Non-Hodgkin Lymphoma (NHL)

The term lymphoma describes a heterogeneous group of malignancies with different biology and prognosis. In general, lymphomas are divided into 2 large groups of neoplasms: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is 68 years,[3] although Burkitt lymphoma and lymphoblastic lymphoma occur in younger patients.

NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy. With respect to prognosis, NHLs can be divided into two groups, indolent and aggressive.[4]

Currently, several NHL classification schemas exist, reflecting the growing understanding of the complex diversity of the NHL subtypes. The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade). In the 1990s, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. The World Health Organization (WHO) classification further elaborates upon the REAL approach. This classification divides NHL into those of B-cell origin and those of T-cell and natural killer (NK)–cell origin.

A study by Shustik et al found that within the WHO classification, the subdivisions of grade 3A and 3B had no difference in outcome or curability with anthracycline-based therapy.[5]

For clinical oncologists, the most practical way of sorting the currently recognized types of NHL is according to their predicted clinical behavior. Each classification schema contributes to a greater understanding of the disease, which dictates prognosis and treatment.

Although a variety of laboratory and imaging studies are used in the evaluation and staging of suspected NHL (see Workup), a well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis. The treatment of NHL varies greatly, depending on tumor stage, grade, and type and various patient factors (eg, symptoms, age, performance status; see Treatment and Guidelines).

For discussion of individual subtypes of NHL, see the following:

• Anaplastic Large Cell Lymphoma
• Follicular Lymphoma
• B Cell Lymphoma
• Diffuse Large Cell Lymphoma
• Diffuse Mixed Lymphoma
• Lymphoblastic Lymphoma
• Mantle Cell Lymphoma
• Mycosis Fungoides
• Primary CNS Lymphoma
• Cutaneous T-Cell Lymphoma

NHLs are tumors originating from lymphoid tissues, mainly of lymph nodes. Various neoplastic tumor cell lines correspond to each of the cellular components of antigen-stimulated lymphoid follicles.

NHL represents a progressive clonal expansion of B cells or T cells and/or NK cells arising from an accumulation of lesions affecting proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. These oncogenes can be activated by chromosomal translocations (ie, the genetic hallmark of lymphoid malignancies), or tumor suppressor loci can be inactivated by chromosomal deletion or mutation. In addition, the genome of certain lymphoma subtypes can be altered with the introduction of exogenous genes by various oncogenic viruses. Several cytogenetic lesions are associated with specific NHLs, reflecting the presence of specific markers of diagnostic significance in subclassifying various NHL subtypes.

Almost 85% of NHLs are of B-cell origin; only 15% are derived from T/NK cells, and the small remainder stem from macrophages. These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histologic pattern of growth.

For many of the B-cell NHL subtypes, the pattern of growth and cell size may be important determinants of tumor aggressiveness. Tumors that grow in a nodular pattern, which vaguely recapitulate normal B-cell lymphoid follicular structures, are generally less aggressive than lymphomas that proliferate in a diffuse pattern. Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness. However, some subtypes of high-grade lymphomas are characterized by small cell morphology.

NHLs may result from chromosomal translocations, infections, environmental factors, immunodeficiency states, and chronic inflammation.

Chromosomal translocations

Chromosomal translocations and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.

The t(14;18)(q32;q21) translocation is the most common chromosomal abnormality associated with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of higher-grade NHLs. This translocation results in the juxtaposition of the bcl -2 apoptotic inhibitor oncogene at chromosome band 18q21 to the heavy chain region of the immunoglobulin (Ig) locus within chromosome band 14q32.

The t(11;14)(q13;q32 translocation has a diagnostic nonrandom association with mantle cell lymphoma. This translocation results in the overexpression of bcl -1 (cyclin D1/PRAD 1), a cell-cycle regulator on chromosome band 11q13.

The 8q24 translocations lead to c-myc dysregulation. This is frequently observed in high-grade small noncleaved lymphomas (Burkitt and non-Burkitt types), including those associated with HIV infection.

The t(2;5)(p23;q35) translocation occurs between the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK1) gene. It results in the expression of an aberrant fusion protein found in a majority of anaplastic large cell lymphomas.

Two chromosomal translocations, t(11;18)(q21;q21) and t(1;14)(p22;132), are associated with mucosa-associated lymphoid tissue (MALT) lymphomas. The more common (ie, t[11;18][q21;q21]) translocates the apoptosis inhibitor AP12 gene with the MALT1 gene, resulting in the expression of an aberrant fusion protein. The other translocation, t(1;14)(p22;132), involves the translocation of the bcl -10 gene to the immunoglobulin gene enhancer region.

Infection

Some viruses are implicated in the pathogenesis of NHL, probably because of their ability to induce chronic antigenic stimulation and cytokine dysregulation, which leads to uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis. Epstein-Barr virus (EBV) is a DNA virus that is associated with Burkitt lymphoma (especially the endemic form in Africa), Hodgkin disease, lymphomas in immunocompromised patients (eg, from HIV infection,[6] organ transplantation), and sinonasal lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells. This virus is endemic in certain areas of Japan and the Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or lymphoma.

Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions and certain subtypes of NHL (ie, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia), especially in the setting of essential (type II) mixed cryoglobulinemia.

Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based lymphomas in patients with HIV infection and in patients with multicentric Castleman disease.

Helicobacter pylori infection is associated with the development of primary gastrointestinal (GI) lymphomas, particularly gastric mucosa-associated lymphoid tissue (MALT) lymphomas.

Environmental factors

Environmental factors linked to the development of NHL include chemicals (eg, pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts, hair dye), chemotherapy, and radiation exposure. A study by Antonopoulos et al found that maternal smoking during pregnancy may have a modest increase in the risk for childhood NHL but not HL.[7]

Immunodeficiency states

Congenital immunodeficiency states (eg, severe combined immunodeficiency disease [SCID], Wiskott-Aldrich syndrome), acquired immunodeficiency states (eg, AIDS), and induced immunodeficiency states (eg, immunosuppression) are associated with increased incidence of NHL and are characterized by a relatively high incidence of extranodal involvement, particularly of the GI tract, and with aggressive histology. Primary CNS lymphomas can be observed in about 6% of patients with AIDS.

Celiac disease has been associated with an increased risk of malignant lymphomas. The risk of lymphoproliferative malignancy in individuals with celiac disease depends on small intestinal histopathology; no increased risk is observed in those with latent celiac disease.[8]

Chronic inflammation

The chronic inflammation observed in patients with autoimmune disorders, such as Sjögren syndrome and Hashimoto thyroiditis, promotes the development of MALT and predisposes patients to subsequent lymphoid malignancies. Hashimoto thyroiditis is a preexisting condition in 23-56% of patients with primary thyroid lymphomas.

The American Cancer Society estimates that approximately 80,550 new cases of NHL will be diagnosed in 2023.[9]  From the early 1970s to the early 21st century, the incidence rates of NHL nearly doubled. Although some of this increase may be attributable to earlier detection (resulting from improved diagnostic techniques and access to medical care), or possibly to HIV-associated lymphomas, for the most part the rise is unexplained. Since 2015, incidence rates of NHL have declined by about 1% per year.[9]  

NHL is the most prevalent hematopoietic neoplasm, representing approximately 4.1% of all cancer diagnoses and ranking eighth in frequency among all cancers. NHL is more than 5 times as common as Hodgkin lymphoma.[3]

Overall, NHL is most often diagnosed in people aged 65-74; median age at diagnosis is 68 years.[3] The exceptions are high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults. At diagnosis, low-grade lymphomas account for 37% of NHLs in patients aged 35-64 years but account for only 16% of cases in patients younger than 35 years. Low-grade lymphomas are extremely rare in children.

The 5-year relative survival rate of patients with NHL is 74.3%.[3] The survival rate has steadily improved over the last 2 decades, thanks to improvements in medical and nursing care, the advent of novel therapeutic strategies (eg, monoclonal antibodies, chimeric antigen receptor [CAR] T-cell therapy), validation of biomarkers of response, and the implementation of tailored treatment.

The prognosis for patients with NHL depends on the following factors:

• Tumor histology (based on Working Formulation classification)
• Tumor stage
• Patient age
• Tumor bulk
• Performance status
• Serum lactate dehydrogenase (LDH) level
• Beta2-microglobulin level
• Presence or absence of extranodal disease

In general, these clinical characteristics are thought to reflect the following host or tumor characteristics:

• Tumor growth and invasive potential (eg, LDH, stage, tumor size, beta2-microglobulin level, number of nodal and extranodal sites, bone marrow involvement)
• Patient's response to tumor (eg, performance status, B symptoms)
• Patient's tolerance of intensive therapy (eg, performance status, patient age, bone marrow involvement)

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive NHL, also appears to be useful for predicting the outcome of patients with low-grade lymphoma and mantle cell lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, CNS, liver, testis, lung, and spleen. These patients may be considered for clinical trials that aim at improving the current treatment standard.

An age-adjusted model for patients younger than 60 years has been proposed. In younger patients, stage III or IV disease, high LDH levels, and nonambulatory performance status are independently associated with decreased survival rates.

Pediatric and adolescent patients have better outcome than adults with CNS lymphoma.[10] An ECOG performance status score of 0-1 is associated with improved survival. Higher dose methotrexate is associated with slightly better response.

Clinical features included in the IPI that are independently predictive of survival include the following:

• Age - Younger than 60 years versus older than 60 years
• LDH level - Within the reference range versus elevated
• Performance status - Eastern Cooperative Oncology Group ( ECOG) grade 0-1 versus 2-4
• Ann Arbor stage - Stage I-II versus III-IV
• Number of extranodal sites - Zero to 1 versus more than 1

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%

For patients with follicular lymphoma—the second most common subtype of NHL—the Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more discriminating than the IPI.[11] The FLIPI score is calculated on the basis of 5 adverse prognostic factors, as follows:

• Age (> 60 y)
• Ann Arbor stage (III-IV)
• Hemoglobin level (< 12 g/dL)
• Number of nodal areas (> 4)
• Serum LDH level (above normal)

Three risk groups are defined by FLIPI score:

• Low risk (0-1 adverse factor)
• Intermediate risk (2 factors)
• Poor risk (3 or more adverse factors)

Biomarkers in tumor cells such as the expression of bcl- 2 or bcl- 6 proteins and cDNA microarray provide useful prognostic information.

Patients with congenital or acquired immunodeficiency have an increased risk of lymphoma and respond poorly to therapy.

Time to achieve complete remission (CR) and response duration has prognostic significance. Patients who do not achieve CR by the third cycle of chemotherapy have a worse prognosis than those who achieve rapid CR.

Immunophenotype is also a factor. Patients with aggressive T- or NK-cell lymphomas generally have worse prognoses than those with B-cell lymphomas, except the Ki-1 anaplastic large T- or null-cell lymphomas.

Cytogenetic abnormalities and oncogene expression affect prognosis. Patients with lymphomas with 1, 7, and 17 chromosomal abnormalities have worse prognoses than those with lymphomas without these changes.

Low-grade lymphomas have indolent clinical behavior and are associated with a comparatively prolonged survival (median survival is 6-10 y), but they have little potential for cure when the disease manifests in more advanced stages. They also have the tendency to transform to high-grade lymphomas.

Approximately 70% of all patients with intermediate- and high-grade NHL relapse or never respond to initial therapy. Most recurrences are within the first 2 years after therapy completion. Patients with relapsed or resistant NHL have a very poor prognosis (< 5-10% are alive at 2 years with conventional salvage chemotherapy regimens).

Drake et al found that low levels of vitamin D were associated with a decrease in clinical end points (event-free survival and overall survival) in subsets of patients with aggressive B-cell lymphoma (ie, diffuse large B-cell lymphoma or T-cell lymphoma).[12] Although the results of this study suggest an association between vitamin D levels and its metabolism with the biology of some aggressive lymphomas, further studies are needed before conclusions can be drawn.

A study by Change et al also found a protective effect associated with vitamin D and also concluded that routine residential UV radiation exposure may have a protective effect against lymphomagenesis through mechanisms possibly independent of vitamin D.[13]

Survivors of NHL are at risk for development of a second primary malignancy. A review of Surveillance, Epidemiology, and End Results data from 1992-2008 found hazard ratios for a second cancer to be 2.70 for men and 2.88 for women.[14]

Patients should receive a clear and detailed explanation of all the available treatment options, prognosis, and adverse effects of treatment. Advise patients to call their oncologists as necessary and educate patients about oncologic emergencies that require an immediate emergency department visit. Suggest psychosocial counseling.

For patient education information, see Lymphoma.

The clinical manifestations of non-Hodgkin lymphoma (NHL) vary with such factors as the location of the lymphomatous process, the rate of tumor growth, and the function of the organ being compromised or displaced by the malignant process.

The Working Formulation classification groups the subtypes of NHL by clinical behavior—that is, low-grade, intermediate-grade, and high-grade. Because the Working Formulation is limited to classification based upon morphology, it cannot encompass the complex spectrum of NHL disease, excluding important subtypes such as mantle cell lymphoma or T cell/natural killer cell lymphomas. However, it continues to serve as a basis for understanding the clinical behavior of groups of NHLs.

Low-grade lymphomas

Peripheral adenopathy that is painless and slowly progressive is the most common clinical presentation in these patients. Spontaneous regression of enlarged lymph nodes can occur in low-grade lymphoma, potentially causing confusion with an infectious condition.

Primary extranodal involvement and B symptoms (ie, temperature >38°C, night sweats, weight loss >10% from baseline within 6 mo) are not common at presentation, but they are common in patients with advanced, malignant transformation (ie, evolution from a low-grade to an intermediate- or high-grade lymphoma) or end-stage disease.

Bone marrow is frequently involved and may be associated with cytopenia or cytopenias.[1] Fatigue and weakness are more common in patients with advanced-stage disease.

Intermediate- and high-grade lymphomas

These types of lymphomas cause a more varied clinical presentation. Most patients present with adenopathy. More than one third of patients present with extranodal involvement; the most common sites are the gastrointestinal (GI) tract (including the Waldeyer ring), skin, bone marrow, sinuses, genitourinary (GU) tract, thyroid, and central nervous system (CNS). B-symptoms are more common, occurring in approximately 30-40% of patients.

Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anterior superior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal disease with cranial nerve palsies.

Patients with Burkitt lymphoma (occurring in the United States) often present with a large abdominal mass and symptoms of bowel obstruction. Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the ureters can also be observed in these patients.

Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomas originating in the CNS are large cell lymphomas or immunoblastomas, and they account for 1% of all intracranial neoplasms. These lymphomas are more commonly observed in patients who are immunodeficient because of conditions such as Wiskott-Aldrich syndrome, transplantation, or AIDS (see HIV-Associated Opportunistic Neoplasms-CNS Lymphoma for more information on this topic).[6]

Fernberg et al examined time trends in risk and risk determinants in posttransplant patients with lymphoma and found that posttransplant NHL risk decreased during the 2000s compared with the 1990s among patients who underwent nonkidney transplants.[15]

Low-grade lymphomas may produce peripheral adenopathy, splenomegaly, and hepatomegaly. Splenomegaly is observed in approximately 40% of patients; the spleen is rarely the only involved site at presentation.

Intermediate- and high-grade lymphomas may produce the following physical examination findings:

• Rapidly growing and bulky lymphadenopathy
• Splenomegaly
• Hepatomegaly
• Large abdominal mass : this usually occurs in Burkitt lymphoma
• Testicular mass
• Skin lesions: lesions are associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large-cell lymphoma, and angioimmunoblastic lymphoma ^[2]

Potential disease-related complications include the following:

• Cytopenias (ie, neutropenia, anemia, thrombocytopenia) secondary to bone marrow infiltration; alternatively, autoimmune hemolytic anemia is observed in some types of NHL (eg, small lymphocytic lymphoma /chronic lymphocytic leukemia [SLL/CLL])

• Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation (DIC), or vascular invasion by the tumor

• Infection secondary to leukopenia, especially neutropenia

• Cardiac problems secondary to large pericardial effusion or arrhythmias secondary to cardiac metastases

• Respiratory problems secondary to pleural effusion and/or parenchymal lesions

• Superior vena cava (SVC) syndrome secondary to a large mediastinal tumor

• Spinal cord compression secondary to vertebral metastases

• Neurologic problems secondary to primary CNS lymphoma or lymphomatous meningitis

• GI obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be caused by chemotherapy)

• Pain secondary to tumor invasion

• Leukocytosis (lymphocytosis) in leukemic phase of disease

The workup in a patient with suspected non-Hodgkin lymphoma (NHL) should include the following:

• Complete blood cell (CBC) count
• Serum chemistry studies, including lactate dehydrogenase (LDH)
• Serum beta2-microglobulin level
• HIV serology
• Chest radiography
• Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis
• Positron emission tomography (PET) scan
• Excisional lymph node biopsy
• Bone marrow aspirate and biopsy
• Hepatitis B testing in patients in whom rituximab therapy is planned, because reactivation has been reported

Other studies may be indicated, depending on the clinical presentation.

In the early stage of disease, patients with NHL may have blood counts within the reference range. As the disease progresses, a CBC count with differential and platelet count in patients with NHL may show the following:

• Anemia secondary to bone marrow infiltration, autoimmune hemolysis (particularly associated with small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]), bleeding, anemia of chronic disease

• Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow infiltration or autoimmune cytopenias

• Lymphocytosis with circulating malignant cells (common in patients with low-grade lymphomas)

• Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive secondary to blood loss)

Serum chemistry studies may show the following:

• Elevated lactate dehydrogenase (LDH): Indicates poor prognosis; correlates with increased tumor burden

• Abnormal liver function test (LFT) results: Secondary to hepatic involvement, hypermetabolic tumor growth, chronic inflammation

• Hypercalcemia: In patients with acute form of adult T-cell lymphoma-leukemia (ATLL)

An elevated beta2-microglobulin level may be seen. Elevated levels correlate with a poor prognosis.

Occasionally, NHL is associated with monoclonal gammopathy. A Coombs test may be positive result (especially in SLL/CLL). Hypogammaglobulinemia may be present.

HIV serology should be obtained, especially in patients with diffuse large cell immunoblastic or small noncleaved histologies. HTLV-1 serology should be obtained in patients with ATLL.

In a February 2013 study, researchers measured serum levels of the chemokine CXCL13 in 179 men diagnosed with HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL) and 179 male controls to determine whether levels are elevated before an AIDS-NHL diagnosis. Results showed that CXCL13 levels were elevated for more than 3 years, 1 to 3 years, and 0 to 1 year before diagnosis, suggesting CXCL13 may serve as a biomarker for early AIDS-NHL detection.[16]

A chest radiograph yields positive information in approximately one fourth of patients with NHLs. It may identify hilar or mediastinal adenopathy, pleural or pericardial effusions, and parenchymal involvement. The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma. See the images below.

Posteroanterior (PA) chest radiograph in a man with thoracic non-Hodgkin lymphoma (NHL) shows mediastinal widening due to grossly enlarged right paratracheal and left paratracheal nodes.

Posteroanterior (PA) chest radiograph in a 16-year-old male adolescent with thoracic non-Hodgkin lymphoma (NHL) shows subtle enlargement of the lower paratracheal lymph nodes.

Posteroanterior (PA) chest radiograph shows a large mass in the right parahilar region extending into the right upper and middle zones, with silhouetting of the right pulmonary artery. Smaller mass is seen in the periphery of the right lower zone. The masses did not respond to a trial of antibiotics. Core-needle biopsy of the larger lesion revealed NHL deposits in the lung.

Obtain an upper GI series with small bowel follow-through in patients with head and neck involvement (eg, tonsil, base of tongue, nasopharynx, Waldeyer ring) and those with a GI primary lesion.

A CT scan of the neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes, hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most widely used test for initial staging, assessing treatment response, and conducting follow-up care.[17] See the images below.

Nonenhanced CT scan through the mediastinum shows multiple enlarged lymph nodes in the prevascular space, in the right and left paratracheal region. Nodes in the left paratracheal region cause the trachea to be indented and narrowed on the left side. Note the small, bilateral pleural effusion

Nonenhanced CT scan through the mediastinum at the level of the carina shows enlarged tracheobronchial and subcarinal nodes. Note the small bilateral pleural effusion.

Contrast-enhanced axial CT scan in a child shows hypoattenuating, enlarged, subcarinal lymph nodes with splaying of the tracheal bifurcation.

A bone scan is ordered only in patients with bone pain, elevated alkaline phosphatase, or both. Bone lesions are particularly associated with the acute form of ATLL and diffuse large B-cell lymphomas.

Gallium scans are an option in selected cases of NHL. These scans can detect initial sites of disease, reflect therapy response, and detect early recurrences. This scan is positive in nearly all patients with aggressive and highly aggressive lymphomas and in approximately 50% of patients with indolent lymphomas at diagnosis. See the image below.

This 28-year-old man was being evaluated for fever of unknown origin. Gallium-67 study shows extensive uptake in the mediastinal lymph nodes due to non-Hodgkin lymphoma (NHL).

Whole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan can be used for the initial evaluation of patients with NHL; however, this scan is more useful for posttreatment evaluation to differentiate early recurrences or residual disease from fibrosis or necrosis. This PET scan has a higher predictive value for relapse than classic CT scan imaging.[18] A study by Zinzani et al determined that midtreatment scanning using PET allowed physicians to better make crucial decisions on further treatment.[19]

A study by Terezakis found that incorporating FDG-PET into CT-based treatment planning in patients with lymphoma resulted in beneficial changes in management, volume definition, and normal tissue dosimetry for a significant amount of patients.[20]

In a study of 130 patients with diffuse large B-cell lymphoma, Khan et al found PET-CT scanning to be highly accurate in identifying marrow disease.[21] PET-CT scanning identified 33 of 35 patients found to have marrow involvement, compared with 14 cases identified by marrow histology. The investigators found that PET scanning had a sensitivity of 94% and a specificity of 100%, whereas iliac crest biopsy had a sensitivity of 40% and a specificity of 100%. See the image below.

Positron emission tomography (PET) CT in an 80-year-old woman with diffuse, large B-cell NHL of the skin and subcutaneous tissues that recently transformed from previous low-grade non-Hodgkin lymphoma (NHL). PET shows high level of uptake in the anterior subcutaneous nodule in the chest (white arrows). CT scan of similar nodules (arrowheads) on the anterior left chest does not show PET uptake; these may represent regions of lower-grade NHL. PET image of posterior lesions shows only mild uptake (gray arrow).

Obtain an ultrasound image of the opposite testis in male patients with a testicular primary lesion.

A multiple gated acquisition (MUGA) scan should be performed to measure the left ventricular ejection fraction (LVEF) of patients who are being considered for treatment with anthracyclines, given the risk of cardiotoxicity with that drug class. In general, anthracyclines should not be administered to patients with an LVEF of less than 50%.

Obtain an MRI of the brain and spinal cord of patients who are suspected of having primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma. An MRI scan can also be performed to identify focal areas of marrow involvement in those patients suspected to have bone marrow involvement but in whom random bone marrow biopsy findings have been negative. See the images below.

T1-weighted coronal MRI of the thorax in a 55-year-old woman with lower dorsal pain. Note the signal-intensity changes in the body of D12; these are associated with a right-sided, large, paravertebral soft-tissue mass involving the psoas muscle. Biopsy confirmed non-Hodgkin lymphoma (NHL).

T1-weighted coronal MRI of the thorax in a 55-year-old woman with lower dorsal pain (same patient as in the previous image). Note the signal-intensity changes in the body of D12; these are associated with a right-sided, large, paravertebral soft-tissue mass involving the psoas muscle. Biopsy confirmed non-Hodgkin lymphoma (NHL).

A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis. Excisional lymph node biopsy is required because lymphoma diagnosis relies heavily on careful assessment of altered nodal architecture accompanying lymphomatous infiltrates. Fine-needle aspiration (FNA) is insufficient for establishing a diagnosis; needle-core biopsies have a limited role in establishing a diagnosis of NHL.

Bone marrow aspirate and biopsy

Perform this procedure for staging rather than diagnostic purposes. Bilateral bone marrow aspirate and biopsy should be performed because bone marrow involvement is usually patchy. In bone marrow sections, the neoplastic cells may infiltrate in a focal (ie, paratrabecular or nonparatrabecular, depending on the type of lymphoma), interstitial, or diffuse pattern.

Biopsy of extranodal sites

In approximately 30-35% of adult patients with NHL, the extranodal sites are the primary presenting sites. The most common site is the GI tract.

Processing extranodal biopsy material for lymphoma protocol studies is important whenever suspicion of a hematolymphoid neoplasm exists.

Lumbar puncture for cerebrospinal fluid (CSF) examination should be performed in patients with the following conditions:

• Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or two or more extranodal sites of disease

• High-grade lymphoblastic lymphoma

• High-grade small noncleaved cell lymphomas (eg, Burkitt and non-Burkitt types)

• HIV-related lymphoma

• Primary CNS lymphoma

• Neurologic signs and symptoms

NHLs are a heterogeneous group of lymphoproliferative malignancies, with varying morphologic features depending on the specific subtype. The abnormal lymphocytes in the lymph node, bone marrow, or extranodal sites can be small cleaved or noncleaved, intermediate, or large cell and can have a follicular or diffuse pattern. In contrast with reactive follicular hyperplasia, lymphomas usually alter the lymph node architecture, and the capsule is usually involved.

Immunophenotypic analysis of lymph node, bone marrow, peripheral blood (if positive for neoplastic cells), or a combination of these complements and confirms the results of routine tissue section and may be useful in resolving a diagnostic dilemma in patients with an atypical morphology.

This analysis provides information about lineage and clonality, which are complementary to the histology of a given case. Analysis is also useful for subclassifying certain lymphoma subtypes, which has therapeutic and prognostic importance.

Immunophenotypic analysis helps to distinguish reactive from neoplastic lymphoid infiltrates, lymphoid from nonlymphoid malignancies, and specific lymphoid neoplasms. Although bcl -2 expression distinguishes follicular lymphoma from reactive follicular hyperplasia, bcl -1 expression strongly favors a diagnosis of mantle cell lymphoma. CD30 expression is important for the recognition of anaplastic large cell lymphoma, and it can also be found in the majority of Hodgkin lymphomas.

These studies have contributed to the understanding of the biology and prognosis of lymphoma. Cytogenetic studies are critical to the discovery of oncogene abnormalities that now are known to be intimately involved in the pathogenesis of NHL.

Staging is important in selecting a treatment and determining prognosis. CT scans of the neck, chest, abdomen, and pelvis, as well as bilateral bone marrow aspirate and biopsy, are necessary to stage the lymphoma. Noncontiguous lymph node involvement, uncommon in Hodgkin disease, is more common among patients with NHL.

The Ann Arbor staging system is the most commonly used staging system for patients with NHL. This system divides NHL into 4 stages, as follows:

• Stage I NHL involves a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)

• Stage II NHL involves 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE)

• Stage III involves lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localized involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE)

• Stage IV represents disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

In addition to the 4 stage designations, subscript letters designate involvement of extralymphatic organs, as follows:

• L - lung

• H - Liver

• P - Pleura

• B - Bone

• M - Bone marrow

• D - Skin

• E - Extranodal lymphoid malignancies in tissues that are separate from but near the major lymphatic aggregates

The stages can also be appended by A or B designations. Patients with A disease do not have systemic symptoms. The B designation is applied in patients with any of the following symptoms:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis

• Unexplained fever with temperature above 38°C

• Drenching night sweats

Risk stratification scoring systems

In addition to staging, risk stratification is important in patients with NHL. Prospectively validated scoring systems that can be used to determine prognosis include the International Prognostic Index (IPI) for patients with diffuse large B-cell lymphoma and the Follicular Lymphoma International Prognostic Index, (FLIPI) for patients with follicular B-cell lymphomas. The greater the number of risk factors present, the higher the risk.

The IPI for NHL is as follows:

• Age older than 60 years

• ECOG grade greater than or equal to 2

• Elevated LDH value

• Two or more extranodal sties

• Ann Arbor stage III or IV

The FLIPI score is as follows:

• Number of nodal sites of 5 or more

• Elevated LDH value

• Age 60 years or older

• Ann Arbor stage III–IV

• Hemoglobin value less than 12 g/dL

The treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on the following factors:

• Tumor stage
• Phenotype (B-cell, T-cell or natural killer [NK] cell/null-cell)
• Histology (ie, low, intermediate, or high grade)
• Symptoms
• Performance status
• Patient age
• Comorbidities

Most of the chemotherapy for NHL, whether combination or single-drug, can be administered in an outpatient setting, at an infusion clinic. In the infusion clinic, specially trained oncology nurses, who are supervised by oncologists, administer the chemotherapy. Growth factor support (eg, granulocyte-colony stimulating factor [GCSF], granulocyte macrophage–colony stimulating factor [GM-CSF], erythropoietin) is also administered in an outpatient treatment setting.

Infusional chemotherapy (eg, infusional cyclophosphamide, doxorubicin, and etoposide [CDE], which should be administered continuously for 4 days) should be administered as inpatient treatment. High-dose chemotherapy and bone marrow and/or stem cell transplantation are administered in an inpatient setting of a tertiary hospital with an approved transplant center.

For the initial treatment of patients with intermediate- or high-grade lymphoma and patients with bulky disease, an inpatient setting is recommended in order to monitor for tumor lysis syndrome and to manage appropriately.

Admit patients with NHL for complications of disease progression (eg, pain control for intractable pain) or adverse effects from chemotherapy (eg, dehydration secondary to diarrhea, vomiting requiring IV hydration, severe mucositis). Patients with fever during neutropenia should be admitted for broad-spectrum antibiotic therapy.

Ensure that patients understand their diagnosis, treatment options, and prognosis and complications of therapy, which, in rare occasions, may result in a fatal event (eg, death secondary to severe infection unresponsive to antimicrobial therapy, in a patient with severe neutropenia). Start the treatment only after the patient has signed an informed consent form.

Follicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal).

Indolent stage I and contiguous stage II NHL

Standard management consists of radiotherapy alone. Forty percent of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe.[22] No randomized study has shown combined chemotherapy and radiation to be better than radiation alone.

A study by Rossier et al found that low-dose involved-field radiotherapy is effective in treating patients with recurrent low-grade lymphoma.[23]

Radiation therapy (2500-4000 cGy) produces a 10-year failure-free survival (FFS) rate of 50-60%, with an overall survival (OS) rate of 60-80%. Offering adjuvant chemotherapy to selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in asymptomatic patients has not been shown to improve survival.

Rituximab is another treatment option for symptomatic patients for whom radiation therapy is contraindicated or who prefer an alternative treatment.[4] The use of rituximab—a monoclonal antibody that targets the CD20 antigen, which is present in benign and malignant B-cells—in combination with systemic chemotherapy, has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas, compared with chemotherapy alone. Prospective studies and two meta-analyses suggest that rituximab-chemotherapy, also known as chemo-immunotherapy, may change the natural progression of indolent lymphomas.

Indolent noncontiguous stage II, III, and IV NHL

The treatment of indolent B-cell lymphomas continues to evolve as new therapies with potent antitumor activity and limited toxicity are becoming available. Monoclonal antibodies are changing the treatment paradigm of patients with B-cell lymphomas. However, controversies persist regarding the best treatment strategy and the best time to initiate treatment.

The disease course of indolent lymphomas is characterized by a continuous decrease in the quality and the duration of response with each subsequent treatment or treatments. This effect is primarily due to the acquisition of chemotherapy resistance.

Advanced indolent lymphomas have been accepted to be not curable with currently available therapies. However, sustained complete remissions can be achieved with various treatment modalities.

Asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. Early intervention in asymptomatic patients does not appear to prolong survival. The median time to progression is 4-6 years, and OS is 6-10 years.

The treatment of symptomatic patients with indolent lymphomas should focus on achieving the best possible quality of response without producing excessive toxicity. Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. However, only a few achieve remission; most achieve palliation.

A study by Gaulard et al found that rituximab plus low-dose CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-miniCHOP) offered a good compromise between efficacy and safety in patients older than 80 years. The authors concluded that R-miniCHOP should be considered the new standard of treatment in these patients.[24]

Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Bendamustine plus rituximab has demonstrated efficacy for the first-line treatment of advanced follicular, indolent, and mantle cell lymphomas.[25]  Current NCCN guidelines list  the following as preferred first-line regimens for follicular lymphoma[26] :

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

Combination agents are useful in bulky and rapidly progressive disease and have higher response rates than single agents, but there is no improvement in overall survival.[27, 28, 29]

A study by Watanabe et al found that a denser-dose R-CHOP strategy was not associated with improved progression-free survival in patients with untreated indolent B-cell lymphoma.[30]

Randomized trials have shown that adding rituximab to chemotherapy regimens results in higher response rates, longer time to progression, and longer survival than chemotherapy. For example, Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy (R-CHOP).[31]  Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of high tumor burden.

Subcutaneous rituximab/hyaluronidase (Rituxan Hycela) may be substituted for rituximab after patients have received the first dose of rituximab by IV infusion. FDA-approved biosimilar rituximab may also be used as a substitute for rituximab.

Maintenance therapy with rituximab after induction chemotherapy has been reported to prolong progression-free survival (PFS) in comparison with observation alone in patients with indolent lymphoma. However, long-term follow-up in a randomized phase 3 study found that weekly rituximab every 6 months for 2 years did not influence overall survival, although the PFS benefit was maintained. These researchers concluded that maintenance rituximab should be considered optional for patients with indolent B-cell lymphoma.[32]

In patients with indolent NHL that is refractory to rituximab, obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy, with manageable toxicity. A phase 3 trial by Sehn et al reported significantly longer PFS with obinutuzumab plus bendamustine (median not reached) than with bendamustine monotherapy (14.9 months; P=0.0001).[33]

Diffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas (high-grade lymphomas). Mantle cell lymphomas also behave aggressively.

Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHL

Based on 2 large randomized trials (ie, Southwest Oncology Group [SWOG], Eastern Cooperative Oncology Group [ECOG]), the preferred treatment option for patients with intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field radiation therapy.

According to SWOG data, patients who are treated with chemotherapy and involved-field radiation therapy have significantly better progression-free survival rates (ie, 77% versus 66%) and 5-year overall survival (OS) rates (ie, 82% versus 72%) compared with patients surviving 8 cycles of chemotherapy (ie, CHOP) alone. Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP.

Aggressive noncontiguous stage II, III, and IV NHL

Approximately 40-50% of these patients are cured with standard therapy, approximately 35-40% will respond but ultimately progress or relapse, and the remainder will be have disease that is refractory to primary treatment. Scoring systems such the IPI score have been developed and validated to estimate the response rate or survival rate of a given patient with aggressive lymphomas.

For many years, the treatment of aggressive lymphomas consisted of chemotherapy regimens using multiple drugs. Initial clinical studies were focused on investigating the use of more toxic regimens (higher doses or more drugs).

A prospective randomized trial in patients with diffuse large-cell lymphoma showed no difference in response rate (RR), OS, or time to treatment failure (TTF) at 3 years with any of the following regimens[34] :

• CHOP

• Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM)

• Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD)

• Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B)

• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab has been shown to achieve a high rate of durable remission in patients with mantle cell lymphoma. It is a toxic regimen and is typically used in patients with good performance status, who can tolerate it; otherwise, R-CHOP is used.[35]

• Bendamustine and rituximab combination has been successfully used in patients with mantle cell lymphoma in the first and second-line setting.[36] A study by Weidmann et al found that bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in elderly patients who are not eligible for R-CHOP because of its efficacy and low toxicity.[37]

Bortezomib has also been used in patients with relapsed or refractory mantle cell lymphoma.[38]

ProMACE-CytaBOM, m-BACOD, and MACOP-B all proved more toxic than CHOP. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in some subtypes of NHL such as primary mediastinal large B-cell NHL.

After more than 2 decades of scientific investigations, the treatment of aggressive lymphomas was changed by the clinical development of rituximab. Currently, 6-8 cycles of CHOP chemotherapy in combination with rituximab is the standard of care in patients with advanced disease.

The GELA (Groupe d'Etude des Lymphomes de l'Adulte) study was the first phase III trial to demonstrate the efficacy of combining rituximab with standard doses of CHOP chemotherapy for elderly (older than 60 y) patients with diffuse large B-cell lymphoma. At 5-year follow-up, OS was 58% with rituximab and CHOP versus 46% with CHOP alone.[39] The results of this study were further validated by other international randomized studies favoring the use of rituximab and chemotherapy in elderly patients with aggressive B-cell lymphomas.

Studies in younger patients also showed the benefit of combining rituximab and CHOP chemotherapy. A large international study, the MabThera International Trial (MInT,) supported the role of rituximab-chemotherapy in young patients with aggressive B-cell lymphomas.[40] The study, which has been presented only in an abstract form, was a phase III trial in which 823 patients (ages 18-60 y) with diffuse large B-cell, CD20+ NHL (DLBCL).

These patients were randomized to receive either rituximab plus a standard anthracycline-containing chemotherapy regimen (standard chemotherapy) or standard chemotherapy alone as induction therapy. The rituximab plus standard chemotherapy regimens increased 2-year overall survival (OS) from 86% to 95% compared with standard chemotherapy alone and resulted in significant improvement in time to treatment failure and projected overall survival.[40]

Ongoing research is being focused on identifying patients at risk for treatment failure and developing tailored treatment for patients with aggressive lymphoma based on clinical scores (IPI score) or gene profiles. Patients at high risk of relapse (IPI intermediate or poor risk groups) might have an improved 5-year event-free survival/overall survival from autologous and allogeneic bone marrow or peripheral stem cell transplantation following chemotherapy.

CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial.

Treatment of acute lymphoblastic lymphoma, a very aggressive form of NHL, is usually patterned after acute lymphoblastic leukemia (ALL) therapy. Other subtypes of high-grade lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, including the addition of high-dose methotrexate or other chemotherapy drugs and higher doses of cyclophosphamide.

In general, treatment with standard agents rarely produces a cure in patients who have relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse usually ensues. Favorable survival after relapse has been associated with age younger than 60 years, prior complete remission rather than partial remission, and duration of response longer than 1 year. For relapse that remains low grade, the following are possible treatment options:

• Single alkylating agents (chlorambucil or bendamustine)

• Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, and temsirolimus[41]

• Combination chemotherapy - CVP, CHOP, and others

• Purine analogues - Fludarabine, 2-CDA

• Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration

• Radioimmunotherapy

131Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity.[42] Tositumomab (a murine IgG2a lambda monoclonal antibody directed against CD20 antigen) plus 131I (Bexxar) has been approved by the US Food and Drug Administration (FDA) for relapsed or refractory, low-grade, follicular, or transformed NHL.[43, 44]

Ibritumomab tiuxetan plus 90yttrium (Zevalin) also has been approved for use in relapsed indolent lymphoma. These radioimmunotherapy agents typically are used only in patients with less than 25% bone marrow involvement with lymphoma and in patients refractory to rituximab.

Local relapse can be treated with radiotherapy. High-dose chemotherapy plus stem cell transplantation is being investigated to determine whether it can produce significantly better survival rates compared with conventional chemotherapy.[45]

In 2019, the FDA approved lenalidomide in combination with a rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma, the first nonchemotherapeutic regimen approved for those conditions. Approval was based on the AUGMENT study, in which patients were randomized to receive either lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The objective response was 80% in the lenalidomide plus rituximab arm compared with 55% in the control arm. Progression-free survival improved for lenalidomide plus rituximab arm versus control arm, with median duration of 39.4 months versus 14.1 months.[46]

Current NCCN guidelines recommend phosphoinositide 3-kinase (PI3K) inhibitors for relapsed or refractory indolent NHL that has failed to respond to 2 prior therapies. PI3K inhibitors include idelalisib, copanlisib, and duvelisib.[26]

Idelalisib (Zydelig) is the first PI3K inhibitor to receive accelerated approval from the FDA for relapsed follicular B-cell NHL and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. In this single-group, phase II, open-label study,  patients received idelalisib 150 mg PO BID until disease progression or study withdrawal. The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. [47]

Copanlisib and duvelisib were also FDA-approved for follicular lymphoma in patients who failed to respond to two prior therapies. For copanlisib, approval was based on a phase II trial that reported an objective response rate was 59%, with 12% complete responses. The median duration of response (DoR) was 22.6 months. The median progression-free survival was 11.2 months, with the median overall survival not yet reached.[48]

Duvelisib is a selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. The open label, global, phase II DYNAMO trial reported an overall response rate (ORR) of 47.3%. The estimated median DoR was 10 months, and the estimated median progression-free survival was 9.5 months.[49]

Although PI3K inhibitors provide therapeutic benefits, there have been concerns of severe adverse reactions, including severe infections (eg, Pneumocystis jirovecii pneumonia [PJP]) and long-term immune-related toxicities. Therefore, concomitant PJP prophylaxis is strongly recommended for patients receiving treatment with idelalisib and should be considered in those receiving copanlisib or duvelisib. 

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

Approval was based on two single-arm cohorts of an open-label, multicenter trial, in patients with MZL who received at least 1 prior therapy and in patients with FL after at least 2 prior systemic therapies. Patients received umbralisib 800 mg PO once daily until disease progression or unacceptable toxicity. For patients with MZL, the overall response rate was 49% (95% CI: 37.0, 61.6) with 16% achieving complete responses. Median DOR was not reached (95% CI: 9.3, NE) in these patients. For patients with FL, the ORR was 43% (95% CI: 33.6, 52.2) with 3% achieving complete responses. Median DOR was 11.1 months (8.3, 16.4). [50]

High-dose chemotherapy plus stem-cell transplantation is the treatment of choice for patients who have recurrent aggressive lymphomas. Preliminary studies indicate that approximately 20-40% of patients have a long-term disease-free status, but the precise percentage depends on patient selection and specific treatment used.

In 2019, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the FDA for use in combination with bendamustine and a rituximab product for adults with relapsed or recurrent DLBCL who have received at least 2 prior therapies and are not candidates for transplantation. FDA approval was based on a study in which the addition of polatuzumab vedotin to bendamustine plus rituximab led to increased rates of complete and objective responses and prolonged progression-free and overall survival, with manageable toxicity.[51]

Second-line chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone, high-dose cytarabine, cisplatin), or EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone) are usually used with rituximab if the tumor is CD20 positive. A retrospective study by Tixier et al concluded that regimens combining dexamethasone and high-dose cytarabine with oxaliplatin (DHAOX) or carboplatin (DHAC) have more favorable toxicity profiles than DHAP; in particular, they are far less likely to cause renal toxicity.[52]

Gemcitabine and navelbine are also being attempted in these relapsed patients. Chemotherapy is usually followed by stem-cell transplantation.

In the PARMA trial, patients with relapsed NHL who were randomized to autologous bone marrow transplantation followed by involved-field radiation therapy did better than those randomized to conventional chemotherapy and involved-field radiation therapy.[53, 54] After a 5-year median follow-up study, the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the overall survival (OS) rate was also better (53% versus 32%).

Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants.[55]

In general, patients who respond to initial therapy and who respond to conventional salvage therapy prior to bone marrow transplantation have better survival outcomes. Patients who relapse late (> 12 mo after diagnosis) have better OS than patients who relapse earlier. Patients who are not candidates for transplantation can be treated with chemotherapy with or without monoclonal antibodies. If possible, these patients should be enrolled into clinical trials.

Chimeric antigen receptor T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is approved for use in adult patients with relapsed or refractory large B-cell lymphoma, after two or more lines of systemic therapy. The following CAR T-cell therapies have FDA approval:

• Axicabtagene ciloleucel (Yescarta) -  Indications include 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) - Indications include DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

• Lisocabtagene maraleucel (Breyanzi) - Indicated for 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.

For full discussion, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T Cells.

The treatment of T-cell lymphomas continues to be challenging. T-cell lymphomas are divided into 2 subgroups: cutaneous or systemic T-cell disorders. Typically, cutaneous T-cell lymphomas (CTCL) are managed with topical agents and oral disease modifiers during the early stage of the disease. See Cutaneous T-Cell Lymphoma for more information on this topic. Systemic chemotherapy is usually incorporated late in the course of the disease, with modest activity. Systemic T-cell lymphomas represent a challenge to the practicing oncologist.

The complexity of each subtype of T-cell lymphomas, the low incidence, and poor response to standard therapies are important factors that contribute to the poor clinical outcomes of this group of neoplasms. Most patients with T-cell lymphomas are better served by participating in clinical trials exploring dose-intense regimens, early bone marrow transplantation, and/or novel chemotherapeutic agents. Treatment options for T-cell lymphoma can be categorized as follows:

• Combination chemotherapy regimens - CHOP, CHOP plus etoposide, gemcitabine-based regimens

• Single chemotherapy agents - Pralatrexate

• Monoclonal antibodies - Alemtuzumab (effective in prolymphocytic T-cell leukemia and hepatosplenic gamma-delta T-cell lymphoma)

• Immunotoxin - Denileukin diftitox (discontinued January 2014)

• Novel biological agents and small molecule inhibitors - Histone deacetylase inhibitors (vorinostat, panobinostat, romidepsin, belinostat), lenalidomide, and bortezomib

The US Food and Drug Administration (FDA) granted accelerated approval for pralatrexate injection (Folotyn) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).[56]

In 2011, the FDA granted accelerated approval for romidepsin (Istodax) for treatment of PTCL in patients who have received at least one prior therapy.[57]  However, a subsequent confirmatory phase III trial study evaluating romidepsin plus CHOP versus CHOP in first-line PTCL patients failed to meet the primary efficacy endpoint of progression-free survival, so in August 2021 the manufacturer voluntarily withdrew this indication in the US.[58]

In 2014, the FDA approved the histone deacetylase inhibitor belinostat (Beleodaq) for treatment of relapsed or refractory PTCL. Approval was based on the results of a multicenter, single-arm, nonrandomized trial of 120 patients with refractory or relapsed PTCL and included patients with baseline platelet levels below 100,000/μL. The overall complete and partial response rates were 10.8% and 15.0%, respectively. The median response duration (first date of response to disease progression or death) was 8.4 months.[59, 60]

Jacobsen et al concluded that hematopoietic stem cell transplantation (HSCT) can result in long-term remissions in patients with relapsed or refractory T-cell lymphoma, especially those with nodal histologies.[61]

The role of surgery in the treatment of patients with NHL is limited. Surgery is useful in selected situations (eg, GI lymphoma), particularly if the disease is localized or if risk of perforation, obstruction, and massive bleeding is present. Orchiectomy is part of the initial management of testicular lymphoma.

Potential chemotherapy and other treatment-related complications include the following:

• Cytopenias (ie, neutropenia, anemia, thrombocytopenia)
• Nausea or vomiting
• Infection
• Fatigue
• Neuropathy
• Dehydration after diarrhea or vomiting
• Cardiac toxicity from doxorubicin
• Catheter-related sepsis
• Catheter-related thrombosis
• Secondary malignancies
• Tumor lysis syndrome
• Atherosclerosis

Tumor lysis syndrome

This syndrome commonly occurs after treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy, which is caused by their high proliferative capacity. Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and renal failure. Death from cardiac asystole can occur from hyperkalemia.

Measures to prevent this complication include aggressive hydration, allopurinol administration, and urine alkalinization. Frequent monitoring of input and output, electrolytes, uric acid, and creatinine is necessary. Dialysis is sometimes required.

Atherosclerosis

In a 3-year study, Bilora et al found evidence that patients receiving radiotherapy and chemotherapy for lymphoma (either NHL or Hodgkin lymphoma) are predisposed to early development of atherosclerosis.[62] In 96 patients, the investigators found increased intima-media thickness at 1-year follow-up; thickness had decreased at 3-year follow-up, but reduction in flow-mediated dilatation measured in the patients at 1 year had not improved by the 3-year examination.[62]

Usually, a regular diet is adequate, except when the patient is neutropenic. Patients with neutropenia should not eat raw fruits or vegetables.

Transplant patients who have severe mucositis, decreasing albumin levels, or both may be administered total parenteral nutrition (TPN) until they can tolerate oral feedings.

The following restrictions apply to patients who are neutropenic, thrombocytopenic, or both:

• Avoid exposure to or contact with other patients with communicable or infectious diseases
• Use a soft toothbrush during episodes of neutropenia and thrombocytopenia
• Do not shave with a razor

Ideally, patients with neutropenia should be admitted directly to a private room and should not stay long in the emergency department for evaluation. All medical personnel should wash hands before and after examining these patients

Children

Pediatric patients with NHL are best treated by pediatric oncologists.

Pregnant women

NHL during pregnancy is uncommon, but it presents an ethical dilemma. Remission may be obtained with chemotherapy, but chemotherapy has potentially harmful effects to the fetus. Consider fetal exposure to transplacental chemotherapy when evaluating therapy options and carefully evaluate the timing of delivery.

For patients diagnosed with NHL during the second or third trimester of pregnancy, few literature reports suggest that they can be treated with chemotherapy without significant toxicity to the fetus. If possible, alkylating agents should be avoided. If the fetus can be delivered safely prior to administration of chemotherapy and a short wait will not affect the treatment outcome and prognosis of the patient, starting the treatment after the birth of the baby is better.

If the patient has high-grade NHL (eg, Burkitt or lymphoblastic lymphoma) diagnosed during the first trimester of pregnancy, immediate institution of therapy is necessary; otherwise, the condition could be fatal. Discuss at length with the patient and family that chemotherapy treatment at this period of pregnancy is very risky for the fetus, and whether therapeutic termination of pregnancy should be performed before the patient is treated should be decided. Consultation with the ethical committee of the hospital should be obtained in these very difficult situations.

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

The FDA has approved the following four CAR T-cell therapies for treatment of NHL in adults:

• Axicabtagene ciloleucel (Yescarta) – Indicated for large B-cell lymphoma and follicular lymphoma
• Brexucabtagene autoleucel (Tecartus) – Indicated for mantle cell lymphoma
• Lisocabtagene maraleucel (Breyanzi) – Indicated for large B-cell lymphoma
• Tisagenlecleucel (Kymriah) – Indicated for large B-cell lymphoma

Axicabtagene ciloleucel

The FDA approved axicabtagene ciloleucel (Yescarta) in 2017 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.[63]

Approval was based on the primary results from the ZUMA-1 study, an open-label, multicenter trial enrolling 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. Two-year follow-up data from ZUMA-1 included the following[64] :

• Objective responses were seen in 83% of patients; complete responses were seen in 58%.
• Median duration of response was 11.1 months (4.2months to not estimable).
• Median overall survival was not reached; median progression-free survival was 5.9 months.
• Grade 3 or worse serious adverse events occurred in 48% of patients, including grade 3 or worse cytokine release syndrome occurred in 11% and grade 3 or worse neurologic events in 32%. 

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

A hematologist-oncologist should treat patients with NHL.

Consult a radiation oncologist for treatment of patients with localized or limited-stage low-grade lymphoma and for palliative radiation therapy (eg, for treatment of SVC syndrome, treatment of painful metastases [especially to bone] as an adjunctive treatment for CNS lymphomas).

Consult an infectious disease specialist for the management of patients with neutropenic fever who are not responding to the usual broad-spectrum antibiotics.

Surgical consultation is needed for lymph node biopsy, palliative procedures, or placement of a venous access device (eg, Port-a-Cath, Hickman catheter) for blood drawing and chemotherapy access.

Treatment and follow-up care of patients with NHL are usually performed on an outpatient basis. Monitoring patients’ blood cell counts while they are receiving chemotherapy (eg, prior to each treatment cycle and 10-14 d after each treatment cycle) is important.

Monitor adverse effects of chemotherapy with a detailed patient history, an examination, a CBC, and serum chemistries (especially liver function tests, electrolytes, lactate dehydrogenase, and blood urea nitrogen [BUN]/creatinine).

Treat symptomatic adverse effects such as nausea, vomiting, diarrhea, mucositis, anorexia, pain, and fatigue. Administer packed red blood cell (PRBC) transfusions for patients with symptomatic anemia and provide platelet transfusions for patients with a platelet count less than 10,000- 20,000/mm3. Provide growth factor (eg, granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], erythropoietin) support as necessary.

Perform a disease and response to treatment evaluation by obtaining patient history, physical examination (at intervals q2-3mo), and imaging studies (eg, CT scans at intervals q4-12mo).

Provide psychosocial support for the patient and family.

Guidelines contributors: Priyank P Patel, MD, Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo; Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

Classification

Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of malignancies of different biology and prognosis. NHL includes many subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.

The National Comprehensive Cancer Network (NCCN) guidelines for NHL provide general recommendations on classification, differential diagnosis and supportive care, as well as specific guidance for the management of the most common subtypes.[26]

The European Society for Medical Oncology (ESMO) has published separate guidelines for the management and treatment of the following subtypes:

• Follicular lymphoma
• Mantle cell lymphoma
• Diffuse large B cell lymphoma
• Primary cutaneous lymphoma
• Gastric marginal zone lymphoma of the mucosa-associated lymphatic tissue (MALT) type

NHL Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

• National Cancer Institute’s Working Formulation (IWF) ^[65]
• Revised European-American Classification of Lymphoid Neoplasms (REAL) ^[66]
• World Health Organization (WHO) classification ^[67]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J.[1] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities.[66]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin.[67]

National Cancer Institute’s Working Formulation (IWF)

Although considered obsolete, the IWF classification is still used mainly for historical data comparisons.[65]

Low-grade NHL subtypes in the IWF classification are as follows:

1. Small lymphocytic, consistent with chronic lymphocytic leukemia
2. Follicular, predominantly small-cleaved cell
3. Follicular, mixed small-cleaved, and large cell

Intermediate-grade NHL subtypes in the IWF classification are as follows:

D. Follicular, predominantly large cell

E. Diffuse, small-cleaved cell

F. Diffuse mixed, small and large cell

G. Diffuse, large cell, cleaved, or noncleaved cell

High-grade NHL subtypes in the IWF classification are as follows:

H. Immunoblastic, large cell

I. Lymphoblastic, convoluted, or nonconvoluted cell

J. Small noncleaved-cell, Burkitt, or non-Burkitt

World Health Organization classification

The WHO modification of the REAL classification of NHL is based on morphology and cell lineage. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.[67]

The WHO classification subtypes for NHL precursors are as follows:

• Precursor B–lymphoblastic leukemia/lymphoma, with subdivisions by genetic abnormality
• Precursor T–lymphoblastic lymphoma/leukemia

The WHO classification of mature B-cell neoplasms includes are as follows:

• B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Lymphoplasmacytic lymphoma/immunocytoma
• Mantle cell lymphoma
• Follicular lymphoma
• Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
• Nodal marginal zone B-cell lymphoma (± monocytoid B cells)
• Splenic marginal zone lymphoma (± villous lymphocytes)
• Hairy cell leukemia
• Plasmacytoma/plasma cell myeloma
• Diffuse large B-cell lymphoma (DLBCL)
• Burkitt lymphoma

The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:

• T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
• T-cell granular lymphocytic leukemia
• Mycosis fungoides/Sézary syndrome
• Peripheral T-cell lymphoma, not otherwise characterized
• Hepatosplenic gamma/delta T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Angioimmunoblastic T-cell lymphoma
• Extranodal T-/NK-cell lymphoma, nasal type
• Enteropathy-type intestinal T-cell lymphoma
• Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
• Anaplastic large cell lymphoma, primary systemic type
• Anaplastic large cell lymphoma, primary cutaneous type
• Aggressive NK-cell leukemia

The National Comprehensive Cancer Network (NCCN) recommendations for the diagnostic evaluation of non-Hodkgin lymphoma are as follows[26] :

• Morphology and immunophenotyping is required for diagnosis according to the World Health Organization (WHO) classification

• Incisional or excisional biopsy is preferred for the initial diagnosis; core needle biopsy is discouraged except for cases where 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

• Differential diagnosis is based on morphology and clinical features, which determine the choice of studies

• A broad but limited panel of antibodies should be tested

• Additional panels are added on the basis of initial results; unless clinically urgent, panels of unnecessary antibodies should be avoided

• Genetic studies may be ordered as needed

• Bone marrow biopsy is required when clonal lymphocytosis is identified by flow cytometry, except in chronic lymphocytic leukemia, where bone marrow biopsy is not necessary unless indicated because of cytopenias and suspicion for bone marrow involvement)

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.[68]  In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system.[26]

The revised recommendations for staging include the following[68] :

• 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[26, 68] :

  Table 1. 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, 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.[69]  Separate indices have been developed for follicular and mantle cell lymphoma.[70, 11, 71]

The IPI includes the following risk factors[69] :

• 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[69] :

• 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 divided follicular lymphoma (FL) into 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.[67, 72] Current National Comprehensive Cancer Network (NCCN) guidelines note that grade 3B is commonly treated as diffuse large B-cell lymphoma (DLBCL); 3A can be treated as either FL or DLBCL, but management of these cases is controversial.[26]

Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. Since 2008, it has been classified a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL[26] :

• 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

European Society for Medical Oncology (ESMO) guidelines are in agreement with the NCCN that diagnosis follows the WHO classification and excisional biopsy is preferred. Core biopsy is considered only in cases where lymph nodes are not easily accessible. Fine-needle aspiration is not recommended.[73]

Risk Stratification

The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary[74] :

• Three nodes in three distinct areas, with each node ≥3 cm in diameter
• A tumor ≥7 cm in diameter
• Presence of systemic symptoms
• Symptomatic spleen enlargement
• Ascites or pleural effusion
• 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
• Four 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)[70] :

• 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 follows[70] :

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

With this model, relapse-free and overall survival rates at 5 years are as follows[70] :

• 0-1 risk factors - 79%
• Two risk factors - 51%
• Three or more risk factors - 20%

FLIPI1 and FLIPI2 are used to predict prognosis but are not used to select treatment options.

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows[26, 73] :

• Involved-site radiation therapy (ISRT), 24-30 Gy, is the preferred treatment option for stage I or II
• If significant toxicity is expected from radiotherapy, initial observation may be more appropriate
• Other first-line treatment options include rituximab, alone or in combination with other agents, and radioimmunotherapy
• Combination treatment with involved-field radiation therapy (IFRT) and chemotherapy (see below) and/or radioimmunotherapy is recommended for more advanced stages
• In asymptomatic patients with advanced-stage, low tumor burden disease, initiate treatment when the patients become symptomatic, as there is no survival advantage with immediate treatment versus a watch-and-wait approach

NCCN-recommended chemotherapy regimens (category 1) for FL are as follows:

• Bendamustine + obinutuzumab or rituximab
• CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) + obinutuzumab or rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumab or rituximab
• Single-agent rituximab can be used in elderly patients and patients with poor performance status

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 gastric mucosa–associated lymphoid tissue (MALT) lymphoma[26] :

• Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, BCL6, cyclin D1

• Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10

• Helicobacter pylori testing

• Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for detection of t(11;18) (p21;p21) to identify patients who are unlikely to respond to antibiotic therapy

European Society for Medical Oncology (ESMO) guidelines for clinical management of marginal zone lymphomas of MALT type provide similar recommendations.[75]

Staging

The following two systems are currently used for staging gastric marginal zone lymphoma:

• Lugano staging system (1994) ^[76]
• Paris staging system (2003) ^[77]

The Lugano system is a modification of the Ann Arbor staging system, and the Paris system corresponds to the tumor-node-metastasis (TNM) system for staging gastric cancer, which presents more accurately the depth of gastric wall involvement, a factor in the response to H pylori eradication. See Table 2, below.

Table 2. Comparison of Lugano and Paris staging systems (Open Table in a new window)

Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement

Both the NCCN and ESMO recommend that early staging procedures include gastroduodenal endoscopy, with multiple biopsies taken from each region of the stomach, duodenum, gastroesophageal junction, and any abnormal-appearing site. Endoscopic ultrasound is recommended to evaluate regional lymph nodes and gastric wall infiltration. Attention to other MALT sites and autoimmune diseases is necessary. As in other lymphomas, staging procedures should include CT scanning, laboratory studies, and bone marrow examination.[26, 75]

Treatment

Both the NCCN and ESMO recommend antibiotic eradication of Helicobacter pylori as first-line treatment for H pylori–positive patients, including t(11;18)-positive patients. However, patients with t(11;18) are unlikely to respond to antibiotic therapy, or to alkylating agents as a sole treatment; they should be treated with involved-site radiation therapy (ISRT) or rituximab. In H pylori–negative patients, ISRT, 30 Gy, is the preferred treatment option. Rituximab is an option if radiation therapy is contraindicated.[26, 75]

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. The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL[26] :

• 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 2008 MCL International Prognostic Index (MIPI) for risk stratification.[78]  The MIPI includes the following risk factors[71] :

• Age: 50-59 (1 point); 60-69 (2 points); ≥70 (3 points)

• Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (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 (× 109/L): 6700-9999 (1 point); 10,000-14,999 (2 points); ≥15,000 (3 points)

Based on the MIPI score, patients can be categorized as follows[71] :

• 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.[26, 78]

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows[26, 78]

• 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 with a combination regimen such as the LyMA, NORDIC, or TRIANGLE regimen, 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 treatment regimens, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) 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 bendamustine, bortezomib, temsirolimus, ibrutinib or lenalidomide with rituximab; allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation

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)[26] :

• 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.[79]

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.[26, 80]

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-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)[69] :

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

Based on the aa-IPI score, patients can be categorized as follows[69] :

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

Treatment

National Comprehensive Cancer Network recommendations

NCCN treatment recommendations for stage I/II (nonbulky) disease are as follows[26] :

• R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) for three cycles, followed by involved-field radiation therapy (IFRT)

• R-CHOP for six cycles with or without IFRT is an acceptable alternative

• Patients who are not candidates for chemotherapy should receive involved-site radiation therapy (ISRT)

For stage II bulky disease, NCCN recommends R-CHOP for six cycles, with or without radiation therapy.

For stage III/IV (advanced-stage) disease, NCCN treatment recommendations are as follows[26] :

• R-CHOP every 21 days for six cycles is preferred

• Consider radiation therapy for bulky sites

• Other regimens that may be considered include dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) plus rituximab or dose-dense R-CHOP-14

• In patients at increased risk for central nervous system relapse (eg, disease involving the paranasal sinus, testis, epidural, bone marrow, HIV lymphoma, kidney or adrenal involvement or > 2 extranodal sites, elevated LDH or concomitant expression of BCL2 and MYC protein), four to eight doses of intrathecal methotrexate and/or cytarabine, or 3-3.5 g/m2 of systemic methotrexate for prophylaxis is recommended

For relapse or refractory disease, high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) is the treatment of choice. Before or after HDC and ASCRA, IFRT is given to previous disease sites. Second-line regimens for HDC include the following, which may be given with or without rituximab :

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

Patients with relapsed disease who are not eligible for HDC and ASCR should be enrolled in a clinical trial. If one is not available, they should receive palliative chemotherapy.

European Society for Medical Oncology recommendations

The ESMO guidelines contain specific recommendations for patients < 60 years old based on aaIPI risk.[80]

For aa-IPI=0 without bulky disease, treatment recommendations are as follows:

• R-CHOP every 21 d for six cycles is preferred
• Radiation therapy has no proven benefit

For aa-IPI=0 with bulky disease or aa-IPI=1, treatment recommendations are as follows:

• R-CHOP every 21 d for six cycles with IFRT, or

• R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, prednisolone) and sequential consolidation

For aa-IPI≥2, ESMO notes that no standard of care has been established; enrollment in a clinical trial is preferred. R-CHOP every 21 days for eight cycles is one possible regimen.

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.[26]

Classification

The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL)[67] :

• 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) considers the following studies essential for establishing a diagnosis of Burkitt lymphoma[26] :

•  Immunohistochemistry panel: CD45, CD20, CD3, CD5, CD10, Ki-67, BCL2, BCL6, TdT with or without cell surface marker analysis by flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT

• Karyotype ± fluorescence in situ hybridization (FISH): t(8;14) or variants; MYC, BCL2; BCL6 rearrangement

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[81] :

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

Treatment

Because of the complexity of the disease, NCCN guidelines recommend that treatment of Burkitt lymphoma be given at centers with expertise in the management of the disease. Recommended chemotherapy regimens include the following[26] :

• Cancer and Leukemia Group B (CALGB) 10002 regimen

• CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine) – Original or modified, with or without addition of rituximab

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin [hydroxydaunorubicin]), with rituximab (DA-EPOCH-R)

• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) with rituximab (R-hyper-CVAD)

Other treatment recommendations are as follows[26] :

• Enrollment in available clinical trials for all patients
• CHOP is not considered adequate therapy
• Central nervous system prophylaxis with systemic and/or intrathecal chemotherapy with methotrexate and/or cytarabine
• Prophylaxis for tumor lysis syndrome is mandatory

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.[26]

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).[82]

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[83] :

• 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[26] :

• 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.[84]

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.[26, 82]  The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options.[26]

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.[26]

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.[82]

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.[26, 82] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed.[82] .

Classification

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following[83] :

• Mycosis fungoides

• Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)

• Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)

• Subcutaneous panniculitis-like T-cell lymphoma (provisional)

• Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

CTCLs with aggressive clinical behavior include the following[26] :

• Sézary syndrome

• Adult T-cell leukemia/lymphoma

• Extranodal NK/T-cell lymphoma, nasal type

• Primary cutaneous peripheral T-cell lymphoma, unspecified

• Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)

• Cutaneous gamma/delta-positive T-cell lymphoma (provisional)

Mycosis Fungoides/Sezary syndrome

In addition to the NCCN guidelines, the European Organization for Research and Treatment of Cancer (EORTC) published consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2006.[85]  In 2013, the European Society for Medical Oncology (ESMO) included treatment recommendations in its guidelines for primary cutaneous lymphoma.[86]

Diagnosis

The NCCN recommends the following studies to establish a diagnosis of MF/SS[26] :

• Immunohistochemistry panel of skin biopsy: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD25, CD56, T1A1, granzyme B, βF1, TCR-CyM1

• Molecular analysis of skin biopsy: TCR gene rearrangements by polymerase chain reaction (PCR)

• Assessment of peripheral blood for Sezary cells

• Biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)

• Assessment of HTLV-1 serology in at-risk populations

Staging

In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease.[87]  See Table 4, below.

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)

The ISCL/EORTC system was further modified to update clinical staging classifications.[87]  See Table 5, below.

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Treatment

The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis.[26]

In 2011, the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC issued a joint consensus statement proposing new clinical end points and response criteria for use in clinical trials of MF/SS.[88]  The NCCN includes the new criteria in its current recommendations.[26]

All three guidelines recommend treatment selection based on clinical stage.[26, 85, 86]

Mycosis fungoides

In general, topical therapies are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments.[26, 85, 86]

Localized therapies endorsed by the guidelines include the following[26, 85, 86]

• Psoralens + ultraviolet A (PUVA)—For thick plaques
• Narrow-band ultraviolet B (UVB)—For patch or thin plaques
• Topical corticosteroids
• Localized radiation therapy (12-36 Gy)
• Topical chemotherapy (ie, nitrogen mustard or carmustine)
• Topical retinoids (ie, bexarotene)

Because of the high toxicity of total skin electron beam therapy (TSEBT), both NCCN and EOTRTC recommend TSEBT only after other treatments have failed.[26, 85]

Systemic therapies recommended for advanced stages include the following[26, 85, 86]

• Retinoids (ie, bexarotene)
• Interferons (IFN-alpha, IFN-gamma)
• Histone deacetylase (HDAC)-inhibitors (vorinostat, romidenpsin)—not approved in Europe
• Extracorporeal photopheresis (ECP)
• Methotrexate (≤100 mg/wk)

All three guidelines recommend IFN-alpha and PUVA or PUVA and retinoids (including bexarotene) as second-line combination therapies for MF stages IA, IB, and IIA.[26, 85, 86]

Other NCCN recommended combination therapies for advanced disease include the following[26] :

• PUVA and ECP
• TSEBT and ECP
• Retinoids and interferons
• ECP and retinoids
• ECP and interferons
• ECP and retinoids and interferons

Sezary syndrome and erythrodermic mycosis fungoides

Participation in a clinical trial as a treatment option for all patients with SS or advanced-stage MF is recommended by both the NCCN and EOTRTC.[26, 85]  Treatment for SS or erythrodermic MF (stage IV) is palliative. The preferred modality is ECP, either alone or in combination with other treatments.[26, 85, 86]

In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs).[89]

Classification

Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features.[83]

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following[26] :

• Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation

• Mycosis fungoides can be comorbid

• Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes

• Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1

• Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH

• Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance

• Molecular analysis of skin biopsy: TCR gene rearrangements

• Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)

• Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)

• Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease

Staging

EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome.[84, 89]

Treatment

Both guidelines give similar treatment recommendations for PC-ALCL, as follows[26, 89] :

• For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment

• Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated

• For multifocal lesions, low-dose methotrexate may be used, based on expert consensus; retinoids and interferon alpha are alternative treatments for multifocal disease that is not responsive to other therapies, but data are limited on effectiveness. Newer promising agents include pralatrexate and CD30 antibody-drug conjugate brentuximab vedotin[90, 91]

• Multi-agent chemotherapy is not recommended for multifocal or relapsing PC-ALCL limited to the skin; it is recommended only for extracutaneous spread

Multiple chemotherapeutic agents are active against non-Hodgkin lymphoma (NHL) and can be used alone or in combination, depending on the histology and stage of the disease and whether the patient can tolerate chemotherapy. In addition, several biological therapies are currently available for these patients, including interferons, rituximab, and radiolabeled antibodies (the newest biological therapy).

Alkylating agents impair cell function by forming covalent bonds with DNA, ribonucleic acid (RNA), and proteins. These agents are not cell cycle phase–specific and are used for hematologic and nonhematologic malignancies.

Anthracycline antibiotics bind to nucleic acids by intercalation with base pairs of the DNA double helix, interfering with the DNA synthesis. They cause inhibition of DNA topoisomerases I and II.

Vinca alkaloids inhibit microtubule assembly, causing metaphase arrest in dividing cells. Vinca alkaloids are also cell cycle phase–specific at the M and S phase.

Glucocorticoids cause lysis of lymphoid cells, which led to their use against acute lymphoblastic leukemia (ALL), multiple myeloma, and NHL. These agents are also used as adjunctive antiemetic agents, to decrease vasogenic edema associated with tumors, and as prophylactic medication to prevent hypersensitivity reactions associated with some chemotherapeutic drugs.

Antimetabolites cause tumor cell death by inhibiting enzymes that are important in DNA synthesis.

Biological response modulators control the response of the patient's immune system to tumor cells, infecting organisms, or both.

Class Summary

These agents inhibit cell growth and proliferation.

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.

Doxorubicin

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.

Pralatrexate (Folotyn)

This agent is a folate inhibitor. It is indicated for relapsed or refractory peripheral T-cell lymphoma.

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.

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

Mitoxantrone inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

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.

Bendamustine (Bendeka, Treanda)

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.

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.

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.

Gemcitabine

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.

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.

Polatuzumab vedotin (Polivy, polatuzumab vedotin-piiq)

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

Class Summary

These agents can induce the termination of cell growth, which, in turn, leads to cell death. Agents include vorinostat and romidepsin.

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.

Romidepsin (Istodax)

This agent inhibits HDAC, which results in the accumulation of acetyl groups. This leads to alterations in chromatin structure and transcription factor activation, causing the termination of cell growth, which, in turn, leads to cell death. Indicated for CTCL in patients who have received at least 1 prior therapy.

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.

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 is a phosphoinositide 3-kinase (PI3K) delta inhibitor. 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. 

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

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

Rituximab (Rituxan, Truxima)

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 binding to CD20 mediates B-cell lysis. The antibody is an immunoglobulin G1 (IgG1) kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. It is available as an IV formulation. 

Rituximab/hyaluronidase (Rituxan Hycela)

The SC product is combined with hyaluronidase human, which increases subcutaneous tissue permeability. It is indicated for previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

Ibritumomab tiuxetan (Zevalin)

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 2 low doses of rituximab, an imaging dose, 2-3 whole body scans, and a therapeutic dose, all of which are delivered in an outpatient setting over 8 days.

Alemtuzumab (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.

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.

Class Summary

Agents in this class may cause cell-cycle arrest and apoptosis.

Bortezomib (Velcade)

This is the first drug approved of the anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts the pathways supporting cell growth, thus decreases cancer cell survival.

Class Summary

Agents in this class halt the cell cycle at the G1 phase in tumor cells.

Temsirolimus (Torisel)

Temsirolimus is a water-soluble ester of sirolimus. It binds with high affinity to immunophilin FKBP (FK506-binding protein). This complex inhibits mammalian target of rapamycin (mTOR) kinase, a key protein in cells that regulate the gene translation responsible for cell-cycle regulation. mTOR also reduces the cell growth factors (eg, vascular endothelial growth factor) involved in new blood vessel development.

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

Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive T-cell therapy in which the patient's T cells are genetically engineered to express a CAR.

For CAR T-cell preparation, the patient’s T lymphocytes are collected by apheresis and the CAR molecule is introduced into the 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. After the anti-CD19 CAR T cells bind with target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades, which eventually leads to killing of CD19-expressing cells. Axicabtagene ciloleucel is approved for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Indications include 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 cells. It is indicated in adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, after 2 or more 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 primary CNS lymphoma.

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 disuse 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

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

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.

Darbepoetin alfa (Aranesp)

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

Filgrastim (Neupogen)

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

Pegfilgrastim (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.

Class Summary

These drugs regulate key events responsible for immune reactions.

Interferon alfa-2a (Roferon-A) or alfa-2b (Intron A)

These drugs regulate key events responsible for immune reactions.

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

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 (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.