Non-Hodgkin Lymphomas

Adult T-cell leukemia-lymphoma, which is associated with human T-lymphotropic virus 1 (HTLV-1), has a fulminating clinical course with skin infiltrates, lymphadenopathy, hepatosplenomegaly, and leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more . The leukemic cells are malignant T cells, many with convoluted nuclei. Hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more often develops, related to humoral factors rather than to direct bone invasion.

Anaplastic large cell lymphoma may cause rapidly progressive skin lesions, adenopathy, and visceral lesions. This disease may be mistaken for Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more or metastatic undifferentiated carcinoma.

Enlarged lymph nodes are biopsied. If a node is palpable, no imaging is required initially, although CT or ultrasonography may be needed to properly plan subsequent tests.

If the lesion is easily palpable, an open biopsy is preferred. If the lesion is in the lung or abdomen, a core needle biopsy (18- to 20-gauge needle) done using CT or ultrasound guidance can often obtain an adequate specimen for diagnosis. A fine needle biopsy (percutaneous or bronchoscopic) frequently will not produce adequate tissue, especially for initial diagnosis; core biopsy is preferred if deemed safe.

Biopsies should be reviewed by a pathologist with expertise in lymphoma diagnosis so that the lymphoma can be correctly classified. If this review is not available locally, the slides should be sent to a reference laboratory with hematopathology expertise. The proper classification of non-Hodgkin lymphoma is critical for treatment planning. Non-Hodgkin lymphomas are potentially curable, but without a precise diagnosis, optimal therapy may not be chosen.

Histologic criteria on biopsy include destruction of normal lymph node architecture and invasion of the capsule and adjacent fat by characteristic neoplastic cells. Immunophenotyping studies to determine the cell of origin are of great value in identifying specific subtypes and helping define prognosis and management; these studies also can be done on peripheral cells if they are present, but typically these stains are applied to formalin-fixed, paraffin-embedded tissue. Demonstration of the leukocyte common antigen CD45 by immunoperoxidase rules out metastatic cancer, which is often in the differential diagnosis of “undifferentiated” cancers. The test for leukocyte common antigen, most surface marker studies, and gene rearrangement (to document B-cell or T-cell clonality) can be done on fixed tissues. Cytogenetics and flow cytometry require fresh tissue.

Once the diagnosis of lymphoma is made, staging tests are done.

A combined fluorodeoxyglucose (FDG)-PET/CT scan of the chest, abdomen, and pelvis is recommended. PET/CT provides accurate location of lesions, their size (from CT) and tumor metabolism (from FDG-PET). If combined FDG-PET/CT is not available, a contrast-enhanced CT scan of the chest, abdomen, and pelvis is done.

Unilateral bone marrow aspiration and biopsy is often done in patients with non-Hodgkin lymphoma. Bone marrow assessment in low-grade (indolent) non-Hodgkin lymphoma or T-cell non-Hodgkin lymphoma can be limited to cases where findings will change management or are needed to assess cytopenias.

Blood tests typically include complete blood count with white blood cell differential, kidney function and liver tests (including serum creatinine, bilirubin, calcium, aspartate aminotransferase, albumin, alkaline phosphatase, and lactate dehydrogenase), uric acid, beta-2 microglobulin, and vitamin D levels. Serum protein electrophoresis with IgG, IgA, and IgM immunoglobulin levels are also done.

Other tests are done depending on findings (eg, MRI of brain and/or spinal cord for neurologic symptoms). If uric acid levels are high, serum glucose-6-phosphate dehydrogenase (G6PD) level is checked because G6PD deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in people with African ancestry that can result in hemolysis after acute illnesses or intake of oxidant... read more precludes treatment with rasburicase, which is often given to prevent tumor lysis syndrome Tumor Lysis and Cytokine Release Syndromes Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more but may cause hemolytic anemia in patients with G6PD deficiency.

Patients with non-Hodgkin lymphoma are initially screened for HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more and hepatitis B and C viruses Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more . Patients diagnosed with adult T-cell leukemia/lymphoma (ATLL) are also checked for human T-cell lymphotropic virus type 1 (HTLV-1 HTLV Infections ).

After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma ) incorporates

Although stage I non-Hodgkin lymphoma does occur, the disease is typically disseminated when first recognized.

For stage I indolent non-Hodgkin lymphoma (uncommon because most patients have stage II o IV when diagnosed), external beam radiation therapy can be the sole initial treatment. Regional radiation therapy may offer long-term control and possibly cure in about 40% of stage I patients. Stage II indolent non-Hodgkin lymphoma is most commonly treated as advanced-stage disease.

Limited-stage aggressive non-Hodgkin lymphomas can be managed with a combination of chemotherapy plus radiation therapy or with chemotherapy alone (plus anti-CD20 monoclonal antibodies for B-cell lymphomas).

Patients with stage I Burkitt lymphoma Burkitt Lymphoma Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma occurring in children and adults. Endemic (African), sporadic (non-African), and immunodeficiency-related forms exist. (See also... read more are treated with intensive combination chemotherapy with meningeal prophylaxis.

Stage II non-Hodgkin lymphoma is managed as advanced stage disease in many circumstances. Most patients with all types of non-Hodgkin lymphoma who have stage II to IV disease are candidates for chemoimmunotherapy. In these cases, radiation therapy may be used to limit the number of cycles of chemoimmunotherapy or provide localized treatment for residual sites of bulk disease.

For indolent lymphomas, treatment varies considerably. Because these lymphomas are highly treatable but not reliably curable, treatment may not be recommended initially for asymptomatic patients, although some patients are given anti-CD20 immunotherapy using rituximab alone. This strategy can delay the need for myelosuppressive chemotherapy, but early immunotherapy alone has not been shown to impact overall survival. Patients with symptoms or bulky disease that puts vital organs at risk are treated with chemoimmunotherapy. In selected cases (eg, chemo-refractory with limited bone marrow involvement), radiolabeled anti-CD20 antibody can be used to target radiation to the tumor cell with potentially fewer effects on nearby normal organs.

In patients with aggressive B-cell lymphomas (eg, diffuse large B cell), the standard drug combination is rituximab plus cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine, and prednisone (R-CHOP). A complete response with disease regression is expected in 80% of cases, with an overall cure rate of about 60%. These results vary significantly by IPI score. Patients who are disease free at ≥ 24 months from diagnosis have a life expectancy similar to that of the age- and sex-matched population. This key factor can guide follow-up strategies in this patient population. Patients with lower IPI scores may benefit from adding the antibody-drug conjugate polatuzumab vedotin, a CD79b-directed antibody-drug conjugate to R-CHOP.

The approach in peripheral T-cell non-Hodgkin lymphoma and primary central nervous system lymphoma is different. In these patients, autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more may be offered to initial responders before relapse occurs with the intention of improving the likelihood of cure. In autologous stem cell transplantation, stem cells are obtained from the patient by peripheral blood leukopheresis and are transfused back into the patient after high-dose chemotherapy. Similarly, in some younger patients with mantle cell lymphoma who have responded to initial therapy, autologous stem cell transplantation may be is done to prolong remission.

Patients with aggressive non-Hodgkin lymphoma not in remission at end of therapy or who relapse are treated with second-line chemotherapy regimens followed by autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more if they are relatively young and in good health. In some patients at very high risk of relapse as well as in those for whom autologous transplant is not feasible or has already failed, stem cells from a matched sibling or unrelated donor (allogeneic transplants) can be effective. In general, the older the patient, the less likely an allogeneic transplantation will be offered because older patients have higher rates of transplantation complications.

Patients with diffuse large B-cell lymphoma (DLBCL) who have persistent lymphoma despite at least 2 prior lines of therapy may be candidates for chimeric antigen receptor (CAR) T cells. CAR T cells are T cells (most commonly autologous T cells) that have been genetically engineered to recognize a tumor antigen (eg, CD19). After infusion, they undergo activation and expansion. About one third of patients achieve a durable response from this therapy.

Patients not eligible for the above therapies, or for whom they have failed, may receive treatment with various therapies, mostly for palliation. These therapies vary widely and are constantly changing as new treatments are developed.

In indolent lymphomas, patients may be managed using a wide variety of strategies depending on

Many of the same drugs used for first-line treatment may be given to patients in relapse. In some cases, the same treatment may be repeated if it was previously effective and well tolerated. High-dose chemotherapy with autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is used occasionally in patients who have high-risk lymphoma biology (including a poor response to chemotherapy), and although cure remains unlikely, remission may be superior to that with secondary palliative therapy alone. Reduced intensity allogeneic transplantation is a potentially curative option in some patients with indolent lymphoma.

The mortality rate of patients undergoing myeloablative transplantation has decreased dramatically to 1 to 2% for most autologous procedures and to 15 to 20% for most allogeneic procedures (depending on age).

An immediate complication of most therapies is infection that occurs during periods of neutropenia Neutropenia Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more . Although use of growth factors that stimulate white blood cell production has helped, infection continues to pose a problem.

The gastrointestinal adverse effects of chemotherapy can be largely relieved or prevented by antiemetics and bowel programs.

Patients receiving anthracyclines are at risk of cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more and/or arrhythmias Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more .

After successful treatment, patients should be referred to a cancer survivorship clinic for a care plan that can be implemented by the patient's primary care team. This plan is tailored to the patient's comorbidities and risks specific to the treatment they received.

Drugs and radiation therapy have late complications. In the first 10 years after treatment, there is a risk of myelodysplasia Myelodysplasia and Iron-Transport Deficiency Anemia In myelodysplastic syndrome, anemia is commonly prominent. The anemia is usually normocytic or macrocytic, and a dimorphic (large and small) population of circulating cells can be present. ... read more or acute leukemia Acute leukemias Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more due to bone marrow damage from certain chemotherapy agents. After 10 years, the risk of secondary cancers increases, especially in patients who received radiation to the chest.