B-Cell Lymphoma

NHL can be divided into two general prognostic groups: indolent lymphomas and aggressive lymphomas. Indolent lymphomas carry a relatively good prognosis, with median survival as long as 10 years, but those that have progressed to advanced stages are not usually curable. Early-stage (stage I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of cases are curable with combination chemotherapy regimens.

With modern treatment of patients with NHL, the overall survival rate at 5 years is 73.8%.[2] Although relapse is common in advanced-stage NHL, patients can often be retreated with considerable success as long as the disease histology remains low grade. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients with a divergent histology of both indolent and aggressive disease.

Patients who present with aggressive forms of NHL, or whose disease converts to an aggressive form, may achieve complete remission with combination chemotherapy regimens, with or without aggressive high-dose consolidation therapy with marrow or stem cell support. Aggressive lymphomas are increasingly observed in patients who are HIV positive, and treatment of these patients requires special consideration.

B-cell neoplasms are clonal tumors of mature and immature B cells at various stages of differentiation. B-cell neoplasms tend to mimic stages of normal B-cell differentiation, and the resemblance to normal cell stages is a major basis for their classification and nomenclature.[3]

The World Health Organization (WHO) classification divides B-cell malignancies into two broad categories[3] : (1) precursor B-cell neoplasms, which include B lymphoblastic leukemia/lymphoma with or without recurrent genetic abnormalities, and (2) mature B-cell neoplasms.

The following classification deals with only the mature B-cell neoplasms. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For instance, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma (SLL) are different manifestations of the same neoplasm, as are lymphoblastic lymphomas and T-cell acute lymphocytic leukemias.

The WHO classification of mature B-cell neoplasms is as follows[3] :

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Monoclonal B-cell lymphocytosis
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• Splenic B-cell lymphoma/leukemia, unclassifiable
• Splenic diffuse red pulp small B-cell lymphoma
• Hairy cell leukemia–variant
• Lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia
• Monoclonal gammopathy of undetermined significance (MGUS), IgM
• Heavy-chain diseases (μ, γ, α)
• MGUS, IgG/A
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Monoclonal immunoglobulin deposition diseases
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
• Nodal marginal zone lymphoma
• Pediatric nodal marginal zone lymphoma
• Follicular lymphoma
• In situ follicular neoplasia
• Duodenal-type follicular lymphoma
• Pediatric-type follicular lymphoma
• Large B-cell lymphoma with IRF4 rearrangement
• Primary cutaneous follicle center cell lymphoma
• Mantle cell lymphoma
• In situ mantle cell neoplasia
• Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
• Germinal center B-cell type
• Activated B-cell type
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)–positive DLBCL, NOS
• EBV-positive mucocutaneous ulcer
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Human herpesvirus 8 (HHV-8)–associated DLBCL, NOS
• Burkitt lymphoma
• Burkitt-like lymphoma with 11q aberration
• High-grade B-cell lymphoma with MYC and BLC2 and/or BCL6 rearrangements
• High-grade B-cell lymphoma, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Any of the following may play a role in the etiology of non-Hodgkin lymphoma (NHL) in a particular patient:

• Genetic abnormalities
• Environmental factors
• Viral infections
• Immunodeficiency states
• Connective-tissue disorders

Chromosomal translocations and molecular rearrangements

Non-random chromosomal and molecular rearrangements (see the table below) play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.

Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma (Open Table in a new window)

The most common chromosomal abnormality associated with NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 25-30% of intermediate-grade NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic inhibitor oncogene at band 18q21 to the heavy-chain region of the immunoglobulin (Ig) locus within band 14q32, resulting in its overexpression.

The t(11;14)(q13;q32) translocation results in overexpression of bcl -1 (cyclin-D1/PRAD1), a cell cycle control gene on band 11q13, and is diagnostic of mantle cell lymphoma.

For the workup of any high-grade B-cell lymphoma of germinal center origin, fluorescence in situ hybridization (FISH) studies for evaluation of myc, bcl-6, and bcl-2 rearrangements should typically be ordered, in order to establish classification of "double hit" lymphomas. Double hit B-cell lymphomas are a specific subtype of diffuse large B-cell lymphoma (DLBCL) that have a much more aggressive clinical course and are associated with translocations of two of the three oncogenes (myc, bcl-2, and bcl-6).

Environmental factors

The risk of NHL is increased in certain workers, including the following:

• Farmers
• Pesticide applicators
• Flour millers
• Meat workers
• Painters
• Mechanics
• Workers in the petroleum, rubber, plastics, and synthetics industries

Chemicals that have been linked to the development of NHL include the following:

• Pesticides and herbicides (eg, organophosphates, chlorophenols)
• Solvents and organic chemicals (eg, benzene, carbon tetrachloride)
• Wood preservatives

Patients who receive cancer chemotherapy, radiation therapy, or both are at increased risk of developing NHL.

Viruses

Several viruses have been implicated in the pathogenesis of NHL. Epstein-Barr virus (EBV) is linked to Burkitt lymphoma (especially in endemic areas of Africa), sinonasal lymphoma in Asia and South America, and lymphomas in immunocompromised patients. Human T-lymphotropic virus 1 (HTLV-1) is linked to adult T-cell lymphoma/leukemia. Human herpesvirus 8 (HHV-8) is implicated in body cavity–based lymphomas in patients with HIV infection.

Results of an Italian study support a role for chronic hepatitis C virus infection in NHL, and suggest involvement of hepatitis B virus infection. Associations were clearest for B-cell NHL and diffuse large B-cell lymphoma.[4]

Immunodeficiency states

Immunodeficiency states that seem to predispose to NHL include congenital immunodeficiency states (eg, ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, and severe combined immunodeficiency), as well as acquired immunodeficiency states (eg, HIV infection and iatrogenic immunosuppression for solid organ or bone marrow transplant recipients).[5]

Connective-tissue disorders

Connective-tissue disorders associated with an increased risk of NHL include the following:

• Sjögren syndrome
• Rheumatoid arthritis
• Chronic lymphocytic thyroiditis
• Systemic lupus erythematosus (SLE)

Other disease states

Increased incidence of gastrointestinal (GI) lymphomas is observed in patients with celiac sprue and inflammatory bowel disease. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is observed most frequently, but not exclusively, in association with Helicobacter pylori infection.

United States statistics

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 2010-2019, rates of new cases fell on average 1.0% each year, and from 2011-2020, death rates fell on average 2.2% each year.[2]

The lifetime risk of being diagnosed with NHL is 2.1%.[2] The American Cancer Society estimates that 80,550 new cases of NHL will be diagnosed in 2023, with 20,180 deaths. In US males, NHL is the seventh most common cancer, accounting for 4% of new cancers and cancer-related deaths; in females it is the sixth most common cancer, accounting for 4% of new cancers and 3% of cancer deaths.[6]

International statistics

Perry and colleagues identified the following significant differences in the epidemiology of NHL in developing countries, compared with the developed countries[7] :

• Higher percentage of males
• Lower median age at diagnosis for both low- and high-grade B-cell lymphoma
• Lower frequency of B-cell lymphoma and a higher frequency of T- and NK-cell lymphoma
• Approximately 20% more cases of high-grade B-cell lymphoma and 10% fewer cases of low-grade B-cell lymphoma

In developing regions, diffuse large B-cell lymphoma was the most common subtype (42.5%) Other subtypes seen more frequently were Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%) and extranodal natural killer (NK)/T-cell lymphoma (2.2%).[7]

In Europe, NHL is the 11th most common cancer, representing 3% of the total cancer diagnoses in 2012.[8]

Certain endemic geographic factors appear to influence the development of NHL in specific areas. For example, in equatorial Africa, a variant of Burkitt lymphoma associated with Epstein-Barr virus (EBV) is the most common childhood malignancy.

In the Middle East, heavy-chain disease (alpha) is a disorder of B-lymphoid cells that is characterized by diffuse thickening of the small intestine caused by a lymphoplasmacytic infiltrate with secretion of incomplete immunoglobulin A (IgA) heavy chains. This clinicopathologic entity is rarely encountered in individuals who are not of Mediterranean ethnicity.

Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, and the Middle East.

Age-, sex-, and race-associated differences in incidence

NHL is most frequently diagnosed in  persons 65-74 years old. High-grade lymphoblastic and small noncleaved-cell lymphomas are the only subtypes of B-cell NHL that are observed more commonly in children and young adults.

NHL is more common in men: the reported incidence is 23.0 cases per 100,000 population in men, compared with 15.8 cases per 100,000 population in women. However, the incidence of NHL in some anatomic sites, such as the thyroid, may be higher in women.[2]

The incidence of NHL is highest in Whites: it is reported to be 24.7 cases per 100,000 population in White men, compared with 20.2 and 17.4 cases per 100,000 population in Hispanic and African-American men, respectively. The incidence rates are lowest among Asians, Pacific Islanders, and Native Americans.[2]

Overall, the prognosis for non-Hodgkin lymphoma (NHL) varies with the histology, the stage of disease at diagnosis, the response of disease to therapy, and other factors as listed in the International Prognostic Index (IPI) score.

 The IPI was originally designed as a prognostic factor model for aggressive NHL, but can be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen.[9] Separate indices have been developed for follicular and mantle cell lymphoma.[10, 11, 12]

The IPI includes the following risk factors (for each factor that is present, the patient receives 1 point)[9] :

• Age ≥60 y
• Elevated lactate dehydrogenase (LDH) level
• Stage III or IV disease
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2
• Two or more extranodal sites

Based on the IPI score, patients can be categorized as follows:

• Low risk (0-1)
• Low-intermediate risk (2)
• High-intermediate risk (3)
• High risk (4-5)

With this model, relapse-free and overall survival rates at 5 years are as follows:

• 0-1 risk factors - 75%
• 2-3 risk factors - 50%
• 4-5 risk factors - 25%

Lymphadenopathy is the most common manifestation of lymphoma. Lymphadenopathy may wax and wane. Spontaneous remissions have been documented, most commonly in patients with low-grade lymphomas.

Systemic symptoms (B symptoms) known to be associated with adverse prognosis include the following:

• Unexplained fevers
• Night sweats
• Weight loss

Organ-specific symptoms that may lead to identification of specific sites of involvement include the following:

• Shortness of breath, chest pain, cough
• Abdominal pain and distention
• Bone pain
• Central nervous system (CNS) symptoms

Typical physical examination findings include the following:

• Pallor (suggesting anemia)
• Purpura, petechiae, or ecchymoses (suggesting thrombocytopenia)

Findings in patients with an advanced high-grade lymphoma may include the following:

• High fever
• Tachycardia
• Respiratory distress

Examples of findings that might direct further investigations and subsequent therapy include the following:

• Pharyngeal involvement
• Thyroid mass
• Evidence of pleural effusion
• Abdominal mass
• Testicular mass
• Cutaneous lesions

The initial evaluation of the patient with newly diagnosed non-Hodgkin lymphoma (NHL) must establish the precise histologic subtype, the extent and sites of disease (localized or advanced; nodal or extranodal), and the patient's general health status. These studies help to determine the appropriate therapy and the patient's prognosis.

Tissue Biopsy

Incisional or excisional biopsy is preferred for the initial diagnosis; core needle biopsy is discouraged except for cases in which a lymph node is not easily accessible. Fine-needle aspiration is not an acceptable diagnostic tool; however, in selected circumstances it can be used in combination with immunohistochemistry and flow cytometry.

Flow cytometry and immunohistochemical stains of the biopsied material should be performed to confirm the diagnosis and for accurate subtyping

Laboratory studies are as follows:

• Complete blood cell count (CBC) with differential and examination of a peripheral smear – To assess bone marrow function and rule out the presence of abnormal circulating cells in the peripheral blood
• Screening chemistries – To assess renal and hepatic function and measure serum glucose, calcium, albumin, lactate dehydrogenase (LDH), and beta2-microglobulin
• Serum protein electrophoresis – Frequently appropriate
• HIV serology – Appropriate for patients with risk factors, especially those with large cell or small noncleaved-cell histologies

Immunoglobulin gene rearrangement

Immunoglobulin (Ig) gene rearrangement is useful for differentiating a B-cell lymphoproliferative process from a monoclonal or reactive proliferation of lymphocytes. This technique not only provides a specific marker for B cells but also is a true marker for monoclonality.

Polymerase chain reaction

Polymerase chain reaction (PCR) is used to assess minimal residual disease. This technique has generally been applied to the t(14;18) translocation and the associated bcl-2 gene.

Whereas PCR positivity for bcl-2 gene rearrangements can be found in healthy individuals, patients with lymphoma in remission who show positive results for bcl-2 gene rearrangements by PCR in the blood or bone marrow are more likely to experience relapse than patients who do not have this abnormality. However, the correlation between relapse and PCR positivity is not perfect, and, at present, PCR is still considered a research tool.

Fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) is the preferred imaging modality for staging FDG-avid nodal lymphomas, while CT alone is preferred for FDG-nonavid and variably FDG-avid histologies.[1]

For these purposes, essentially all nodal lymphoma histologies are considered FDG-avid except the following:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
• Mycosis fungoides
• Marginal zone lymphoma

Although PET/CT is generally not useful for staging these more indolent histologies, it may be helpful in some circumstances (eg, to identify a preferred biopsy site if aggressive transformation is suspected).  

A dedicated contrast-enhanced CT scan may be required in addition to the PET/CT to define the extent of disease in special situations, such as in the setting of lymphadenopathy close to bowel or if there is compression or thrombosis of blood vessels. Additional tests may be helpful in the evaluation of specific disease sites. Specific evaluation of the gastrointestinal tract, liver, spleen, central nervous system, skeleton, or genitourinary tract is reserved for patients with symptoms or those at particularly high risk for involvement of these sites.

The histologic findings in B-cell non-Hodgkin lymphoma (NHL) are varied. The salient features of the most common subtypes are described below.

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) is a neoplasm composed of monomorphic small, round to slightly irregular B lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, admixed with prolymphocytes and paraimmunoblasts forming proliferation centers in tissue infiltrates.

The lymph node architecture is effaced, with a pseudofollicular pattern of regularly distributed pale areas corresponding to proliferation centers containing larger cells in a dark background of small cells. The predominant cell type is the small lymphocyte. Mitotic activity is usually low. The size of proliferation centers and the number of paraimmunoblasts vary from case to case, but there is no correlation between lymph node histology and clinical course.

On peripheral blood smears and bone marrow aspirate smears the CLL/SLL cells are small lymphocytes with clumped chromatin and scant cytoplasm. Smudge or basket cells are typically seen in peripheral blood smears.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal lymphoma composed of morphologically heterogeneous small B cells, including marginal zone (centrocytelike) cells, small lymphocytes, and scattered immunoblast and centroblastlike cells.

The lymphoma cells infiltrate around reactive B-cell follicles, external to a preserved follicle mantle, in a marginal zone distribution and spread out to form larger confluent areas that eventually overrun some or most of the follicles. There is plasma cell differentiation in a proportion of the cases. In epithelial tissues, the neoplastic cells typically infiltrate the epithelium, forming lymphoepithelial lesions.

Nodal marginal zone lymphoma

Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell neoplasm that morphologically resembles lymph nodes involved by marginal zone lymphoma of extranodal or splenic types, but without evidence of extranodal or splenic disease.

Follicular lymphoma

Follicular lymphoma is a neoplasm composed of follicle center B cells (typically both centrocytes and centroblasts) that usually has at least a partially follicular pattern. It is graded by counting or estimating the absolute number of centroblasts in 10 neoplastic follicles, expressed per 40× high-power microscopic field (hpf). Grade 1 and grade 2 cases have a marked predominance of centrocytes and only a few centroblasts (grade 1, 0-5 centroblasts/hpf; grade 2, 6-15 centroblasts/hpf; grade 3, >15 centroblasts/hpf).

Neoplastic follicles comprising cleaved cells (centrocytes) and larger cells with vesicular nuclei and prominent 2-3 nucleoli (centroblasts).

If diffuse areas of any size composed predominantly or entirely of blastic cells are present in any case of follicular lymphoma, a diagnosis of diffuse large B-cell lymphoma (DLBCL) is also made. Peripheral blood involvement sufficient to produce lymphocytosis (usually < 20,000/µL) is observed in about 10% of patients. Bone marrow involvement occurs in 65% of patients and characteristically takes the form of paratrabecular lymphoid aggregates. Splenic white pulp and hepatic portal triads are also frequently involved.

Mantle cell lymphoma

Mantle cell lymphoma is a B-cell neoplasm generally composed of monomorphic small to medium-sized lymphoid cells with irregular nuclear contours and a cyclin-D1 translocation (see the image below). Neoplastic transformed cells resembling centroblasts, immunoblasts, or paraimmunoblasts and proliferation centers are absent. Hyalinized small vessels are commonly seen.

Mantle cell lymphoma. Small lymphoid cells with oval to slightly irregular nuclei and clumped chromatin and rare admixed pink histiocytes.

A spectrum of morphologic variants is recognized. The blastoid and pleomorphic variants are considered to have poorer prognosis and to be of important clinical significance. Further evaluation of the proliferation fraction, either by counting mitotic figures or estimating the proportion of Ki67-positive nuclei, is important because of its prognostic impact.

Diffuse large B-cell lymphoma

The common morphologic features that unite the various forms of DLBCL are the relatively large cell size (usually 4-5 times that of a small lymphocyte) and a diffuse pattern of growth.[13] In other respects, a fair degree of morphologic variation exists.

In most cases, the tumor cells have a round or oval nucleus that appears vesicular because of margination of chromatin at the nuclear membrane, but large multilobed or cleaved nuclei predominate in some cases (see the image below). Nucleoli may be 2-3 in number and located adjacent to the nuclear membrane, or they may be single and centrally placed. Cytoplasm is usually present in moderate abundance and may be pale or basophilic.

Diffuse large B-cell non-Hodgkin lymphoma. Large cells with abundant cytoplasm and large round-ovoid nuclei with thick nuclear membrane and multiple prominent nucleoli.

Other more anaplastic tumors may contain multinucleated cells with large inclusionlike nucleoli that closely resemble Reed-Sternberg cells, and phenotyping is often necessary to distinguish these 2 entities.

An immunophenotypical subdivision of DLBCL has been proposed that uses a combination of antibodies to CD10, bcl-6, and MUM-1 to divide DLBCL into germinal center B cell-like (GCB) and nongerminal center B cell-like (non-GCB) varieties. Cases that are CD10 positive or CD10 negative and bcl-6 positive but MUM-1 negative are regarded as GCB type, whereas all others are regarded as non-GCB or activated B-cell (ABC) type.

This immunophenotypical subdivision does not completely correlate with gene expression-based subgrouping of DLBCL. In the non-GCB or the ABC, bcl-2 expression is known to be associated with poor patient outcome.

DLBCL may be classified in several different ways. Common morphologic variants of DLBCL, not otherwise specified, include centroblastic, immunoblastic, anaplastic, and rare morphologic variants. Molecular subgroups include GCB and ABC. Immunohistochemical subgroups include CD5-positive DLBCL, GCB, and non-GCB.

DLBCL subtypes include the following:

• T-cell/histiocyte rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg
• Epstein-Barr virus (EBV)–positive DLBCL of the elderly

Other lymphomas of large B cells include the following:

• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma
• Plasmablastic lymphoma
• Large B-cell lymphoma arising in human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease
• Primary effusion lymphoma

Borderline cases include the following:

• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin disease

Burkitt lymphoma

Burkitt lymphoma is a B-cell lymphoma with an extremely short doubling time that often presents in extranodal sites or as an acute leukemia. Involved tissues are effaced by a diffuse infiltrate of monomorphic, medium-sized (nuclei similar or smaller to those of histiocytes) transformed lymphoid cells.

The nuclei are round with finely clumped and dispersed chromatin, with multiple basophilic medium-sized paracentrically situated nucleoli. The cytoplasm is deeply basophilic and usually contains lipid vacuoles (see the images below). A high mitotic index is typical, as is apoptotic tumor cell death, accounting for the presence of numerous tissue macrophages with their ingested tissue debris. These macrophages are often surrounded by a clear space, creating the characteristic starry sky pattern.

Burkitt lymphoma. Normal architecture is entirely replaced by lymphoma cells and evenly dispersed macrophages, starry sky (250×).

Burkitt lymphoma cells with round noncleaved nuclei and strongly basophilic cytoplasm (1000×).

Primary mediastinal (thymic) large B-cell lymphoma

Primary mediastinal large B-cell lymphoma is a diffuse large B-cell lymphoma that arises in the mediastinum from a putative thymic B-cell origin and has distinctive clinical, phenotypic, and genotypic features. Histologically, it is commonly associated with compartmentalizing alveolar fibrosis (see the image below). The cells are medium-sized to large and have abundant clear/pale cytoplasm and round to oval nuclei. A few cases have multilobated and pleomorphic nuclei resembling the Reed-Sternberg cells of Hodgkin lymphoma.

Compartmentalizing fibrosis and infiltrate of medium-sized to large lymphoid cells.

Flow cytometry analysis can help provide accurate diagnosis of some categories of B-cell lymphoma. Characteristic immunophenotypes are associated with major types of lymphoma (see the table below).

Table 2. Characteristic Immunophenotypes of Major Subtypes of Lymphoma (Open Table in a new window)

The Ann Arbor staging system has commonly been used for patients with non-Hodgkin lymphoma (NHL).[14] This system divides NHL into four stages and subclassifies it into A and B categories. The B designation is applied to individuals with any of the following well-defined generalized symptoms:

• Unexplained loss of greater than 10% of body weight in the 6 months before diagnosis
• Unexplained fever with temperature higher than 38°C
• Drenching night sweats

In 2014, the International Conference on Malignant Lymphomas (a multidisciplinary team of researchers representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan, and Australasia) met in Lugano, Italy and created a modification of the Ann Arbor system, the Lugano classification.[15] The 2015 NCCN Non-Hodgkin’s Lymphomas guidelines adopted the Lugano classification.[16]

The Lugano classification (see Table 3, below) includes four stages. However, the A and B subclassifications are not required in NHL since they are not prognostic.

Table 3. Lugano Modification of the Ann Arbor Staging System. (Open Table in a new window)

Other staging considerations

The following factors are not a part of the Ann Arbor staging system, but have important prognostic value in B-cell NHL:

• Age
• Performance status
• Tumor size
• Lactate dehydrogenase (LDH) values
• Number of extranodal sites involved

To identify subgroups of patients most likely to relapse, the International Prognostic Index (IPI) was compiled for 2031 patients with aggressive NHL.[9] The IPI has been validated by several cancer centers and has been incorporated into new trials designed by various cooperative groups. (See Prognosis.)

Treatment of B-cell lymphoma varies according to the disease type. See Guidelines for first- and second-line treatment recommendations. 

Chimeric antigen receptor (CAR) T-Cell therapy

In CAR T-cell therapy, the patient's own T-cells are genetically engineered to express a specific CAR; in the case of B-cell lymphoma, this is typically CD19. After a blood sample has been obtained 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.

The infused T cells become activated when they recognize the target antigen on the surface of the tumor. Once activated, the T cells undergo massive expansion in the body, proliferating and producing multiple different cytokines. These cytokines improve the T cells’ function, helping them traffic to the tumor site and start killing the tumor cells by expressing cytotoxic molecules (eg, granzymes and perforins).

Cytokine release syndrome is a potentially life-threatening adverse effect of CAR T-cell therapy. Tocilizumab is approved for the treatment of   severe or life-threatening cytokine release syndrome induced by CAR T-cell therapy.[17]

For full discussion of CAR T-cell therapy, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T-Cells

Axicabtagene ciloleucel 

In 2017, the US Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta), a CD19-directed CAR T-cell therapy, for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after at least two other lines of systemic treatment have failed. It is not indicated for the treatment of patients with primary central nervous system lymphoma.

FDA approval was based on results from the ZUMA-1 study, an open-label, multicenter trial that enrolled 111 patients from 22 institutions. Study patients received the target dose of axicabtagene ciloleucel (2 × 106 cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with R/R DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. After receiving axicabtagene ciloleucel, 40% of patients maintained their complete response at 6-month follow-up.[18, 19]

The trial had a median survival follow-up of 8.7 months. Common adverse reactions included cytokine release syndrome, hypotension, encephalopathy and febrile neutropenia. In addition, prolonged cytopenias, hypogammaglobulinemia, and serious infections can occur.[18]

Tisagenlecleucel 

Tisagenlecleucel (Kymriah) is approved for treatment of R/R DLBCL in adult patients who have received 2 or more lines of systemic therapy. Indications include DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Approval was based on the single-arm, open-label, multicenter, phase 2 JULIET trial in adults with R/R 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 stem cell transplantation.[20]

Study patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy. The overall response rate for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a complete response (CR) rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared with a best overall response of partial response (PR). In patients who achieved CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration in patients in PR was 3.4 months (95% CI: 1.0, NE). Common adverse reactions included cytokine release syndrome, hypogammaglobulinemia, infections, and encephalopathy.[21]

Lisocabtagene maraleucel

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

Safety and efficacy were evaluated in TRANSCEND, an open-label, multicenter, single-arm trial. Patients (n=268) with R/R large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of those patients, 54% achieved CR (95% CI: 47%-61%) and 19% achieved PR (95% CI:14%-26%). Median duration of response for all responders was 16.7 months (CR was not reached; PR: 1.4 months [95% CI: 1.1-2.2 months). Among all responders, 65% had remission for at least six months and 62% had remission lasting at least nine months. Most common adverse reactions were fatigue, cytokine release syndrome, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.[22]

Natural killer cell therapy

Unlike anti-CD19 CAR T-cell therapy, treatment with natural killer (NK) cells that have been modified to express an anti-CD19 has been shown to promote no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. A phase 1/2 trial of HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood, in 11 patients with relapsed or refractory CD19-positive cancer, reported response to treatment in the majority of cases, without the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease.[23]

Monoclonal antibodies

Polatuzumab vedotin-piiq (Polivy) is an FDA-approved anti-CD79b antibody drug indicated for multiply relapsed or refractory DLBCL. A clinical trial has shown longer duration of remission when polatuzumab is added to bendamustine and rituximab. Common reported adverse effects include progressive multifocal leukoencephalopathy (PML), peripheral neuropathy, tumor lysis syndrome and fetal toxicity.[24, 25]

Other monoclonal antibodies undergoing phase 2 clinical trials include the following:

• Brentuximab vedotin 
• Blinatumomab 
• Tafasitamab 

Mosunetuzumab is the newest monoclonal antibody; it binds to CD3 and CD20. A phase 1/2 clinical trial showed long-lasting responses with a very tolerable safety profile in patients with B-cell non-Hodgkin lymphoma (NHL) who had received at least 1 prior therapy, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and for whom there was no available therapy that would be expected to improve survival. Compared with patients who had already progressed despite CAR T-cell therapy, patients treated with mosunetuzumab showed better response (objective response rate 37%,complete remission 22%). Common adverse reaction included cytokine release syndrome, headache, and insomnia.[26]

Hematopoietic cell transplantation 

Patients with relapsed or refractory DLBC should be considered for autologous hematopoietic cell transplantation (HCT) when CAR T-cell therapy is not available. For transplant-ineligible patients, the goal of care should be limiting the symptoms. CAR T-cell therapy can be administered. Such patients can participate in newer clinical trials.[16]

Complications arising from therapy include the following:

• Neutropenic fever after chemotherapy is not uncommon and can be life-threatening if associated with sepsis.
• Tumor lysis syndrome after chemotherapy is possible in patients with bulky disease.
• Severe hemorrhagic cystitis is sometimes observed after high-dose cyclophosphamide therapy.
• Cytokine release syndrome (CRS) is sometimes associated with CAR-T therapy. 

Radiation oncologists are often consulted because radiation plays a role in management of B-cell lymphoma; it is considered the treatment of choice in early-stage indolent lymphoma and has a role in consolidation of treatment in localized aggressive lymphoma.

A surgical consultation is indicated when central venous access devices are employed, especially when stem cell or bone marrow transplantation is considered.

Patients with lymphoma who are being managed at peripheral health care facilities may require their care to be transferred to a tertiary care or research institute for access to clinical trials and investigational agents.

Patients who are profoundly ill or are experiencing significant complications from either the disease or its therapy also warrant transfer to a facility that is better equipped to handle such emergencies.

Typically, no dietary restrictions exist for patients with non-Hodgkin lymphoma (NHL). Patients with prolonged neutropenia following chemotherapy, especially those undergoing high-dose chemotherapy with hematopoietic precursor cell rescue, are provided with a reduced-bacteria diet. Patients with high tumor burden undergoing chemotherapy may be at risk for tumor lysis syndrome and sometimes require a diet low in uric acid and potassium.

In 2014, the International Conference on Malignant Lymphomas (a multidisciplinary team of researchers representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan, and Australasia) published guidelines for the evaluation, staging, and response assessment of patients with malignant lymphomas. This staging system is known as the Lugano Modification of the Ann Arbor staging system.[15]  In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system.[16]

The revised recommendations for staging include the following[15] :

• Positron emission tomography–computed tomography (PET-CT) is preferred for fluorodeoxyglucose (FDG)-avid lymphomas; CT is indicated for non-avid lymphomas

• PET-CT is preferred for pretreatment assessment and routine staging

• Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning

• PET-CT is preferred for determining splenic involvement, with cutoff for splenomegaly of more than 13 cm

• Bone marrow biopsy is usually not required if the PET-CT scan indicates bone or marrow involvement but if the scan is negative, a bone marrow biopsy is indicated to identify involvement by discordant histology, if clinically relevant

• Liver size is not a reliable measure; liver involvement is suggested by diffusely increased or focal uptake, with or without focal or disseminated nodules

• Prior Ann Arbor staging divided patients according to absence (A) or presence (B) of disease-related symptoms (B symptoms include weight loss >10%, fever, drenching night sweats); these are not required in NHL staging since they are not prognostic

In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification, as shown in Table 1, below[16, 15] :

  Table 4. Non-Hodgkin lymphoma staging. (Open Table in a new window)

*Stage II bulky disease is considered limited or advanced; this distinction is made on the basis of histology and a number of prognostic factors.

Suffixes A and B are not required. X for bulky disease replaced with documenting of largest tumor diameter. Definition of “bulky” disease varies, depending on lymphoma histology.

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive non-Hodgkin lymphoma (NHL), also appears to be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen.[9]  Separate indices have been developed for follicular and mantle cell lymphoma.[10, 11, 12]

The IPI includes the following risk factors[9] :

• Age ≥ 60 y
• Elevated lactate dehydrogenase (LDH) level
• Stage III or IV disease
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2
• Two or more extranodal sites

Each factor is worth 1 point. Based on the IPI score, patients can be categorized as follows[9] :

• Low risk (0-1 point)
• Low-intermediate risk (2 points)
• High-intermediate risk (3 points)
• High risk (4-5 points)

With this model, relapse-free and overall survival rates at 5 years are as follows:

• 0-1 risk factors - 75%
• 2-3 risk factors - 50%
• 4-5 risk factors - 25%

World Health Organization Classification

In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes.[3, 28]

National Comprehensive Cancer Network (NCCN) guidelines note that that grade 3B is commonly treated as diffuse large B-cell lymphoma (DLBCL), whereas opinion is divided on whether to treat grade 3A as FL or DLBCL. FL of any grade that is found to contain an area of DLBCL should be managed as a DLBCL.[16]

Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.[3]

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL[16] :

• Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, or CD23
• Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
• Molecular analysis to detect: antigen receptor gene rearrangements; BCL2 rearrangements
• Karyotype or FISH: t(14;18); BCL6, 1p36, IRF4/MUM1 rearrangements
• Immunohistochemistry panel: Ki-67; IRF4/MUM1 for FL grade 3, cyclin D1

Risk stratification

The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary[29] :

• Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm
• Any nodal or extranodal tumor mass with a diameter of ≥7 cm
• B symptoms
• Splenomegaly
• Pleural effusions or peritoneal ascites
• Cytopenias (leukocytes < 1.0 x 10 ⁹/L and/or platelets < 100 x 10 ⁹/L)
• Leukemia (>5.0 x 10 ⁹/L malignant cells)

The NCCN recommends both the GELF criteria and the 2004 Follicular Lymphoma International Prognostic Index (FLIPI) for risk stratification. The FLIPI includes the following risk factors[11] :

• Age >60 y
• Ann Arbor Stage III-IV
• Lactate dehydrogenase (LDH) level above the upper limit of normal
• Hemoglobin level < 12 g/dL
• Five or more nodal sites of disease

For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows[11] :

• Low risk (0 or 1 point)
• Intermediate risk (2 points)
• High risk (≥3 points)

In 2009, the International Follicular Lymphoma Prognostic Factor Project published an updated score, FLIPI2. The FLIPI2 includes the following risk factors (as with FLIPI1, each factor is worth 1 point)[10] :

• Age >60y
• β2-microglobulin (B2M) above the upper limit of normal
• Bone marrow involvement
• Hemoglobin level < 12 g/dL
• Longest diameter of the largest involved node >6 cm

Based on the FLIPI2 score, patients can be categorized as low, intermediate, or high risk.[10]

Treatment

The NCCN guidelines recommend the following regimens as preferred first-line therapy (in alphabetical order)[16] :

• Bendamustine + obinutuzumab or rituximab
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + obinutuzumab or rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumab or rituximab
• Lenalidomide + rituximab

Rituximab (375 mg/m2 weekly for 4 doses) may be considered for patients with a low tumor burden. Lenalidomide + obinutuzumab (category 2B recommendation)

For elderly or infirm patients who, in the opinion of treating physician, are unlikely to tolerate most of the above regimens, suggested options for first-line, second-line, and subsequent therapy include the following:

• Rituximab (preferred) (375 mg/m ² weekly for 4 doses)
• Chlorambucil ± rituximab
• Cyclophosphamide ± rituximab
• Chlorambucil ± rituximab
• Ibritumomab tiuxetang (category 2B)

First-line regimens for consolidation or extended dosing (optional) include the following:

• Rituximab maintenance – 375 mg/m ², one dose every 8 to 12 wk for 12 doses, for patients initially presenting with high tumor burden (category 1)
• Obinutuzumab maintenance – 1000 mg every 8 wk for 12 doses
• Rituximab consolidation –375 mg/m ² one dose every 8 weeks for 4 doses If initially treated with single-agent rituximab
• Ibritumomab tiuxetan (category 2B)

Preferred regimens for second-line and subsequent therapy are as follows:

• Bendamustine + obinutuzumab or rituximab
• CHOP + obinutuzumab or rituximab
• CVP + obinutuzumab or rituximab
• Rituximab
• Lenalidomide ± rituximab
• Ibritumomab tiuxetan
• Lenalisomide if patient is not a candidate for anti-CD20 monoclonal antibody therapy
• Lenalidomide + obinutuzumab
• Obinutuzumab
• PI3K inhibitors for relapsed or refractory after 2 prior therapies

  • Copanlisib
  • Duvelisib
  • Idelalisib
• Umbralisib- Dual inhibitor of PI3K and casein kinase epsilon

Options for second-line consolidation or extended dosing (optional) include the following:

• Rituximab maintenance – 375 mg/m ^{2 ,}one dose every 12 wk for 2 years (category 1)
• Obinutuzumab maintenance for rituximab-refractory disease (1 g every 8 wk for total of 12 doses)
• High-dose therapy with autologous stem cell rescue
• Allogeneic stem cell transplant for highly selected patients

Histologic transformation to DLBC

• Anti-CD19 CAR T-cell therapy (only after 2 prior chemoimmunotherapy regimens)

  • Axicabtagene ciloleucel
  • Tisagenleclecleucel
  • Lisocabtagene maraleucel

Mucosa-associated lymphoid tissue (MALT) lymphomas are usually localized and are most often observed in the stomach, lung, salivary gland, thyroid, orbit, conjunctiva, and lacrimal gland. An association of MALT lymphomas with autoimmune disease is well known.

The development of gastric MALT lymphomas has been attributed to antigenic stimulation associated with chronic Helicobacter pylori gastritis. Indeed, both the NCCN and ESMO guidelines recommend antibiotic eradication of H pylori as first-line treatment for H pylori–positive patients, including t(11;18)-positive patients. After eradication of H pylori, t(11;18) patients have a < 5% response rate to the tumor. They will require involved-site radiation therapy (ISRT) or rituximab. In H pylori –negative patients, involved-site radiation therapy (ISRT), 30 Gy, is the preferred treatment option. Rituximab is an option if radiation therapy is contraindicated.[16]

For non-gastric MALT lymphomas, radiotherapy is preferred but surgery is also an appropriate treatment (and in most cases is required to make the diagnosis). Further treatment may not be needed. When the tumor is incompletely excised, radiotherapy should be considered. In the minority of patients presenting with a more widespread disease, systemic chemotherapy is effective. The majority of stage III-IV MALT lymphomas respond to treatment similar to that for follicular lymphoma.[16]

Therapy for gastric MALToma

European Society for Medical Oncology (ESMO) guidelines for treatment of gastric marginal zone lymphoma of the MALT type include the following recommendations[30] :

• Helicobacter pylori eradication therapy must be given to all gastric MALT lymphomas, independently of stage, and may be considered for H pylori–negative cases
• Following initiation o f Helicobacter pylori treament, testing should be  at least 6 weeks after starting eradication therapy and at least 2 weeks after PPI withdrawl to confirm eradication. 
• If  Helicobacter pylori is persistant, alternative antibiotics and PPI should be considered
• If eradicated, endoscopy assessment with biopsy should be done within 3 to 6 months to see regression of lymphoma.
• After antibiotic treatment, radiation and systemic oncological therapies should be used, depending on the stage of disease
• Radiotherapy might be the preferred option for localized disease (eg, 24–30 Gy to the stomach and perigastric nodes given in 3 to 4 weeks)
• Chemoimmunotherapy is preferred in cases of histological transformation or contraindications to radiotherapy; patients with t(11;18) will most probably be unresponsive to alkylating agents as a sole treatment
• No accepted standard chemotherapy has been established, but oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogues (fludarabine, cladribine) and the combination of rituximab and bendamustine or chlorambucil or linalidomide have shown benefit
• No data support a rituximab maintenance strategy.
• Aggressive anthracycline-containing regimens are not usually necessary and should be reserved for the few patients with a very aggressive clinical course or histological transformation
• Surgery has no role in initial treatment

Diagnosis

Mantle cell lymphoma (MCL) is diagnosed in accordance with the World Health Organization criteria for hematological neoplasms and detection of Cyclin D1 expression or the t(11;14) translocation along with mature B-cell proliferation.[30] The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL[16] :

• Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, Ki-67
• Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
• Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(11;14),  t(14;18).
• Immunohistochemistry for SOX 11, which is expressed in approximately 90% of MCLs but is negative in all other B-cell lymphoid neoplasms except Burkitt lymphomas and lymphoblastic lymphomas

Risk stratification

The European Society for Medical Oncology (ESMO) recommends the combined MCL International Prognostic Index (cMIPI) for risk stratification.[31]  The MIPI includes the following risk factors[12] :

• Age: 50-59 (1 point); 60-69 (2 points); ≥70 (3 points)
• Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (2 points)
• Lactate dehydrogenase level (ratio to upper limit of normal): 0.67-0.99 (1 point); 1.00-1.49 (2 points); ≥1.50 (3 points)
• White blood cell count (× 10 ⁹/L): 6700-9999 (1 point); 10,000-14,999 (2 points); ≥15,000 (3 points)

An Internet-based cMIPI calculator is available web-based calculator: www.european-mcl.net/de/clinical_mipi.php.

Based on the MIPI score, patients can be categorized as follows[12] :

• Low risk (0-3 points)
• Intermediate risk (4-5 points)
• High risk (≥6 points)

In addition, both the NCCN and ESMO recommend assaying Ki-67 proliferative antigen to evaluate cell proliferation. Low Ki-67 (< 30%) is associated with a more favorable prognosis; however, it is not used to guide treatment decisions.[16, 31]

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows[16, 31]

• Chemotherapy followed by involved-site radiation therapy (ISRT), 30-36 Gy, is the preferred treatment option for limited stage I or II (non-bulky) disease, although this presentation is rare

• For advanced-stage disease in younger patients and selected elderly fit patients, the recommended approach is aggressive induction therapy, followed by consolidation therapy consisting of high-dose therapy with autologous stem cell rescue

• Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.

• In elderly fit patients, less-aggressive induction regimens followed by rituximab maintenance is recommended by both NCCN and ESMO

• For elderly patients who are not candidates for any of the above chemotherapy regimens, palliative chemotherapy should be considered, using milder chemo-immunotherapy regimens (eg, chlorambucil plus rituximab, bendamustine plus rituximab)

• For relapsed or refractory disease, recommendations include high-dose therapy with autologous stem cell rescue and second-line agents; allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation

Induction therapy

For induction therapy, aggressive regimens include the following:

• HyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone, alternating with high-dose methotrexate and cytarabine) + rituximab
• NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine)
• Alternating R-CHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone)/(rituximab, dexamethasone, high-dose cytarabine [Ara-C], cisplatin [Platinol])
• RDHAP (rituximab, dexamethasone, cytrabine, platinum)
• Other recommended regimens include Bendamustine + rituximab

Less aggressive regimens include the following:

• Bendamustine + rituximab
• VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin [Adriamycin], and prednisone)
• R-CHOP
• Lenalidomide + rituximab
• Modified rituximab-HyperCVAD in patients older than 65 y
• RBAC500 (Rituximab, bendamustine, cytarabine) 
• Maintenance therapy: Rituximab maintenance every 8 weeks until progression or intolerance (category 1 following RCHOP; 2-5 y following modified Rituximab-HyperCVAD).

Consolidation therapy

In patients who are candidates for it, high-dose therapy followed with autologous stem cell rescue shouild be considered.

Second-line therapy

Second-line therapy regimens include the following:

• Bendamustine ± rituximab
• Bendamustine, bortezomib, and rituximab (category 2B)
• Bortezomib ± rituximab
• Cladribine + rituximab
• FC (fludarabine, cyclophosphamide) ± rituximab (category 3)
• Ibrutinib
• Ibrutinib, lenalidomide, rituximab (category 2B)
• Lenalidomide ± rituximab
• PCR (pentostatin, cyclophosphamide, rituximab) (category 3)
• PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab (category 3)
• Venetoclax
• See second-line therapy for DLBCL (BCEL-C 2 of 4) without regard to transplantability

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of diffuse large B-cell lymphoma (DLBCL)[16] :

• Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, MYC
• Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20
• Additional IHC panel for subtyping: Cyclin D1, kappa/lambda, CD30, CD138, EBER-ISH, ALK, HHV8
• Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(14;18),  t(3;v),  t(8;14),  t(8;v)

IHC should include adequate markers to differentiate the two subtypes of DLBCL: activated B-cell type (ABC) and germinal center B-cell type (GCB). The subtypes are genetically different diseases, and survival in patients with the ABC subtype is worse than in those with GCB.[32]

Risk stratification

The NCCN and the European Society for Medical Oncology (ESMO) recommend use of the International prognostic index (IPI) for all patients. Age-adjusted International Prognostic Index (aa-IPI) should be used for risk stratification of patients aged 60 years and younger.[16, 33]

The IPI includes the following risk factors:

• Age >60 years
• Elevated serum lactate dehydrogenase (LDH) level
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2
• Stage III or IV disease
• Extranodal involvement >1 site

Each risk factor is worth 1 point. On the basis of the IPI score, patients can be categorized as follows:

• Low risk (0-1 point)
• Low-intermediate risk (2 points)
• High-intermediate risk (3 points)
• High risk (4-5 points)

The aa-IPI includes the following risk factors (1 point is allotted for each factor)[9] :

• Elevated LDH level
• Stage III or IV disease
• ECOG performance status ≥2

Based on the aa-IPI score, patients can be categorized as follows[9] :

• Low risk (0 points)
• Low-intermediate risk (1 point)
• High-intermediate risk (2 points)
• High risk (3 points)

Treatment

National Comprehensive Cancer Network recommendations[16]

First-line therapy (in alphabetical order) options are as follows:

• R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine, prednisone) (category1)
• Dose-dense R-CHOP (category 3)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin) + rituximab (category 2B)

First-line therapy options for patients who have poor left ventricular function or are very frail are as follows:

• RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine)
• RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone)
• DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab
• RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone)
• RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)

Regimens for patients >80 years of age with comorbidities are as follows:

• R-mini-CHOP
• RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)

First-line consolidation (optional) regimens are as follows:

• For patients 60–80 y of age: Lenalidomide maintenance (category 2B)
• For age-adjusted IPI high-risk disease: High-dose therapy with autologous stem cell rescue (category 2B) 

Regimens for concurrent presentation with CNS disease are as follows:

• Parenchymal: 3 g/m ² or more of systemic methotrexate given on day 15 of a 21-day R-CHOP cycle with growth factor support
• Leptomeningeal: Intrathecal methotrexate/cytarabine; consider Ommaya reservoir placement and/or systemic methotrexate (3–3.5 g/m ²)

Second-line and subsequent therapy (intention to proceed to high-dose therapy) regimens are as follows:

• DHAP (dexamethasone, high-dose cytarabine [Ara-C], cisplatin [Platinol]) ± rituximab
• ESHAP (etoposide, methylprednisolone [Solu-Medrol], high-dose cytarabine, cisplatin) ± rituximab
• GDP (gemcitabine, dexamethasone, cisplatin or carboplatin) ± rituximab
• GemOx (gemcitabine, oxaliplatin) ± rituximab
• ICE (ifosfamide, carboplatin, etoposide) ± rituximab
• MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab

Second-line and subsequent therapy regimens, for patients who are not candidates for high-dose therapy, include the following:

• Bendamustine ± rituximab
• Brentuximab vedotin for CD30+ disease (category 2B)
• CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± rituximab - PO and IV
• CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± rituximab
• DA-EPOCH ± rituximab
• GDP ± rituximab or (gemcitabine, dexamethasone, carboplatin) ± rituximab
• GemOx ± rituximab
• Gemcitabine, vinorelbine ± rituximab (category 3)
• Lenalidomide ± rituximab (non-GCB DLBCL)
• Rituximab

Follow-up

A PET-CT scan should be performed to confirm complete remission (CR). Patients in CR should receive clinical follow-up with a history and physical examination and laboratory studies (eg, complete blood cell count, comprehensive metabolic panel, lactate dehydrogenase level) every 3-6 months for 5 years and then yearly or as clinically indicated. Imaging studies (CT scan) should be performed no more often than every 6 mo for 2 years after the completion of treatment, and then only as clinically indicated.[16]

Classification

The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL)[3] :

• Endemic (eBL) – The most common form of childhood malignancy in equatorial Africa, associated with Epstein-Barr virus (EBV) infection
•  Sporadic (sBL) – The majority of cases are in the United States and Europe; up to 30% are associated with EBV
•  Immunodeficiency associated – Occurs in patients with HIV infection, post-transplantation immunosuppression, and congenital immunodeficiency         

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of Burkitt lymphoma[16] :

• Immunohistochemistry panel: CD45(LCA), CD20, CD3, BCL2, BCL6, Ki-67, TdT  or
• Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT
• Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(8;14),  MYC
• Epstein-Barr encoding region in situ hybridization (EBER-ISH) can be used to identify EBV

Risk stratification

A prognostic scoring system was developed in 2013 using the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors and points assigned are as follows[16] :

• Age 40-59 years or black race/ethnicity: 1 point
• Age 60-79 years or stage III/IV disease: 2 points
• Age 80 years and older: 4 points

The four risk groups based on the scoring system are as follows:

• Low risk (0-1 point)
• Low-intermediate risk (2 points)
• High-intermediate risk (3 points)
• High risk (≥4 points)

With this model, relative survival rates at 5 years are as follows:

• Low risk - 71%
• Low-intermediate risk - 55%
• High-intermediate risk - 41%
• High risk - 29%

Treatment

Induction therapy for low-risk Burkitt lymphoma includes the following:

• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) ± rituximab (3 cycles)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)

Induction therapy for high-risk Burkitt lymphoma includes the following:

• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) ± rituximab

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (for high-risk patients not able to tolerate aggressive treatments) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)

• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)

Second-line therapy (for patients with dsease relapse >6 mo after appropriate first-line therapy)

While no definitive second-line therapies exist, limited data support the following regimens:

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)
• RICE (rituximab, ifosfamide, carboplatin, etoposide); intrathecal methotrexate if have not received previously
• RIVAC (rituximab, ifosfamide, cytarabine, etoposide); intrathecal methotrexate if have not received previously
• RGDP (rituximab, gemcitabine, dexamethasone, cisplatin)High-dose cytarabine + rituximab

Follow-up

The NCCN recommends follow up every 2-3 months for the first year after complete response, then every 3 months for the next year, and every 6 months thereafter. Relapse is rare after 2 years.[16]

In addition to the National Comprehensive Cancer Network (NCCN), the European Organization for Research and Treatment of Cancer (EORTC) and the International Society for Cutaneous Lymphoma (ISCL) published guidelines for the management of primary cutaneous B-cell lymphomas (CBCL).[34]

Classification

The NCCN and EORTC/ISCL guidelines recommend use of the WHO-EORTC classification for cutaneous B-cell lymphomas (CBCL), which distinguishes the following three main types[35] :

• Primary cutaneous marginal zone lymphoma (PC-MZL)

• Primary cutaneous follicle center cell lymphoma (PC-FCL)

• Primary cutaneous diffuse large B-cell, leg type (PC-DLBCL, LT)

Of note, a germinal (or follicle) center phenotype and large cells in a skin lesion is not equivalent to diffuse large B-cell lymphoma (DLBCL) but is consistent with primary cutaneous germinal/follicle center lymphoma.

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of CBCL[16] :

• Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, BCL2, BCL6, IRF4/MUM1

• Additional IHC panel for subtyping: Ki-67, CD43, CD21, CD23, Cyclin D1, kappa/lambda

• Assessment of IgM and IgD expression to distinguish between PC-FCL and PC-DLBCL, leg type

• Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(14;18)

• Bone marrow biopsy in PC-FCL, optional for PC-MZL

Staging

The 2007 TNM classification system of the ISCL/EORTC is used for staging, as shown in Table 3, below.[36]

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma (Open Table in a new window)

Treatment

PC-FCL and PC-MZL

Both the NCCN and EORTC/ISCL guidelines recommend local radiation therapy or excision for T1-2 PC-FCL and PC-MZL.[16, 34]  The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options.[16]

For T3 disease, the NCCN recommends radiation therapy; chlorambucil; or cyclophosphamide, vincristine, and prednisone (CVP) with or without rituximab. Extracutaneous disease should be managed using the treatment guidelines for follicular lymphoma.[16]

EORTC/ISCL guidelines recommend systemic rituximab as the first choice of treatment for patients with extensive skin lesions. Combination chemotherapy (eg, R-COP, R-CHOP) should be considered only in exceptional cases, such as in patients with progressive disease not responding to rituximab or patients developing extracutaneous disease.[34]

PC-DBCL, LT

Both guidelines caution that radiation therapy is less effective in PC-DBCL, LT. R-CHOP with local radiation therapy is recommended as first line of treatment for all stages of DBCL, LT.[16, 34] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed.[34] .

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

Class Summary

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

Pegfilgrastim (Neulasta)

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

Epoetin alfa (Epogen, Procrit)

This agent 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. The biological activity of epoetin alfa 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.

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Ibritumomab tiuxetan (Zevalin Y-90)

A murine monoclonal antibody that targets the CD20 antigen, ibritumomab tiuxetan is chelated to the radioisotopes indium-111 or yttrium-90. It is used in conjunction with rituximab to treat B-cell NHL or rituximab-refractory follicular NHL. The regimen consists of two low doses of rituximab, an imaging dose, two-three whole-body scans, and a therapeutic dose, all of which are delivered in an outpatient setting over 8 days.

Ofatumumab (Arzerra)

Ofatumumab is an anti-CD20 human monoclonal antibody that inhibits B-cell activation in early stages. It is indicated for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

Alemtuzumab (Lemtrada, Campath)

Alemtuzumab is a monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all chronic lymphocytic leukemia cells. It binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an immunoglobulin G1 (IgG1) kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Polatuzumab vedotin (Polatuzumab vedotin-piiq, Polivy)

Polatuzumab is a CD79b-directed antibody-drug conjugate with activity against dividing B cells. MMAE is an antimitotic agent covalently attached to the antibody via a cleavable linker. The monoclonal antibody binds to CD79b, where polatuzumab is internalized and linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis. It is indicated, in combination with bendamustine and a rituximab product is indicated for relapsed or refractory DLBCL, not otherwise specified, after at least 2 prior therapies.

Class Summary

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

Dexamethasone (Decadron, Dexamethasone intensol)

A component of the m-BACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, Oncovin, and dexamethasone) regimen, dexamethasone 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.

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

Prednisone (Prednisone Intensol, Rayos, Deltasone)

A component of several regimens, such as CHOP, 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 metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose dependent or duration dependent.

Class Summary

These agents inhibit cell growth and proliferation and lead to cell death.

Chlorambucil (Leukeran)

Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. It is used mainly to treat indolent lymphomas, particularly chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia. This agent may be preferable for elderly patients with serious comorbid medical problems who require treatment for lymphoma. It is well absorbed orally.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. This agent can be used alone but is mostly used as a component of multiple combination chemotherapy regimens.

Bendamustine (Bendeka, Treanda)

Bendamustine is an alkylating agent that is a bifunctional mechlorethamine derivative. It forms covalent bonds with electron-rich nucleophilic moieties that can lead to cell death. It is active against both quiescent and dividing cells and is indicated for chronic lymphocytic leukemia (CLL).

Cisplatin

Cisplatin is a platinum-containing compound that exerts its antineoplastic effect by covalently binding to DNA, with preferential binding to the 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 to cytoplasmic protein. A bifunctional alkylating agent, once cisplatin is activated to the aquated form in the cell, it binds to DNA, resulting in interstrand and intrastrand cross-linking and denaturation of the double helix.

Doxorubicin (Adriamycin)

An anthracycline antibiotic that can intercalate with DNA, doxorubicin affects many of the functions of DNA, including synthesis. It forms DNA-cleavable complexes by interaction with topoisomerase II, which is responsible for the cytocidal activity of the drug. Doxorubicin is administered IV and distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. It does not cross the blood-brain barrier and is excreted primarily in bile. It forms an important part of multiple chemotherapeutic regimens for lymphomas, including cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone (CHOP).

Vincristine (Vincasar PFS)

The mechanism of action of vincristine is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production; however, neither of these mechanisms fully explains the effect in thrombocytopenic purpura and hemolytic-uremic syndrome. Vincristine is used in hematologic and nonhematologic malignancies. It is a component of CHOP and other regimens for lymphoma.

Fludarabine

Fludarabine is a purine analogue that interferes with DNA synthesis by inhibiting ribonucleotide reductase. It is also incorporated into RNA, causing inhibition of RNA and protein synthesis; however, its primary effect may result from activation of apoptosis.

Nelarabine (Arranon)

Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). It is converted to the active 5'-triphosphate, ara-GTP, a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death

Cytarabine

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

Gemcitabine (Gemzar)

Gemcitabine is a cytidine analog. It is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is cell-cycle specific for the S phase. Gemcitabine is indicated as first-line treatment for locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) pancreatic adenocarcinoma.

Etoposide (Toposar)

Etoposide is a glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect through stabilization of the normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks. This causes cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

Mitoxantrone

Related to anthracyclines. Mitoxantrone intercalates into DNA. This results in cross-links and strand breaks. Binds to nucleic acids and inhibits DNA and RNA synthesis by template disordering and steric obstruction. Replication is decreased by binding to DNA topoisomerase II. Active through entire cell cycle.

Carboplatin

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. It has same efficacy as cisplatin, but with a better toxicity profile. The main advantages over cisplatin include less nephrotoxicity and ototoxicity, the lack of a need for extensive prehydration, and a smaller likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

Bleomycin

This agent is composed of 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.

Vorinostat (Zolinza)

Vorinostat is a histone deacetylase (HDAC) inhibitor. HDAC inhibition results in hypoacetylation of core nucleosomal histones, it condenses the chromatin structure, and it represses gene transcription. It is indicated for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

Belinostat (Beleodaq)

Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibiting this action induces cell cycle arrest and/or apoptosis.

Umbralisib (Ukoniq)

Umbralisib is a dual inhibitor of PI3K-delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells.  It was granted accelerated approval to umbralisib (Ukoniq) for the treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least 1 prior anti-CD20-based regimen and for adults with relapsed or refractory follicular lymphoma (FL) who have received at least 3 prior lines of systemic therapy.

Class Summary

Ibrutinib received accelerated approval from the FDA for marginal zone lymphoma following analysis of phase 2 data in 63 patients who had a median follow-up of 19.4 months. Of these patients, 3% (n=2) treated with ibrutinib achieved complete responses (CR) and 45% (n=27) achieved partial responses (PR). Overall, 78% of patients experienced tumor reduction. Median progression-free survival was 14.2 months.[37]

Ibrutinib (Imbruvica)

Bruton’s tyrosine kinase (BTK) inhibitor forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. It is indicated for mantle cell lymphoma in patients who have received at least 1 previous therapy. It also indicated for marginal zone lymphoma (MZL) in patients who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

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.

Copanlisib (Aliqopa)

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)

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.

Duvelisib (Copiktra)

Duvelisib is a selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. Inhibiting PI3K induces growth inhibition and reduces viability in cell lines derived from malignant B cells. It is indicated for adults with relapsed/refractory follicular cell lymphoma after at least 2 prior systemic therapies. 

Class Summary

These agents antagonize or inhibit the development of new blood vessels.

Lenalidomide (Revlimid)

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

Class Summary

Monoclonal antibodies that bind the programmed cell death-1 protein (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production.

Pembrolizumab (Keytruda)

Indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

Class Summary

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

Loncastuximab tesirine (Zynlonta)

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

Tafasitamab (Monjuvi)

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

Class Summary

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).

Axicabtagene ciloleucel (Yescarta)

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)

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.

Lisocabtagene maraleucel (Breyanzi)

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