Diffuse Large Cell Lymphoma

Back

Practice Essentials

Diffuse large cell lymphoma (see the image below) is the most common lymphoma, representing 31% of the non-Hodgkin lymphomas (NHLs), and it is rapidly fatal if untreated. Treatment recommendations and prognosis vary with different subtypes of the disease.



View Image

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

Diffuse large cell lymphomas 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 diffuse large cell lymphoma 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

Chemotherapeutic regimens used in the treatment of diffuse large cell lymphoma include the following:

Salvage chemotherapeutic regimens used in relapse therapy include the following:

After the first relapse, however, the duration of the second complete response to treatment is frequently shorter than 1 year. Patients whose condition relapses and who have chemoresponsive disease, as evaluated after salvage therapy, should be considered for high-dose chemotherapy followed by stem cell rescue.

See Treatment and Medication for more detail.

Background

Diffuse large cell lymphoma is the most common lymphoma, representing 31% of the non-Hodgkin lymphomas (NHLs), and it is rapidly fatal if untreated. Clinically, patients with this type of lymphoma usually present with advanced, often extranodal disease. Histologically, these lymphomas contain an equal number of small and large cells (see the images below). (See Prognosis, Presentation, and Workup.)

Under the International Working Formulation, with regard to the classification of intermediate-grade diffuse large cell lymphomas, approximately 79% of these lymphomas were of B-cell origin; 16%, of T-cell origin; and 5%, unclassifiable. Exceptional cases expressed both B-cell and T-cell markers. (See Etiology.)

Incorporation of the Revised European-American Lymphoma (REAL) classification system for lymphomas has been strongly encouraged. In addition to morphologic descriptions, this schema includes immunologic, cytogenetic, and molecular information to define distinct lymphoma entities. Currently, diffuse large B-cell lymphoma is designated under the REAL classification as classic diffuse large cell lymphoma of B-cell origin defined by the working formulation. Lymphomas of T-cell or NK-cell origin exhibit biologic and clinical features distinct from diffuse large B-cell lymphomas. (See Workup.)

Diffuse large cell lymphoma of the REAL classification combines the large cell and the immunoblastic categories of the working formulation. These lymphomas are currently considered a single group, because they behave similarly and, therefore, have similar prognoses.

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 working formulation provided a conceptual framework that groups lymphomas as low grade (indolent), intermediate grade, or high grade, with respect to their natural histories.[3]

In 1994, the International Lymphoma Study Group proposed the REAL classification schema.[4] It classifies NHLs as being derived from B or T/NK cells, and it includes disease entities that were not part of the working formulation.

Symptom classification

The presence of systemic symptoms, including fever higher than 38°C, night sweats, and/or weight loss of more than 10% of body weight in the 6 months preceding diagnosis, is denoted by the suffix B. Staging of asymptomatic patients is denoted by the suffix A.

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, 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 diffuse large B-cell lymphomas demonstrate rearrangements of the immunoglobulin genes by deoxyribonucleic acid (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.[5] A number of cytogenetic abnormalities have been reported in these neoplasms, including t(14;18), t(8;14), trisomy 12, and deletion of 6q.[6, 7]

A study by Pasqualucci et al found that the diffuse large B-cell lymphoma 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.[8]

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.[9]

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 stabilzed. From 2007-2016, rates of new cases fell on average 0.9% each year and death rates fell on average 2.2% each year.The current US age-adjusted rate is 19.6 cases per 100,000 person-years for both sexes.[12] The estimated rate for diffuse large cell lymphomas is approximately 4.68 cases per 100,000 person-years.

It is estimated that approximately 74,200 new cases of NHL will be diagnosed and 19,970 patients will die from NHL, despite currently available treatment.[13] Lymphomas are a heterogeneous group of malignancies with diverse biology, clinical behavior, and prognosis.

In general, lymphomas can be divided into two groups, Hodgkin (HL) and NHL. While infrequent, HL (8,110 estimated new cases in 2019) 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 the United States, accounting for 4.2% of all cancers, and the eighth leading cause of cancer deaths, accounting for 3.3% of cancer-related deaths.[12] 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.[14]

DLBCL typically affects patients in their sixth decade, except for primary mediastinal DLBCL variant, which affects mostly females 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 human immunodeficiency virus (HIV) infection epidemic.[15]

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.[1]

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

White individuals have higher rates than people of African or Asian descent[16] ; 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.[17] 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 diffuse large B-cell lymphoma. According to the study (a retrospective cohort analysis of 533 white patients with diffuse large B-cell lymphoma and 144 black patients with the disease), 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).[18]

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 (cyclophosphamide, Adriamycin, vincristine, prednisone plus rituximab) therapy.

There is a slight male disease preponderance, with a male-to-female disease incidence ratio of 1.3:1. However, diffuse large B-cell lymphoma affects females more often than males.

Although diffuse large cell lymphomas can occur at any age, they generally develop in middle-aged and older adults. Most patients with diffuse large B-cell lymphoma are diagnosed during the seventh or eighth decade of life, with a median age of 63 years.

Prognosis

Data suggest that 5-year survival rates in diffuse large cell lymphoma 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.[19]

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 diffuse large B-cell lymphoma (DLBCL) and should be performed before starting therapy.

The International Prognostic Index (IPI) score system was the result of a collaborative effort of 16 institutions in Europe and North America that used a dataset containing clinical information of almost 2000 patients.[20] 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 ≥ 65 y, performance status ≥ 2, elevated lactate dehydrogenase (LDH), Ann Arbor stage III or IV, and ≥2 extranodal sites of disease). Based on the total score, DLBCL patients are assigned into 4 risk category groups (low, low-intermediate, high-intermediate, and high) with overall survival ranging from 23-75%.

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 non-Hodgkin lymphoma (NHL).[21]

In addition, modifications from the original predictive score have been formulated, such as the age-adjusted IPI score for patients younger than 65 years and the rituximab-IPI score with similar prognostic power.

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[22] .

Prognostic factors in early-stage disease

A number of studies have analyzed factors predicting better or worse survival rates for patients with limited-stage diffuse large cell lymphoma (stage IA and IIA, nonbulky) treated with combined modality programs.

In a study by the Southwestern Oncology Group (SWOG), a subgroup analysis showed that the 5-year survival rate was better in patients who had a favorable IPI score.[23] Similar results were found in a study of 308 patients with limited disease treated with 3 cycles of a doxorubicin-containing regimen followed by radiotherapy.

In an Eastern Cooperative Oncology Group (ECOG) study, the 6-year disease-free survival rate for patients who achieved complete remission was greater in patients who received chemotherapy plus radiation therapy than it was in patients who received only chemotherapy (73% vs 56%, respectively).[24] The study compared 8 courses of a regimen of cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP), with or without radiation, in patients with previously untreated bulky or extranodal stage I or II diffuse large cell lymphoma.

Despite the differences in disease-free survival, overall survival rates in the 2 groups were similar (64% for the radiation group vs 60% for the other patients).[24] Patients with 3 or more disease sites or a poor performance status were more likely to have treatment failure with the CHOP regimen, with or without radiotherapy.

The results from all of these studies suggest that combined modality therapy can be used to successfully treat patients with limited stage I disease and a stage-modified IPI score of zero. This approach appears to be less successful in patients with bulky stage I or II disease, 3 or more involved disease sites, and/or a stage-modified IPI score of 1 or more.

Prognostic factors in advanced-stage disease

The International Non-Hodgkin Lymphoma Prognostic Factors Project developed a predictive model of outcome for aggressive non-Hodgkin lymphoma (NHL); ie, stage II bulky or stage III or IV.[20] The specific 5 pretreatment characteristics that independently were statistically significant for higher-risk disease were as follows:

Based on these 5 characteristics, patients were stratified into 4 categories, as follows:

When patient outcomes were analyzed by risk stratification, they had different outcomes with regard to complete response, disease-free survival, and overall survival. For example, patients with a low risk had a complete response rate of 87% and a 5-year survival rate of 73%, as compared with a complete response rate of 44% and a 5-year survival rate of 26% in the high-risk group.

Subsequent studies have confirmed the reproducibility of the IPI for predicting clinical outcome for patients with diffuse large cell lymphoma. Currently, poor-risk patients (despite achieving complete response) may be considered for aggressive therapy with high-dose chemotherapy and peripheral stem cell/bone marrow transplantation in first remission.

Complications

Tumor lysis syndrome

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. TLS can lead to a sudden death from electrolyte abnormalities. Treatment that includes aggressive intravenous hydration, urine alkalinization, and administration of allopurinol usually prevents 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

Uric acid nephropathy, with or without tumor lysis syndrome, 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 with the fluoroquinolones [eg, ciprofloxacin, levofloxacin]) has been shown to be effective in preventing neutropenic infections.

Other

Chemotherapy-associated complications may also include the following:

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 (1) long-term complications of higher doses of chemoradiotherapy and (2) mortality rates as high as 3-5% from the conditioning regimen in patients who require HDC and ASCT.

For patient education information, see Leukemia and Lymphoma and Non-Hodgkin Lymphoma.

History

The clinical manifestations of diffuse large cell lymphomas 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. Pain in an enlarged lymph node or organ may be noted if the lymphomatous mass enlarges rapidly.

As with other types of non-Hodgkin lymphoma (NHL), diffuse large cell lymphomas can present with B-symptoms, including fever, drenching night sweats, and weight loss. Generalized pruritus may also be present.

Other symptoms can include the following:

Medical history should include inquiries about the following:

Physical Examination

On physical examination, keep in mind that diffuse large cell lymphomas appear 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, is more frequently associated with Burkitt and non-Burkitt lymphoma, HIV-associated lymphoma, human T-cell leukemia virus (HTLV) type 1–associated lymphoma, primary CNS lymphoma, and primary testicular diffuse large cell lymphoma.

The following are common findings on physical examination:

The clinical spectrum observed in lymphoma patients is diverse and is influenced by the subtype of lymphoma its anatomical 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, renal, hepatic or cardiac 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 diffuse large B-cell lymphoma (DLBCL) patients is aimed at determining the stage of the disease, assessing for end-organ damage by the disease and/or preexisting comorbid conditions, and identifying situations that may affect treatment design. The evaluation of patients with lymphoproliferative disorders should include a detailed history and physical examination.

Complete blood cell (CBC) count with differential

Laboratory testing to assess bone marrow and immunological function includes CBC count with differential and platelet counts, which 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, lactic dehydrogenase (LDH), renal function, and hepatic function. In addition, perform serum β2 microglobulin (B-cell lymphoma) testing.

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

Elevated levels of lactate dehydrogenase (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.[25] An elevated uric acid level also signifies an increased likelihood of tumor lysis syndrome with chemotherapy

Computed tomography (CT) scanning

Routine CT scanning of the neck, chest, abdomen, and pelvis is the standard imaging study for patients with lymphoma.

Functional imaging

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 (HL), and mantle cell lymphoma (MCL). Most academic institutions recommend routine PET scanning to complement staging and posttreatment evaluation of all patients with aggressive lymphoma. Retrospective studies have demonstrated that midtreatment and/or end-of-treatment PET scanning provides strong prognostic information in terms of progression-free survival (PFS) and overall survival (OS). The adequate timing for PET scanning for response assessment is a subject of controversy and recommendations vary among academic institutions.[26]

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 imaging and lumbar puncture

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).

Gastrointestinal imaging

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

Cardiac evaluation

Cardiac studies evaluating ejection fraction are required in patients expected to receive anthracycline-based chemotherapy.

Serological evaluation for pathogens

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

Serological 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 fulminate hepatic failure due to active hepatitis B or C have been reported in DLBCL patients undergoing chemoimmunotherapy. Therefore, routine HBV and HCV serology is recommended.

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

Flow Cytometry and Genetic Studies

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.

Cytogenetic or fluorescent in situ hybridization (FISH) studies may reveal common chromosomal translocations, such as the following:

Gene expression profiling may be able to distinguish 2 separate subtypes of diffuse large B-cell lymphomas (normal germinal center B-cell pattern vs activated B-cell–like), each of which has a different prognosis. In addition, results from gene rearrangement studies can be used to establish clonality.[27, 28]

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.)



View Image

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



View Image

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



View Image

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



View Image

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 ....

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 (67 Ga) 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 of67 Ga occurs in approximately 50% of indolent lymphomas and in most aggressive and highly aggressive types.67 Ga scans are also sometimes used as a means of assessing sites of relapse. (See the image below.)



View Image

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....

MUGA scanning

Multigated acquisition (MUGA) scans are used to evaluate 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) scans are increasingly being used to stage disease through the use of fluorodeoxyglucose (FDG), since findings for glucose uptake can indicate areas of increased metabolic activity.[29] PET-scan data can also be useful in helping to determine whether residual masses represent scars or persistent lymphoma.

PET scan findings are being investigated for use as prognostic indicators during treatment (after 2-4 cycles), but the clinical utility of this is still unclear.

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

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 should also be performed as part of the staging.

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.

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.

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.)



View Image

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



View Image

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 diffuse large B-cell lymphoma (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.[30, 4] 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).[30, 4, 3]

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).[31, 32] While each of these 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.[33] Germinal center–associated markers CD10 and Bcl-6 are expressed in approximately 30-40% and 60%, respectively. Bcl-6 expression has been associated with a prolonged progression-free survival (PFS) and overall survival (OS) following rituximab chemotherapy in retrospective studies.[34, 35] 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.[36]

Subclassification of DLBCL

Under the WHO and/or REAL classification of lymphoid malignancies, the following histological variants are considered clinical and/or pathological distinct subtypes of DLBCL:

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.[37, 38, 39]

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 classic Hodgkin lymphomas (HLs), 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, the use of the GEP studies has not been validated prospectively and widespread use as a routine diagnostic tool is still not practical. Hence, GEP studies are not recommended outside from a clinical trial. Recently, GEP results have been translated into a clinically applicable approaches using immunohistochemistry (IHC).[40, 41, 42]

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.[40, 41, 43] The Hans algorithm reproduces the gene expression-based classification of DLBCL and has a misclassification rate of 20%.[40] Both algorithms have been evaluated as predictors of clinical outcomes in DLBCL patients undergoing front-line therapy with standard chemotherapy or chemoimmunotherapy.[42, 43] 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 recently completed or ongoing clinical studies.[44, 45, 46]

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.[47, 48]

The clinical value of testing for genetic aberrations in DLBCL continues to grow in recognition. Recently, a subset of DLBCL patients carrying both c-Myc and Bcl-2 translocations as detected by fluorescence in situ hybridization (FISH) were identified. Those patients are known as having “double-hit DLBCL” which represents approximately 8% of newly diagnosed DLBCL patients. It exhibits a poor response to standard doses of rituximab chemotherapy regimens and has a poor OS.[49, 50, 51, 52] Moreover, IHC studies have demonstrated that concurrent over-expression of c-Myc and Bcl-2 is associated with a poor clinical outcome.[53, 54] 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%).

Molecular Biology of DLBCL

Numerous genetic and molecular changes accumulate through a multistep process leading to the selective growth advantage of a malignant clone. 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 (1) the recombination of the V, D, and J gene segments necessary for assembling of the immunoglobulins’ heavy and light chains; (2) somatic hypermutation; and (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 and normal B cells are susceptible to the development of undesirable chromosomal translocations or gene mutations, leading to the development of B-cell lymphoma.[55]

Abnormalities in the process of B-cell maturation lead to the development of lymphoid malignancies. 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.[56] 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] vs activated B-cell [ABC] DLBCL).[55]

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.[57] 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).[58] 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- but not GCB-DLBCL lines.[59] Clinically, it has been observed that ABC-DLBCL patients are 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.[60] Moreover, pharmacological inhibitors of NFkB activity (ie, lenalidomide or bortezomib) appear to have selective activity in non–GCB-DLBCL.[45, 46]

Recently, 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).[61] The CBM complex is required for activation of the classic NFkB pathway downstream of the antigen receptors in B and T cells.[62] 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.[63] 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.[64]

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.[65] The 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.[66] Upon antigen stimulation, clustering of the BCRs occurs, leading to signal transduction via the CD79A and B subunits.[67] 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.[68]

Genetic aberrations in DLBCL group patients

Distinct cytogenetic abnormalities have been described in DLBCL patients. It is unclear to what degree such abnormalities contribute to the development or disease biology. Cytogenetic abnormalities vary between different DLBCL subtypes.

GCB-DLBCL

The most common translocation is t(14,18), with rearrangements of the BCL2 and IGH chain genes.[58] 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 few patients is deletion of the tumour suppressor gene PTEN.

ABC-DLBCL

The most common aberration in ABC-DLBCL is translocation involving the BCL6 gene.[59] Another frequent aberration in the ABC group is trisomy 3.[60] Approximately 18 % of the patients diagnosed with ABC-DLBCL are diagnosed 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.

Primary mediastinal lymphoma (PML)

Gain of the long arm of chromosome 9 is reported.[61] Duplication or multiplication of this locus is associated with up-regulation of the Janus kinase 2 (JAK2) gene. A gain of this gene is observed in 50% of the patients with PML.[62]

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.

The staging of lymphoma patients provides information necessary for treatment planning and has prognostic significance, especially in Hodgkin lymphoma (HL). 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. Carefully examine the peripheral blood smear for any abnormal lymphoid cells.

Note that tumor lysis syndrome manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium; this can lead to a sudden death from electrolyte abnormalities.

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:

Cotswold’s modifications are as follows:

Approach Considerations

Therapy for aggressive non-Hodgkin lymphoma (NHL) has evolved significantly in the last 30 years. For example, high-dose chemotherapy in the setting of stem cell/bone marrow transplantation has become a useful treatment modality in the management of diffuse large cell lymphoma.

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 diffuse large cell lymphomas 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 diffuse large B-cell lymphoma who underwent surgery and chemotherapy was lower than that of patients who underwent chemotherapy alone, the difference was acceptable.[69] Thus, surgical resection followed by chemotherapy may be an effective treatment strategy for these patients.

Unless contraindicated because of significant and preexisting comorbid conditions, the treatment of diffuse large B-cell lymphoma (DLBCL) should include the use of rituximab- and anthracycline-based-multiagent chemotherapy, 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 stage.

R-CHOP regimen

The cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen was among the first combinations to produce complete response rates and long-term survivors. For patients with advanced diffuse large cell lymphoma, another standard therapy exists; specifically, the addition of rituximab (Rituxan; a chimeric antibody that targets CD20+ B cells) to CHOP (R-CHOP).[70, 71, 72]

Rituximab produces a 48% response rate in patients with low-grade lymphomas[73] and has activity in diffuse large cell lymphoma.

A phase II pilot study of rituximab in combination with CHOP in patients with previously untreated diffuse large cell lymphoma or high-grade NHL reported an overall response rate of 97% (32 of 33 patients), with a 61% complete remission rate, a 36% partial remission rate, and a 3% progressive disease rate.[70] Severe adverse events were similar to those observed with CHOP alone.

In a study of 435 patients with diffuse large cell lymphoma, Villa et al found that the risk of CNS relapse was significantly reduced with the addition of rituximab to the CHOP regimen compared with risk reduction for patients treated with CHOP alone.[74] This reduction was even more evident in patients who achieved a complete response.

A study by Phan et al found that overall survival and progression-free survival were significantly improved among patients who received consolidation radiation treatment after undergoing R-CHOP therapy.[75]

A study of 215 patients treated with R-CHOP revealed improved event-free survival (EFS) in patients treated with epratuzumab plus R-CHOP (ER-CHOP). ER-CHOP is well tolerated, and these results suggest that combination therapy is promising.[76]

Récher et al compared the efficacy of R-CHOP with that of treatment consisting of rituximab added to a regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) and found significant improvement in survival with the R-ACVBP regimen among patients aged 18-59 years with diffuse large B-cell lymphoma and low intermediate risk.[77]

Relapse therapy

Early evidence suggested that in germinal center B (GCB)-like DLBCL, the cell of origin has a better response to rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) than to rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) .[44]  Options for relapsed disease continued to make progress.

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, has shown significantly improved outcomes for r/rDLBCL in patients ineligible for allogeneic stem cell transplantation (ASCT) when combined with bendamustine and rituximab (BR) compared with BR alone.[78]

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 samples 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 erythropoietin or darbepoetin alfa (Aranesp) injections may be required for patients with persistently low hemoglobin values due to disease or chemotherapy.

Multidisciplinary 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, and the management of such patients requires an abbreviated course of combined systemic chemoimmunotherapy following by involved-field radiation therapy (IF-XRT).[79, 80]

A phase II study conducted by the British Columbia Cancer Agency treated 308 DLBCL patients with 3 cycles of chemotherapy followed by IF-XRT. The overall progression-free survival (PFS) and overall survival (OS) rates were 80-81% at 5 years and 63-74% at 10 years, respectively.[81]

The Southwestern Oncology Group (SWOG) study 8736 randomly assigned 401 patients with nonbulky stage I or II aggressive B-cell lymphoma to receive either 3 cycles of the cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen followed by IF-XRT at 40-50 cGy versus 8 cycles of CHOP chemotherapy alone.[82] Patients managed with CHOP followed by IF-XRT had better PFS (77% and 64%, respectively, P =.03) and OS (82% and 72%, respectively, P =.02) than patients treated with 8 cycles of CHOP.[83]

An updated analysis after 10 years of follow up showed an increased frequency of late recurrences that explained the absence of a plateau effect in the survival curve.

Radiation therapy in early-stage DLBCL

The role of radiation therapy in the management of early-stage DLBCL had been challenged by 2 studies conducted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). The first study randomized patients younger than 60 years to either 3 cycles of CHOP chemotherapy followed by IF-XRT or an intense regimen consisting of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) for 6 cycles.[83] After a median follow-up period of 7.7 years, OS and PFS were significantly better in the group given ACVBP than in the group given CHOP plus radiotherapy. The 5-year estimates of event-free survival were 82% for patients receiving chemotherapy alone and 74% for those receiving chemotherapy/radiotherapy. The respective 5-year estimates of OS were 90% and 8%. In contrast to previous clinical trials, this study included patients with bulky disease.[84]

On the other hand, the ACVBP regimen was associated with increased chemotherapy-related toxicity and a high frequency of hospitalizations.[84] Moreover, vindesine is not commercially available in the United States. Hence, chemotherapy was considered to be superior to chemo-radiotherapy.

In the second study, DLBCL patients older than 60 years with localized disease and no International Prognostic Index (IPI) factors were randomized to 4 cycles of CHOP plus IF-XRT or chemotherapy alone with 4 cycles of CHOP. After a median follow-up of 7 years, the median OS and PFS were not significantly different between the 2 treatment arms. The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of OS were 72% and 68%, respectively.[85]

On the other hand, the Eastern Cooperative Oncology Group (ECOG) assessed the value of radiation as a consolidation after 8 cycles of standard chemotherapy in a randomized clinical trial. The study enrolled 352 patients older than 60 years with stage I or II bulky disease, who were assigned to receive CHOP chemotherapy and randomly selected to receive IF-XRT or no further treatment as consolidation in those who achieved complete response (CR). Among the 172 CR patients, the 6-year disease-free survival rate was 73% for low-dose radiotherapy versus 56% for observation. Although improvement occurred in the estimated disease-free survival after 6 years of follow up, no significant differences were noted in OS.[24]

Rituximab in early-stage DLBCL

The use of monoclonal antibodies, particularly rituximab, has 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 in normal and most of the malignant B-cells. The mechanisms by which rituximab elucidates its antitumor activity has been characterized and includes antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models have demonstrated that rituximab potentiates the effect of several chemotherapeutic agents.[86] In contrast to what has been observed in low-grade lymphomas, rituximab monotherapy has limited activity in DLBCL.[87] The addition of rituximab to standard doses of chemotherapy in DLBCL has resulted in improved clinical outcomes without adding significant toxicity.

Only a few studies addressing the role of rituximab in the management of early-stage DLBCL have been conducted. The Mabthera International Trial (MInT) was studied the role of adding rituximab to standard therapy in young patients with stage I bulky or stage II-IV DLBCL.[88] The MInT enrolled 824 young patients (ie, < 60 y) with aggressive lymphoma and good IPI score (< 1 IPI risk factor). Patients were randomized to receive 6 cycles of CHOP-like chemotherapy with or without rituximab. After a median follow-up period of 3 years, the event-free survival (EFS) and OS were improved significantly by the addition of rituximab to systemic chemotherapy. Of interest, in a subset analysis of the patients with early stage or bulky disease, the addition of IF-XRT as consolidation following chemoimmunotherapy did not improve clinical endpoints.[88]

The addition of rituximab to combined-modality treatment in DLBCL was evaluated in a Southwest Oncology Group (SWOG) study and reported by Persky et al.[89] The SWOG conducted a phase II clinical trial evaluating the addition of rituximab to an abbreviated course of CHOP chemotherapy followed by IF-XRT. The study enrolled 60 patients with limited-stage DLBCL. PFS and OS were 88% and 92%, respectively, and were considered superior to historical (chemotherapy–IF-XRT) controls, for which PFS was 78% and OS was 88%.[89] The current literature supports the addition of rituximab in the management of early-stage DLBCL to standard doses of CHOP chemotherapy.

The length of therapy and the use of radiation continue to be a subject of debate. Some clinicians strongly recommend the use of a short course (usually 3 cycles) of systemic chemoimmunotherapy followed by IF-XRT, while other physicians consider 6 cycles of rituximab in combination with CHOP equivalent and thus avoid the delayed toxicity from IF-XRT. On the other hand, it is important to stress that the multidisciplinary approach of early-stage DLBCL should be tailored according to site of disease involvement (eg, mediastinum, stomach), disease response using functional imaging, and patient comorbid conditions in an attempt to optimize the achievement of a CR that can translate into improved OS.

As the addition of rituximab to CHOP chemotherapy increases the CR, PFS, and OS of DLBCL patients, clinicians are questioning again the role of IF-XRT in the post-rituximab era. Tomita et al demonstrated that a standard strategy of 3 cycles of rituximab/CHOP (R-CHOP) followed by IF-XRT for limited-stage DLBCL could be effectively replaced by 6 cycles of R-CHOP alone. A total of 190 previously untreated patients with limited-stage DLBCL were treated with R-CHOP alone and were studied retrospectively. IF-XRT was only administered to patients achieving a CR to R-CHOP (N=5). The 5-year PFS and OS were 84% and 90, respectively.[90]

Treatment of Advanced-Stage Disease

Historical perspective

The use of systemic chemotherapy to successfully eradicate disseminated diffuse large B-cell lymphoma (DLBCL) was first described in the early 1970s.[91, 92] After these original reports, the cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen (given every 21 days, ie, CHOP-21) became the standard of care for aggressive lymphomas in the United States.

Multiple attempts to improve survival in DLBCL patients led investigators to evaluate more intensive regimens. Fisher et al on behalf of the Southwest Oncology Group (SWOG) reported the results of a large clinical trial conducted in the United States.[93] The study compared CHOP-21 chemotherapy with 3 intense chemotherapy regimens. The study failed to demonstrate any superiority with the intense regimens tested, and CHOP-21 was found to be equivalent but less toxic. After a follow up of 6 years, the overall survival (OS) and progression-free survival (PFS) rates were not statistically significantly different between the chemotherapeutic regimens tested.

Alternative chemotherapies evaluated against CHOP

In the last decade, 2 alternative chemotherapy regimens were evaluated against standard CHOP in patients with advanced DLBCL. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) compared the efficacy of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) against CHOP-21 in 635 patients aged 61-69 years with advanced-stage DLBCL with at least one International Prognostic Index (IPI) score risk factor.[93]

While the complete response rate was similar between the 2 groups (58% vs 56%), the event-free survival (EFS) and OS rates were significantly better in patients treated with ACVBP than in those treated with CHOP-21. At 5 years of follow up, the EFS was 39% in the ACVBP groups and 29% in the CHOP-21 group (P =.005) and the OS was significantly longer for patients treated with ACVBP (46%) than patients treated with CHOP-21 (38%, P =.036). Of interest, CNS progressions or relapses were more frequent in the CHOP-21 group (P =.004).[93]

The German Study Lymphoma Group (GSLG) evaluated the concept of dose-dense in DLBCL patients. Elderly patients with DLBCL were randomized into 4 cohorts and received CHOP-21 (given every 21 days) with or without etoposide (E) or dose-dense CHOP (given every 14 days, CHOP-14) with or without etoposide. The addition of etoposide to CHOP chemotherapy did not affect the clinical end points of the study. On the other hand, the delivery of CHOP in a dose-dense schema proved superior in terms of PFS and OS with a similar toxicity profile (43.8% vs 32.5%, P =.003 and 53.3% vs 40.6%, P< .001).[94]

A subsequent study, the NHL-B1, evaluated the same regimens in young patients with advanced DLBCL. The study confirmed the value of dose-dense CHOP, and, of interest, in younger patients with DLBCL, the addition of etoposide to CHOP (CHOEP-14 or CHOEP-21) was associated with better PFS and OS when compared with CHOP-21. In spite of an increased degree of myelosuppression, these regimens were well tolerated.[95]

Rituximab in advanced-stage DLBCL

Despite the clinical superiority of CHOEP-14 and ACVBP over CHOP-21 in patients with DLBCL, the parallel development and incorporation of rituximab into standard doses of CHOP-21 has challenged the clinical value of such toxic regimens in the post-rituximab era.

Based on results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas,[96] a phase II study evaluating the combination of rituximab and CHOP in aggressive B-cell lymphomas was conducted by Vose et al.[70] The overall response rate (ORR) to the combination of CHOP and rituximab was 94%, with 20 of 33 patients achieving a complete response (CR). At the time of the updated publication and after a median follow-up time of 63 months, the PFS rate was 82% and the OS rate was 88%.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the GELA and presented by Coiffier et al. The GELA enrolled patients with newly diagnosed aggressive B-cell lymphomas who were older than 60 years and randomized them to receive either 8 cycles of CHOP or rituximab in combination with CHOP at 21-day intervals.[97] The study included patients with stage I-IV DLBCL, and 59% had 3 or more IPI score risk factors and 80% had Ann Arbor stage III or IV disease. The addition of rituximab to CHOP chemotherapy resulted in higher response rates than CHOP alone (76% vs 63%, respectively, P =.005). PFS and OS at the interim analysis (after 18-month follow-up) were significantly better in the R-CHOP arm (P< .001 and P =.007, respectively) when compared with CHOP.

A long-term analysis of the study after 5 years of follow up confirmed the efficacy of combining rituximab with systemic chemotherapy in terms of PFS (54% vs 30%; P< .0001) and OS (58% vs 45%; P =.0004).[97, 98]

The LNH-98.5 Study was recently updated after 10 years of follow up.[99] The 10-year PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively. Moreover, the 10-year OS rate was better in R-CHOP–treated DLBCL patients (43.5%) compared with patients treated with CHOP alone (27.6%). According to this study, the addition of rituximab to CHOP showed a clear benefit

Another study conducted primarily in the United States was conducted to try to validate the results from the GELA study. Data from the Eastern Cooperative Oncology Group (ECOG) study 4944 in previously untreated elderly DLBCL patients randomized to R-CHOP versus CHOP and in responders to subsequent observation versus rituximab maintenance showed that the addition of rituximab to chemotherapy either during induction treatment or during maintenance improved the time to progression (TTP) compared with patients treated with CHOP chemotherapy alone.[100] Similar findings were found in younger patients with DLBCL with 0-1 IPI score risk factors as described above.

Pfreundschuh et al reported a statistically significant benefit by adding rituximab to CHOP or CHOP-like chemotherapy in 824 patients with DLBCL in terms of PFS and OS.[88] After a follow-up period of 3 years, patients randomized to receive chemotherapy and rituximab had higher EFS (79% vs 59%, P< .0001) and had increased OS (93% vs 84%; P =.0001) than patients assigned to chemotherapy alone.

The benefit of adding rituximab to high-intermediate and high-risk DLBCL patients younger than 60 years has not been formally studied. The use of rituximab in combination with CHOP chemotherapy in this group of patients has been extrapolated from the results of the GELA and Mabthera International Trial (MInT) studies. While the addition of rituximab to standard doses of CHOP chemotherapy has improved the outcomes of patients with DLBCL, a significant number of patients do not to respond or relapse after initial responses, stressing the need to develop novel therapeutic strategies.

To further study the role of dose-dense chemotherapy in DLBCL in the post-rituximab era, the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) evaluated the benefit of adding rituximab to CHOP-14 in elderly patients with DLBCL. Pfreundschuh et al reported the results of the rituximab with CHOP over age 60 years (RICOVER-60) trial.[101]

In this study, 1222 elderly patients (aged 61-80 years) were randomized to receive either 6 or 8 cycles of CHOP-14 with or without rituximab. Involved-field radiation therapy (IF-XRT) was planned for extranodal or bulky sites. The results of this study demonstrated that the addition of rituximab to systemic chemotherapy improved the EFS and OS in DLBCL patients and that 6 cycles of chemotherapy were as effective as 8 cycles. After a 3-year period of follow up, the EFS was 47.2% after 6 cycles of CHOP-14, 53% after 8 cycles of CHOP-14, 66.5% after 6 cycles of R-CHOP-14, and 63.1% after 8 cycles of R-CHOP-14. In addition, OS after 3 years of follow up was 67% and 66% in patients treated with 6 or 8 cycles of CHOP-14, in contrast to 78.1% or 72.5% for those patients treated with 6 or 8 cycles of R-CHOP-14, respectively.

Of the 4 regimens assessed in this study, 6 cycles of R-CHOP-14 was found to be the preferred treatment for elderly patients, with which other approaches should be compared.

A topic of debate continues to be if R-CHOP-14 is superior to R-CHOP-21. A quick glance to the data presented by the GELA or the RICOVER-60 trial could suggest that R-CHOP-14 appears to yield higher PFS and OS rates at 3-year follow-up. However, it is important to note that the DLBCL patients enrolled in both studies are different. The GELA study included more patients with DLBCL (84% vs 78%) stage I/II (20% vs 55%) and/or high-intermediate/high-risk IPI score categories (59% vs 39%) than the RICOVER-60 study. The GELA group recently completed the accrual of a randomized study comparing R-CHOP-21 to R-CHOP-14 in patients with DLBCL. Results from this study failed to demonstrate any clinical benefit from using R-CHOP-14 over R-CHOP-21 in the management of patients with DLBCL.[102]

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, have studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (DA-EPOCH) in combination with rituximab in previously untreated DLBCL.[103] In this particular regimen, the doses of etoposide, vincristine, cyclophosphamide, and doxorubicin 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 aged at least 18 years and had stage II or higher disease. Patients received 6-8 cycles of rituximab and DA-EPOCH. IF-XRT was not permitted. Correlative studies were performed to address biomarkers of disease response by immunohistochemistry (IHC). At 5 years, PFS and OS were 79% and 80%, respectively.[103, 104]

An ongoing randomized phase III study from the Cancer and Leukemia Group B (CALGB) is comparing R-CHOP-21 to rituximab in combination with DA-EPOCH in previously untreated DLBCL. Correlative studies planned in this study will validate prospectively gene expression profiling (GEP) studies in DLBCL.

Four alternative strategies currently have been or are being evaluated in clinical studies, with promising activity in DLBCL patients: (1) the concept of dose-dense rituximab (ie, 12 doses of rituximab delivered concomitantly with 6 cycles of CHOP-14), (2) targeting of the ubiquitous proteasome with bortezomib as a means to potentiate the antitumor activity of chemoimmunotherapy, (3) the use of rituximab maintenance in the relapsed/refractory setting (CORAL study), and (4) the use of high dose-chemotherapy and autologous stem cell support (HDC-ASCS) in first remission, especially for those patients with high risk-disease.[105, 106, 107, 108, 109, 110]

Treatment of Relapsed/Refractory DLBCL

HDC-ASCS in patients with R-CHOP relapsed/refractory DLBCL

The role of HDC-ASCS in the treatment of relapsed/refractory DLBCL was confirmed by the only international randomized phase III clinical trial known as the PARMA study.[111] In this particular study, 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. The results of this study demonstrated that 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 for the patients 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.[111] 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 was focused on the development of tools to predict which patients were most likely to benefit from HDC-ASCS, such as the value of age-adjusted the International Prognostic Index (IPI) score or positron emission tomography (PET) scanning after salvage chemotherapy.[112, 113, 114]

Rituximab in R-CHOP relapsed/refractory DLBCL

As rituximab changed the treatment paradigm of patients with DLBCL, it has been postulated that the current subset of patients with refractory or relapsed DLBCL represent a different patient population than the one studied in pre-rituximab clinical trials. Several investigators are questioning if the response to second-line chemotherapy or if 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.[115] 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 only 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 rates to R-ESHAP was 67% and 37% for DLBCL patients previously treated with rituximab-CHOP versus 81% and 56% for patients previously treated with CHOP (P =.045, P =.015), respectively. In addition, the PFS and OS rates at 3 years were significantly higher for the patients in the R- group (57% and 64%) compared with those patients in the R+ group (38% and 17%) (P< .0001, P =.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.[115] The results of this retrospective study suggest that DLBCL patients who relapse or do not respond to rituximab chemotherapy as first-line therapy have a more resistant type of disease and represent an emerging 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 are developing resistance to chemoimmunotherapy.

On the other hand, it is uncertain if 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. Two groups of investigators have shown improved response rates by adding rituximab to salvage regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, high-dose cytarabine, and cisplatin (DHAP) compared with historical controls.[116, 117] 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 which 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 =.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.[98]

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.

Chemoimmunotherapy

In June 2019, polatuzumab, 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 after at least 2 prior therapies. 

Accelerated approval of polatuzumab was based on a study in which 40% of patients treated with polatuzumab vedotin plus BR achieved CR (n=16/40; 95% CI: 25-57) compared with 18% of those receiving BR alone (n=7/40; 95% CI: 7-33). The study also showed an OR of 45% with polatuzumab plus BR at the end of treatment (n=18/40; 95% CI: 29-62) compared with 18% for BR alone (n=7/40; 95% CI: 7-33). Of patients who achieved a complete or partial response, duration of response was at least 6 months in 64% (n=16/25) of those receiving polatuzumab plus BR, compared with 30% (n=3/10) for BR alone. Additionally, response lasting at least 1 year was observed in 48% (n=12/25) of patients receiving polatuzumab plus BR compared with 20% (n=2/10) for BR alone.[78]

Salvage chemotherapy regimens for DLBCL

There are a vast number of regimens used in the treatment of patients with relapsed/refractory DLBCL, and they are primarily based on non–cross-resistant chemotherapy agents to those used in the frontline setting plus/minus 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:

The only randomized phase III trial that compared established salvage regimens in combination with rituximab (R-ICE vs R-DHAP) was the ongoing CORAL study.[118] Recently, the investigators reported an interim analysis of 200 patients enrolled that demonstrated factors affecting EFS include second-line age-adjusted IPI (aaIPI) of 0-1 (39% vs 56% P =.0084), relapse less than 12 months after completion of first-line therapy (36% vs 68%, P< .001), and prior rituximab exposure in the frontline setting (34% vs 66%, P< 0.001).[118] The preliminary results of the CORAL study validate the predictive factor of the aaIPI at the time of relapse, as previously described, and stress again that rituximab chemotherapy in the frontline is selective for forms of DLBCL more difficult to control in the salvage setting.

Final results of this study are eagerly awaited to further define the optimal salvage regimen and the role of rituximab maintenance following HDC-ASCS in relapsed/refractory DLBCL.

In general, when selecting the optimal salvage regimen, consider regimens with higher response rates, especially higher complete response (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.[119, 111, 115, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129] 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 hematological and, to a lesser degree nonhematological, 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.[119, 111, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129]

In addition nonhematological toxicity seen with these regimens includes renal 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). Recently several investigators had evaluated the possibility of replacing cisplatin/carboplatin with oxaliplatin given its favorable toxicity profile. However, no significant changes in the antitumor activity or toxicity profile of current available salvage regimens has been demonstrated by this strategy.[126]

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 regimens such as methylprednisolone, ifosfamide, mitoxantrone, and etoposide (MINE); ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD); ifosfamide, epirubicin, and etoposide (IEV), or busulphan, etoposide, cytarabine, and melphalan (Mini-BEAM) is comparable to that observed with platinum-based regimen.[130, 131, 132, 133] Response rates to any of these 3 regimens in relapsed/refractory DLBCL (never exposed to rituximab) vary from 64-75%, and the safety profile is similar to platinum-containing regimens.[130, 131, 132, 133]

On the other hand, the use of these regimens has declined overtime 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 nonhematological and hematological toxicity from high-dose ifosfamide-containing regimens by combining this agent with a platinum compound.

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 after HDC-ASCT), or those patients with multiple comorbid conditions. The hematological 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.[134, 135]

Another strategy used by other investigators 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.[136] The incident of cardiac toxicity was extremely low (3%), despite the fact that 94% of the patients enrolled had prior anthracycline exposure.[136, 137] Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell non-Hodgkin lymphoma treated with rituximab-EPOCH.[138]

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.

CNS Prophylaxis in DLBCL

CNS relapse is a rare but significant complication in the management of patients with diffuse large B-cell lymphoma (DLBCL). It has been estimated that the probability of CNS relapse after 1 year of diagnosis is 2.3-4.5%.[139, 140] The risk of CNS relapse appears to be higher in subsets of DLBCL (4- to 15-fold increase in risk), and identification of such patients is imperative in an attempt to implement prophylactic therapy (ie, intrathecal chemotherapy).

Boehme et al retrospectively evaluated the incidence and risk factors of CNS recurrence in 1693 patients with aggressive lymphomas.[141] In a multivariate analysis, only an elevated lactate dehydrogenase (LDH) level at diagnosis and lymphoma involvement of 2 or more extranodal sites were identified as predictor factors for CNS relapse. Similar findings had been observed in patients receiving chemoimmunotherapy.

Boehme et al studied the factors associated with CNS relapse in patients treated with rituximab and the 14-day cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) (R-CHOP-14) regimen. In this retrospective study, the estimated 2-year incidence of CNS relapse was 6.9%. Using a Cox regression analysis, the investigators found that involvement of more than one extranodal site or the presence of B-symptoms was a predictor factor for CNS relapse.[141]

Recommendations for intrathecal chemotherapy

Routine intrathecal chemotherapy is strongly recommended in patients with DLBCL with the following characteristics:

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.

In October 2017, 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 diffuse large B-cell lymphoma (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.[142]

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 x 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.[143]

In May 2018, tisagenlecleucel gained approval for adults with relapsed or refractory large B-cell lymphoma (r/rDLBCL), including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥ 2 lines of systemic therapy.[144]

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 to 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).[145, 146]

For more information, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T-Cells

Investigative Treatment Regimens

A German trial explored the safety and feasibility of dose-escalated CHOP-etoposide with 3 autologous stem cell transplantations (ASCTs) as aggressive up-front therapy in young patients with high lactate dehydrogenase (LDH) levels.[147] The investigators found the therapy to be safe and feasible, but its role is unclear. Rituximab was not used, and whether these intensive regimens are better than less intense chemotherapy plus rituximab is currently under investigation.

Antisense therapy (Bcl-2 antisense therapy) has entered clinical trials with promising results. However, its role outside of these trials has not yet been established.

The addition of bortezomib, a protease inhibitor approved for the treatment of myeloma, to treatment using CHOP plus rituximab (R-CHOP), is also being investigated, in phase I and II trials.[148]

Multicenter trials of radioimmunotherapy with ibritumomab tiuxetan (yttrium-90 [90 Y] Zevalin) and iodine-131 (131 I) tositumomab (Bexxar), CD20-targeting radiolabeled antibodies approved for use in follicular lymphomas, are also ongoing.

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 renal failure 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 intravenous 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, administered subcutaneously once weekly, or darbepoetin alfa 300 mcg, with weekly subcutaneous administration.

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 tumor lysis syndrome, neutropenic fever, and anemia and thrombocytopenia.

Tumor lysis syndrome

Patients with a high tumor burden may need to be admitted to the hospital to receive prophylaxis with allopurinol and alkaline hydration for prevention of this potentially life-threatening condition

Neutropenic fever

Patients are usually expected to be neutropenic approximately 10-14 days after a dose of chemotherapy, with individuals being most susceptible to infections at this point. If febrile, they should be admitted to the hospital and treated with intravenous antibiotics.

Anemia and thrombocytopenia

Transfusions (red blood cells or platelets) should be administered as clinically indicated for anemia and thrombocytopenia.

Diet and Activity

Diet

No specific diet is recommended for patients with diffuse large cell lymphoma except a salt restriction when steroids are administered as part of the chemotherapy regimen.

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

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. In addition, the patient may feel substantial fatigue due to the lymphoma, its treatment, or both.

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:

Medication Summary

The goals of pharmacotherapy are to induce cancer remission, reduce morbidity, and prevent complications.

Cyclophosphamide

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

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 (Vincasar PFS)

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 (Toposar)

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.

Cytarabine

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

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.

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.

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 (Mustargen)

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

Methotrexate (Trexall)

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.

Polatuzumab vedotin (Polivy, polatuzumab vedotin-piiq)

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.

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.

Class Summary

These agents inhibit cell growth and proliferation.

Prednisone

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

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 (Depo-Medrol, Solu-Medrol, Medrol, A-Methapred)

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 (Rituxan)

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)

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 (r/rDLBCL) including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥2 lines of systemic therapy.

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).

Epoetin alfa (Epogen, Procrit)

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).

Class Summary

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

Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

Clinical Context:  Trimethoprim/sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. The antibacterial activity of trimethoprim/sulfamethoxazole includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

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.

Ketoconazole

Clinical Context:  Imidazole broad-spectrum antifungal agent; it inhibits the synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death.

Class Summary

An antifungal may be used in the ProMACE-CytaBOM regimen. The mechanism of action may involve the inhibition of pathways (eg, enzyme, substrate, transport) that are necessary for sterol and/or cell membrane synthesis.

Ondansetron (Zofran, Zuplenz)

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 (Kytril, Granisol)

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

Palonosetron (Aloxi)

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 (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 (Compro)

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.

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

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

References

  1. Howell JM, Auer-Grzesiak I, Zhang J, et al. Increasing incidence rates, distribution and histological characteristics of primary gastrointestinal non-Hodgkin lymphoma in a North American population. Can J Gastroenterol. Jul 2012. 26(7):452-6.
  2. [Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Version 3.2019 — May 6, 2019; Accessed: June 12, 2019.
  3. National Cancer Institute. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer. 1982 May 15. 49(10):2112-35. [View Abstract]
  4. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1. 84(5):1361-92. [View Abstract]
  5. Nakamura H, Said JW, Miller CW, Koeffler HP. Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas. Blood. 1993 Aug 1. 82(3):920-6. [View Abstract]
  6. Stein H, Dallenbach F. Diffuse Large cell lymphomas of B and T Cell type. Knowles DM, ed. Neoplastic Hematology. Baltimore, Md: Williams and Willkins; 1992. 675.
  7. Hu CR, Wang JH, Wang R, Sun Q, Chen LB. Both FOXP1 and p65 expression are adverse risk factors in diffuse large B-cell lymphoma: a retrospective study in China. Acta Histochem. 2013 Mar. 115(2):137-43. [View Abstract]
  8. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011 Jul 31. 43(9):830-7. [View Abstract]
  9. Alizadeh AA, Gentles AJ, Alencar AJ, et al. Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. Blood. 2011 Aug 4. 118(5):1350-8. [View Abstract]
  10. Hartge P, Devesa SS, Fraumeni JF Jr. Hodgkin's and non-Hodgkin's lymphomas. Cancer Surv. 1994. 19-20:423-53. [View Abstract]
  11. De Roos AJ, Davis S, Colt JS, et al. Residential proximity to industrial facilities and risk of non-Hodgkin lymphoma. Environ Res. 2010 Jan. 110(1):70-8. [View Abstract]
  12. Cancer Stat Facts: Non-Hodgkin Lymphoma. National Cancer Institute. Available at https://seer.cancer.gov/statfacts/html/nhl.html. Accessed: June 12, 2019.
  13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan. 69 (1):7-34. [View Abstract]
  14. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin's lymphoma. Oncogene. 2004 Aug 23. 23(38):6524-34. [View Abstract]
  15. Hartge P, Devesa SS. Quantification of the impact of known risk factors on time trends in non-Hodgkin's lymphoma incidence. Cancer Res. 1992 Oct 1. 52(19 Suppl):5566s-5569s. [View Abstract]
  16. Wu XC, Andrews P, Chen VW, Groves FD. Incidence of extranodal non-Hodgkin lymphomas among whites, blacks, and Asians/Pacific Islanders in the United States: anatomic site and histology differences. Cancer Epidemiol. 2009 Nov. 33(5):337-46. [View Abstract]
  17. Ries LAG, Miller BA, Hankey BF. SEER Cancer Statistics Review 1973-1991: Tables and Graphs. Bethesda, Md: National Cancer Institute; 1994. 94-2789.
  18. Flowers CR, Shenoy PJ, Borate U, et al. Examining racial differences in diffuse large B-cell lymphoma presentation and survival. Leuk Lymphoma. 2013 Feb. 54(2):268-76. [View Abstract]
  19. Lu Y, Prescott J, Sullivan-Halley J, et al. Body size, recreational physical activity, and B-cell non-Hodgkin lymphoma risk among women in the California teachers study. Am J Epidemiol. 2009 Nov 15. 170(10):1231-40. [View Abstract]
  20. International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30. 329(14):987-94. [View Abstract]
  21. Blay J, Gomez F, Sebban C, Bachelot T, Biron P, Guglielmi C. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood. 1998 Nov 15. 92(10):3562-8. [View Abstract]
  22. Alinari L, Gru A, Quinion C, Huang Y, Lozanski A, Lozanski G, et al. De novo CD5+ Diffuse Large B-cell Lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multi-center, rituximab treated cohort. Am J Hematol. 2016 Jan 22. [View Abstract]
  23. Coltman CA, Dahlberg S, Jones SE, et al. Southwest Oncology Group Studies in diffuse large cell lymphoma: a subset analysis. Kimura K, ed. Cancer Chemotherapy: Challenges for the Future. Tokyo, Japan: Excerpta Medica; 1988. 194-202.
  24. Horning SJ, Weller E, Kim KM, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-hodgkin's lymphoma: Eastern Cooperative Oncology Group Study 1484 [abstract]. J Clin Oncol. 2004 Aug 1. 22(15):3032-8.
  25. Sweetenham JW. Diffuse large B-cell lymphoma: risk stratification and management of relapsed disease. Hematology Am Soc Hematol Educ Program. 2005. 252-9. [View Abstract]
  26. Juweid ME, Cheson BD. Role of positron emission tomography in lymphoma. J Clin Oncol. 2005 Jul 20. 23(21):4577-80. [View Abstract]
  27. Martín-Subero JI, Kreuz M, Bibikova M, et al. New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood. 2009 Mar 12. 113(11):2488-97. [View Abstract]
  28. Zainuddin N, Berglund M, Wanders A, et al. TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype. Leuk Res. 2009 Jan. 33(1):60-6. [View Abstract]
  29. Terasawa T, Nagai H. Current clinical evidence on interim fluorine-18 fluorodeoxy glucose positron emission tomography for advanced-stage Hodgkin lymphoma and diffuse large B-cell lymphoma to predict treatment outcomes. Leuk Lymphoma. 2009 Nov. 50(11):1750-2. [View Abstract]
  30. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009. 523-31. [View Abstract]
  31. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997 Jun 1. 89(11):3909-18. [View Abstract]
  32. Good DJ, Gascoyne RD. Classification of non-Hodgkin's lymphoma. Hematol Oncol Clin North Am. 2008 Oct. 22(5):781-805, vii. [View Abstract]
  33. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008 Apr 15. 111(8):3941-67. [View Abstract]
  34. Lossos IS, Jones CD, Warnke R, et al. Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood. 2001 Aug 15. 98(4):945-51. [View Abstract]
  35. Winter JN, Weller EA, Horning SJ, Krajewska M, Variakojis D, Habermann TM. Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study. Blood. 2006 Jun 1. 107(11):4207-13. [View Abstract]
  36. Hartmann EM, Ott G, Rosenwald A. Molecular biology and genetics of lymphomas. Hematol Oncol Clin North Am. 2008 Oct. 22(5):807-23, vii. [View Abstract]
  37. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3. 403(6769):503-11. [View Abstract]
  38. Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002 Jan. 8(1):68-74. [View Abstract]
  39. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jun 20. 346(25):1937-47. [View Abstract]
  40. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004 Jan 1. 103(1):275-82. [View Abstract]
  41. Muris JJ, Meijer CJ, Vos W, van Krieken JH, Jiwa NM, Ossenkoppele GJ. Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J Pathol. 2006 Apr. 208(5):714-23. [View Abstract]
  42. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppä S. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol. 2009 Aug. 22(8):1094-101. [View Abstract]
  43. Colomo L, Lopez-Guillermo A, Perales M, Rives S, Martinez A, Bosch F. Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood. 2003 Jan 1. 101(1):78-84. [View Abstract]
  44. Thieblemont C, Briere J, Mounier N, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol. 2011 Nov 1. 29(31):4079-87. [View Abstract]
  45. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011 Nov 15. 117(22):5058-66. [View Abstract]
  46. Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11. 113(24):6069-76. [View Abstract]
  47. Morgensztern D, Lossos IS. Molecular prognostic factors in diffuse large B-cell lymphoma. Curr Treat Options Oncol. 2005 Jul. 6(4):269-77. [View Abstract]
  48. Lossos IS. Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol. 2005 Sep 10. 23(26):6351-7. [View Abstract]
  49. Snuderl M, Kolman OK, Chen YB, Hsu JJ, Ackerman AM, Dal Cin P. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol. 2010 Mar. 34(3):327-40. [View Abstract]
  50. Li S, Lin P, Fayad LE, Lennon PA, Miranda RN, Yin CC. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012 Jan. 25(1):145-56. [View Abstract]
  51. Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ. Double-hit B-cell lymphomas. Blood. 2011 Feb 24. 117(8):2319-31. [View Abstract]
  52. Kobayashi T, Tsutsumi Y, Sakamoto N, Nagoshi H, Yamamoto-Sugitani M, Shimura Y. Double-hit lymphomas constitute a highly aggressive subgroup in diffuse large B-cell lymphomas in the era of rituximab. Jpn J Clin Oncol. 2012 Nov. 42(11):1035-42. [View Abstract]
  53. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012 Oct 1. 30(28):3460-7. [View Abstract]
  54. Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A. MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2013 Feb 28. [View Abstract]
  55. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010 Apr 15. 362(15):1417-29. [View Abstract]
  56. Nogai H, Dorken B, Lenz G. Pathogenesis of non-Hodgkin's lymphoma. J Clin Oncol. 2011 May 10. 29(14):1803-11. [View Abstract]
  57. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26. 47(6):921-8. [View Abstract]
  58. Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012. 30:565-610. [View Abstract]
  59. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001 Dec 17. 194(12):1861-74. [View Abstract]
  60. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001 Feb. 107(3):241-6. [View Abstract]
  61. Ngo VN, Davis RE, Lamy L, Yu X, Zhao H, Lenz G. A loss-of-function RNA interference screen for molecular targets in cancer. Nature. 2006 May 4. 441(7089):106-10. [View Abstract]
  62. Thome M, Charton JE, Pelzer C, Hailfinger S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol. 2010 Sep. 2(9):a003004. [View Abstract]
  63. Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL. Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity. 2005 Dec. 23(6):561-74. [View Abstract]
  64. Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008 Mar 21. 319(5870):1676-9. [View Abstract]
  65. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005 Apr. 5(4):251-62. [View Abstract]
  66. Clark MR, Tanaka A, Powers SE, Veselits M. Receptors, subcellular compartments and the regulation of peripheral B cell responses: the illuminating state of anergy. Mol Immunol. 2011 Jun. 48(11):1281-6. [View Abstract]
  67. Reth M. Antigen receptor tail clue. Nature. 1989 Mar 30. 338(6214):383-4. [View Abstract]
  68. Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen receptor signaling 101. Mol Immunol. 2004 Jul. 41(6-7):599-613. [View Abstract]
  69. Kim SJ, Kang HJ, Kim JS, et al. Comparison of treatment strategies for patients with intestinal diffuse large B-cell lymphoma: surgical resection followed by chemotherapy versus chemotherapy alone. Blood. 2011 Feb 10. 117(6):1958-65. [View Abstract]
  70. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001 Jan 15. 19(2):389-97. [View Abstract]
  71. Pfreundschuh M, Truemper L, Gill D, et al. First analysis of the completed Mabthera International (Mint) Trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favorable subgroup with IPI=O and no bulky disease [abstract 157]. Blood. 2004. 104:48a.
  72. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005 Aug 1. 23(22):5027-33. [View Abstract]
  73. Gao G, Liang X, Jiang J, et al. A systematic review and meta-analysis of immunochemotherapy with rituximab for B-cell non-Hodgkin's lymphoma. Acta Oncol. 2010. 49(1):3-12. [View Abstract]
  74. Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, Savage KJ. Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol. 2010 May. 21(5):1046-52. [View Abstract]
  75. Phan J, Mazloom A, Medeiros LJ, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol. 2010 Sep 20. 28(27):4170-6. [View Abstract]
  76. Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011 Oct 13. 118(15):4053-61. [View Abstract]
  77. Récher C, Coiffier B, Haioun C, et al. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26. 378(9806):1858-67. [View Abstract]
  78. Sehn LH, Herrera AF, Matasar MJ, et al. Addition of polatuzumab vedotin to bendamustine and rituximab (BR) improves outcomes in transplant-ineligible patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) versus BR alone: Results from a randomized phase 2 study. Blood. 2017. 130:2821.
  79. Persky DO, Miller TP. Localized large cell lymphoma: is there any need for radiation therapy?. Curr Opin Oncol. 2009 Sep. 21(5):401-6. [View Abstract]
  80. Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008 Oct. 22(5):941-52, ix. [View Abstract]
  81. Shenkier TN, Voss N, Fairey R, Gascoyne RD, Hoskins P, Klasa R. Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency. J Clin Oncol. 2002 Jan 1. 20(1):197-204. [View Abstract]
  82. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2. 339(1):21-6. [View Abstract]
  83. Miller TP, Chase EM, Dorr R, Dalton WS, Lam KS, Salmon SE. A phase I/II trial of paclitaxel for non-Hodgkin's lymphoma followed by paclitaxel plus quinine in drug-resistant disease. Anticancer Drugs. 1998 Feb. 9(2):135-40. [View Abstract]
  84. Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005 Mar 24. 352(12):1197-205. [View Abstract]
  85. Bonnet C, Fillet G, Mounier N, Ganem G, Molina TJ, Thieblemont C. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007 Mar 1. 25(7):787-92. [View Abstract]
  86. Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res. 2001 Mar. 7(3):709-23. [View Abstract]
  87. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998 Sep 15. 92(6):1927-32. [View Abstract]
  88. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May. 7(5):379-91. [View Abstract]
  89. Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10. 26(14):2258-63. [View Abstract]
  90. Tomita N, Takasaki H, Miyashita K, Fujisawa S, Ogusa E, Matsuura S. R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma. Br J Haematol. 2013 May. 161(3):383-8. [View Abstract]
  91. Levitt M, Marsh JC, DeConti RC, Mitchell MS, Skeel RT, Farber LR. Combination sequential chemotherapy in advanced reticulum cell sarcoma. Cancer. 1972 Mar. 29(3):630-6. [View Abstract]
  92. DeVita VT Jr, Canellos GP, Chabner B, Schein P, Hubbard SP, Young RC. Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet. 1975 Feb 1. 1(7901):248-50. [View Abstract]
  93. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8. 328(14):1002-6. [View Abstract]
  94. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rube C. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1. 104(3):634-41. [View Abstract]
  95. Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rudolph C. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1. 104(3):626-33. [View Abstract]
  96. Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordon L, LoBuglio AF. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan. 17(1):268-76. [View Abstract]
  97. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24. 346(4):235-42. [View Abstract]
  98. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20. 23(18):4117-26. [View Abstract]
  99. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23. 116(12):2040-5. [View Abstract]
  100. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006 Jul 1. 24(19):3121-7. [View Abstract]
  101. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb. 9(2):105-16. [View Abstract]
  102. Delarue R, Tilly H, Mounier N, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May. 14(6):525-33. [View Abstract]
  103. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15. 99(8):2685-93. [View Abstract]
  104. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1. 26(16):2717-24. [View Abstract]
  105. Pfreundschuh M. How I treat elderly patients with diffuse large B-cell lymphoma. Blood. 2010 Dec 9. 116(24):5103-10. [View Abstract]
  106. Ribrag V, Gisselbrecht C, Haioun C, et al. Efficacy and toxicity of 2 schedules of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone plus bortezomib in patients with B-cell lymphoma: a randomized phase 2 trial from the French Adult Lymphoma Study Group (GELA). Cancer. 2009 Oct 1. 115(19):4540-6. [View Abstract]
  107. Vitolo U, Liberati AM, Cabras MG, Federico M, Angelucci E, Baldini L. High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an "Intergruppo Italiano Linfomi" randomized trial. Haematologica. 2005 Jun. 90(6):793-801. [View Abstract]
  108. Vitolo U, Chiappella A, Angelucci E, Rossi G, Liberati AM, Cabras MG. Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study. Haematologica. 2009 Sep. 94(9):1250-8. [View Abstract]
  109. Haioun C, Lepage E, Gisselbrecht C, Salles G, Coiffier B, Brice P. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol. 2000 Aug. 18(16):3025-30. [View Abstract]
  110. Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec. 20(12):1985-92. [View Abstract]
  111. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7. 333(23):1540-5. [View Abstract]
  112. Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Maertens J, Bormans G. Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. Blood. 2003 Jul 1. 102(1):53-9. [View Abstract]
  113. Derenzini E, Musuraca G, Fanti S, Stefoni V, Tani M, Alinari L. Pretransplantation positron emission tomography scan is the main predictor of autologous stem cell transplantation outcome in aggressive B-cell non-Hodgkin lymphoma. Cancer. 2008 Nov 1. 113(9):2496-503. [View Abstract]
  114. Lerner RE, Thomas W, Defor TE, Weisdorf DJ, Burns LJ. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin's lymphoma in second complete or partial remission. Biol Blood Marrow Transplant. 2007 Apr. 13(4):486-92. [View Abstract]
  115. Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008 Dec. 93(12):1829-36. [View Abstract]
  116. Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15. 111(2):537-43. [View Abstract]
  117. Kewalramani T, Zelenetz AD, Nimer SD, Portlock C, Straus D, Noy A. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004 May 15. 103(10):3684-8. [View Abstract]
  118. Hagberg H, Gisselbrecht C. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006 May. 17 Suppl 4:iv31-2. [View Abstract]
  119. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan. 71(1):117-22. [View Abstract]
  120. Moskowitz CH, Bertino JR, Glassman JR, Hedrick EE, Hunte S, Coady-Lyons N. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec. 17(12):3776-85. [View Abstract]
  121. Josting A, Sieniawski M, Glossmann JP, et al. High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study. Ann Oncol. 2005 Aug. 16(8):1359-65. [View Abstract]
  122. Witzig TE, Geyer SM, Kurtin PJ, Colgan JP, Inwards DJ, Micallef IN. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leuk Lymphoma. 2008 Jun. 49(6):1074-80. [View Abstract]
  123. Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest. 2006 Oct. 24(6):593-600. [View Abstract]
  124. Olivieri A, Brunori M, Capelli D, Montanari M, Massidda D, Gini G. Salvage therapy with an outpatient DHAP schedule followed by PBSC transplantation in 79 lymphoma patients: an intention to mobilize and transplant analysis. Eur J Haematol. 2004 Jan. 72(1):10-7. [View Abstract]
  125. Soussain C, Souleau B, Gabarre J, et al. Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin's lymphoma. Results of a single-centre study of 65 patients. Leuk Lymphoma. 1999 May. 33(5-6):543-50. [View Abstract]
  126. Lopez A, Gutierrez A, Palacios A, Blancas I, Navarrete M, Morey M. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008 Feb. 80(2):127-32. [View Abstract]
  127. Crump M, Baetz T, Couban S, Belch A, Marcellus D, Howson-Jan K. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer. 2004 Oct 15. 101(8):1835-42. [View Abstract]
  128. Chau I, Harries M, Cunningham D, Hill M, Ross PJ, Archer CD. Gemcitabine, cisplatin and methylprednisolone chemotherapy (GEM-P) is an effective regimen in patients with poor prognostic primary progressive or multiply relapsed Hodgkin's and non-Hodgkin's lymphoma. Br J Haematol. 2003 Mar. 120(6):970-7. [View Abstract]
  129. Ng M, Waters J, Cunningham D, Chau I, Horwich A, Hill M. Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma. Br J Cancer. 2005 Apr 25. 92(8):1352-7. [View Abstract]
  130. van Besien K, Rodriguez A, Tomany S, et al. Phase II study of a high-dose ifosfamide-based chemotherapy regimen with growth factor rescue in recurrent aggressive NHL. High response rates and limited toxicity, but limited impact on long-term survival. Bone Marrow Transplant. 2001 Feb. 27(4):397-404. [View Abstract]
  131. Pocali B, De Simone M, Annunziata M, Palmieri S, D'Amico MR, Copia C. Ifosfamide, epirubicin and etoposide (IEV) regimen as salvage and mobilization therapy for refractory or early relapsing patients with aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2004 Aug. 45(8):1605-9. [View Abstract]
  132. Schütt P, Passon J, Ebeling P, Welt A, Müller S, Metz K. Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas. Eur J Haematol. 2007 Feb. 78(2):93-101. [View Abstract]
  133. Girouard C, Dufresne J, Imrie K, Stewart AK, Brandwein J, Prince HM. Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation. Ann Oncol. 1997 Jul. 8(7):675-80. [View Abstract]
  134. Papageorgiou ES, Tsirigotis P, Dimopoulos M, Pavlidis N, Fountzilas G, Papageorgiou S. Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B-cell lymphoma: a phase-II trial by the Hellenic Cooperative Oncology Group. Eur J Haematol. 2005 Aug. 75(2):124-9. [View Abstract]
  135. Müller-Beissenhirtz H, Kasper C, Nückel H, Duhrsen U. Gemcitabine, vinorelbine and prednisone for refractory or relapsed aggressive lymphoma, results of a phase II single center study. Ann Hematol. 2005 Nov. 84(12):796-801. [View Abstract]
  136. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol. 1993 Aug. 11(8):1573-82. [View Abstract]
  137. Gutierrez M, Chabner BA, Pearson D, et al. Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: an 8-year follow-up study of EPOCH. J Clin Oncol. 2000 Nov 1. 18(21):3633-42. [View Abstract]
  138. Jermann M, Jost LM, Taverna Ch, Jacky E, Honegger HP, Betticher DC. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004 Mar. 15(3):511-6. [View Abstract]
  139. Boehme V, Zeynalova S, Kloess M, et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma--a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Ann Oncol. 2007 Jan. 18(1):149-57. [View Abstract]
  140. van Besien K, Ha CS, Murphy S, McLaughlin P, Rodriguez A, Amin K. Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood. 1998 Feb 15. 91(4):1178-84. [View Abstract]
  141. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2009 Apr 23. 113(17):3896-902. [View Abstract]
  142. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm. October 18, 2017; Accessed: October 21, 2017.
  143. Frederick L, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [abstract]. Proceedings of the American Association for Cancer Research Annual Meeting 2017. 2017 Apr 1-5. Available at http://cancerres.aacrjournals.org/content/77/13_Supplement/CT019
  144. U.S. Food and Drug Administration. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. 2018 May 03. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606540.htm?utm_campaign=Oncology%205%2F1%2F2018_Kymriah&utm_medium=email&utm_source=Eloqua&elqTrackId=5578022d641d45d5a723adaf982a493c&elq=933c3d8ba491426680135d5ae119dcc6&elqaid=3339&elqat=1&e
  145. Schuster S, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. 59th American Society of Hematology Annual Meeting and Exposition. Abstract #577. Atlanta, GA. December 9-12, 2017.
  146. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28. 377 (26):2545-2554. [View Abstract]
  147. Glass B, Kloess M, Bentz M, et al. Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma. Blood. 2006 Apr 15. 107(8):3058-64. [View Abstract]
  148. Leonard JP, Furman RR, Cheung YKK, et al. Phase I/II trial of bortezomib + CHOP-rituximab in diffuse large B cell (DLBCL) and mantle cell lymphoma (MCL): phase I results [abstract]. Blood. 2005. 106:491a.
  149. Skarin AT, Dorfman DM. Non-Hodgkin's lymphomas: current classification and management. CA Cancer J Clin. 1997 Nov-Dec. 47(6):351-72. [View Abstract]

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.

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.

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.