• The etiology of non-Hodgkin lymphoma (NHL) is not known, although several risk factors and conditions are associated with an increased risk of developing lymphoma, including congenital immunosuppression conditions (ataxia-telangiectasia, Wiskott- Aldrich syndrome, and X-linked lymphoproliferative syndrome), acquired immunodeficiency states (e.g., HIV and following solid organ transplantation), viruses (e.g., human T-lymphotrophic virus (HTLV)-1 and hepatitis C virus), and autoimmune disorders (e.g., Sjögren’s syndrome, celiac sprue, and systemic lupus erythematosus).
• Patients most commonly present clinically with enlarged lymph nodes, splenomegaly, and bone marrow involvement, but they may also present with other extranodal disease sites (e.g., stomach, skin, liver, bone, brain).
• NHL has many different clinicopathologic subtypes—more than 70 types are included in the WHO classification of lymphoid neoplasms. The natural history and prognosis of these vary greatly from indolent and slow-growing types (over many years) to highly aggressive (within weeks) types.
• Excisional lymph node resection is the gold standard procedure in establishing the precise NHL histology. Expert hematopathology review incorporating morphologic, immunophenotypic, and genetic features is essential for an accurate diagnosis.
• Indolent lymphomas are low-grade and represent slow-growing non-Hodgkin lymphoma (NHL) that may remain stable with low tumor burden not warranting therapy for several years. The disease is highly responsive to treatment with a variety of treatment options (remission rates exceeding 90% with combined rituximab/chemotherapy), although the clinical course is characterized by repetitive relapses. Outside of early-stage disease and therapy with allogeneic stem cell transplantation, low-grade NHLs are not curable.
• Transformation of follicular lymphoma to a high-grade NHL occurs in 30% to 40%, or 3% to 4% of patients each year; it is less common in other indolent subtypes. Transformation is typically heralded by an aggressive change in the patient’s clinical condition.
• Diffuse large B-cell lymphoma (DLBCL), the most common aggressive NHL, is curable in all stages in the majority of patients with rituximab (Rituxan)-based chemotherapy. A variety of primary extranodal DLBCL clinical subtypes warrant specialized therapy, such as primary central nervous system lymphoma.
• Long-term survivors are at increased risk for second cancers. The highest relative risk of developing a secondary malignancy occurs more than 21 to 30 years after original diagnosis. Patients who received an anthracycline (e.g., doxorubicin [Adriamycin]) as part of therapy are at a long-term increased risk for cardiovascular disease.
The term malignant lymphoma was originally introduced by Billroth in 1871 to describe neoplasms of lymphoid tissue. Generally speaking, lymphomas are neoplasms of the immune system. Traditionally, lymphomas are divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
There are many different clinicopathologic subtypes of NHL (>60). By cell of origin, the majority of NHLs are of B-cell origin (85%–90%); T-cell NHLs account for 10% to 15% of lymphomas in the United States, whereas natural killer cell or histiocytic lymphomas are rare (<1%).
NHLs manifest most commonly clinically with involvement of lymph nodes, spleen, and bone marrow, but they can involve other extranodal sites (stomach, skin, liver, bone, brain, etc.). Peripheral blood involvement uncommonly occurs (leukemic phase of lymphoma). The natural history and prognosis vary greatly among the different subtypes of NHL from indolent subtypes that are often slow-growing (i.e., therapy not warranted for years) to very aggressive and rapidly fatal types (within weeks) if not treated. Most NHL subtypes are highly treatable with initial remission rates over 90% to 95% using combined rituximab/chemotherapy; however, indolent NHLs are generally incurable, whereas the goal of treating most aggressive NHLs is cure.
Currently, NHL represents approximately 5% of all cancer diagnoses, being the seventh most common cancer in women and the seventh in men. Estimates from the American Cancer Society indicate that in 2017 approximately 72,240 new cases of NHL will be diagnosed in the United States and approximately 20,140 people will die of the disease. In addition, there are approximately 600,000 people living with NHL in the United States.
The incidence of NHL varies throughout the world, in general being more common in developed countries, with rates in the United States of more than 15 per 100,000 compared with 1.2 per 100,000 in China. In the United States, the incidence rates of NHL more than doubled between 1975 and 1995, representing one of the largest increases of any cancer. The increases have been more pronounced in whites, males, the elderly, and those with NHL diagnosed at extranodal sites. Similar findings have been reported in other developed countries. The incidence rates of NHL began to stabilize in the late 1990s, although the temporal trends vary by histologic subtype as well as by race and sex (Figure 1). Some of the increase may be related to improved diagnostic techniques and access to medical care and the increased risk of NHL attributable to HIV infection. However, additional factors are likely responsible for this unexpected increase in incidence.
FIGURE 1 SEER observed incidence, SEER delay adjusted incidence and US death rates for non-hodgkin lymphoma, by race and sex.
Overall, NHL incidence rises exponentially with increasing age. In persons older than 65 years, the incidence is 90.9 per 100,000 population compared with 7.1 per 100,000 population for persons aged 20 to 49 years. Except for high-grade lymphoblastic and Burkitt lymphomas (the most common types of NHL seen in children and young adults), the median age at presentation for most subtypes of NHL exceeds 60 years.
Race and Ethnicity
Incidence varies by race and ethnicity, with whites overall having a higher risk than African Americans and Asian Americans (incidence rates increased 50% to 60% in whites compared with blacks), Most NHL subtypes are more common in whites than in blacks; however, peripheral T-cell lymphoma, mycosis fungoides, and Sézary syndrome occur more often in blacks than in whites.
Etiology and Risk Factors
Chromosomal Translocations and Molecular Rearrangements
Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and often correlate with histology and immunophenotype. These chromosomal changes often result in oncogenic gene products; for example, t(11;14) (q13;q32) translocation results in overexpression of bcl-1 (cyclin D1) in mantle-cell lymphoma, while translocation with 8q24 leads to c-myc overexpression in nearly all Burkitt lymphomas and in 10-15% of patients with diffuse large B-cell lymphoma. Research to discover more information regarding the prognostic and pathogenic importance of these oncogenes continues, although they are currently used primarily in clinical practice for diagnostic purposes.
Additionally, these genes serve as potential targets for novel therapeutics.
Environmental factors may also play a role in the development of NHL, including particular occupations (e.g., chemists, painters, mechanics, machinists) and chemicals (solvents and pesticides).
Patients who receive chemotherapy or radiation therapy for any indication are also at increased risk for developing NHL as a secondary cancer as discussed later.
Several viruses have been implicated in the pathogenesis of NHL, including Epstein-Barr virus, human T-cell lymphotropic virus 1 (HTLV-1), Kaposi sarcoma–associated herpesvirus (KSHV, also known as human herpesvirus 8 [HHV-8]), and hepatitis C virus (HCV). Meta-analyses have shown 13% to 15% seroprevalence of HCV in certain geographic regions among persons with B-cell NHL. Further, HCV infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL, particularly in the setting of essential (type II) mixed cryoglobulinemia. HTLV-1 is a human retrovirus that establishes a latent infection through reverse transcription in activated T-helper cells. A minority (5%) of carriers will develop adult T-cell leukemia lymphoma. KSHV-like DNA sequences are often detected in primary effusion lymphomas in patients with HIV infection and in those with multicentric (plasma cell variant) Castleman’s disease.
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is seen most often, but not exclusively, in association with Helicobacter pylori infection. Infection with Borrelia burgdorferi has been detected in about 35% of patients with primary cutaneous B-cell lymphoma in Scotland. Studies indicate that Campylobacter jejuni and immunoproliferative small intestinal disease are related. European reports have noted an association between infection with Chlamydia psittaci and ocular adnexal lymphoma. The infection was found to be highly specific and does not reflect a subclinical infection among the general population.
Furthermore, remission of NHL to antibiotics have been reported. Attempts to confirm this association in the Western hemisphere have been unsuccessful.
Patients with congenital conditions of immunosuppression are at increased risk of NHL. These conditions include ataxia-telangiectasia; Wiskott-Aldrich syndrome; X-linked lymphoproliferative syndrome; severe combined immunodeficiency; acquired immunodeficiency states, such as HIV infection; and iatrogenic immunosuppression.
Relative risk of NHL is increased 150- to 250-fold among patients with AIDS; patients usually develop high grade NHLs, such as Burkitt’s lymphoma or diffuse large B-cell lymphoma. The incidence of posttransplantation lymphoproliferative disorders (PTLD) after solid organ transplantation ranges from 1% to 3% in kidney transplant recipients to 10% to 12% in heart and multi-organ transplant recipients, the latter whom require more potent immunosuppressive therapy.
An increased incidence of gastrointestinal lymphomas is seen in patients with celiac (nontropical) sprue and inflammatory bowel disease, particularly Crohn’s disease. An aberrant clonal intraepithelial T-cell population can be found in up to 75% of patients with refractory celiac sprue before overt T-cell lymphoma develops.
Sjögren’s disease is associated with a 6-fold increased risk of NHL overall with risk varying in part on severity of disease (5 to 200 times); moreover, the risk specifically of parotid marginal zone lymphoma is increased 1000-fold. Additionally, systemic lupus erythematosus and rheumatoid arthritis have been associated with a slightly increased risk of B-cell lymphoma.
Several studies have implicated a role for genetic variants in the risk of NHL, including genes that influence DNA integrity and methylation, genes that alter B-cell survival and growth, and genes that involve innate immunity, oxidative stress, and xenobiotic metabolism.
Signs and Symptoms
Fever, weight loss, and night sweats, referred to as B symptoms, are more common in advanced and aggressive subtype NHLs, but they may be present at all stages and in any histologic subtype.
Low-Grade or Indolent Lymphomas
Painless, slowly progressive peripheral adenopathy is the most common clinical presentation in patients with low-grade lymphomas. Patients sometimes report a history of waxing and waning adenopathy before seeking medical attention. Spontaneous regression of enlarged lymph nodes can occur, which may cause a low-grade lymphoma to be confused with an infectious condition. Primary extranodal involvement and B symptoms are uncommon at presentation; however, both are more common in advanced or end- stage disease and in particular indolent NHL subtypes (e.g., gastric MALT and nongastric extranodal MALT). Bone marrow is frequently involved, sometimes in association with cytopenias. Splenomegaly is seen in about 40% of patients, but the spleen is rarely the only involved site besides the specific subtype of splenic marginal zone lymphoma.
High-Grade or Aggressive Lymphomas
The clinical presentation of high-grade lymphomas is more varied. Although the majority of patients present with adenopathy, more than one third present with extranodal involvement alone or with adenopathy, the most common sites being the gastrointestinal tract (including Waldeyer’s ring), skin, bone marrow, sinuses, genitourinary tract, bone, and central nervous system. B symptoms are more common, occurring in about 30% to 40% of patients.
Lymphoblastic lymphoma often manifests with an anterior superior mediastinal mass, superior vena cava syndrome, and leptomeningeal disease. American patients with Burkitt lymphoma often present with a large abdominal mass and symptoms of bowel obstruction. In addition, certain histologic NHL subtypes manifest with symptoms unique to that particular lymphoma subtype; for example, angioimmunoblastic T-cell lymphoma (AITL) in addition to lymphadenopathy presents with disease features including organomegaly, skin rash, pleural effusions, arthritis, eosinophilia, and varied immunologic abnormalities such as positive Coombs’ test, cold agglutins, hemolytic anemia, antinuclear antibodies, and polyclonal hypergammaglobulinemia.
No effective methods are currently available for screening patients or populations for NHL.
A definitive diagnosis can be made only by biopsy of pathologic lymph nodes or tumor tissue. It is critical in most cases to perform an excisional lymph node resection to avoid false-negative results and inaccurate histologic classification; fine-needle aspirations or core biopsies are often insufficient for diagnostic purposes. When clinical circumstances make surgical biopsy of involved lymph nodes or extranodal sites prohibitive, a core biopsy obtained under CT or ultrasonographic guidance may suffice, but it often requires the integration of histologic examination and immunophenotypic and molecular studies for accurate diagnosis. A formal review by an expert hematopathologist is mandatory. In addition to morphologic review and immunostaining of tissue, other studies such as detailed cellular immunophenotyping and genotyping for relevant oncogenes are often needed to complete the diagnosis.
In addition to a detailed history and physical examination, baseline staging studies are warranted. These consist of blood tests (complete blood count with differential, complete metabolic panel including liver function tests, and lactate dehydrogenase), CT of chest, abdomen, and pelvis, and bilateral bone marrow biopsy and aspirate (Box 1). For aggressive NHL histologies, functional imaging is advocated (i.e., FDG-PET [fluorodeoxyglucose (18F) positron emission tomography]), as is assessment of ejection fraction in anticipation of anthracycline-based chemotherapy. Testing for history of hepatitis B virus (HBV) is recommended, especially before starting anti-CD20 antibody therapy; evidence suggests that anti-CD20 antibody therapy (e.g., rituximab) increases the risk of HBV reactivation above the known rate of chemotherapy-associated reactivation. HIV serology should be obtained in patients with relevant risk factors, especially for diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma.
HTLV-1 serology is recommended in patients who present with cutaneous T-cell lymphoma lesions, especially if they have hypercalcemia.
|Initial Assessment and Work-up for Non- Hodgkin Lymphoma|
|Excisional tissue resection
Detailed history and physical examination
CBC with differential, metabolic panel (including liver function), and LDH
CT scans (chest, abdomen, pelvis)
Nuclear functional imaging (i.e., FDG-PET)*
Bone marrow biopsy and aspirate
Heart function (e.g., MUGA) if anthracycline therapy anticipated EGD, colonoscopy, or both†
HIV and HBV testing (with risk factors and/or if monoclonal antibody therapy planned)
Consider TB testing (i.e., PPD with anergy panel) with history of exposure
Assessment of CSF (when applicable or with risk factors)‡ Consider early institution of TLS prophylaxis (e.g., intravenous fluids, allopurinol [Zyloprim])*
Abbreviations: CBC = complete blood count; CSF = cerebrospinal fluid; CT = computed tomography;
EGD = esophagogastroduodenoscopy; FDG-PET = fluorodeoxyglucose (18F) positron emission tomography; HBV = hepatitis B virus; LDH = lactate dehydrogenase; MCL = mantle-cell lymphoma; MUGA = multigated acquisition [scan]; NHL = non-Hodgkin’s lymphoma; PPD = purified protein derivative [tuberculosis test]; TB = tuberculosis; TLS = tumor lysis syndrome.
|* Primarily for aggressive NHL subtypes.
† With clinical suspicion of involvement; EGD for NHL head and neck involvement (e.g., tonsil, base of tongue, nasopharynx), and consider colonoscopy for MCL (if symptomatic).
‡ Consider for aggressive histologies with <1 extranodal site and elevated LDH and for particular unique lymphoma locations (e.g., testicular, sinus, breast, paraspinal).
Examination of cerebrospinal fluid and consideration of intrathecal chemotherapy prophylaxis is applicable for patients with DLBCL with bone marrow, epidural, testicular, paranasal sinus, breast, or multiple extranodal sites (especially when in conjunction with elevated lactate dehydrogenase). Testing is mandatory for high-grade lymphoblastic lymphoma and Burkitt lymphoma and its variants and primary central nervous system lymphoma if there is no evidence of increased intracranial pressure. Upper gastrointestinal endoscopy or gastrointestinal series with small bowel follow-through is recommended in patients with head and neck involvement (tonsil, base of tongue, nasopharynx) and those with primary gastrointestinal disease. Mantle cell lymphoma is associated with a high incidence of occult gastrointestinal involvement. In addition, MRI of the complete craniospinal axis and ocular examination is advocated with any brain or leptomeningeal disease involvement to rule out multifocal disease.
The 1965 Rappaport’s Classification of malignant lymphomas was based solely on architecture and cytology. Since then, with the help of advanced cellular and genetic technologies, numerous new unique NHL entities have emerged. The World Health Organization (WHO) classification was revised in 2016, which continues to emphasize immunophenotyping, genotyping, and clinical features (Table 1).
Another way to group the many different lymphoma histologies is by clinical presentation and prognosis (Table 2).
2016 WHO Classification of Mature Lymphoid, Histiocytic, and Dendritic Neoplasms
From: Swerdlow SH et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016 127:2375-2390
Provisional entities are listed in italics.
* Changes from the 2008 classification.
Clinical Prognostic Classification of Adult Immunocompetent Non-Hodgkin Lymphomas*
Abbreviation: MALT = mucosa-associated lymphoid tissue.
* Subtypes are listed in order of most to least common.
International Prognostic Index
The International Prognostic Index was developed as a prognostic factor model for aggressive NHLs treated with doxorubicin- containing regimens (Box 2). In the pre-rituximab era, persons with no risk factors or one risk factor had a predicted 5-year overall survival of 73%, compared with 26% for high-risk patients with four or five risk factors. In the post-rituximab era, the survival rates have improved (see Box 2). A variant of the International Prognostic Index (IPI) is also useful in predicting outcome in patients with follicular low-grade lymphoma (FLIPI) or mantle cell lymphoma (MIPI) and in patients who have relapsed or refractory large B-cell lymphoma.
|Enhanced International Prognostic Index (NCCN-IPI) Risk Factors and Associated Approximate Cure Rates for Diffuse Large B-Cell Lymphoma|
>40 to ≤60: 1
>60 to ≤75: 2
>1 to ≤3: 1
Ann Arbor stage III-IV: 1
*Extranodal disease: 1
Performance status ≥2: 1
Five-Year Progression-Free Survival Rates Based on Score at Diagnosis
Score 0-1: 91%
Score 2-3: 74%
Score 4-5: 51%
Score =/> 6: 30%
* Disease in bone marrow, CNS, liver/GI tract, or lung.
DNA microarray technology for gene expression profiling has identified distinct prognostic subgroups in many NHL subtypes including DLBCL and follicular NHL. Patients with germinal center B- like DLBCL have an improved overall survival compared with other molecular profiles. Recent studies in follicular NHL have identified gene expression signatures that also predicted survival. Interestingly, the genes that defined the prognostic signatures were not expressed in the tumor cells, but were expressed by the nonmalignant tumor- infiltrating cells—primarily T cells, macrophages, and dendritic cells.
The therapeutic approach for NHL differs for each clinicopathologic subtype. Chemotherapy remains the most important modality.
However, in some instances, radiation therapy or, rarely, surgical resection plays a role. Biological approaches, including monoclonal antibodies and antibody-drug conjugates have shown significant activity and are now incorporated into most treatment paradigms. Autologous and allogeneic stem-cell transplantation are mostly reserved for patients with recurrent or refractory disease.
Indolent B-Cell Non-Hodgkin Lymphomas
Indolent lymphomas are low-grade and represent slow-growing NHLs that may be stable with low tumor burden that may not warrant therapy for several years. The disease is responsive to treatment (remission rates above 90% with combined rituximab/chemotherapy), although the clinical course is characterized by repetitive relapses. Outside of early-stage disease and therapy with an allogeneic stem cell transplant, low-grade NHLs are not curable.
The median survival of patients with advanced-stage follicular lymphoma in the pre-rituximab era was 9 to 10 years, although that is significantly longer now (approximately 15–17 years). Transformation to a high-grade NHL occurs in 30% to 40% (3%–4% of patients each year) of follicular lymphoma patients (less common in other indolent subtypes) and is typically heralded by an aggressive change in the patient’s clinical condition (e.g., B symptoms, rapidly rising LDH).
Only a minority of patients present with early-stage disease (i.e., stage I or II). Low dose involved field radiotherapy is a valid treatment option for these patients (especially stage I and not central sites of disease), and associated 15- to 20-year disease-free survival rates are greater than 50%. Treatment for patients with advanced-stage disease ranges from observation (i.e., watchful waiting) to anti-CD20 monoclonal antibody therapy (rituximab [Rituxan]) with or without chemotherapy. Treatment choice depends in part on tumor burden and the patient’s individual disease characteristics and baseline functional status. Treatment with frontline rituximab chemotherapy (outpatient therapy given once every 3–4 weeks typically for 6–8 cycles) for patients with high tumor burden is associated with median progression-free survival rates of approximately 4 to 5 years.
Treatment options for relapsed indolent lymphoma include repeating rituximab with or without a different chemotherapy regimen, radioimmunotherapy, or stem-cell transplantation.
Autologous stem-cell transplantation is an option for patients with relapsed disease, although an improvement in overall survival is debated. Allogeneic stem cell transplantation is a potential curative modality for patients with relapsed or refractory disease, although patient selection is critical owing to potential morbidity and mortality related to this therapeutic option.
Localized gastric MALT lymphoma cases often may be managed with therapy for H. pylori infection; radiation is typically reserved for failure to eradicate H. pylori. Patients with lymphoplasmacytic lymphoma (Waldenström’s macroglobulinemia) can present clinically with hyperviscosity or cryoglobulinemia, which may be managed acutely with plasmapheresis, but ultimately systemic therapy similar to that for other indolent NHLs is warranted.
Aggressive or High-Grade Non-Hodgkin Lymphomas
High-grade B- and T-cell NHLs are typically aggressive lymphomas that are fatal in weeks to a few months if not treated. However, many of these NHLs are curable with multiagent chemotherapy.
DLBCL, the most common aggressive NHL, is curable in all stages in the majority of patients (60%–70%). A key to treatment is anti-CD20 monoclonal antibody combined with anthracycline-based chemotherapy: rituximab-CHOP (R-CHOP) (cyclophosphamide, doxorubicin, vincristine, prednisone). The number of treatment cycles depends on stage of disease and response to treatment. Standard therapy for advanced-stage disease is 6 R-CHOP cycles, whereas patients with early-stage disease may receive 3 or 4 cycles followed by involved field radiation. There are emerging data regarding the prognostic importance of MYC rearrangement (from tumor testing) as a single finding and especially in conjunction with BCL-2 and/or BCL6 (i.e., double or triple hit) by molecular studies as well as with immunohistochemical staining. Outcomes with R-CHOP for DLBCL patients with a molecular double hit (e.g., presence of MYC and BCL-2) are modest; more intensive and novel therapeutic options should be considered. Therapy for relapsed DLBCL typically includes abbreviated salvage non–cross resistant chemotherapy followed by autologous stem-cell transplantation (autoSCT) for patients who have chemotherapy-sensitive disease, which is curative in approximately 35% to 45% of patients.
Mantle cell lymphoma is a B-cell NHL with initial high remission rates (>90–95%), but it has more modest long-term outcomes, and it is difficult to cure. With standard chemotherapy regimens (e.g., R- CHOP), the median progression-free survival rates are only 18 to 20 months. With more-intensive chemotherapy regimens (e.g., R- hyperCVAD/R-MA [rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone/rituximab, methotrexate]), 5-year progression-free survival rates are near 70%. Some groups induction therapy with aggressive high-dose cytarabine1 (Cytosar-U)-based chemotherapy followed by consolidative autologous stem-cell transplantation in first remission. As noted later, there has been the integration of several novel therapeutic agents into the treatment paradigm of mantle-cell lymphoma.
Burkitt’s lymphoma and related high-grade NHLs (e.g., lymphoblastic lymphomas) are often rapidly growing malignancies with a doubling time of 24 hours. Prompt initiation of therapy, including aggressive supportive care measures, is often warranted. With aggressive chemotherapy regimens, including prophylactic intrathecal chemotherapy, the majority of Burkitt’s patients younger than age 50 years are cured (>70%–80%). In addition, there are data showing high efficacy using lower intensity treatment consisting of infused etoposide (Toposar1), doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) for patients with untreated Burkitt’s lymphoma.
Systemic (i.e., non-cutaneous) peripheral T-cell NHLs are mostly aggressive malignancies; they are treatable, however, cure rates are significantly lower compared with most aggressive B-cell NHLs.
Standard therapy consists typically of CHOP-based chemotherapy with or without autologous SCT in first remission as consolidation. Associated five-year disease-free survival rates are approximately 20% to 30%. Several novel targeted agents have also been FDA approved over the last several years for the treatment of T-cell NHL (see below).
There are several clinical subtypes of DLBCL that present as primary extranodal manifestations such as primary testicular DLBCL and primary gastric DLBCL. If these lymphomas are localized, treatment typically consists of abbreviated cycles (3–4) of R-CHOP followed by involved field radiation. In addition, intrathecal chemotherapy prophylaxis is warranted for testicular DLBCL given the predilection of CNS involvement.
Primary central nervous system lymphoma is typically DLBCL; high-dose methotrexate chemotherapy is a key component of therapy.
A long-standing therapeutic maneuver for solid organ transplant related PTLDs has been reduction of immunosuppression, although using this approach alone, mortality rates have ranged from 50% to 60% in most series. Recent evidence with use of initial rituximab- based therapy suggests significantly improved outcomes in the modern era.
The majority of AIDS-related NHLs are aggressive or high-grade types: DLBCL or Burkitt lymphoma. Similar therapy as immunocompetent NHL is often recommended. Response to therapy, including cure rate, has improved significantly with better control of opportunistic infections and highly active antiretroviral therapy (HAART).
Mycosis fungoides and Sézary syndrome are cutaneous T-cell lymphomas that initially might show eczematous lesions. It is often difficult to establish diagnosis, but eventually the lesions develop into plaques and tumors. Lymph nodes, spleen, and visceral organs may be involved. Sézary syndrome is a variant of mycosis fungoides and shows peripheral blood involvement; patients usually have diffuse erythroderma. Skin-targeted modalities for treatment of early-stage mycosis fungoides include psoralens with ultraviolet A light (PUVA), narrowband-ultraviolet light, skin electron-beam radiation, and topical steroids, retinoids, carmustine (BiCNU), and nitrogen mustard (Mustargen).1 Treatment goals in advanced stages are to reduce tumor burden and to relieve symptoms. Treatment options also include mono- or polychemotherapy including CHOP, extracorporeal photopheresis, interferons, retinoids, monoclonal antibodies, and recombinant toxins.
During therapy for aggressive/high-grade NHLs, attention should be paid to preventing tumor lysis syndrome. Measures to prevent this complication include aggressive hydration, allopurinol (Zyloprim), alkalinization of the urine, and frequent monitoring of electrolytes, uric acid, and creatinine. Rasburicase (Elitek), a recombinant urate oxidase enzyme, is an expensive but potent agent for treating hyperuricemia.
Novel Treatment Options and Modalities
Many new agents targeting specific molecular targets have become available for the treatment of lymphoma. Novel agents in lymphoma include bortezomib (Velcade) and lenalidomide (Revlimid), which are FDA approved for relapsed or refractory mantle-cell lymphoma, and histone deacetylase inhibitors, which are approved for cutaneous T- cell lymphoma and peripheral T-cell NHLs as well. In addition, bortezomib was recently FDA approved for untreated mantle-cell lymphoma patients (in combination with immunochemotherapy). Other new agents which are FDA approved for the treatment of patients with chronic lymphocytic leukemia (CLL), including in higher risk patient populations (e.g., p53 mutated), are idelalisib (Zydeliq), an inhibitor of PI3K delta; an inhibitor of Bruton’s tyrosine kinase (BTK), ibrutinib (Imbruvica), which is also FDA approved for patients with CLL Mantle cell lymphoma (MCL); and venetoclax (Venclexta), a BH3 mimetic acting as an inhibitor of BCL2. New anti- CD20 antibodies have also been approved for the treatment of CLL (e.g., obinutuzumab (Gazyva) and antibody drug conjugates, such as brentuximab vedotin (Adcetris), which is FDA approved for relapsed anaplastic (T-cell) large-cell lymphoma. These novel therapeutic agents are mostly FDA approved for patients with relapsed or refractory disease, however, there are a multitude of ongoing studies in the frontline/untreated setting and in varied sequences and combinations. There also remains great excitement in the continued application of new immunotherapy approaches in NHL such as via checkpoint inhibitors (e.g., programmed death-1 (PD-1) inhibitors) as well as chimeric antigen receptor (CAR) T-cell therapy, which involve removal of T-cells from patients followed by bioengineered CARs (e.g., CD19) that facilitate antigen/tumor recognition when re-infused into the patient.
Follow-Up of Long-Term Survivors
Among patients with aggressive lymphomas, such as DLBCL, most recurrences are seen within the first 2 years after the completion of therapy, although later relapses occur uncommonly. Physical examination and laboratory testing at 2- to 3-month intervals and follow-up CT scans at 6-month intervals for the first 2 years following diagnosis are recommended, however, there is ongoing debate regaring the impact that post-surveillance scans have on disease outcomes. Detection of recurrent disease is important in part because these patients may be candidates for potentially curative therapy (e.g., stem-cell transplantation). Patients with advanced low-grade NHL are at a constant risk for relapse, as discussed before.
Long-term NHL survivors are at an increased risk for second cancers. Generally, the risk is increased with history of radiation use, but it is also seen with chemotherapy. In a survey of 28,131 Dutch registry patients with NHL who survived 2 years or longer, significant excesses of second cancers were seen for nearly all solid tumors as well as acute myelogenous leukemia (AML) and Hodgkin’s lymphoma. The standardized incidence ratio (SIR) for solid tumors after NHL was 1.65. The SIRs for solid tumors are increased for up to 30 years after NHL diagnosis, with the highest relative risk of developing a secondary malignancy occurring more than 21 to 30 years after original diagnosis.
Late Treatment Complications
There has been more selective use of radiation as part of therapy for NHL. Thus, the risk of certain radiation-induced complications has been reduced in patients treated more recently. Nevertheless, the risk still exists. Transplant recipients are at increased risk for secondary myelodysplasia and AML, regardless of whether they received radiation. All chemotherapy agents may cause long-term morbidity; in particular, patients who received an anthracycline (e.g., doxorubicin [Adriamycin]) are at a long-term increased risk of cardiovascular disease. Among Dutch and Belgian NHL patients treated with at least six cycles of doxorubicin-based chemotherapy, cumulative incidence of cardiovascular disease was 12% at 5 years and 22% at 10 years. Risk of coronary artery disease matched that of the general population; however, risk of chronic heart failure was significantly increased (SIR, 5.4) as was stroke (SIR, 1.8). Risk factors associated with excess risk included younger age at start of NHL treatment (<55 years), preexisting hypertension, any salvage treatment, and use of radiotherapy; risk relating to radiotherapy was dose-dependent. Continued studies are needed to develop optimal secondary prevention strategies.
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1 Not FDA approved for this indication