Non-Hodgkin Lymphoma (NHL)

Practice Essentials

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.

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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....

Signs and symptoms

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:

Peripheral adenopathy: Painless and slowly progressive; can spontaneously regress
Primary extranodal involvement and B symptoms: Uncommon at presentation; however, common with advanced, malignant transformation or end-stage disease
Bone marrow: Frequent involvement; may be associated with cytopenias(s); fatigue/weakness more common in advanced-stage disease

Intermediate- and high-grade lymphomas have a more varied clinical presentation, including the following:

Adenopathy: Most patients
Extranodal involvement: More than one third of patients; most common sites are GI/GU tracts (including Waldeyer ring), skin, bone marrow, sinuses, thyroid, CNS
B symptoms: Temperature >38°C, night sweats, weight loss >10% from baseline within 6 months; in approximately 30-40% of patients

See Presentation for more detail.

Diagnosis

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:

Rapidly growing and bulky lymphadenopathy
Splenomegaly
Hepatomegaly
Large abdominal mass: Usually in Burkitt lymphoma
Testicular mass
Skin lesions: Associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large-cell lymphoma, and angioimmunoblastic lymphoma

Testing

Laboratory studies in a patient with suspected NHL should include the following:

CBC count: May be normal in early-stage disease; in more advanced stages, may demonstrate anemia, thrombocytopenia/leukopenia/pancytopenia, lymphocytosis, thrombocytosis
Serum chemistry studies: May show elevated LDH and calcium levels, abnormal liver function tests
Serum beta2-microglobulin level: May be elevated
HIV serology: Especially in patients with diffuse large cell immunoblastic or small noncleaved histologies
Human T-cell lymphotropic virus–1 serology: For patients with adult T-cell leukemia/lymphoma
Hepatitis B testing: In patients in whom rituximab therapy is planned, because reactivation has been reported

Other tests that may be helpful in evaluating suspected NHL include the following:

Immunophenotypic analysis of lymph node, bone marrow, peripheral blood
Cytogenetic studies: NHL occasionally associated with monoclonal gammopathy; possible positive Coombs test; maybe hypogammaglobulinemia

Imaging tests

The following imaging studies should be obtained in a patient suspected of having NHL:

Chest radiography
Upper GI series with small bowel follow-through: In patients with head and neck involvement and those with a GI primary lesion
CT scanning of the neck, chest, abdomen, and pelvis
PET scanning
Bone scanning: Only in patients with bone pain, elevated alkaline phosphatase, or both
Testicular ultrasonography: For opposite testis in male patients with a testicular primary lesion
Multiple gated acquisition (MUGA) scanning: To assess cardiac function, in patients being considered for treatment with anthracyclines
MRI of brain/spinal cord: For suspected primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma

Procedures

The diagnosis of NHL relies on pathologic confirmation following appropriate tissue biopsy. The following are procedures in cases of suspected NHL:

Bone marrow aspiration and biopsy: For staging rather than diagnostic purposes
Excisional lymph node biopsy (extranodal biopsy): For lymphoma protocol studies

Perform lumbar puncture for CSF analysis in patients with the following conditions:

Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or 2 or more extranodal sites of disease
High-grade lymphoblastic lymphoma
High-grade small noncleaved cell lymphomas
HIV-related lymphoma
Primary CNS lymphoma
Neurologic signs and symptoms

See Workup for more detail.

Management

The treatment of NHL varies greatly, depending on various factors. Common therapies include the following:

Chemotherapy: Most common; usually combination regimens
Biologic agents (eg, rituximab, obinutuzumab, lenalidomide): Typically in combination with chemotherapy
Radiation therapy
Bone marrow transplantation: Possible role in relapsed high-risk disease
Chimeric antigen receptor (CAR) T-cell therapy: In relapsed or refractory large B-cell lymphoma
Radioimmunotherapy
Transfusions of blood products
Antibiotics

Pharmacotherapy

Medications used in the management of NHL include the following:

Cytotoxic agents (eg, chlorambucil, cyclophosphamide, doxorubicin, vincristine, fludarabine, pralatrexate, nelarabine, etoposide, mitoxantrone, cytarabine, bendamustine, carboplatin, cisplatin, gemcitabine, denileukin diftitox, bleomycin)
Histone deacetylase inhibitors (eg, vorinostat, romidepsin, belinostat)
Colony-stimulating factor growth factors (eg, epoetin alfa, darbepoetin alfa, filgrastim, pegfilgrastim)
Monoclonal antibodies (eg, rituximab, ibritumomab tiuxetan, alemtuzumab, ofatumumab, obinutuzumab, pembrolizumab)
mTOR (mechanistic [mammalian] target of rapamycin) kinase inhibitors (eg, temsirolimus)
Proteasome inhibitors (eg, bortezomib)
Immunomodulators (eg, interferon alfa-2a or alfa-2b)
Corticosteroids (eg, dexamethasone, prednisone)

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.

References

Background

The term lymphoma describes a heterogeneous group of malignancies with different biology and prognosis. In general, lymphomas are divided into 2 large groups of neoplasms: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is 68 years,^[1]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.^[2]

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.^[3]

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).

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

Anaplastic Large Cell Lymphoma
Follicular Lymphoma
B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Lymphoblastic Lymphoma
Mantle Cell Lymphoma
Primary CNS Lymphoma
Cutaneous T-Cell Lymphoma (eg, mycosis fungoides, Sézary syndrome)

Primary NHL of bone (primary bone lymphoma) is a rare condition, accounting for less than 1-2% of adult NHL and approximately 7% primary bone tumors. Most cases occur in adults of age 45-60 years; rare cases occur in children with a mean age of 12 years.

The most common presenting symptom is local bone pain that is unrelieved by rest. One or more bones may be involved. The most common sites are the long bones of adults, especially the femur. Other common locations include the vertebral column and pelvis. In children, cases appear with a similar frequency in the pelvis, vertebral column, and long bones. Regardless of age, presentations in the mandible, rib, palate, clavicle, and scapula have also been reported. Less commonly, patients can also present with a palpable mass, swelling, limp, night pain, pathologic fractures, spinal cord compression, and systemic B symptoms.^[4]

Imaging findings vary and can be nonspecific in some cases. On plain x-rays, common patterns include lytic-destructive, blastic-sclerotic, and mixed lytic-sclerotic; subtle or near-normal lesions have also been reported. CT and MRI may disclose soft tissue extension, and CT can guide biopsy, as histology with immunohistochemistry is essential for definite diagnosis.^[4]

Due to the rarity of primary bone lymphoma, recommended strategies are derived from retrospective studies. Radiation, the traditional standard of care, may be given alone or, more commonly, combined with chemotherapy. Surgery is generally limited to stabilization of pathologic fractures or laminectomy.^[4]

References

Etiology

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

Chromosomal translocations

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

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

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

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

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

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

Infection

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

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]

Immunodeficiency states

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

Celiac disease has been associated with an increased risk of malignant lymphomas. The risk of lymphoproliferative malignancy in individuals with celiac disease depends on small intestinal histopathology; no increased risk is observed in those with latent celiac disease.^[7]

Chronic inflammation

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

References

Prognosis

The 5-year relative survival rate of patients with NHL is 74.3%.^[1]The survival rate has steadily improved over the last 2 decades, thanks to improvements in medical and nursing care, the advent of novel therapeutic strategies (eg, monoclonal antibodies, chimeric antigen receptor [CAR] T-cell therapy), validation of biomarkers of response, and the implementation of tailored treatment.

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

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

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

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

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive NHL, also appears to be useful for predicting the outcome of patients with low-grade lymphoma. 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.^[9]An ECOG performance status score of 0-1 is associated with improved survival. Higher dose methotrexate is associated with slightly better response.

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

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

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

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

For patients with follicular lymphoma—the second most common subtype of NHL—the Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more discriminating than the IPI.^[10]The FLIPI score is calculated on the basis of 5 adverse prognostic factors, as follows:

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

Three risk groups are defined by FLIPI score:

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

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

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

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

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

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

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

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

Drake et al found that low levels of vitamin D were associated with a decrease in clinical end points (event-free survival and overall survival) in subsets of patients with aggressive B-cell lymphoma (ie, diffuse large B-cell lymphoma or T-cell lymphoma).^[11]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.^[12]

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.^[13]

References

History

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

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

Low-grade lymphomas

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

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

Bone marrow is frequently involved and may be associated with cytopenia or cytopenias.^[14]Fatigue and weakness are more common in patients with advanced-stage disease.

Intermediate- and high-grade lymphomas

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

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

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

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

References

Staging

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

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

Stage I NHL involves a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)
Stage II NHL involves 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE)
Stage III involves lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localized involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE)
Stage IV represents disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

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

L - lung
H - Liver
P - Pleura
B - Bone
M - Bone marrow
D - Skin
E - Extranodal lymphoid malignancies in tissues that are separate from but near the major lymphatic aggregates

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

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

Risk stratification scoring systems

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

The IPI for NHL is as follows:

Age older than 60 years
ECOG grade greater than or equal to 2
Elevated LDH value
Two or more extranodal sties
Ann Arbor stage III or IV

The FLIPI score is as follows:

Number of nodal sites of 5 or more
Elevated LDH value
Age 60 years or older
Ann Arbor stage III–IV
Hemoglobin value less than 12 g/dL

References

Approach Considerations

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

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

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

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

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

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

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

References

Management of Indolent NHL

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

Indolent stage I and contiguous stage II NHL

Standard management consists of radiotherapy alone. Forty percent of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe.^[23]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.^[24]

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

Rituximab is another treatment option for symptomatic patients for whom radiation therapy is contraindicated or who prefer an alternative treatment.^[2]The use of rituximab—a monoclonal antibody that targets the CD20 antigen, which is present in benign and malignant B-cells—in combination with systemic chemotherapy, has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas, compared with chemotherapy alone. Prospective studies and two meta-analyses suggest that rituximab-chemotherapy, also known as chemo-immunotherapy, may change the natural progression of indolent lymphomas.

Indolent noncontiguous stage II, III, and IV NHL

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

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

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

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

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

A study by Gaulard et al found that rituximab plus low-dose CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-miniCHOP) offered a good compromise between efficacy and safety in patients older than 80 years. The authors concluded that R-miniCHOP should be considered the new standard of treatment in these patients.^[25]

Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Bendamustine plus rituximab has demonstrated efficacy for the first-line treatment of advanced follicular, indolent, and mantle cell lymphomas.^[26] Current NCCN guidelines list the following as preferred first-line regimens for follicular lymphoma^[27]:

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

Combination agents are useful in bulky and rapidly progressive disease and have higher response rates than single agents, but there is no improvement in overall survival.^{[28, 29, 30]}

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.^[31]

Randomized trials have shown that adding rituximab to chemotherapy regimens results in higher response rates, longer time to progression, and longer survival than chemotherapy. For example, Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy (R-CHOP).^[32] Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of high tumor burden.

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

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

References

Management of Aggressive NHL

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

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

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

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

Aggressive noncontiguous stage II, III, and IV NHL

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

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

A prospective randomized trial in patients with diffuse large-cell lymphoma showed no difference in response rate (RR), OS, or time to treatment failure (TTF) at 3 years with any of the following regimens^[35]:

CHOP
Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM)
Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD)
Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B)
Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab has been shown to achieve a high rate of durable remission in patients with mantle cell lymphoma. It is a toxic regimen and is typically used in patients with good performance status, who can tolerate it; otherwise, R-CHOP is used.^[36]
Bendamustine and rituximab combination has been successfully used in patients with mantle cell lymphoma in the first and second-line setting.^[37]A study by Weidmann et al found that bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in elderly patients who are not eligible for R-CHOP because of its efficacy and low toxicity.^[38]

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.

References

Management of Indolent Recurrent NHL

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

Single alkylating agents (chlorambucil or bendamustine)
Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, and temsirolimus^[42]
Combination chemotherapy - CVP, CHOP, and others
Purine analogues - Fludarabine, 2-CDA
Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration
Radioimmunotherapy

¹³¹Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity.^[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.

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.^[46]

In 2019, the FDA approved lenalidomide in combination with a rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma, the first nonchemotherapeutic regimen approved for those conditions. Approval was based on the AUGMENT study, in which patients were randomized to receive either lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The objective response was 80% in the lenalidomide plus rituximab arm compared with 55% in the control arm. Progression-free survival improved for lenalidomide plus rituximab arm versus control arm, with median duration of 39.4 months versus 14.1 months.^[47]

Current NCCN guidelines recommend phosphoinositide 3-kinase (PI3K) inhibitors for relapsed or refractory indolent NHL that has failed to respond to 2 prior therapies. PI3K inhibitors include idelalisib, copanlisib, and duvelisib.^[27]

Idelalisib (Zydelig) is the first PI3K inhibitor to receive accelerated approval from the FDA for relapsed follicular B-cell NHL and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. In this single-group, phase II, open-label study, patients received idelalisib 150 mg PO BID until disease progression or study withdrawal. The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. ^[48]

Copanlisib and duvelisib were also FDA-approved for follicular lymphoma in patients who failed to respond to two prior therapies. For copanlisib, approval was based on a phase II trial that reported an objective response rate was 59%, with 12% complete responses. The median duration of response (DoR) was 22.6 months. The median progression-free survival was 11.2 months, with the median overall survival not yet reached.^[49]

Duvelisib is a selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. The open label, global, phase II DYNAMO trial reported an overall response rate (ORR) of 47.3%. The estimated median DoR was 10 months, and the estimated median progression-free survival was 9.5 months.^[50]

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

Umbralisib was withdrawn from the market a year following accelerated approval based on updated overall survival (OS) data from the Phase 3 UNITY-CLL trial that showed an increasing imbalance in OS. It is a dual inhibitor of PI3K-delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells. It was granted accelerated approval in 2021 for or refractory MZL who have received at least 1 prior anti-CD20-based regimen and for relapsed or FL who have received at least 3 prior lines of systemic therapy.

Accelerated approval was based on two single-arm cohorts of an open-label, multicenter trial, in patients with MZL who received at least 1 prior therapy and in patients with FL after at least 2 prior systemic therapies. Patients received umbralisib 800 mg PO once daily until disease progression or unacceptable toxicity. For patients with MZL, the overall response rate was 49% (95% CI: 37.0, 61.6) with 16% achieving complete responses. Median DOR was not reached (95% CI: 9.3, NE) in these patients. For patients with FL, the ORR was 43% (95% CI: 33.6, 52.2) with 3% achieving complete responses. Median DOR was 11.1 months (8.3, 16.4). ^[51]

References

Management of Aggressive Recurrent Adult NHL

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

In 2019, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the FDA for use in combination with bendamustine and a rituximab product for adults with relapsed or recurrent DLBCL who have received at least 2 prior therapies and are not candidates for transplantation. FDA approval was based on a study in which the addition of polatuzumab vedotin to bendamustine plus rituximab led to increased rates of complete and objective responses and prolonged progression-free and overall survival, with manageable toxicity.^[52]

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.^[53]

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.^{[54, 55]}After a 5-year median follow-up study, the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the overall survival (OS) rate was also better (53% versus 32%).

Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants.^[56]

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

Chimeric antigen receptor T-cell therapy

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

Axicabtagene ciloleucel (Yescarta) - Indications include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Tisagenlecleucel (Kymriah) - Indications include DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Lisocabtagene maraleucel (Breyanzi) - Indicated for DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for primary CNS lymphoma.

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

References

Management of T-cell Lymphomas

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

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

Combination chemotherapy regimens - CHOP, CHOP plus etoposide, gemcitabine-based regimens
Single chemotherapy agents - Pralatrexate
Monoclonal antibodies - Alemtuzumab (effective in prolymphocytic T-cell leukemia and hepatosplenic gamma-delta T-cell lymphoma)
Immunotoxin - Denileukin diftitox (discontinued January 2014)
Novel biological agents and small molecule inhibitors - Histone deacetylase inhibitors (vorinostat, panobinostat, romidepsin, belinostat), lenalidomide, and bortezomib

The US Food and Drug Administration (FDA) granted accelerated approval for pralatrexate injection (Folotyn) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).^[57]

In 2011, the FDA granted accelerated approval for romidepsin (Istodax) for treatment of PTCL in patients who have received at least one prior therapy.^[58] However, a subsequent confirmatory phase III trial study evaluating romidepsin plus CHOP versus CHOP in first-line PTCL patients failed to meet the primary efficacy endpoint of progression-free survival, so in August 2021 the manufacturer voluntarily withdrew this indication in the US.^[59]

In 2014, the FDA approved the histone deacetylase inhibitor belinostat (Beleodaq) for treatment of relapsed or refractory PTCL. Approval was based on the results of a multicenter, single-arm, nonrandomized trial of 120 patients with refractory or relapsed PTCL and included patients with baseline platelet levels below 100,000/μL. The overall complete and partial response rates were 10.8% and 15.0%, respectively. The median response duration (first date of response to disease progression or death) was 8.4 months.^{[60, 61]}

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.^[62]

References

CAR T-cell Therapy

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

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

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

Axicabtagene ciloleucel

The FDA approved axicabtagene ciloleucel (Yescarta) in 2017 for treatment of large B-cell lymphoma after at least two other kinds of therapy have failed. Approved uses include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.^[64]

Approval was based on the primary results from the ZUMA-1 study, an open-label, multicenter trial enrolling 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 x 10⁶ cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. Five-year follow-up data from ZUMA-1 included the following^[65]:

Objective responses were seen in 83% of patients; complete responses were seen in 58%; responses were ongoing in 31%.
Median overall survival was 25.8 months; median progression-free survival was 5.9 months.
Estimated 5-year disease-specific survival rate was 51.0%.
Grade 3 or worse neurologic adverse events occurred in 30% of patients, and grade 3 or worse cytokine release syndrome occurred in 11%.

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

References

Where does non-Hodgkin lymphoma (NHL) originate?Which factors determine the clinical presentation of non-Hodgkin lymphoma (NHL)?What are the signs and symptoms of low-grade non-Hodgkin lymphoma (NHL)?What are the signs and symptoms of intermediate- and high-grade non-Hodgkin lymphoma (NHL)?Which physical findings are characteristic of non-Hodgkin lymphoma (NHL)?Which lab tests are performed in the workup of suspected non-Hodgkin lymphoma (NHL)?Which imaging studies are performed in the workup of suspected non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) diagnosed?When is lumbar puncture indicated in the workup of non-Hodgkin lymphoma (NHL)?What is included in the standard of care for non-Hodgkin lymphoma (NHL)?What is non-Hodgkin lymphoma (NHL)?What is the pathophysiology of non-Hodgkin lymphoma (NHL)?What causes non-Hodgkin lymphoma (NHL)?What are the genetic causes of non-Hodgkin lymphoma (NHL)What is the role of viral infection in the etiology of non-Hodgkin lymphoma (NHL)?Which environmental factors increase the risk of non-Hodgkin lymphoma (NHL)?What is the role of immunodeficiency in the etiology of non-Hodgkin lymphoma (NHL)?What is the role of celiac disease in the etiology of non-Hodgkin lymphoma (NHL)?What is the role of chronic inflammation in the etiology of non-Hodgkin lymphoma (NHL)?What is the prevalence of non-Hodgkin lymphoma (NHL)?Which age group has the highest prevalence of non-Hodgkin lymphoma (NHL)?What are the survival rates of non-Hodgkin lymphoma (NHL)?Which factors affect the prognosis of non-Hodgkin lymphoma (NHL)?How is the prognosis of non-Hodgkin lymphoma (NHL) determined?Which factors have prognostic significance in non-Hodgkin lymphoma (NHL)?What is included in patient education about non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) graded?Which clinical history findings are characteristic of low-grade non-Hodgkin lymphoma (NHL)?Which clinical history findings are characteristic of intermediate- and high-grade non-Hodgkin lymphoma (NHL)?Which physical findings are characteristic of low-grade non-Hodgkin lymphoma (NHL)?Which physical findings are characteristic of intermediate- and high-grade non-Hodgkin lymphoma (NHL)?What are the possible complications of non-Hodgkin lymphoma (NHL)?Which conditions are included in the differential diagnoses of non-Hodgkin lymphoma (NHL)?What are the differential diagnoses for Non-Hodgkin Lymphoma (NHL)?Which studies are performed in the diagnostic workup of non-Hodgkin lymphoma (NHL)?Which serum chemistry findings are characteristic of non-Hodgkin lymphoma (NHL)?What is the significance of a finding of elevated beta2-microglobulin in non-Hodgkin lymphoma (NHL)?Which lab results are occasionally found in non-Hodgkin lymphoma (NHL)?When is HIV serology indicated in the workup of non-Hodgkin lymphoma (NHL)?What is the significance of a finding of elevated CXCL13 in non-Hodgkin lymphoma (NHL)?What is the role of chest radiography in the workup of non-Hodgkin lymphoma (NHL)?What is the role of CT scanning in the workup of non-Hodgkin lymphoma (NHL)?What is the role of bone scanning in the workup of non-Hodgkin lymphoma (NHL)?What is the role of Gallium scanning in the workup of non-Hodgkin lymphoma (NHL)?What is the role of PET scanning in the workup of non-Hodgkin lymphoma (NHL)?What is the role of ultrasonography in the workup of non-Hodgkin lymphoma (NHL)?What is the role of MRI in the workup of non-Hodgkin lymphoma (NHL)?What is the role of biopsy in the workup of non-Hodgkin lymphoma (NHL)?What is the role of bone marrow aspirate in the workup of non-Hodgkin lymphoma (NHL)?What is the role of extranodal biopsy in the workup of non-Hodgkin lymphoma (NHL)?What is the role of CSF analysis in the workup of non-Hodgkin lymphoma (NHL)?Which histologic findings are characteristic of non-Hodgkin lymphoma (NHL)?What is the role of immunophenotypic analysis in the workup of non-Hodgkin lymphoma (NHL)?What is the role of cytogenic studies in the workup of non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) staged?How is risk stratified in non-Hodgkin lymphoma (NHL)?Which CBC count findings are characteristic of non-Hodgkin lymphoma (NHL)?What is the role of MUGA in the workup of non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) treated?Which non-Hodgkin lymphomas (NHLs) are classified as indolent?How are indolent stage I and indolent contiguous stage II non-Hodgkin lymphoma (NHL) treated?How are indolent noncontiguous stages II, III and IV non-Hodgkin lymphoma (NHL) treated?Which non-Hodgkin lymphomas (NHLs) are classified as aggressive?How are aggressive stage I and aggressive contiguous stage II non-Hodgkin lymphoma (NHL) treated?How are aggressive noncontiguous stages II, III and IV non-Hodgkin lymphoma (NHL) treated?How is indolent recurrent non-Hodgkin lymphoma (NHL) treated?How is aggressive recurrent non-Hodgkin lymphoma (NHL) treated?What is the role of chimeric antigen receptor (CAR) T-cell therapy in the treatment of aggressive recurrent non-Hodgkin lymphoma (NHL)?How are T-cell non-Hodgkin lymphomas (NHLs) treated?What is the role of surgery in the treatment of non-Hodgkin lymphoma (NHL)?What are the possible treatment-related complications of non-Hodgkin lymphoma (NHL)?What is tumor lysis syndrome in non-Hodgkin lymphoma (NHL) and how is it treated?What is the risk of atherosclerosis following treatment of non-Hodgkin lymphoma (NHL)?Which dietary modifications are used in the treatment of non-Hodgkin lymphoma (NHL)?Which activity modifications are used in the treatment of non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) treated during pregnancy?What is the role of CAR T-cell therapy in the treatment of non-Hodgkin lymphoma (NHL)?Which specialist consultations are beneficial to patients with non-Hodgkin lymphoma (NHL)?What is included in the long-term monitoring of patients with non-Hodgkin lymphoma (NHL)?What is included in the NCCN guidelines on non-Hodgkin lymphoma (NHL)?What guidelines have been issued by ESMO on the diagnosis and treatment of non-Hodgkin lymphoma (NHL)?How is non-Hodgkin lymphoma (NHL) classified?What are the NCCN guidelines on the diagnosis of non-Hodgkin lymphoma (NHL)?What are the NCCN guidelines on the staging of non-Hodgkin lymphoma (NHL)?What is the International Prognostic Index (IPI) for non-Hodgkin lymphoma (NHL)?What is the WHO classification of follicular lymphoma (FL)?What are the NCCN and ESMO guidelines on the diagnosis of follicular lymphoma (FL)?What are the GELF criteria for follicular lymphoma (FL) risk stratification?What are the NCCN recommendations for follicular lymphoma (FL) risk stratification?What is the FLIPI2 index for follicular lymphoma (FL) risk stratification?What are the NCCN and ESMO guidelines on the treatment of follicular lymphoma (FL)?What are the NCCN-recommend chemotherapy regimens for follicular lymphoma (FL)?What are the NCCN and ESMO guidelines on the diagnosis of gastric MALT lymphoma?How is gastric MALT lymphoma staged?What are the NCCN and ESMO guidelines on staging gastric MALT lymphoma?What are the NCCN and ESMO guidelines on the treatment of gastric MALT lymphoma?What are the NCCN guidelines on the diagnosis of mantle cell lymphoma?How is mantle cell lymphoma staged?What are the NCCN and ESMO guidelines on the treatment of mantle cell lymphoma?What are the NCCN guidelines on the diagnoses of diffuse large B-cell lymphoma (DLBCL)?What is the IPI for risk stratification of diffuse large B-cell lymphoma (DLBCL)?What are the NCCN guidelines on the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the ESMO guidelines on the treatment of diffuse large B-cell lymphoma (DLBCL)?What are the NCCN guidelines for long-term monitoring of diffuse large B-cell lymphoma (DLBCL)?What is the WHO classification of Burkitt lymphoma (BL)?What are the NCCN guidelines on the diagnosis of Burkitt lymphoma (BL)?How is risk stratified for Burkitt lymphoma (BL)?What are the NCCN guidelines on the treatment of Burkitt lymphoma (BL)?What are the NCCN guidelines for long-term monitoring of Burkitt lymphoma (BL)?Which organizations have published guidelines on the treatment of primary cutaneous B-cell lymphomas (CBCL)?How is primary cutaneous B-cell lymphomas (CBCL) classified?What are the NCCN guidelines on the diagnosis of primary cutaneous B-cell lymphomas (CBCL)?How is primary cutaneous B-cell lymphomas (CBCL) staged?What are the treatment guidelines for PC-FCL and PC-MZL?What are the treatment guidelines for PC-DBCL, LT?How is cutaneous T-cell lymphoma (CTCL) classified?Which organizations have published guidelines on the treatment of mycosis fungoides/Sezary syndrome (MF/SS)?What are the NCCN guidelines on the diagnosis of mycosis fungoides/Sezary syndrome (MF/SS)?How is mycosis fungoides/Sezary syndrome (MF/SS) staged?What are the guidelines on the treatment of mycosis fungoides/Sezary syndrome (MF/SS)?Which organizations have issued guidelines on the treatment of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?How are primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs) classified?What are the NCCN guidelines on the diagnosis of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?How are primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs) staged?What are the guidelines on the treatment of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?Which medications are used in the treatment of non-Hodgkin lymphoma (NHL)?Which medications in the drug class Immunomodulators are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Colony-Stimulating Factor Growth Factors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastics, Anti-CD19 Monoclonal Antibodies are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class CAR T-cell Therapy are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastics, Angiogenesis Inhibitor are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastic Agents, mTOR Kinase Inhibitors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastic Agents, Proteasome Inhibitors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Monoclonal Antibodies are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastics, PI3K Inhibitors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Antineoplastic Agents, Histone Deacetylase Inhibitors are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Cytotoxic agents are used in the treatment of Non-Hodgkin Lymphoma (NHL)?Which medications in the drug class Corticosteroids are used in the treatment of Non-Hodgkin Lymphoma (NHL)?

References

Author

Sanjay Vinjamaram, MD, MPH, Physician in Hematology/Oncology, Essentia/Innovis Health Cancer Center