Non-Hodgkin lymphomas (NHLs) are tumors originating from lymphoid tissues, mainly of lymph nodes. These tumors may result from chromosomal translocations, infections, environmental factors, immunodeficiency states, and chronic inflammation. See the image below.
View Image | 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 no.... |
The clinical manifestations of 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.
Signs and symptoms of low-grade lymphomas include the following:
Intermediate- and high-grade lymphomas have a more varied clinical presentation, including the following:
See Presentation for more detail.
Examination in patients with low-grade lymphomas may demonstrate peripheral adenopathy, splenomegaly, and hepatomegaly.
Intermediate- and high-grade lymphomas may result in the following examination findings:
Testing
Laboratory studies in a patient with suspected NHL should include the following:
Other tests that may be helpful in evaluating suspected NHL include the following:
Imaging tests
The following imaging studies should be obtained in a patient suspected of having NHL:
Procedures
The diagnosis of NHL relies on pathologic confirmation following appropriate tissue biopsy. The following are procedures in cases of suspected NHL:
Perform lumbar puncture for CSF analysis in patients with the following conditions:
See Workup for more detail.
The treatment of NHL varies greatly, depending on various factors. Common therapies include the following:
Chemotherapy: Most common; usually combination regimens
Pharmacotherapy
Medications used in the management of NHL include the following:
Surgery
Surgical intervention in NHL is limited but can be useful in selected situations (eg, GI lymphoma), particularly in localized disease or in the presence of risk of perforation, obstruction, and massive bleeding. Orchiectomy is part of the initial management of testicular lymphoma.
See Treatment and Medication for more detail.
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, namely non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is the sixth decade of life, 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.[3]
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.[4]
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:
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 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.
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,[5] 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 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.[6]
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.[7]
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 74,200 new cases of NHL will be diagnosed in 2019.[8] 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. From 2011 to 2015, incidence rates declined by 0.6% per year; however, patterns vary by subtype.[8]
NHL is the most prevalent hematopoietic neoplasm, representing approximately 4.2% of all cancer diagnoses and ranking seventh in frequency among all cancers. NHL is more than 5 times as common as Hodgkin disease.[9]
Overall, NHL is most often diagnosed in people aged 65-74; median age at diagnosis is 67 years.[9] 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 71.4%.[9] 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 (ie, monoclonal antibodies), validation of biomarkers of response, and the implementation of tailored treatment.
The prognosis for patients with NHL depends on the following factors:
In general, these clinical characteristics are thought to reflect the following host or tumor characteristics:
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:
With this model, relapse-free and overall survival rates at 5 years are as follows:
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:
Three risk groups are defined: low risk (0-1 adverse factor), intermediate risk (2 factors), and 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 chemotherapy. 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 the Blood and Lymphatic System Center, as well as 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.
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.
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).[5]
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:
Potential disease-related complications include the following:
The workup in a patient with suspected non-Hodgkin lymphoma (NHL) should include the following:
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:
Serum chemistry studies may show the following:
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.
View Image | Posteroanterior (PA) chest radiograph in a man with thoracic non-Hodgkin lymphoma (NHL) shows mediastinal widening due to grossly enlarged right parat.... |
View Image | Posteroanterior (PA) chest radiograph in a 16-year-old male adolescent with thoracic non-Hodgkin lymphoma (NHL) shows subtle enlargement of the lower .... |
View Image | Posteroanterior (PA) chest radiograph shows a large mass in the right parahilar region extending into the right upper and middle zones, with silhouett.... |
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.
View Image | Nonenhanced CT scan through the mediastinum shows multiple enlarged lymph nodes in the prevascular space, in the right and left paratracheal region. N.... |
View Image | Nonenhanced CT scan through the mediastinum at the level of the carina shows enlarged tracheobronchial and subcarinal nodes. Note the small bilateral .... |
View Image | 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.
View Image | 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 no.... |
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.
View Image | 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 transf.... |
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.
In general, anthracyclines should not be administered to those patients with 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.
View Image | 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 a.... |
View Image | 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.... |
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.
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.
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:
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:
In addition to the 4 stage designations, subscript letters designate involvement of extralymphatic organs, as follows:
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:
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:
The FLIPI score is as follows:
The treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on the following factors:
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).
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.
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.
The use of rituximab, a monoclonal antibody targeting 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 be changing the natural progression of indolent lymphomas.
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 be focused 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.
Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are CHOP (cyclophosphamide, hydroxydaunomycin [Adriamycin], vincristine [Oncovin], and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and fludarabine alone or in combination (eg, with cyclophosphamide or mitoxantrone). 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.[24, 25, 26]
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 (RCHOP).[27] 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.
Bendamustine plus rituximab has demonstrated efficacy for the first-line treatment of advanced follicular, indolent, and mantle cell lymphomas.[28] Current National Comprehensive Cancer Network guidelines give bendamustine plus rituximab, bendamustine plus obinutuzumab, CHOP, RCHOP, CVP (cyclophosphamide, vincristine, prednisone), and CVP plus rituximab (RCVP) category 1 recommendations for first-line therapy of follicular lymphoma.[29] Promising outcomes have been seen with the combination of lenalidomide plus rituximab for both rituximab-refractory and non–rituximab-refractory indolent NHL.[30]
A study by Gaulard et al found that rituximab plus low-dose CHOP (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.[31]
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.[32]
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.[33]
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).[34]
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.
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.
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[35] :
Bortezomib has also been used in patients with relapsed or refractory mantle cell lymphoma.[39]
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.[40] 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.[41] 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.[41]
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:
131Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity.[43] 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.[44, 45]
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.
Idelalisib (Zydelig), a phosphoinositide 3-kinase (PI3K) delta inhibitor, received accelerated approval from the FDA in July 2014 for relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. The accelerated approval was based on a phase II, open-label study involving 125 patients with indolent NHL that had not responded to treatment with rituximab and an alkylating agent or had relapsed within 6 months afterward.[46]
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. Similar response rates were observed across all subtypes of indolent non-Hodgkin lymphomas.[46]
The accelerated approval program allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while confirmatory clinical trials are being conducted.
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.[47]
In May 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 was approved based on the AUGMENT study. 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 to 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.[48]
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 June 2019, polatuzumab, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the FDA for adults with relapsed or recurrent DLBCL in combination with bendamustine and a rituximab product after at least 2 prior therapies and not candidates for ASCT.
Accelerated approval of polatuzumab was based on a study in which 40% of patients treated with polatuzumab vedotin plus BR achieved CR (n=16/40; 95% CI: 25-57) compared with 18% of those receiving BR alone (n=7/40; 95% CI: 7-33). The study also showed an OR of 45% with polatuzumab plus BR at the end of treatment (n=18/40; 95% CI: 29-62) compared with 18% for BR alone (n=7/40; 95% CI: 7-33). Of patients who achieved a complete or partial response, duration of response was at least 6 months in 64% (n=16/25) of those receiving polatuzumab plus BR, compared with 30% (n=3/10) for BR alone. Additionally, response lasting at least 1 year was observed in 48% (n=12/25) of patients receiving polatuzumab plus BR compared with 20% (n=2/10) for BR alone.[49]
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.[50]
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.[51, 52] After a 5-year median follow-up study, the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the OS rate was also better (53% versus 32%).
Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants.[53]
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.
Tumor vaccines are still being investigated for use in patients with lymphoma. Novel biological and small agents showing promising results in ongoing clinical trials include CMC-544, lenalidomide, bortezomib, and temsirolimus.[42]
A study by Witzig et al concluded that lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive NHL.[54]
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:
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).[55]
In June 2011, the FDA granted accelerated approval for romidepsin (Istodax) for treatment of PTCL in patients who have received at least one prior therapy.[56]
In July 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.[57, 58]
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.[59]
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:
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.
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.[60] 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.[60]
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:
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
Pediatric patients with NHL are best treated by pediatric oncologists.
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.
In October 2017, FDA approved axicabtagene ciloleucel (Yescarta) for treatment of large B-cell lymphoma after at least two other kinds of therapy have failed. Approved uses include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.[61]
Approval was based on the results from the ZUMA-1 study, an open-label, multicenter trial enrolling of 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 x 106 cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with relapsed/refractory DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. At 6-month follow-up, 40% of patients had maintained their complete response. The trial had a median survival follow-up of 8.7 months.[62]
Two-year follow-up data from ZUMA-1 included the following[63] :
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
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.[29]
The European Society for Medical Oncology (ESMO) has published separate guidelines for the management and treatment of the following subtypes:
The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:
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.[65]
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.[66]
National Cancer Institute’s Working Formulation (IWF)
Although considered obsolete, the IWF classification is still used mainly for historical data comparisons.[64]
Low-grade NHL subtypes in the IWF classification are as follows:
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.[66]
The WHO classification subtypes for NHL precursors are as follows:
The WHO classification subtypes for peripheral B-cell neoplasms are as follows:
The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:
The National Comprehensive Cancer Network (NCCN) recommendations for the diagnostic evaluation of non-Hodkgin lymphoma are as follows[29] :
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.[67] In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system.[29]
The revised recommendations for staging include the following[67] :
In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification, as shown in Table 1, below[29, 67] :
Table 1. Non-Hodgkin lymphoma staging.
View Table | See Table |
*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.[68] Separate indices have been developed for follicular and mantle cell lymphoma.[69, 11, 70]
The IPI includes the following risk factors[68] :
Each factor is worth 1 point. Based on the IPI score, patients can be categorized as follows[68] :
With this model, relapse-free and overall survival rates at 5 years are as follows:
In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes. National Comprehensive Cancer Network (NCCN) 2015 guidelines suggest that grade 3B should be treated as diffuse large B-cell lymphoma (DLBCL), whereas 3A can be treated as either FL or DLBCL.[66, 71]
Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.
In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL[29] :
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.[72]
The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary[73] :
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] :
For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows[11] :
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)[69] :
Based on the FLIPI2 score, patients can be categorized as follows[69] :
With this model, relapse-free and overall survival rates at 5 years are as follows[69] :
FLIPI1 and FLIPI2 are used to predict prognosis but are not used to select treatment options.
The NCCN and ESMO offer similar treatment recommendations, as follows[29, 72] :
NCCN-recommended chemotherapy regimens (category 1) for FL are as follows:
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[29] :
European Society for Medical Oncology (ESMO) guidelines for clinical management of marginal zone lymphomas of MALT type provide similar recommendations.[74]
The following two systems are currently used for staging gastric marginal zone lymphoma:
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
View Table | See Table |
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.[29, 74]
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.[29, 74]
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[29] :
The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification.[77] The MIPI includes the following risk factors[70] :
Based on the MIPI score, patients can be categorized as follows[70] :
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.[29, 77]
The NCCN and ESMO offer similar treatment recommendations, as follows[29, 77]
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)[29] :
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.[78]
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.[29, 79]
The IPI includes the following risk factors:
Each risk factor is worth 1 point. On the basis of the IPI score, patients can be categorized as follows:
The aa-IPI includes the following risk factors (1 point is allotted for each factor)[68] :
Based on the aa-IPI score, patients can be categorized as follows[68] :
National Comprehensive Cancer Network recommendations
NCCN treatment recommendations for stage I/II (nonbulky) disease are as follows[29] :
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[29] :
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 :
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.[79]
For aa-IPI=0 without bulky disease, treatment recommendations are as follows:
For aa-IPI=0 with bulky disease or aa-IPI=1, treatment recommendations are as follows:
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.
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.[29]
The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL)[66] :
In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of Burkitt lymphoma[29] :
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[80] :
The four risk groups based on the scoring system are as follows:
With this model, relative survival rates at 5 years are as follows:
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[29] :
Other treatment recommendations are as follows[29] :
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.[29]
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).[81]
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[82] :
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.
In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of CBCL[29] :
The 2007 TNM classification system of the ISCL/EORTC is used for staging, as shown in Table 3, below.[83]
Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma
View Table | See Table |
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.[29, 81] The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options.[29]
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.[29]
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.[81]
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.[29, 81] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed.[81] .
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[82] :
CTCLs with aggressive clinical behavior include the following[29] :
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.[84] In 2013, the European Society for Medical Oncology (ESMO) included treatment recommendations in its guidelines for primary cutaneous lymphoma.[85]
The NCCN recommends the following studies to establish a diagnosis of MF/SS[29] :
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.[86] 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
View Table | See Table |
The ISCL/EORTC system was further modified to update clinical staging classifications.[86] See Table 5, below.
Table 5. Staging classifications for mycosis fungoides and Sezary syndrome
View Table | See Table |
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.[29]
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.[87] The NCCN includes the new criteria in its current recommendations.[29]
All three guidelines recommend treatment selection based on clinical stage.[29, 84, 85]
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.[29, 84, 85]
Localized therapies endorsed by the guidelines include the following[29, 84, 85]
Because of the high toxicity of total skin electron beam therapy (TSEBT), both NCCN and EOTRTC recommend TSEBT only after other treatments have failed.[29, 84]
Systemic therapies recommended for advanced stages include the following[29, 84, 85]
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.[29, 84, 85]
Other NCCN recommended combination therapies for advanced disease include the following[29] :
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. [29, 84] Treatment for SS or erythrodermic MF (stage IV) is palliative. The preferred modality is ECP, either alone or in combination with other treatments.[29, 84, 85]
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).[88]
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.[82]
The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following[29] :
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.[83, 88]
Both guidelines give similar treatment recommendations for PC-ALCL, as follows[29, 88] :
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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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).
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: This agent is a folate inhibitor. It is indicated for relapsed or refractory peripheral T-cell lymphoma.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Mitoxantrone inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.
Clinical Context: 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.
Clinical Context: Alkylating agent indicated for treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Included as part of a regimen containing polatuzumab vedotin and rituximab.
Clinical Context: Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to action of these drugs in the G1 and S phases. 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: CD79b-directed antibody-drug conjugate. It is indicated in combination with bendamustine and a rituximab product for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2 prior therapies.
Clinical Context: 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.
Clinical Context: 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 and PTCL in patients who have received at least 1 prior therapy.
Clinical Context: 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.
These agents can induce the termination of cell growth, which, in turn, leads to cell death. Agents include vorinostat and romidepsin.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Filgrastim is a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) consisting of a 175–amino acid protein with a molecular weight of 18,800 d. It is produced by Escherichia coli bacteria into which the human G-CSF gene is inserted. This protein has an amino acid sequence identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Because it is produced in E coli, the product is nonglycosylated and thus differs from G-CSF isolated from human cells.
Clinical Context: Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant granulocyte colony-stimulating factor (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating the production, maturation, migration, and cytotoxicity of neutrophils.
These agents can induce an increase in reticulocyte counts, with a subsequent increase in hematocrit and hemoglobin levels.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.
Clinical Context: Pan class I phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. By inhibiting several key cell-signaling pathways may induce apoptosis and inhibition of proliferation of premalignant B cells and in turn cause tumor cell death. It is indicated for relapsed follicular lymphoma (FL) in patients who have received at least 2 prior systemic therapies.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Thalidomide analogue; inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells. Indicated for in combination with rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma.
Clinical Context: 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.
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.
Clinical Context: CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following the binding anti-CD19 CAR T cells with target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades which eventually leads to killing of CD19-expressing cells. It is indicated for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive T-cell therapy in which T cells are genetically engineered to express a CAR.
CAR T cells preparation begins with obtaining a blood sample from the patient. The CAR molecule is introduced into the patient’s T cells through viral or nonviral approaches. The cells undergo a brief round of expansion in the laboratory and are then infused back into the patient. T cells become activated when they recognize the target antigen on the surface of the tumor, in this case, CD19. When T cells are activated, they undergo massive expansion in the body. The cells start to produce multiple different cytokines and proliferate. These cytokines improve the T cells’ function, help them traffic to the tumor site, and start killing the tumor cells by expressing cytotoxic molecules (eg,granzymes and perforins).
In October 2017, FDA approved axicabtagene ciloleucel (Yescarta) for large B-cell lymphoma after at least two other kinds of treatment have failed. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.
FDA approval is based on results from the ZUMA-1 study, an open-label, multicenter trial enrolling of 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 x 106cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with relapsed/refractory DLBCL, the response rates are approximately 60-80%, with complete responses seen in 40-70 %t of patients. Following axicabtagene ciloleucel, 40% of patients maintain their complete response at six-month follow-up. The trial had a median survival follow-up of 8.7 months.[62]
Clinical Context: These drugs regulate key events responsible for immune reactions.
Clinical Context: 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.
Clinical Context: 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.
These drugs have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
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.
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).
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).
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.
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).
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).
Stage Area of Involvement Extranodal (E) Status I Single node or adjacent group of nodes Single extranodal lesions without nodal involvement II Multiple lymph node groups on same side of diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement II bulky* Multiple lymph node groups on same side of diaphragm with “bulky disease” N/A III Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement N/A IV Multiple noncontiguous extranodal sites N/A
Lugano Staging System Paris Staging System Stage Area of Involvement TNM Tumor extension IE1 Confined to GI tract—mucosa, submucosa T1m N0 M0
T1sm N0 M0Mucosa
SubmucosaIE2 Confined to GI tract—muscularis propria, serosa T2 N0 M0
T3 N0 M0Muscularis propria
SerosaIIE1 Extending into abdomen—local nodal involvement T1-3 N1 M0 Perigastric lymph nodes IIE2 Extending into abdomen—distant nodal involvement T1-3 N2 M0 More distant regional nodes IIE Penetration of serosa to involve adjacent organs or tissues T4 N0 M0 Invasion of adjacent structures IV T1-4 N3 M0
T1-4 N0-3 M1Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)
Tumor Involvement Node Involvement Metastatic Spread Involvement T1 Solitary skin involvement
T1a: ≤5 cm diameter
T1b: >5 cm diameterN0 No lymph node involvement M0 No evidence of extracutaneous non-lymph node disease T2 Multiple lesions limited to one body region or two contiguous body regions
T2a: all-disease in a < 15-cm diameter
T2b: all-disease in a >15- and < 30-cm diameter
T2c: all-disease in a >30-cm diameterN1 Involvement of one peripheral lymph node region M1 Evidence of extracutaneous non-lymph node disease T3 Generalized skin involvement
T3a: multiple lesions involving two noncontiguous body regions
T3b: multiple lesions involving three body regionsN2 Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement N3 Central lymph nodes involvement
Skin Involvement Node Involvement Viscera Involvement T1 Patchy or plaquelike skin disease involving ≤10% of the skin surface area N0 No abnormal lymph nodes M0 No visceral organ involvement T2 Patchy or plaquelike skin disease involving ≥10% of the skin surface area N1 Histopathology Dutch Gr 1 or NCI LN 0-2 M1 Visceral organ involvement T3 Tumors are present ≥1 cm in diameter N2 Histopathology Dutch Gr 2 or NCI LN 3 MX Abnormal visceral site; no histologic confirmation T4 Erythroderma ≥80% of body area N3 Histopathology Dutch Gr 3-4 or NCI LN 4 Blood Involvement Nx Abnormal lymph nodes; no histologic confirmation B0 ≤5% of peripheral blood lymphocytes are Sezary cells B1 >5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria B2 ≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells
Clinical Stage 5-year Survival [86] TNM (B) Stage IA 96-100% T1N0M0B0 T1N0M0B1 IB 73-86% T2N0M0B0 T2N0M0B1 IIA 49-73% T1N1M0B0 T1N1M0B1 T1N2M0B0 T1N2M0B1 T2N1M0B0 T2N1M0B1 T2N2M0B0 T2N2M0B1 IIB 40-65% T3N0M0B0 T3N0M0B1 T3N1M0B0 T3N1M0B1 T3N2M0B0 T3N2M0B1 IIIA 50-57% T4N0M0B0 T4N1M0B0 T4N2M0B0 IIIB T4N0M0B1 T4N1M0B1 T4N2M0B1 IVA 15-40% T1N0M0B2 T2N0M0B2 T3N0M0B2 T4N0M0B2 T1N1M0B2 T2N1M0B2 T3N1M0B2 T4N1M0B2 T1N2M0B2 T2N2M0B2 T3N2M0B2 T4N2M0B2 T1N3M0B0 T2N3M0B0 T3N3M0B0 T4N3M0B0 T1N3M0B1 T2N3M0B1 T3N3M0B1 T4N3M0B1 T1N3M0B2 T2N3M0B2 T3N3M0B2 T4N3M0B2 IVB 0-15% T1N0M1B0 T2N0M1B0 T3N0M1B0 T4N0M1B0 T1N1M1B1 T2N1M1B1 T3N1M1B1 T4N1M1B1 T1N2M1B2 T2N2M1B2 T3N2M1B2 T4N2M1B2 T1N3M1B3 T2N3M1B3 T3N3M1B3 T4N3M1B3