularly caspase recruitment domain 11 (CARD11) mutations. The survival of most ABC-DLBCL cell lines depends on the CBM complex (a signaling hub consisting of CARD11, BCL-10, and MALT1).[14]  The CBM complex is required for activation of the classic NFkB pathway downstream of the antigen receptors in B and T cells.[15]  CARD11 is a multidomain signaling adapter that contains (1) an amino-terminal CARD and coiled-coil domains, (2) an intervening linker domain, and (3) a C-terminal membrane-associated guanylate kinase (MAGUK) domain.

In normal resting conditions, CARD11 is located in the cytosol, where it is presumably kept in an inactive conformation through an intramolecular interaction between its coiled-coil and linker domains. Following signaling via the BCR, protein kinase C (PKC) beta–dependent serine phosphorylation within the CARD11 linker domain occurs and activates CRD11.[16]  CARD11 is then able to translocate into the plasma membrane, where it binds to BCL10 and MALT1, forming the CBM complex. Subsequently, the CBM complex plays a pivotal role in the phosphorylation and proteasome degradation of IkB. CARD11 mutations resulting in constitutive engagement of the CBM complex have been described in 10% of ABC-DLBCL patients.[17]

NF kappa-B activation via tonic BCR signaling

Activation of NFkB has also been described in ABC-DLBCL with wild-type CARD11. In this subtype of DLBCL, BCR signaling appears to play a key regulatory role. BCRs present in the surface of B cells are responsible for downstream proliferation and survival signals.{ref19The BCR affects B-cell development, antigen-driven clonal selection, and humoral immunity. Structurally, the BCR consists of antigen-binding IgH and immunoglobulin L (IgL) chains noncovalently coupled to CD79A and CD79B subunits.[18]  Upon antigen stimulation, clustering of the BCRs occurs, leading to signal transduction via the CD79A and B subunits.[19]  CD79A or B mutations have been described in 20% of patients with ABC-DLBCL and lead to the over-expression of CD79 and over-amplification of BCR signaling.[20]

Cell-of-origin classification 

Distinct cytogenetic abnormalities have been described in different DLBCL subtypes. The ABC-DLBCL and GCB-DLBCL subtypes in the cell-of-origin (COO) classification have different genetic mutation landscapes, pathobiology, and responses to treatment.[21]

GCB-DLBCL

The most common translocation is t(14,18), with rearrangements of the BCL2 and IGH chain genes.[9]  Because of the increased expression of BCL2, the cells are immortalized. Increased BCL2 expression is associated with a poor prognosis and shorter survival. The second most frequent cytogenetic aberration in the GCB subgroup is translocation leading to rearrangement of the MYC gene. A recurrent change noted in a few patients is deletion of the tumor suppressor gene PTEN.

ABC-DLBCL

The most common aberration in ABC-DLBCL is translocation involving the BCL6 gene.[10]  Another frequent aberration in the ABC group is trisomy 3.[11]  Approximately 18 % of the patients diagnosed with ABC-DLBCL are found to have a deletion of the tumor suppressor gene P53. Inactivation of P53 results in uncontrolled cell proliferation and subsequent tumor genome instability. Mutations or deletions of P53 decrease the overall survival of all DLBCL patients.

World Health Organization classification

In addition to the GCB and ABC forms of DLBCL not otherwise specified (NOS), the World Health Organization (WHO) 2016 classification of lymphoid neoplasms lists the following subtypes of DLBCL[1] :

Etiology

B-cell restricted markers (CD19, CD20, CD22) are expressed consistently in diffuse large cell lymphoma. Activation antigens are variably expressed by diffuse large B-cell lymphomas (DLBCLs), with human leukocyte antigen (HLA)-DR being the most frequent and CD23 being expressed uncommonly (0-25%). The presence of CD10 or CD5 suggests that at least one third of diffuse large cell lymphomas may have transformed from follicular lymphomas or a small lymphocytic lymphoma.

The majority of DLBCLs demonstrate rearrangements of the immunoglobulin genes by DNA hybridization techniques, proving their B-cell lineage.

Mutations or allelic losses of the TP53 tumor suppressor gene or 17p13.1 are common in diffuse large cell lymphomas, particularly in the immunoblastic type. Changes in TP53 appear to be particularly involved in the evolution of follicular lymphoma to diffuse large cell lymphoma.[22] A number of cytogenetic abnormalities have been reported in these neoplasms, including t(14;18), t(8;14), trisomy 12, and deletion of 6q.[23, 24]

A study by Pasqualucci et al found that the DLBCL coding genome contains on average more than 30 clonally represented gene alterations per case. Mutations identified included those regulating chromatin methylation (MLL2, seen in 24% of cases) and immune recognition by T cells.[25]

Alizadeh et al concluded that the measurement of LMO2 and TNFRSF9 can be used to predict overall survival in patients with diffuse large cell lymphomas.[26]

Associated conditions

Non-Hodgkin lymphomas (NHLs) have been associated with the following conditions, drugs, and chemical agents:

Epidemiology

Occurrence in the United States

After a striking increase in incidence rates between 1970 and 1995 (which may in part have reflected improved diagnosis), the rates of new non-Hodgkin lymphoma (NHL) cases stabilized. From 2010-2019, rates of new cases fell on average 1.0% each year; and from 2011-2020, death rates fell on average 2.2% each year. The current US age-adjusted rate is 18.6 cases per 100,000 person-years for both sexes.[29] The estimated rate for diffuse large B-cell lymphomas is approximately 4.68 cases per 100,000 person-years.

It is estimated that approximately 80,350 new cases of NHL will be diagnosed and 19,390 patients will die from NHL in 2025, despite currently available treatment.[30] Lymphomas are a heterogeneous group of malignancies with diverse biology, clinical behavior, and prognosis.

In general, lymphomas can be divided into two groups, Hodgkin lymphoma (HL) and NHL. While infrequent, HL (8720 estimated new cases in 2025) is commonly diagnosed in younger patients and is curable with appropriate therapy in 85% of cases. In contrast, NHL is the seventh most common cancer in men and the sixth most common in women in the United States, accounting for 4% of all cancers, and the ninth leading cause of cancer deaths, accounting for 3% of cancer-related deaths.[29] Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL diagnosed in the Western hemisphere, representing 30-40% of all NHL cases diagnosed every year in the United States.[31]

DLBCL typically affects patients in their sixth decade, except for primary mediastinal DLBCL variant, which affects mostly women in their late 20s or early 30s. Over the past decades, the incidence of DLBCL has been increasing, a trend that has been independent of the HIV infection epidemic.[32]

International occurrence

In general, the age-adjusted incidence of diffuse large cell lymphomas is higher in developed countries. For males, it varied from 3.7 to 14 cases per 100,000 persons per year from 1983 to 1987. Since the late 20th century, rates for men and women have increased by 50% or more in 20 different countries.[33]

The rates by subtype, such as the subtypes Burkitt lymphoma (Epstein-Barr virus [EBV]–associated lymphoma) and human T-cell leukemia virus (HTLV) type 1–associated lymphoma/leukemia, also vary widely in different geographic areas, with specific subtypes being much more frequent in their endemic areas.

Race-, sex-, and age-related demographics

Individuals of European descent have higher rates than people of African or Asian descent[34] ; the Surveillance, Epidemiology, and End Results (SEER) registry demonstrates rates in White men that are 49% higher than in Black men, 54% higher than in Japanese American men, and 27% higher than in Chinese American men.[35] These differences also apply to women.

A study by Flowers et al found differences between White and Black patients with regard to presentation by and survival rate for individuals with DLBCL. According to the study (a retrospective cohort analysis of 533 White patients and 144 Black patients), the median age of diagnosis was 50 years for Black patients and 57 years for White patients. A higher percentage of Black patients presented with elevated lactate dehydrogenase (LDH) levels, while more Whites had a family history of lymphoma than did Black patients (8% vs 3%, respectively).[36]  

In the study, the survival rate among Black patients was lower than among White patients, but both groups demonstrated an improved survival rate with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) therapy.

DLBCL affects females more often than males. 

Although DLBCL can occur at any age, they generally develop in middle-aged and older adults. Most patients are diagnosed during the seventh or eighth decade of life, with a median age of 68 years.

Prognosis

For non-Hodgkin lymphoma (NHL) overall, 5-year relative survival is 74.3%, based on 2014-20 data.[29]  The 5-year relative survival by stage is as follows:

Data suggest that 5-year survival rates in diffuse large B-cell lymphoma (DLBCL) are higher for White persons than they are for people of African descent, which may or may not reflect socioeconomic factors. Women also have a better survival outcome, as do patients younger than 65 years.[37]

The clinical outcome of lymphoma patients has improved over the last decades as a result of several factors that include the following:

Risk stratification and prognostic markers in DLBCL

Risk stratification plays an important role in the management of patients with DLBCL and should be performed before starting therapy.

The International Prognostic Index (IPI) score system is a predictive model of outcome for aggressive NHL; ie, stage II bulky or stage III or IV. The IPI was developed by the International Non-Hodgkin Lymphoma Prognostic Factors Project, a collaborative effort of 16 institutions in Europe and North America, using a dataset containing clinical information of almost 2000 patients.[38]

Briefly, the IPI score system is calculated by the sum of the presence or absence of 5 variables easily available in most clinical practices (age ≥ 60 y, performance status ≥ 2, elevated lactate dehydrogenase (LDH), Ann Arbor stage III or IV, and ≥2 extranodal sites of disease). Based on those 5 characteristics, patients were stratified into 4 categories, as follows:

The IPI score has been validated in multiple clinical trials before and after the incorporation of rituximab into the frontline therapy of patients with DLBCL. The IPI score has also been validated in relapsing aggressive NHL.[39]  

Calculators based on the IPI include the following:

While the clinical value of the IPI score is extremely important, especially when analyzing results across multiple clinical trials, it does not provide insightful information in regard to disease biology, including mechanisms of resistance to active treatments. This fact stresses the need to further identify and validate more biologically representative biomarkers of disease response using novel technology such as gene expression profiling (GEP), proteomics, or comparative chromosomal analysis.

In a large multi-center cohort, Alinari et al reported that patients with de novo CD5+ DLBCL have a poor prognosis despite initial rituximab-containing chemotherapy. Moreover, their results suggested that stem cell transplantation fails to salvage the majority of these patients.[40]

Patient Education

Patients with diffuse large B-cell lymphoma should receive information about the following:

Clearly explain transfusions (red blood cells and platelets) and associated complications. In addition, discuss the possibility of long-term complications of higher doses of chemoradiotherapy, and mortality rates as high as 3-5% from the conditioning regimen in patients who require high-dose chemotherapy with autologous stem cell support.

History

The clinical manifestations of  diffuse large B-cell lymphoma (DLBCL) are diverse and depend on the site of disease involvement. These tumors have a rapid growth rate and present as masses, causing symptoms when they infiltrate tissues or obstruct organs. Although lymphadenopathy may initially be painless, pain in an enlarged lymph node or affected organ may be noted if the lymphomatous mass enlarges rapidly.

As with other types of non-Hodgkin lymphoma (NHL), DLBCL can manifest as B symptoms: fever higher than 38°C, night sweats, and/or weight loss of more than 10% of body weight in the preceding 6 months. Generalized pruritus may also be present.

Other signs and symptoms can include the following:

Medical history should include inquiries about the following:

Physical Examination

On physical examination, keep in mind that diffuse large B-cell lymphoma (DLBCL) appears most frequently in lymphoreticuloendothelial tissues, which include the lymph nodes, spleen, liver, and bone marrow. However, any extranodal site may be primarily or secondarily involved, including the central nervous system (CNS), lungs, gastrointestinal tract, genitourinary tract, and bones.

Involvement of sanctuary sites, including the CNS and testicles, occurs more commonly with the following disorders:

The following are common findings on physical examination in patients with DLBCL:

The clinical spectrum observed in lymphoma patients is diverse and is influenced by the subtype of lymphoma and its anatomic relationship with other organs and/or systems. Symptoms vary from painless lymph node enlargement to rapidly progressive lymphadenopathy and extranodal disease associated with end-organ damage (eg, superimposed infection; bone marrow, kidney, liver, or heart failure).

The clinical characteristics observed in lymphoma patients can be grouped in the following categories:

A complete physical examination should include evaluation of the following:

Approach Considerations

The initial evaluation of patients with diffuse large B-cell lymphoma (DLBCL) is aimed at the following:

Complete blood cell (CBC) count with differential

Laboratory testing to assess bone marrow and immunologic function includes CBC count with differential. This should be performed in all newly diagnosed patients to evaluate involvement of the bone marrow, which may result in anemia, thrombocytopenia, and/or leukopenia. In addition, perform a peripheral blood examination for circulating tumor cells by flow cytometry.

Comprehensive metabolic panel

A comprehensive chemistry panel should be performed to help evaluate serum electrolytes, lactate dehydrogenase (LDH), kidney function, and liver function. In addition, perform serum β2 microglobulin (B-cell lymphoma) testing.

Electrolyte abnormalities may occur from renal involvement with lymphoma. Abnormal kidney function may require a chemotherapy dose adjustment.

Elevated levels of LDH and uric acid correspond with the tumor burden. The LDH value is a factor in the International Prognostic Index (IPI) and is a useful indicator of the extent of disease and of the response to treatment. It can be used as an early, nonspecific indicator of disease relapse.[41] An elevated uric acid level also signifies an increased likelihood of tumor lysis syndrome with chemotherapy

Imaging studies

Routine computed tomography (CT) of the neck, chest, abdomen, and pelvis is the standard imaging study for patients with lymphoma.

Functional imaging with positron emission tomography (PET) has become an important diagnostic and prognostic tool in the management of patients with various subtypes of lymphoma, such as DLBCL, Hodgkin lymphoma, and mantle cell lymphoma. Most academic institutions recommend routine PET scanning to complement staging and posttreatment evaluation of all patients with aggressive lymphoma. Midtreatment and/or end-of-treatment PET scanning provides strong prognostic information in terms of progression-free survival (PFS) and overall survival (OS). However, the timing of PET scanning for response assessment is a subject of controversy and recommendations vary among academic institutions.[42]

While gastrointestinal evaluation (ie, upper and/or lower endoscopy) is recommended in patients with mantle cell lymphoma, it is not routinely required in the staging of DLBCL.

Bone marrow sampling

Bone marrow biopsy and aspiration should be performed in all newly diagnosed lymphoma patients. Routine pathological, flow cytometry, and cytogenetic studies should also be performed.

CNS assessment

CNS imaging and cerebrospinal (CSF) analysis should be considered in clinically symptomatic patients or in those patients at high risk for occult CNS disease (eg, high-grade lymphoma, HIV-associated lymphoma, select patients with aggressive lymphoma).

Cardiac evaluation

Cardiac studies evaluating left ventricular ejection fraction (LVEF), such as echocardiography or multiple gated acquisition (MUGA) scan, should be performed in patients who are being considered for treatment with chemotherapy regimens that include potentially cardiotoxic agents (eg, doxorubicin, idarubicin, mitoxantrone).

Serologic evaluation for pathogens

This includes evaluations for hepatitis B virus (HBV), and hepatitis C virus (HCV), and HIV.

Serologic evaluation for HBV and HCV is mandatory for those patients expected to receive monoclonal antibody–based therapy (ie, rituximab). As rituximab use has become an integral part of the management of DLBCL, rare but serious adverse events have been associated with hepatitis B and C reactivation. Fatal cases of fulminant liver failure due to active hepatitis B or C have been reported in DLBCL patients undergoing chemoimmunotherapy.

In addition, serologic testing for HIV infection should be considered in patients with HIV risk factors, aggressive histologies (DLBCL, Burkitt or T-cell lymphoma), or unusual clinical presentations.

Imaging Studies

CT scanning

CT scans of the neck, chest, abdomen, and pelvis are used to help identify the degree of lymphadenopathy, the presence or absence of extranodal disease, and/or the presence of visceral involvement. CT scans are also part of the complete staging workup for diffuse large cell lymphoma.

In addition, baseline CT-scan findings aid in disease follow-up care after chemotherapy to assess the degree of response to therapy; they also aid in planning consolidating radiation therapy, if used. (See the images below.)



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Computed tomography (CT) scan of the abdomen showing mesenteric and retroperitoneal adenopathy in a patient with diffuse large cell lymphoma.



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Patient with diffuse large B-cell lymphoma with extranodal involvement. This computed tomography (CT) scan shows an enlarged spleen and liver as a res....



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Patient with diffuse large B-cell lymphoma with extranodal involvement (same patient as in the previous image). This patient has an enlarged spleen an....

Bone imaging

Patients with unexplained bone pain or elevated alkaline phosphatase levels should be evaluated with a bone scan. Obtain plain radiographs of any abnormal area on the bone scan to check for lymphomatous involvement of the skeleton.

Gallium-67 scanning

Gallium-67 (67Ga) scans are valuable in the staging of diffuse large cell lymphomas (DLCLs). Gallium uptake correlates with disease activity and is useful as an indicator of response and prognosis. Uptake of 67Ga occurs in approximately 50% of indolent lymphomas and in most aggressive and highly aggressive types. 67Ga scans are also sometimes used to assess sites of relapse. (See the image below.)



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This image depicts gallium scans performed as part of a staging workup for a patient with diffuse large B-cell lymphoma. The scans show extensive hepa....

Echocardiography or MUGA scanning

Echocardiography or multigated acquisition (MUGA) scans are used to measure the patient's ejection fraction before chemotherapy, because anthracyclines used in the treatment of diffuse large cell lymphomas have a potential cardiotoxic effect.

PET scanning

Positron emission tomography (PET) scanning with fluorodeoxyglucose (FDG) has become a standard part of DLBCL staging, as well as for interim staging during treatment and assessment of end-of-treatment response.[43, 44] FDG uptake can indicate areas of increased metabolic activity, and PET scan data can be useful in helping to determine whether residual masses represent scars or persistent lymphoma.

PET scanning may be more sensitive than gallium scans for more indolent lymphoproliferative diseases, but definitive data comparing gallium to PET scanning of lymphomas are not available.

Biopsy and Lumbar Puncture

Lymph node biopsy is required to establish a definitive diagnosis of non-Hodgkin lymphoma (NHL); this should be an excisional biopsy rather than a needle biopsy, because nodal architecture is often difficult to assess when small amounts of tissue are used.

Bone marrow aspiration and biopsy is performed as part of the staging process to help rule out involvement with lymphoma. Bilateral iliac crest bone marrow biopsies are customarily performed.

Because bone marrow involvement increases the likelihood of lymphomatous involvement of the meninges, in patients with advanced-stage disease, a lumbar puncture for cytologic and chemical analysis of the cerebrospinal fluid may be necessary.

Flow Cytometry and Genetic Studies

Testing of biopsy specimens with flow cytometry to identify the expression of different immunophenotypes helps in determining a clonal cell population and in differentiating between B- and T-cell origins. Cell surface marker analysis by flow cytometry should include kappa/lambda, CD45, CD3, CD5, CD19, CD10, and CD20.[44]

Cytogenetic or fluorescent in situ hybridization (FISH) studies may reveal chromosomal translocations characteristic of diffuse large B-cell lymphoma (DLBCL), such as the following:

Gene expression profiling may be able to distinguish 2 separate subtypes of DLBCLs: normal germinal center B-cell (GCB) type versus activated B-cell–like (ABC) type. Survival in patients with the ABC subtype is worse than in those with GCB. In addition, results from gene rearrangement studies can be used to establish clonality.[45, 46]

Histologic Findings

The diagnosis of diffuse large cell lymphoma is usually confirmed after positive findings are obtained from a lymph node biopsy specimen. Pathology findings should be reviewed by an expert hematopathologist, because lymphomas can be difficult to classify.

Diffuse large B-cell lymphomas are more or less composed of equal numbers of small and large cells. The small cells are usually slightly larger than normal lymphocytes, and they have a cleaved or indented nucleus and coarse chromatin.

The large cells can be cleaved or noncleaved. The cytoplasm of these cells is pale, and the cells have an irregular, central, indented nucleus with inconspicuous nucleoli. A subset of the large cells has rounded nuclei with 1 or more nucleoli; these are the noncleaved large cells and are somewhat larger than the cleaved cells. (See the images below.)



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Biopsy of a cervical lymph node showing infiltration with a population of large cells (B cells) consistent with diffuse large cell lymphoma.



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Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture ....

Pathology of DLBCL

Pathological evaluation is extremely important in the diagnosis of DLBCL. Sufficient biopsy material and formal consultation by an experienced hematopathologist is mandatory. The preferred diagnostic procedure is an excisional biopsy, unless contraindicated because of significant comorbid conditions, the clinical scenario (eg, rapidly growing nodal masses requiring urgent treatment), or the location of nodal/extranodal-involved sites. In cases in which excisional biopsy cannot be performed, multiple core biopsies are acceptable. Fine-needle aspiration (FNA) has a high yield of false-negative results and is not recommended in the workup and diagnosis of patients with a suspected diagnosis of DLBCL or any other forms of lymphoma.

Pathological classification of lymphomas

The classification of lymphomas has undergone significant modifications over the last 3 decades. Currently, 2 classification systems are widely used: the World Health Organization (WHO) and revised European-American (REAL) classification of lymphoid malignancies.[1, 3] The nomenclature of DLBCL has undergone several changes as a result of revisions in the pathological classification of lymphomas over the last decades. It had been previously named a diffuse histiocytic lymphoma (Rappaport’s classification), centroblastic lymphoma (Kiel’s classification), and a large cleaved follicular center cell or large cell immunoblastic lymphoma (working formulation).[1, 3, 2]

Pathological characteristics of DLBCL

Morphologically, DLBCL is composed of large B cells with a high proliferation index resembling germinal centroblasts. DLBCL usually develops de novo but can also emerge as a clonal transformation in patients with low-grade lymphomas or chronic lymphocytic leukemia (CLL). De novo DLBCL tends to have a better response rate to standard therapy and better prognosis than transformed DLBCL. Several morphologic variants of DLBCL have been described, such as centroblastic, immunoblastic, plasmablastic, T-cell/histiocyte-rich, and anaplastic B-cell lymphoma (usually anaplastic lymphoma kinase [ALK]) positive).[47]  While each of those variants can be determined by pathological evaluation, the clinical prognostic significance remains controversial.

Immunophenotype studies demonstrate that DLBCL co-expresses pan B-cell markers, including CD19, CD20, CD79a, CD45RA, and the nuclear transcription factor PAX5. The expression of additional markers may have prognostic implications. The proliferation factor Ki67 is usually high, at 65% mean percentage. High Ki67 levels (> 80%) have been associated with a shorter survival.[48] Germinal center–associated markers CD10 and Bcl-6 are expressed in approximately 30-40% and 60%, respectively. Absence of Bcl-6 expression has been associated with a prolonged progression-free survival (PFS) and overall survival (OS) in patients treated with rituximab plus chemotherapy.[49]

On the other hand, CD5 is expressed only in 10% of DLBCL cases, and its expression should raise the suspicion of transformation from a more indolent form of NHL such as small lymphocytic lymphoma (SLL) or CLL, and it has been associated with a shorter survival.[50]

Subclassification of DLBCL

Under the WHO classification of lymphoid malignancies, the following histologic variants are considered clinical and/or pathological distinct subtypes of DLBCL[1] :

The WHO classification also contains the following entities:

Gene expression profiling (GEP) studies provide significant insightful information in the understanding of the DLBCL biology. GEP studies have identified and validated 3 different subtypes of DLBCL, (1) germinal center B-cell (GCB) lymphoma, (1) activated B-cell (ABC) lymphoma, and (3) primary mediastinal lymphoma (PML), each with significant differences in terms of prognosis, PFS, and OS following systemic chemotherapy or, more recently, chemoimmunotherapy.[7, 51, 52]

GCB-DLBCL appears to be derived at the postgerminal state, primarily driven by deregulation of apoptosis by Bcl-6, and has an excellent response to rituximab-based chemoimmunotherapy regimens. ABC-DLBCL is driven by high levels of nuclear factor Kappa-B (NFkB) activity and is associated with a poor outcome, despite chemoimmunotherapy. PML shares GEP signatures similar to those of classical Hodgkin lymphoma and, although it has a good prognosis when compared with other DLBCL subtypes, treatment-related toxicities (ie, involved-field radiation) continue to be a significant problem being addressed in clinical trials.

Although GEP studies are the best way to differentiate different subtypes of DLBCL that might be clinically relevant, and a large prospective trial has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy,[53]  the use of GEP studies is limited by several issues, including cost and availability.[54] Hence, GEP studies are not recommended outside a clinical trial.

GEP results have been translated into clinically applicable approaches using immunohistochemistry (IHC).[55, 56, 57]  IHC appears to be an easy and practical method for differentiating DLBCL subgroups. Several attempts to subtype DLBCL cases into GCB and non-GCB have been made, with algorithms using several markers (eg, CD10, Bcl-6, IRF4/MUM1), such as the Hans algorithm and the algorithm proposed by Muris et al.[55, 56, 58]  

The Hans algorithm reproduces the gene expression-based classification of DLBCL and has a misclassification rate of 20%.[55] Both algorithms have been evaluated as predictors of clinical outcomes in DLBCL patients undergoing front-line therapy with standard chemotherapy or chemoimmunotherapy.[57, 58] On the other hand, the differences in the clinical behavior and therapeutic response of patients with relapsed/refractory GBC and non-GBC DLBCL have been defined in clinical studies.[59, 12, 13]

Genetic abnormalities in DLBCL

Information obtained from genetic studies performed in DLBCL tumor specimens stresses the complexity in the biology of this disease. DLBCLs express clonally rearranged immunoglobulin H (IgH) genes with somatic mutations in the variable region. For this reason is thought that DLBCL cells are derived from antigen-exposed B-cells. No gene abnormality is pathognomonic for DLBCL. Recurrent translocations involving the BCL6, BCL2, and MYC genes have been described in approximately 50% of cases. Chromosomal translocation leading to up-regulation of BCL2 [t(14;18)] is present in 20-30% of DLBCL cases and is especially observed GCB variants. Gene abnormalities in ABC-DLBCL are more complex and include trisomies, deletions, and chromosomal inactivation.[60]

The clinical value of testing for genetic aberrations in DLBCL continues to grow in recognition. A subset of DLBCL patients carrying both c-Myc and Bcl-2 translocations as detected by fluorescence in situ hybridization (FISH) has been identified. These cases, termed double-hit DLBCL, represent approximately 8% of newly diagnosed DLBCL; they exhibit a poor response to standard doses of rituximab chemotherapy regimens and have a poor OS.[61, 62, 63, 64] Moreover, IHC studies have demonstrated that concurrent over-expression of c-Myc and Bcl-2 is associated with a poor clinical outcome.[65, 66] Currently, c-Myc and Bcl-2 cytogenetic studies (ie, FISH) and IHC analysis for Bcl2 and c-Myc over-expression should be performed in DLBCL patients exhibiting a high proliferation index (ie, Ki67 ≥90%).

Staging

Clinical staging of patients with diffuse large B-cell lymphoma (DLBCL) is fundamental in order to (1) define the treatment plan (ie, combined-modality vs systemic therapy plus/minus CNS prophylaxis), (2) determine risk stratification according to the International Prognostic Index (IPI) score system, and (3) predict the likelihood of survival following frontline therapy. Currently the Ann Arbor staging system is the preferred staging system for DLBCL (see below).

After histologic and immunologic findings confirm the diagnosis of diffuse large cell lymphoma, a pretreatment staging evaluation should be performed. At minimum, patients should have routine blood counts and blood chemistries, particularly a lactate dehydrogenase (LDH) level, which is a prognostic parameter. The peripheral blood smear must be carefully examined for any abnormal lymphoid cells.

Radiologic staging studies include chest radiography and computed tomography (CT) scanning of the chest, abdomen, and pelvis. Bone, gallium, and PET scans, as well as plain films, may be helpful in selected patients.

Ann Arbor staging system

The Ann Arbor staging system, originally designed for Hodgkin disease, is traditionally used to assess the extent of disease involvement in patients with non-Hodgkin lymphoma (NHL). The stages are characterized as follows:

The Cotswolds modifications are as follows:

Approach Considerations

Unless contraindicated because of significant pre-existing comorbid conditions, the treatment of diffuse large B-cell lymphoma (DLBCL) should include the use of rituximab- and anthracycline-based multiagent chemotherapy, possibly followed by radiation therapy, and the goal should be to achieve a durable complete remission (ie, cure). The treatment is subsequently tailored according to stage or bulk of disease and response to therapy. In general, the frontline management of DLBCL can be divided according to disease stage in 2 groups: localized and advanced.

Therapy for aggressive non-Hodgkin lymphoma (NHL) has evolved significantly in recent decades. For example, high-dose chemotherapy in the setting of autologous hematopoietic stem cell transplantation, and chimeric antigen receptor (CAR) T-cell therapy, have become options for  DLBCL.

Chemotherapy is usually given on an outpatient basis, although patients should be admitted to the hospital if a treatment complication arises. Transfer to an appropriate facility may be necessary for further diagnostic evaluation and medical or surgical interventions.

In general, the role of surgery in the treatment of DLBCL is limited. Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy. However, surgery can be helpful in obtaining tissue for diagnosis or, rarely, to palliate a complication.

A study by Kim et al determined that although the quality of life (QOL) of patients with intestinal DLBCL who underwent surgery and chemotherapy was lower than that of patients who underwent chemotherapy alone, the difference was acceptable.[67] Thus, surgical resection followed by chemotherapy may be an effective treatment strategy for these patients.

R-CHOP regimen

R-CHOP—rituximab in combination with cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone—is the standard immunochemotherapy regimen for DLBCL.[68, 69, 44, 70]  It achieves cures in approximately two thirds of patients with DLBCL.[70]  R-CHOP may be administered in a 14-day or a 21-day cycle,[71]  and may be followed by radiation therapy.[44, 72]

In patients with an absolute contraindication to anthracyclines, etoposide can be substituted for doxorubicin (ie, R-CEOP rather than R-CHOP). A long-term study found that R-CEOP is a valid alternative to R-CHOP in this setting, offering a potential for cure.[73]

Relapse therapy

Options for relapsed disease continue to make progress. Second-line chemotherapy regimens vary, depending on whether autologous hematopoietic stem cell transplantation (ASCT) is being considered.[44, 71]

Options for relapsed or refractory disease in patients being considered for ASCT include the following:

Anti-CD19 CAR T-cell therapy may be considered for patients with DLBCL that relapses less than 12 months after first-line therapy, or that is refractory to first-line therapy.

Second-line therapy options for patient who are not candidates for ASCT include the following:

Venous access devices

Because multiple chemotherapy cycles are usually administered, consult a surgeon regarding implantation of a venous access device, which is helpful for chemotherapy infusions and for the repeated blood sampling required to monitor treatment toxicity.

Patient monitoring

Monitor patients very carefully while they are receiving chemotherapy, which is administered every 3 weeks. Order complete blood count (CBC) and chemistries frequently for outpatient monitoring. Immediately see patients if they develop any chemotherapy-related adverse effects.

Red blood cell transfusions or administration of hematopoietic growth factors (eg, erythropoietin, epoetin alfa, darbepoetin alfa) may be required for patients with persistently low hemoglobin values due to disease or chemotherapy.

Management of Early-Stage DLBCL

Approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases present as early stage. Localized DLBCL is defined as Ann Arbor stage I or II nonbulky disease. The management of such patients requires an abbreviated course of combined systemic chemoimmunotherapy with R-CHOP, typically followed by involved-site radiation therapy (ISRT) or involved-field radiation therapy (IFRT).[74, 75, 76]  

While also recommending R-CHOP for patients with low-risk disease, European guidelines include the use of rituximab with doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone R-ACVBP) for 6 cycles as an option for patients age 60 years or younger with bulky low-risk or low-intermediate risk DLBCL.[71]  An open-label phase III trial in patients aged 18-59 years with low-intermediate risk DLBCL reported significantly improved survival with R-ACVBP compared with standard R-CHOP; however, hematologic toxicity is greater with R-ACVBP, and vindesine is not commercially available in the United States.

The use of monoclonal antibodies, particularly rituximab, changed the treatment paradigm of patients with B-cell non-Hodgkin lymphoma, including DLBCL. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present on normal and most malignant B-cells.

The mechanisms by which rituximab elucidates its antitumor activity includes antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models demonstrated that rituximab potentiates the effect of several chemotherapeutic agents.[77]  The addition of rituximab to standard doses of chemotherapy in DLBCL resulted in improved clinical outcomes without adding significant toxicity.[78, 79]

Various protocols are in use. It is important to stress that the approach to early-stage DLBCL should be tailored according to site of disease involvement (eg, mediastinum, stomach), disease response, and patient comorbid conditions, in an attempt to optimize the achievement of a complete response, which can translate into improved survival. For example, in patients with DLBCL who are older than 80 years but have a good performance status, the use of rituximab with reduced doses of chemotherapy agents—so-called R-mini-CHOP—has proved effective.[80]

For early-stage DLBCL, a 21-day R-CHOP cycle is typically used, involving different numbers of chemoimmunotherapy cycles. One recommended approach for stage I-II nonbulky disease consists of three 21-day cycles of R-CHOP followed by radiation therapy (RT)[44] ; four cycles and six cycles are also used.[71]  Tomita et al demonstrated that in limited-stage DLBCL, three cycles of R-CHOP followed by involved-field radiation therapy (IFRT) could be effectively replaced by six cycles of R-CHOP alone, with IFRT used only in patients with a partial response to R-CHOP. In this retrospective study, which included 190 previously untreated patients with limited-stage DLBCL (5 of whom received IFRT), the 5-year progression-free survival (PFS) and overal survival (OS) rates were 84% and 90%, respectively.[81]

Imaging studies to determine response to R-CHOP can guide the decision whether to use RT. In a National Clinical Trials Network (NCTN) study, 128 patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received three cycles of standard R-CHOP therapy, then underwent an interim positron emission tomography/computed tomography (PET/CT) scan. Those patients with a negative scan received one additional cycle of R-CHOP, whereas those with a positive scan received IFRT followed by radioimmunotherapy with ibritumomab tiuxetan. On median follow-up of almost 5 years, the estimated 5-year PFS was 87% and the estimated OS was 89%, with similar outcomes in patients with positive and negative PET/CT scans.[82]

In 2023, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, was approved by the US Food and Drug Administration (FDA) for use in combination with a rituximab product (ie, rituximab or a biosimilar), cyclophosphamide, doxorubicin, and prednisone (R-CHP) in adult patients with previously untreated DLBCL not otherwise specified (NOS), and who have an International Prognostic Index (IPI) score of 2 or greater.[83]

Approval was based on findings in the POLARIX trial, which compared polatuzumab vedotin plus R-CHP (pola-R-CHP) with R-CHOP (ie, substituting polatuzumab vedotin for vincristine). Both regimens were given in six 21-day cycles, followed by two additional cycles of rituximab alone. On median follow-up of 28.2 months, PFS was 76.7% in the pola-R-CHP group compared with 70.2% in the R-CHOP group; stratified hazard ratio for progression, relapse, or death with pola-R-CHP versus R-CHOP was 0.73. No significant differences in complete response rate, overall survival, or adverse events between the groups.[84]

Treatment of Advanced-Stage Disease

Historical perspective

The use of systemic chemotherapy to successfully eradicate DLBCL was first described in the early 1970s.[85, 86] After these original reports, CHOP (given every 21 days—ie, CHOP-21) became the standard of care for aggressive lymphomas in the United States.

In the late 1990s, results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas[87]  prompted research into the combination of rituximab and CHOP (R-CHOP) for aggressive B-cell lymphomas.[88] This yielded practice-changing results.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and presented by Coiffier et al. It enrolled patients with newly diagnosed stage I-IV aggressive B-cell lymphomas who were older than 60 years and randomized them to receive eight cycles of either CHOP or R-CHOP at 21-day intervals.[89]  Compared with CHOP, R-CHOP chemotherapy resulted in higher response rates (76% vs 63%, respectively, P = 0.005) and, on 18-month follow-up, significantly better PFS and OS (P < 0.001 and P = 0.007, respectively).

Analysis of the study after 5 and 10 years of follow-up continued to show a clear benefit of R-CHOP in DLBCL.[89, 90, 91]  On 10-year follow-up, the PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively, and OS rates were 43.5% versus 27.6%.[91]

Similarly, a study by Habermann et al in untreated DLBCL patients who were 60 years or older found that the 3-year failure-free survival rate was 53% with R-CHOP versus 46% for CHOP. However, no benefit was seen with maintenance rituximab after R-CHOP.[92]  A study by the MabThera International Trial (MInT) group in 824 young patients with good-prognosis DLBC reported that after a follow-up period of 3 years, patients randomized to receive R-CHOP had higher event-free survival (79% vs 59%, P< 0.0001) and OS (93% vs 84%; P = 0.0001) than patients assigned to chemotherapy alone.[78]  The benefit of adding rituximab in high-intermediate and high-risk DLBCL patients younger than 60 years had been extrapolated from the results of the GELA and MInT studies. 

A 14-day (so-called dose dense) R-CHOP cycle has been studied for its potential to improve the worse prognosis in elderly patients with advanced-stage DLBCL. The RICOVER-60 trial conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) demonstrated the benefit of six cycles of R-CHOP-14 in elderly patients with DLBCL.[93]  

On the other hand, in the randomized LNH03-6B trial by the GELA group in elderly patients with untreated DLBCL and at least one adverse prognostic factor, R-CHOP-14 did not improve efficacy compared with R-CHOP-21.[94]  However, that trial was criticized for high treatment-related mortality and low dose intensities in the R-CHOP-14 arm. An analysis by Kühnl et al of the RICOVER-60, LNH03-6B, and UK NCRI R-CHOP14v21 (in patients aged 18–88 years) trials concluded that R-CHOP-21 and R-CHOP-14 are equivalent in elderly patients, but elderly patients with MYC-R and double-hit lymphoma have an inferior prognosis, so other regimens should be considered for them.[95]

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone in combination with rituximab (DA-EPOCH-R) in previously untreated DLBCL.[96] In this regimen, the EPOCH doses are adjusted with each cycle to achieve an absolute neutrophil count nadir of 500 cells/µL. The study enrolled 72 consecutive patients with untreated DLBCL who were at least 18 years old and had stage II or higher disease. Patients received 6-8 cycles of DA-EPOCH-R. IFRT was not permitted. At 5 years, PFS and OS were 79% and 80%, respectively.[96, 97]

In a randomized Alliance/Cancer and Leukemia Group B (CALGB) phase III study comparing R-CHOP-21 with DA-EPOCH-R in previously untreated DLBCL, DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. However, while the trial design assumed a 55% 3-year PFS rate with R-CHOP, the observed 3-year PFS rate in the study was significantly better, at 72% The authors concluded that the more favorable results with R-CHOP may reflect more favorable patient characteristics, so the study results may not be generalizable to specific risk subgroups.[98]

Current practice

R-CHOP remains a regimen of choice for advanced-stage DLBCL. It may be given for six or eight cycles, and both 14-day and 21-day cycles are used.[44, 71]  R-CHOP can usually be used in fit patients up to 80 years of age, but modulation of treatment according to geriatric assessment is recommended. In elderly patients who are unfit or frail or have cardiac dysfunction, other agents can be substituted for doxorubin (eg, gemcitabine, etoposide, liposomal doxorubicin). Current National Comprehensive Cancer Network guidelines recommend both R-CHOP and pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) as preferred regimens for stage II DLBCL with extensive mesenteric disease and stages III-IV DLBCL.[44] More intensive regimens (eg, R-CHOP plus etoposide) may be considered in selected patients.[71]

 

Treatment of Relapsed/Refractory DLBCL

Treatment options for relapsed or refractory DLBCL include the following:

In patients who are not candidates for HDC-ASCS, recommended chemotherapy regimens include the following[44] :

High-dose chemotherapy with autologous stem cell suppport 

The role of HDC-ASCS in the treatment of relapsed/refractory DLBCL was confirmed by an international randomized phase III clinical trial, the PARMA study.[99] In PARMA, patients with relapsed/refractory DLBCL underwent salvage chemotherapy for 2 cycles. Patients with chemotherapy-sensitive DLBCL were randomized to further salvage chemotherapy with cytarabine/platinum-based chemotherapy alone or in combination with ASCS. Event-free survival (EFS) and overall survival (OS) at 5 years in the transplant arm were 46% and 53%, respectively, compared with 12% and 32% in the chemotherapy alone arm.

Moreover, subset analysis revealed that response to salvage chemotherapy was associated with a 5-year progression-free survival (PFS) rate of 43%, in contrast to a 1-year OS rate of 22% for patients with chemotherapy-resistant disease.[99] Based on these results, salvage chemotherapy followed by HDC-ASCS has been adopted as the standard of care for transplant-eligible DLBCL patients.

Subsequent work focused on the development of tools to predict which patients were most likely to benefit from HDC-ASCS, such as the value of the age-adjusted International Prognostic Index (IPI) score or positron emission tomography (PET) scanning after salvage chemotherapy.[100, 101, 102]

Rituximab in relapsed/refractory DLBCL

As rituximab changed the treatment paradigm of DLBCL, it has been postulated that the subset of patients with refractory or relapsed DLBCL represent a different patient population than the one studied in pre-rituximab clinical trials. Investigators have questioned whether the response to second-line chemotherapy or the value of HDC-ASCS in patients with relapsing or primary refractory DLBCL previously treated with R-CHOP has decreased compared with historical controls.

Martin et al, on behalf of the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO Cooperative Group), reported results from a retrospective analysis on the outcome of patients with DLBCL, evaluating the influence of rituximab on response rate to rituximab in combination with etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage therapy.[103] Martin and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received R-ESHAP as second-line therapy; 94 patients were previously treated with rituximab chemotherapy (R+ group) in the frontline setting and 69 patients received chemotherapy alone (R- group).

Response rates were higher in patients who were not previously exposed to rituximab in a univariate analysis but not in a multivariate analysis. The OS and complete response rates to R-ESHAP were 67% and 37% for DLBCL patients previously treated with R-CHOP versus 81% and 56% for patients previously treated with CHOP (P = 0.045, P = 0.015), respectively. In addition, the PFS and OS rates at 3 years were significantly higher for the patients in the CHOP group (57% and 64%) compared with those patients in the R-CHOP group (38% and 17%) (P< 0.0001, P = 0.0005). Of note, the same percentage of patients in both groups subsequently underwent HDC-ASCS.

In a multivariate analysis, prior exposure to rituximab was found to be a prognostic indicator of worse PFS and OS.[103] The results of this retrospective study suggest that DLBCL in patients who experience relapse or do not respond to rituximab chemotherapy as first-line therapy is a more resistant type of disease and represents a challenge for clinicians treating aggressive B-cell lymphomas. It also stresses the need to further study and define at the molecular level the mechanisms by which DLBCLs develop resistance to chemoimmunotherapy.

On the other hand, it is uncertain whether rituximab can enhance the antitumor activity of systemic chemotherapy in the salvage setting or to what extent the use of HDC-ASCS improves the cure rates in previously R-CHOP–treated relapsed/refractory DLBCL. Investigators have shown improved response rates by adding rituximab to salvage regimens such as ICE or DHAP compared with historical controls.[104, 105] However, the majority of the patients included in those clinical trials had not been previously exposed to rituximab in the frontline setting.

Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported a subset analysis with long-term follow up of the 202 DLBCL patients who relapsed/progressed following frontline R-CHOP or CHOP chemotherapy in the context of the landmark study. All 202 patients underwent salvage chemotherapy, of whom 31 received a rituximab-containing salvage regimen (22 and 9 previously treated with CHOP or R-CHOP, respectively). Patients treated with rituximab-containing salvage chemotherapy had a 2 years OS rate of 58%, as opposed to 24% for those treated with salvage chemotherapy alone (P = 0.00067). Of interest and while the numbers are small, the benefit of adding rituximab to the salvage regimen was statistically significant only for those DLBCL patients treated with CHOP chemotherapy in the frontline setting.[90]

While this observation is of interest, the sample size of those R-CHOP patients previously treated for relapsed/refractory DLBCL receiving rituximab-containing salvage chemotherapy was extremely small (9 patients), which should limit the significance of the conclusions derived from this study.

Salvage chemotherapy regimens for DLBCL

A number of regimens are used in the treatment of patients with relapsed/refractory DLBCL, and they are primarily based on chemotherapy agents non–cross-resistant to those used in the frontline setting. They may be given with or without rituximab. The goal of salvage regimens is to achieve maximum tumor burden cytoreduction in preparation for HDC-ASCS. The current salvage regimens available for refractory/relapsed DLBCL have been evaluated in phase II studies. Investigators have also tested the efficacy of adding rituximab to established salvage regimens and compared them with pre-rituximab historical controls. Several chemotherapy regimens have been used in case of disease relapse, as follows:

Early evidence suggested that in germinal center B (GCB)-like DLBCL, the cell of origin has a better response to R-DHAP than to R-ICE.[59]  

The only randomized phase III trial that compared established salvage regimens in combination with rituximab (R-ICE vs R-DHAP) was CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma), which reported similar response rates after three cycles of either regimen (R-ICE, 63.5%; R-DHAP, 62.8%).[106]  The following factors significantly affected response rates:

Patients in CORAL who responded to three cycles of chemotherapy underwent HDC-ASCS. They were then randomly assigned to either rituximab every 2 months for 1 year or observation. The 4-year EFS rates were essentially the same in both groups—52% in the rituximab arm and 53% in the observation arm, and treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100. Consequently, the CORAL researchers recommended against rituximab maintenance after ASCT.[107]

In general, when selecting the optimal salvage regimen, consider regimens with higher response rates, especially higher CR rates, low hematological and nonhematological toxicity, and a lesser degree of stem cell damage to secure effective peripheral blood stem-cell collection (PBSC).

Types of salvage chemotherapy

Depending on the agents used, and outside of a clinical trial, salvage chemotherapy can be divided into the following 2 groups:

Platinum-based regimens in relapsed DLBCL

The antitumor effects of cisplatin, carboplatin, and, most recently, oxaliplatin, against B-cell lymphomas have been demonstrated in preclinical and clinical studies. Cisplatin has been extensively studied in combination with high-dose cytarabine- or gemcitabine-based regimens such as, rituximab plus/minus DHAP, ESHAP, or GDP, in patients with refractory/relapsed DLBCL.[108, 99, 103, 105, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119] In addition, carboplatin has been combined with ifosfamide and etoposide (ICE) with or without rituximab.

In general, platinum-based regimens have response rates ranging from 43-82% and CR rates of 16-61%. Successful PBSC mobilization has been documented in the majority of patients eligible for bone marrow transplantation (BMT) treated with such regimens. On the other hand, significant grade 3 and 4 hematologic and, to a lesser degree nonhematologic, toxicity (grade 1-2) has been observed. Grade 3-4 neutropenia occurs in 50-70% of cases; grade 3-4 thrombocytopenia is observed in 30-90%. From 40-70% of the cases require at least 1 unit of red blood cell transfusion. Hospitalization for febrile neutropenia has been reported in 10-20% of the relapsed/refractory DLBCL patients receiving platinum-based salvage regimens.[108, 99, 103, 104, 105, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119]

In addition nonhematologic toxicity seen with these regimens includes kidney dysfunction, cardiac toxicity (for ifosfamide-containing regimens only), neurotoxicity in the form of confusion (ifosfamide-containing regimens), and cerebellar toxicity (high-dose cytarabine-containing regimens) (< 5% of the cases). Several investigators have evaluated the possibility of replacing cisplatin/carboplatin with oxaliplatin, given its favorable toxicity profile, but this strategy failed to demonstrate significant changes in the antitumor activity or toxicity profile of currently available salvage regimens.[116]

Non–platinum-containing salvage regimens

In the past, 4 non–platinum-containing regimens were used in the salvage regimen in preparation for HDC-ASCS:

The antitumor activity of those regimens is comparable to that observed with platinum-based regimen.[120, 121, 122, 123] Response rates to any of these regimens in relapsed/refractory DLBCL (never exposed to rituximab) vary from 64-75%, and the safety profile is similar to platinum-containing regimens.[120, 121, 122, 123]

On the other hand, the use of these regimens has declined over time for several reasons, such as (1) the restriction of anthracyclines in salvage regimens across previously CHOP/R-CHOP–treated patients to avoid cumulative cardiotoxicity, (2) the protection of stem cells by restricting the use of melphalan or busulphan in the salvage regimen prior to stem cell collection, and (3) the need to decrease nonhematologic and hematologic toxicity from high-dose ifosfamide-containing regimens by combining this agent with a platinum compound.

Currently, the most commonly used non–platinum-containing regimens are primarily gemcitabine based. These particular regimens are well tolerated in elderly patients, in patients with limited bone marrow reserve (ie, relapsed/refractory disease after HDC-ASCT), or those patients with multiple comorbid conditions. The hematologic toxicity observed in clinical trials evaluating the efficacy and toxicity of nonplatinum gemcitabine-based regimens is significantly lower than in platinum-containing regimens. Grade 3-4 neutropenia and thrombocytopenia has been reported in only 20% and 10-25% of the patients, respectively.[124, 125]

Another strategy is to modify the schedule of administration of previously used agents. A good example of this approach is the development of the infusional regimen of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH), with or without rituximab. Wilson et al demonstrated that EPOCH was highly effective (74% overall response rate, with 24% CR) in relapsed/refractory aggressive non-Hodgkin lymphoma, with acceptable hematological and nonhematological toxicity.[126] The incident of cardiac toxicity was extremely low (3%), despite the fact that 94% of the patients enrolled had prior anthracycline exposure.[126, 127] Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell non-Hodgkin lymphoma treated with rituximab-EPOCH.[128]

The emergence of rituximab resistance is starting to be observed in patients with relapsed/refractory DLBCL. The evaluation of other biologically active monoclonal antibodies targeting CD20 (eg, ofatumumab), monoclonal antibodies directed against other key regulatory surface receptors (ie, CD40, CD22), or small-molecule inhibitors (eg, lenalidomide, proteasome inhibitors, mammalian target of rapamycin [mTOR] inhibitors) in combination with systemic chemotherapy is necessary to broaden the therapeutic armamentarium against relapsed/refractory DLBCL.

In summary, the incorporation of rituximab to standard doses of CHOP has resulted in improved clinical outcomes when compared with standard chemotherapy in patients with DLBCL and has raised the bar with respect to which new therapies are being evaluated in patients with aggressive lymphomas. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as frontline treatment of DLBCL is beyond dispute, previously accepted biomarkers of response (eg, Bcl-2 expression, IPI) also need reevaluation to raise new challenges in the therapeutic treatment of those patients in whom chemoimmunotherapy fails or who have relapse after chemoimmunotherapy.

Chemoimmunotherapy

The past several years have seen the advent of the following novel agents for treatment of relapsed or recurrent DLBCL:

Polatuzumab vedotin

In 2019, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the FDA for adults with relapsed or recurrent DLBCL in combination with bendamustine and a rituximab product (ie, rituximab or a biosimilar) after at least 2 prior therapies.[129]

Accelerated approval of polatuzumab was based on a study in which 40% of patients (16/40) treated with polatuzumab vedotin plus bendamustine and rituximab (BR) achieved a complete response (CR) compared with 18% (7/40) of those receiving BR alone. The study also showed an OR of 45% with polatuzumab plus BR at the end of treatment compared with 18% for BR alone. Of patients who achieved a complete or partial response, duration of response was at least 6 months in 64% (16/25) of those receiving polatuzumab plus BR, compared with 30% (3/10) for BR alone. Additionally, response lasting at least 1 year was observed in 48% (12/25) of patients receiving polatuzumab plus BR compared with 20% (2/10) for BR alone.[130]

Selinexor

Selinexor is the first oral selective inhibitor of nuclear export (SINE) compound. In 2020, the FDA granted selinexor accelerated approval for relapsed or refractory DLBCL, including DLBCL arising from follicular lymphoma, in patients previously treated with at least 2 lines of systemic therapy.[131]

Tafasitamab 

In 2020, the FDA granted accelerated approval to tafasitamab, a humanized Fc-modified cytolytic CD19-targeting monoclonal antibody, in combination with lenalidomide for the treatment of relapsed or refractory DLBCL not otherwise specified (NOS), including DLBCL arising from low-grade lymphoma, in adults who are ineligible for ASCT. Approval was based on data from the phase II L-MIND study, an open label, multicenter, single-arm trial that showed an overall response rate (ORR) of 55%, including a CR rate of 37% and a partial response (PR) rate of 18%. The median duration of response (mDOR) was 21.7 months.[132]  

Loncastuximab tesirine

Loncastuximab tesirine, a CD19 antibody-drug complex, gained accelerated approval from the FDA in 2021 for adults with relapsed/refractory large-B-cell lymphoma following 2 or more lines of systemic therapy. The indication includes DLBCL NOS, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. Approval was based on results from the phase II, single-arm, open-label LOTIS-2 trial (n = 145). The trial demonstrated an ORR of 48.3% (70/145 patients), which included a CR rate of 24.1% (35/145 patients) and a PR rate of 24.1% (35/145 patients). Median time to response was 1.3 months and median duration of response for the 70 responders was 10.3 months.[133]  

Epcoritamab 

Epcoritamab is an IgG1-bispecific antibody designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells, and induces T-cell mediated lysis of CD20+ cells. CD20 is expressed on B-cells and is a clinically validated therapeutic target in many B-cell malignancies, including DLBCL. In 2023, the FDA granted accelerated approval to epcoritamab for relapsed or refractory DLBCL NOS, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after at least 2 lines of systemic therapy. 

Approval was based on the phase II EPCORE NHL-1 trial. The trial's efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least 2 prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy. Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm. At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.[134]   

Glofitamab

Glofitamab is another bispecific antibody that binds to CD3 on T-cells and CD20 on B-cells. It is indicated for adults with relapsed or refractory DLBCL NOS or LBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. 

Accelerated approval was granted in 2023 and supported by the phase I/II NP30179 study. Glofitamab was given as a fixed course for with DLBCL in patients whose DLBCL had relapsed or was refractory to prior therapies, including about 30% who had received prior CAR T-cell therapy. Additionally, 83% had disease refractory to their most recent therapy. At a median follow-up of 12.6 months, 39% had a complete response according to independent review. Results were consistent among the 52 patients who had previously received CAR T-cell therapy (35% of whom had a complete response). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37%.[135]  

Brentuximab vedotin

Brentuximab vedotin is a CD30-directed antibody-drug conjugate consisting of chimeric IgG1 antibody cAC10, which is specific for human CD30, and the microtubule disrupting agent vedotin (monomethyl auristatin E [MMAE]). In February 2025, the FDA approved brentuximab vedotin in combination with lenalidomide and a rituximab product treatment of relapsed/refractory large B-cell lymphoma, including DLBCL NOS, DLBCL arising from indolent lymphoma, and high-grade B-cell lymphomaafter two or more lines of systemic therapy who are ineligible for ASCT or CAR T-cell therapy.[136]

Approval was based on the ECHELON-3 trial, in which overall survival was was 13.8 months with this combination regimen, compared with 8.5 months with placebo plus lenalidomide and rituximab. Median PFS was 4.2 months versus 2.6 months, ORR was 64% versus 42% and complete complete response rates were 40% versus 19%, respectively.[137]

CAR T-cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy utilizes each patient’s own T cells, extracted by leukapheresis. The T cells are sent to a processing facility, where they are genetically engineered with CD19 receptors that seek out cancer cells; the T-cell population is then expanded and infused back into the patient, who has undergone conditioning chemotherapy in preparation for the infusion.

The following CAR T-cell therapies are indicated for DLBCL:

Axicabtagene ciloleucel

In 2017, the FDA approved axicabtagene ciloleucel (Yescarta) for treatment of large B-cell lymphoma after at least two other kinds of therapy have failed. Approved uses include DLBCL, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.[138]

Approval was based on the results from the ZUMA-1 study, an open-label, multicenter trial enrolling of 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 × 106 cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with relapsed/refractory DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. At 6-month follow-up, 40% of patients had maintained their complete response. The trial had a median survival follow-up of 8.7 months.[139]

Tisagenlecleucel

In 2018, tisagenlecleucel (Kymriah) gained approval for adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥ 2 lines of systemic therapy.[140] Approval was based on the single-arm, open-label, multicenter, phase 2 JULIET trial in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma. Eligible patients must have been treated with at least 2 prior lines of therapy, including an anthracycline and rituximab, or relapsed following ASCT. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy.

The ORR for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a CR rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared with a best overall response of partial response (PR). Among patients achieving CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration among patients in PR was 3.4 months (95% CI: 1.0, NE).[141]

Lisocabtagene maraleucel

Lisocabtagene maraleucel (Breyanzi) is a CD19-directed CAR T-cell therapy for adults with replapsed/refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for primary CNS lymphoma.

Safety and efficacy were evaluated in the TRANSCEND trial, an open-label, multicenter, single-arm trial. Patients (n=268) with R/R large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of these patients, 54% achieved CR (95% CI: 47%-61%) and 19% achieved PR (95% CI:14%-26%). Median duration of response for all responders was 16.7 months (CR was not reached; PR: 1.4 months [95% CI: 1.1-2.2 months). Among all responders, 65% had remission for at least six months and 62% had remission lasting at least nine months.[142]

Among patients in the TRANSCEND trial, the most common adverse reactions were as follows[142] :

CNS Prophylaxis in DLBCL

Central nervous system (CNS) relapse is a rare but significant complication in the management of patients with DLBCL. The probability of CNS relapse  1 year of diagnosis is estimated to be 2.3-4.5%.[143, 144] The risk of CNS relapse appears to be higher in certain subsets of DLBCL (4- to 15-fold increase in risk), and identification of such patients is imperative in an attempt to implement prophylactic therapy.  

Patients with elevated risk for CNS relapse are those with the following[145, 146] :

Risk of CNS relapse/progression in DLBCL treated with R-CHOP can be estimated using the CNS International Prognostic Index in Diffuse Large B-Cell Lymphoma (CNS-IPI), which classifies patients as low, intermediate, or high risk.[147] See the CNS International Prognostic Index in Diffuse Large B-Cell Lymphoma (CNS-IPI) calculator.

Initially, CNS prophylaxis was most often performed with intrathecal methotrexate. However, in most studies of CNS prophylaxis in DLBCL, intrathecal prophylaxis has not been protective.[146] High-dose intravenous methotrexate, which can cross the blood-brain barrier, is advocated for CNS prophylaxis, but its efficacy is questionable.[148, 71, 149]

Supportive Care in Chemotherapy

Administer intravenous fluids and/or supportive care with analgesics and growth factors, as necessary. Patients often are started on allopurinol with the induction of chemotherapy to avoid acute kidney injury from tumor lysis syndrome (TLS) and uric acid nephropathy.

Antiemetics

Antiemetics are always prescribed before and after the administration of chemotherapy, for the prevention of chemotherapy-induced nausea and vomiting. Antiemetics used include the following:

Another antiemetic, palonosetron (Aloxi), is a selective 5-HT3 receptor antagonist with a long half-life (40 h). The adult dose is 0.25 mg once (30 min before chemotherapy). Administer this agent intravenously over 30 seconds, and do not repeat the dose within 7 days. Palonosetron may cause headache, constipation, diarrhea, or dizziness.

Growth factors

For patients with anemia, consider erythropoietin or epoetin alfa (Procrit) at 40,000-60,000 U or darbepoetin alfa 300 mcg. Both are administered subcutaneously once weekly.

Growth factors stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell hematopoiesis. Recombinant human erythropoietin (epoetin alfa) stimulates erythropoiesis in anemic conditions. Colony-stimulating factors act on hematopoietic cells to stimulate hematopoietic progenitor cell proliferation and differentiation. Interleukins stimulate stem cell proliferation.

Administer growth factor support (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) to patients with a previous episode of febrile neutropenia, during subsequent cycles. Patients who administer growth factors to themselves should be carefully advised on sterile techniques, and patients with fevers during periods of neutropenia should immediately seek the attention of the treating physician.

Inpatient Care

Most patients are treated in an outpatient setting. However, hospitalization may be necessary for patients with disease- or therapy-associated complications such as the following:

Diet and Activity

Diet

No specific diet is recommended for patients with DLBCL, except for salt restriction in those receiving a chemotherapy regimen that incluces corticosteroids.

Patients undergoing cytotoxic chemotherapy may develop severe neutropenia, as defined by an absolute neutrophil count of less than 500/µL. These patients should be advised to maintain a low-microbial diet for the expected duration of neutropenia.

Activity

Patients may feel substantial fatigue due to the lymphoma, its treatment, or both. However, no specific limitation of activity is necessary unless the patient is thrombocytopenic, in which case activity restriction may be necessary to avoid traumatic bleeding or bruising. 

Consultations and Transfer

Consultations

A surgical oncologist may be consulted if an open biopsy is needed for the diagnosis or to treat a complication, such as perforated viscus.

A radiation oncologist may be consulted if the primary therapy involves a combination of chemotherapy and radiotherapy. In addition, an initial large lymphoma mass or a large residual mass following completion of chemotherapy may be considered for involved-field radiotherapy (IFRT).

Transfer

Patients whose condition relapses after multiple treatment regimens or who have poor performance status and who are therefore not candidates for further chemotherapy should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:

Complications

Tumor lysis syndrome and uric acid nephropathy

Tumor lysis syndrome is a potential complication following treatment of diffuse large cell lymphoma. This condition manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium. These electrolyte abnormalities can lead to a sudden death. Aggressive intravenous hydration, urine alkalinization, and administration of allopurinol can usually prevent tumor lysis syndrome. Occasionally, patients with significant tumor volume and rapidly growing disease can avoid tumor lysis syndrome by receiving dose-modified or attenuated chemotherapy as the first treatment, followed by conventional chemotherapy in subsequent treatment cycles.

Uric acid nephropathy is usually observed within 1-2 days after the initiation of chemotherapy and may occur in conjunction with tumor lysis syndrome. It usually can be prevented by administering allopurinol or alkalinizing the urine.

Neutropenic fevers and sepsis

Neutropenic fevers and sepsis are the most common potentially serious complications of chemotherapy. If not recognized and treated aggressively, these infections can cause rapid deterioration of the patient's condition, which could lead to death.

The use of cytokines (granulocyte colony-stimulating factors [G-CSFs] or granulocyte-macrophage colony-stimulating factors [GM-CSFs]) has been helpful in preventing infections by shortening, and in some cases preventing, the neutropenic period. The use of prophylactic antibiotics (especially fluoroquinolones [eg, ciprofloxacin, levofloxacin]) has proved effective in preventing neutropenic infections.

Other complications

Chemotherapy-associated complications may also include the following:

Long-Term Monitoring

For patients in complete remission, National Comprehensive Cancer Network guidelines recommend clinical follow-up with a history and physical examination and laboratory studies (eg, complete blood cell count, comprehensive metabolic panel, lactate dehydrogenase level) every 3-6 months for 5 years and then yearly or as clinically indicated. Imaging studies (CT scan) should be performed no more often than every 6 months for 2 years after the completion of treatment, and then only as clinically indicated.[44]

Guidelines Summary

Guidelines on diffuse large B-cell lymphoma (DLBCL) have been published by the following organizations:

Medication Summary

The goals of pharmacotherapy are to induce cancer remission, reduce morbidity, and prevent complications. The R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains a standard regimen, but platinum-based and chemoimmunotherapy regimens play a role in relapsed or refractory cases.

Cyclophosphamide (Cytoxan, Frindovxy)

Clinical Context:  Cyclophosphamide has antineoplastic activity mediated by its 2 active metabolites. These metabolites are alkylating agents that prevent cell division by cross-linking DNA strands. Cyclophosphamide is absorbed almost completely from the GI tract, making it bioavailable in either oral (PO) or intravenous (IV) forms. Excretion is primarily via urine.

Doxorubicin (Adriamycin, Caelyx, Rubex)

Clinical Context:  Doxorubicin is an anthracycline antibiotic that can intercalate with DNA, affecting many of the functions of DNA, including synthesis. This agent is administered intravenously. Doxorubicin distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. It does not cross the blood-brain barrier, and it is excreted primarily in bile.

Vincristine

Clinical Context:  Vincristine is a vinca alkaloid that is cell cycle specific (M phase). The mitotic apparatus is arrested in metaphase via disruption of the microtubules. Absorption of vincristine through the GI tract is variable; therefore, administer the drug intravenously. It is metabolized extensively in the liver and excreted primarily via bile. Neurotoxicity is the limiting factor during therapy. Peripheral neuropathy is vincristine's most common adverse effect at usual doses.

Etoposide (Etopophos, Toposar, VePesid)

Clinical Context:  Etoposide is an epipodophyllotoxin that induces DNA strand breaks by disrupting topoisomerase II activity.

Cisplatin

Clinical Context:  Cisplatin is a platinum-containing compound that exerts its antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to cause cross-links. The platinum complex also can bind to the nucleus and cytoplasmic protein. Cisplatin is a bifunctional alkylating agent that once activated to an aquated form in the cell, binds to DNA, resulting in interstrand and intrastrand cross-linking and denaturation of the double helix.

Carboplatin

Clinical Context:  Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to action of these drugs in the G1 and S phases.

Carboplatin has the same efficacy as cisplatin but with a better toxicity profile. The main advantages over cisplatin include less nephrotoxicity and ototoxicity, thus not requiring extensive prehydration, and it is less likely to induce nausea and vomiting; however, it is more likely to induce myelotoxicity.

Cytarabine (Cytosar U, DepoCyt)

Clinical Context:  Cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is cell cycle S phase specific. Cytarabine blocks the progression from the G1 to the S phase and, in turn, kills cells that undergo DNA synthesis in the S phase of the cell proliferation cycle.

Bleomycin (Blenoxane)

Clinical Context:  Bleomycin is a group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. The planar end intercalates with DNA, while the amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.

Ifosfamide (Ifex)

Clinical Context:  Ifosfamide binds with nucleic acids and other intracellular structures, causing cross-linking of DNA strands. It inhibits DNA and protein synthesis.

Mechlorethamine (Mechlorethamine hcl, Mustargen, Nitrogen Mustard)

Clinical Context:  This alkylating agent is a component of the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen.

Methotrexate (Jylamvo, Otrexup, Rasuvo)

Clinical Context:  Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, which is necessary for conversion of folate to biologically active tetrahydrofolate.

Procarbazine (Matulane)

Clinical Context:  Procarbazine is an alkylating agent that inhibits DNA, RNA, and protein synthesis. It inhibits cell replication in all phases of the cell cycle.

Bendamustine (Bendeka, Treanda)

Clinical Context:  Alkylating agent indicated for treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Included as part of a regimen containing polatuzumab vedotin and rituximab.

Polatuzumab vedotin (Polatuzumab vedotin-piiq, Polivy)

Clinical Context:  CD79b-directed antibody-drug conjugate. It is indicated in combination with bendamustine and a rituximab product for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2 prior therapies.

Class Summary

These agents inhibit cell growth and proliferation.

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context:  Prednisone is a glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability. Prednisone is readily absorbed via the GI tract and is metabolized in the liver. Inactive metabolites of prednisone are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose or duration dependent.

Dexamethasone (Baycadron, Decadron DSC, Dexamethasone Intensol)

Clinical Context:  A component of the m-BACOD regimen (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, Oncovin, and dexamethasone), dexamethasone is a corticosteroid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.

Dexamethasone is readily absorbed via the GI tract and is metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose dependent or duration dependent.

Methylprednisolone (A-Methapred, DepoMedrol, Medrol)

Clinical Context:  A component of the ESHAP regimen (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), methylprednisolone is a corticosteroid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Rituximab (Riabni, Rituxan, Rituximab-abbs)

Clinical Context:  The rituximab antibody is a genetically engineered chimeric mouse/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and neoplastic B lymphocytes.

The most common adverse reactions to rituximab are infusion reactions, some of which are fatal. Bowel perforation has been reported with rituximab. Patients reporting abdominal pain during therapy should be evaluated for perforation of the intestinal tract.

Reactivation of hepatitis B has been demonstrated; patients at high risk for hepatitis B should be screened prior to initiation of therapy. No studies have been conducted to determine if a dose adjustment is necessary in patients with hepatic or renal dysfunction.

Class Summary

Monoclonal antibodies are antibodies targeted to specific antigenic determinants. They can be specific to growth factors, cytokines, and cell surface molecules found on tumor cells.

Copanlisib (Aliqopa (DSC))

Clinical Context:  Pan class I phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. By inhibiting several key cell-signaling pathways may induce apoptosis and inhibition of proliferation of premalignant B cells and in turn cause tumor cell death. It is indicated for relapsed follicular lymphoma (FL) in patients who have received at least 2 prior systemic therapies.

Idelalisib (Zydelig)

Clinical Context:  Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells; also inhibits several cell- signaling pathways, including B cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. It gained accelerated approval by the FDA (ie, confirmatory clinical trials in progress) in July 2014 for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies.

Class Summary

This drug class inhibits one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, inhibition of which may result in tumor suppression.

Axicabtagene ciloleucel (Yescarta)

Clinical Context:  CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following the binding anti-CD19 CAR T-cells with target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades which eventually leads to killing of CD19-expressing cells. It is indicated for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Tisagenlecleucel (Kymriah)

Clinical Context:  CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. It is indicated in adults with relapsed or refractory large B-cell lymphoma including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥2 lines of systemic therapy.

Lisocabtagene maraleucel (Breyanzi)

Clinical Context:  CD19-directed CAR T-cell therapy genetically modified autologous cell immunotherapy is administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. CAR binding to CD19 expressed on tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells. It is indicated for adults with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for h primary CNS lymphoma.

Class Summary

Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive T-cell therapy in which T cells are genetically engineered to express a CAR. CAR T-cells preparation begins with obtaining a blood sample from the patient. The CAR molecule is introduced into the patient’s T-cells through viral or nonviral approaches. The cells undergo a brief round of expansion in the laboratory and are then infused back into the patient. T-cells become activated when they recognize the target antigen on the surface of the tumor, in this case, CD19. When T-cells are activated, they undergo massive expansion in the body. The cells start to produce multiple different cytokines and proliferate. These cytokines improve the T-cells’ function, help them traffic to the tumor site, and start killing the tumor cells by expressing cytotoxic molecules (eg, granzymes and perforins).

Selinexor (Xpovio)

Clinical Context:  Selinexor is the first oral selective inhibitor of nuclear export (SINE) compound. It is indicated for relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, in patients previously treated with at least 2 lines of systemic therapy.

Class Summary

These agents act on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells.

Loncastuximab tesirine (Loncastuximab tesirine-lpyl, Zynlonta)

Clinical Context:  Indicated for adults with relapsed/refractory large-B-cell lymphoma following 2 or more lines of systemic therapy. Indication includes disuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade lymphoma. 

Tafasitamab (Monjuvi, Tafasitamab-cxix)

Clinical Context:  Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. It is indicated, in combination with lenalidomide for the treatment of adults with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for autologous stem cell transplant (ASCT).

Class Summary

The monoclonal antibody binds to human CD19, a transmembrane protein expressed on surface of cells of B-lineage origin.

Epcoritamab (Epcoritamab-bysp, Epkinly)

Clinical Context:  Indicated for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after at least 2 lines of systemic therapy. 

Glofitamab (Columvi)

Clinical Context:  Indicated for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy.

Class Summary

Bispecific antibodies are designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells, and induce T-cell mediated lysis of CD20+ cells. CD20 is expressed on B-cells and is a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). 

Epoetin alfa (Epoetin alfa-epbx, Epogen, Eprex)

Clinical Context:  Epoetin alfa is a purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Its amino acid sequence is identical to that of endogenous EPO, and its biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

Darbepoetin alfa (Aranesp)

Clinical Context:  Darbepoetin alfa is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in the kidneys that stimulates the development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red blood cell production. Darbepoetin alfa differs from epoetin alfa (recombinant human erythropoietin) in that it contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. Darbepoetin alfa has a longer half-life than epoetin alfa (may be administered weekly or biweekly).

Filgrastim (Filgrastim-aafi, Filgrastim-ayow, Filgrastim-sndz)

Clinical Context:  Filgrastim is a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) consisting of a 175–amino acid protein with a molecular weight of 18,800 d. It is produced by Escherichia coli bacteria into which the human G-CSF gene is inserted. This protein has an amino acid sequence identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Because it is produced in E coli, the product is nonglycosylated and thus differs from G-CSF isolated from human cells.

Pegfilgrastim (Fulphila, Fylnetra, Neulasta)

Clinical Context:  Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant granulocyte colony-stimulating factor (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating the production, maturation, migration, and cytotoxicity of neutrophils.

Class Summary

These agents can induce an increase in reticulocyte counts with a subsequent increase in hematocrit and hemoglobin levels.

Leucovorin

Clinical Context:  Leucovorin is used with folic acid antagonists, such as methotrexate. It is a reduced form of folic acid that does not require enzymatic reduction reaction for activation. It allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. It is an important cofactor for the enzymes used in the production of red blood cells. Leucovorin (folinic acid, which reduces adverse effects) is given on alternating days with methotrexate, until there is a 15% decline in β-HCG over 2 days.

Class Summary

Vitamins are used to correct folic acid deficiency resulting from use of folic acid antagonists.

Mesna (Mesnex)

Clinical Context:  In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity. It inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. The adult dosage is 240 mg IV at 0, 4, 8 hours after the ifosfamide or cyclophosphamide dose.

Mesna may increase warfarin effects. Mesna does not prevent hemorrhagic cystitis in all patients (monitoring for hematuria in the morning prior to ifosfamide or cyclophosphamide dose is required). It does not prevent or alleviate other toxicities associated with ifosfamide or cyclophosphamide. Common adverse effects include hypotension, headache, GI toxicity, and limb pain. Mesna is a pregnancy category B drug.

Class Summary

These agents counteract the toxic effects of drugs.

Ondansetron (Zofran (DSC), Zofran ODT (DSC), Zuplenz (DSC))

Clinical Context:  Ondansetron is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Granisetron (Granisol Oral Solution, Sancuso, Sustol)

Clinical Context:  At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on vagal nerve terminals.

Palonosetron (Aloxi, Posfrea)

Clinical Context:  Palonosetron is a selective 5-HT3 receptor antagonist with a long half-life (40 h). It is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Metoclopramide (Metozolv ODT, Reglan)

Clinical Context:  The antiemetic effect of metoclopramide appears to be the result of its ability to block dopamine receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS). This agent also enhances gastrointestinal motility and accelerates gastric emptying time.

Prochlorperazine (Compazine, Compazine Spansules, Prochlorperazine edisylate)

Clinical Context:  Prochlorperazine may relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and by depressing the reticular activating system.

Class Summary

Antiemetics are always prescribed before and after the administration of chemotherapy, for the prevention of chemotherapy-induced nausea and vomiting.

Lenalidomide (Revlimid)

Clinical Context:  Thalidomide analogue; inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells. Indicated for in combination with rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma.

Brentuximab vedotin (Adcetris)

Clinical Context:  CD30-directed antibody-drug conjugate (ADC) consisting of chimeric IgG1 antibody cAC10, specific for human CD30, and the microtubule disrupting agent monomethyl auristatin E (MMAE, or vedotin). Conjugate binds to cell expressing the CD30 antigen and forms a complex that is internalized within the cell and MMAE is released; MMAE induces cell cycle (G2/M phase) arrest by binding to tubules and disrupting cellular microtubule network.

Indicated in combination with lenalidomide and rituximab for relapsed/refractory large B-cell lymphoma patients ineligible for stem cell transplantation or CAR T-cell therapy

How common is diffuse large B-cell lymphoma (DLBCL)?What are the signs and symptoms of diffuse large B-cell lymphoma (DLBCL)?How is diffuse large B-cell lymphoma (DLBCL) diagnosed?Which chemotherapy regimens are used in the treatment of diffuse large B-cell lymphoma (DLBCL)?How is diffuse large B-cell lymphoma (DLBCL) classified?What is the pathophysiology of diffuse large B-cell lymphoma (DLBCL)?How is the role of NF kappa-B signaling in the pathophysiology of diffuse large B-cell lymphoma (DLBCL)?What is the role of BCR signaling in the pathophysiology of diffuse large B-cell lymphoma (DLBCL)?What are the distinct cytogenetic abnormalities in diffuse large B-cell lymphoma (DLBCL) subtypes?What is the World Health Organization (WHO) classification for diffuse large B-cell lymphoma (DLBCL)?What causes diffuse large B-cell lymphoma (DLBCL)?Which conditions are associated with diffuse large B-cell lymphoma (DLBCL)?What is the prevalence of diffuse large B-cell lymphoma in the US?What is the global prevalence of diffuse large B-cell lymphoma (DLBCL)?What are the racial predilections of diffuse large B-cell lymphoma (DLBCL)?What are the sexual predilections of diffuse large B-cell lymphoma (DLBCL)?Which age groups have the highest prevalence of diffuse large B-cell lymphoma (DLBCL)?What is the prognosis of diffuse large B-cell lymphoma (DLBCL)?How is the risk stratification for diffuse large B-cell lymphoma (DLBCL) determined?What are the prognostic factors in early stage diffuse large cell lymphoma?What are the prognostic factors in advanced stage diffuse large cell lymphoma?What is included in patient education about diffuse large B-cell lymphoma (DLBCL)?Which clinical history findings are characteristic of diffuse large B-cell lymphoma (DLBCL)?What is the focus of the clinical history for suspected diffuse large B-cell lymphoma (DLBCL)? Which physical findings are characteristic of diffuse large B-cell lymphoma (DLBCL)? What is included in the physical exam to evaluate suspected diffuse large B-cell lymphoma (DLBCL)? Which conditions should be included in the differential diagnoses of diffuse large cell lymphoma?What is included in the initial evaluation of diffuse large B-cell lymphoma (DLBCL)? What is the role of CBC count in the workup of diffuse large B-cell lymphoma (DLBCL)? What is the role of a metabolic panel in the workup of diffuse large B-cell lymphoma (DLBCL)? When is CT scanning indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?When is PET scanning indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?When is bone marrow biopsy indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?When is CNS imaging and lumbar puncture indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?When are endoscopic procedures indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?When are cardiac studies indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of serologic testing in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of CT scanning in the workup of diffuse large B-cell lymphoma (DLBCL)?When is bone scanning indicated in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of Gallium-67 scans in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of MUGA scanning in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of PET scans in the workup of diffuse large B-cell lymphoma (DLBCL)?What is the role of biopsy in the workup of diffuse large B-cell lymphoma (DLBCL)? What is the role lumbar puncture in the workup of diffuse large B-cell lymphoma (DLBCL)? What is the role of flow cytometry in the workup of diffuse large B-cell lymphoma (DLBCL)?Which histologic findings are characteristic of diffuse large B-cell lymphoma (DLBCL)? What is the role of a pathological evaluation in the diagnosis of diffuse large B-cell lymphoma (DLBCL)? What is the pathologic classification of diffuse large B-cell lymphoma (DLBCL)? What are the pathologic characteristics of diffuse large B-cell lymphoma (DLBCL)?What are the subclassifications of diffuse large B-cell lymphoma (DLBCL)?Which genetic abnormalities are seen in diffuse large B-cell lymphoma (DLBCL)? How is diffuse large B-cell lymphoma (DLBCL) staged? What is the Ann Arbor staging system for diffuse large B-cell lymphoma (DLBCL)? How is diffuse large B-cell lymphoma (DLBCL) treated?What is the role of the R-CHOP regimen in the treatment of diffuse large B-cell lymphoma (DLBCL)?What is the efficacy of R-DHAP in the treatment of relapsed diffuse large B-cell lymphoma (DLBCL)? Which regimen is effective in treating r/rDLBCL in patients ineligible for allogeneic stem cell transplantation (ASCT)?What is the role of a venous access device in the treatment of diffuse large B-cell lymphoma (DLBCL)?How are patients with diffuse large B-cell lymphoma (DLBCL)?How is advance-stage diffuse large B-cell lymphoma (DLBCL) treated?What are the alternatives to CHOP for the treatment of advance-stage diffuse large B-cell lymphoma (DLBCL)? What is the role of rituximab in the treatment of advanced-stage diffuse large B-cell lymphoma (DLBCL)?What is the role of HDC-ASCS in the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL)? What is the role of rituximab in the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?What is the role of chemoimmunotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?What are the salvage chemotherapy regimens used in the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the types of salvage chemotherapy used in the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the platinum-based chemotherapy regimens used in the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the non-platinum-based chemotherapy regimens used in the treatment of diffuse large B-cell lymphoma (DLBCL)?What is the role of CAR T-cell therapy in the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the risk factors for CNS relapse in diffuse large B-cell lymphoma (DLBCL)?What is the role of intrathecal chemotherapy in the treatment of diffuse large B-cell lymphoma (DLBCL)?What is included in supportive care for diffuse large B-cell lymphoma (DLBCL)?What is the role of antiemetics in the treatment of diffuse large B-cell lymphoma (DLBCL)?What is the role of growth factors in the treatment of diffuse large B-cell lymphoma (DLBCL)?When is impatient care indicated in the treatment of diffuse large B-cell lymphoma (DLBCL)?How is tumor lysis syndrome treated in patients with diffuse large B-cell lymphoma (DLBCL)?How is neutropenic fever treated in patients with diffuse large B-cell lymphoma (DLBCL)?How are anemia and thrombocytopenia treated in patients with diffuse large B-cell lymphoma (DLBCL)?Which dietary modifications are used in the treatment of diffuse large B-cell lymphoma (DLBCL)?Which activity modifications are used in the treatment of diffuse large B-cell lymphoma (DLBCL)?Which specialist consultations are beneficial to patients with diffuse large B-cell lymphoma (DLBCL)?When is patient transfer indicated in the treatment of diffuse large B-cell lymphoma (DLBCL)?What is tumor lysis syndrome in diffuse large B-cell lymphoma (DLBCL) and how is it prevented?How are neutropenic fevers and sepsis prevented in diffuse large B-cell lymphoma (DLBCL)?What are the chemotherapy-related complications in diffuse large B-cell lymphoma (DLBCL)?How is early-stage diffuse large B-cell lymphoma (DLBCL) treated?What is the role of radiation therapy in the treatment of early-stage diffuse large B-cell lymphoma (DLBCL)?What is the role of rituximab in the treatment of early-stage diffuse large B-cell lymphoma (DLBCL)?Which treatment regimens are being investigated for the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the NCCN guidelines on the diagnosis of diffuse large B-cell lymphoma (DLBCL)?What are the NCCN and ESMO recommendations for risk stratification of patients with diffuse large B-cell lymphoma (DLBCL)?What are the NCCN treatment recommendations for diffuse large B-cell lymphoma (DLBCL)?Which organizations have published guidelines on diffuse large B-cell lymphoma (DLBCL)?What are the ESMO treatment recommendations for diffuse large B-cell lymphoma (DLBCL)?What are the NCCN guidelines on long-term monitoring following treatment for diffuse large B-cell lymphoma (DLBCL)?What is the role of medications in the treatment of diffuse large B-cell lymphoma (DLBCL)?Which medications in the drug class Antidotes, Other are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Vitamins are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Colony-Stimulating Factors Growth Factor are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, Anti-CD20 Monoclonal Antibodies are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, Anti-CD19 Monoclonal Antibodies are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Selective Inhibitors of Nuclear Export (SINE) are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class CAR T-cell Therapy are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, PI3K Delta Inhibitors are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Monoclonal Antibodies are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Corticosteroids are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, Other are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antiemetics are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, Anti-CD30 Monoclonal Antibodies are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?Which medications in the drug class Antineoplastics, Angiogenesis Inhibitors are used in the treatment of Diffuse Large B-Cell Lymphoma (DLBCL)?

Author

Shipra Gandhi, MBBS, Resident Physician, Department of Internal Medicine, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Andre M Kallab, MD, Clinical Associate Professor of Oncology, Medical College of Georgia; Consulting Staff, Department of Oncology, Northeast Georgia Diagnostic Clinic

Disclosure: Nothing to disclose.

Francisco J Hernandez-Ilizaliturri, MD, Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Acknowledgements

Asher A Chanan-Khan, MD Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo

Disclosure: Nothing to disclose.

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Disclosure: Nothing to disclose.

Michael Paul Kosty, MD Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic

Disclosure: Nothing to disclose.

Clifford H Pemberton, MD Instructor in Medicine, Jefferson Medical College; Medical Director, Jefferson Hospice and Palliative Care Program; Consulting Staff, Department of Medicine, Division of Hematology/Oncology, Lankenau Hospital

Clifford H Pemberton, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians, American Medical Association, American Society of Hematology, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.

Computed tomography (CT) scan of the abdomen showing mesenteric and retroperitoneal adenopathy in a patient with diffuse large cell lymphoma.

Patient with diffuse large B-cell lymphoma with extranodal involvement. This computed tomography (CT) scan shows an enlarged spleen and liver as a result of lymphomatous involvement.

Patient with diffuse large B-cell lymphoma with extranodal involvement (same patient as in the previous image). This patient has an enlarged spleen and liver as a result of lymphomatous involvement. Extensive retroperitoneal lymphadenopathy is also present.

This image depicts gallium scans performed as part of a staging workup for a patient with diffuse large B-cell lymphoma. The scans show extensive hepatosplenic and multiple sites of nodal involvement with a gallium-avid tumor.

Biopsy of a cervical lymph node showing infiltration with a population of large cells (B cells) consistent with diffuse large cell lymphoma.

Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.

Biopsy of a cervical lymph node showing infiltration with a population of large cells (B cells) consistent with diffuse large cell lymphoma.

Computed tomography (CT) scan of the abdomen showing mesenteric and retroperitoneal adenopathy in a patient with diffuse large cell lymphoma.

Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.

Patient with diffuse large B-cell lymphoma with extranodal involvement. This computed tomography (CT) scan shows an enlarged spleen and liver as a result of lymphomatous involvement.

Patient with diffuse large B-cell lymphoma with extranodal involvement (same patient as in the previous image). This patient has an enlarged spleen and liver as a result of lymphomatous involvement. Extensive retroperitoneal lymphadenopathy is also present.

This image depicts gallium scans performed as part of a staging workup for a patient with diffuse large B-cell lymphoma. The scans show extensive hepatosplenic and multiple sites of nodal involvement with a gallium-avid tumor.

Role of B-cell receptor signaling in promoting proliferation and survival of DLBCL. BCR is the main factor in B-cell biology, playing a key role in B-cell development, antigen-driven clonal selection, and humoral immunity. B-cell receptor signaling activates PI3K-mediated activation of the kinase AKT, which activates many downstream signaling pathways. All these downstream pathways are essential for the survival of B cells. PIP3 is generated as a result of BCR-dependent PI3K activation. BTK also hydrolyzes PIP2 into DAG and IP3. IP3 induces release of calcium stores from the endoplasmic reticulum. Ca and DAG activate PKC, which leads to activation of NF-k B pathyway. PI3K, phosphatidylinositide-3 kinase; AKT, protein kinase B; PTEN, phosphatase and tensin homolog; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-4,5-trisphosphate; IKK, IkB kinase; mTOR, mammalian target of rapamycin; FoxO, Forkhead box transcription factors; GSK3b, glycogen synthase 3-beta; p21, inhibitor of cyclin-dependent kinases.