The Washington Manual of Oncology, 3 Ed.

Non-Hodgkin’s Lymphoma

Nina D. Wagner-Johnston

 I. Non-Hodgkin’s Lymphoma

1. Presentation
2. Subjective. Presenting symptoms of non-Hodgkin’s lymphoma (NHL) vary substantially depending on the pathologic subtype of NHL and the site(s) of disease. Indolent lymphomas such as follicular lymphoma (FL) or small lymphocytic (SLL) lymphomas usually present with painless peripheral adenopathy or occasionally with abdominal pain, bloating, or back pain related to bulky mesenteric or retroperitoneal adenopathy. Because spontaneous regressions occur in up to 20% of patients with FL, the patient may describe a history of waxing and waning adenopathy. Most patients with indolent lymphoma feel well at presentation, and B symptoms, including fevers, drenching night sweats, and weight loss, are unusual. MALT (mucosa-associated lymphoid tissue) lymphomas and indolent lymphomas occurring in extranodal sites, most commonly the stomach and the lung, usually have mild symptoms referable to the site of involvement. Indolent lymphomas are uncommon before the age of 50 years.

 Many aggressive lymphomas, the most common being diffuse large B-cell (DLBCL), also often occur as painless, peripheral adenopathy without other associated symptoms. Fevers, night sweats, or weight loss occur in approximately 20% of patients with advanced-stage disease. Bulky retroperitoneal nodes are common and may be asymptomatic or associated with mild abdominal pain, bloating, or back pain. Mediastinal adenopathy occurs uncommonly, usually among young women with DLBCL with sclerosis, and can present with cough, dyspnea, chest pain, or, rarely, SVC syndrome.

 Primary extranodal large cell lymphomas are common, accounting for 15% to 20% of all large cell lymphomas. NHL should remain in the differential diagnosis of a mass in any organ until pathology is confirmed. Approximately half of the extranodal lymphomas occur in the gastrointestinal tract, including the stomach, bowel, tonsils, nasopharynx, and oropharynx. Other sites include bone, testis, thyroid, skin, orbit, salivary glands, sinuses, liver, kidney, lung, and central nervous system (CNS).

 The very aggressive lymphomas, lymphoblastic and Burkitt, are rare in the adult population but can occur with acute symptoms and can be life threatening without rapid intervention. In adults, lymphoblastic lymphomas occur most commonly in young men, and are frequently associated with acute respiratory compromise due to bulky mediastinal adenopathy, and pleural or pericardial effusions. Burkitt lymphomas often present with abdominal pain and occasionally bowel obstruction related to bulky abdominal adenopathy and intestinal involvement.

 Patients with HIV-associated lymphomas (usually DLBCL or Burkitt subtypes) often have advanced disease, B symptoms, and involvement of liver, bone marrow, or CNS. A unique presentation of HIV-associated lymphomas is primary effusion, or body cavity–based lymphomas, which are characterized by the presence of NHL along serous membranes in the absence of identifiable tumor masses and with ascites or pleural effusions. Primary effusion lymphomas and CNS lymphomas are extremely rare in patients on appropriate antiretroviral therapy.

 Less common subtypes of NHL often have a unique clinical presentation. Examples include, but are not limited to, mycosis fungoides, a primary cutaneous T-cell NHL characterized by pruritic patches and plaques; mantle cell lymphoma (MCL), seen most often in older men with marked hepatosplenomegaly; and splenic marginal zone lymphoma seen as isolated splenomegaly.

2. Objective. Physical examination with accurate documentation of the size and location of all enlarged lymph nodes, tonsillar enlargement, hepatosplenomegaly, and skin involvement is important at the time of initial diagnosis in patients with NHL. Comparable physical examinations during and after therapy will allow evaluation of ongoing response without the need for frequent scans. Patients with active, indolent lymphomas are often observed without therapy at diagnosis. Regular repeated physical examinations are essential to allow for intervention before significant symptoms develop. A thorough neurologic examination should be performed in all patients with lymphoblastic or Burkitt lymphoma, looking for subtle signs of CNS involvement. Active involvement of the cerebrospinal fluid, meninges, or brain parenchyma requires a more intensive approach to the CNS.
3. Workup and staging. An adequate tissue biopsy is critical to the evaluation and treatment of all patients with NHL. The most recent WHO classification includes more than 35 subtypes of NHL, with B-cell neoplasms representing 80% to 90% of cases (Table 26-1). Optimal therapy requires accurate subclassification. Historically, diagnosis and subclassification required an excisional lymph node biopsy or, alternatively, a surgical biopsy of an extranodal site. Although this is still the preferred approach, accurate diagnosis by core needle biopsy is now a realistic possibility in some cases of NHL, for example, SLL, MCL, lymphoblastic lymphoma, and, occasionally, DLBCL. Lymphomas with a unique immunophenotype are those most likely to be diagnosed accurately with limited material. In patients without easily accessible tissue, it is reasonable to start with a radiographically guided core needle biopsy.

 Immunohistochemistry (IHC), now routinely performed in most new cases of NHL, is often necessary for accurate subclassification. Common examples include the differentiation of SLL (CD5⁺, CD23⁺) and MCL (CD5⁺, CD23⁻), the presence of cyclin D1 in MCL, verification of lymphoblastic lymphoma with terminal deoxynucleotidyl transferase (TdT) stains, and identification of peripheral T-cell lymphomas (PTCL) with aberrant expression of one or more of the T-cell markers CD3, CD4, CD5, CD7, and CD8. Even with the aid of IHC, PTCL can be difficult to diagnose because many have a histologic appearance similar to that of a benign, reactive lymph node and do not have a unique immunophenotype. Biopsies on patients in which the clinical history is suggestive of lymphoma but initial histologic review as well as IHC by flow cytometry or on paraffin-embedded tissue sections is nondiagnostic, should be tested for T-cell receptor and immunoglobulin heavy-chain gene rearrangements. Cases in which the pathologic diagnosis seems inconsistent with the clinical history should be reviewed by an expert hematopathologist.

TABLE 26-1

World Health Organization Classification for NHL

B-cell neoplasms

Precursor B-cell lymphoblastic leukemia/lymphoma^a

Mature B-cell neoplasms

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma^b

Mantle cell lymphoma

Follicular lymphoma

Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type

Nodal marginal zone lymphoma

Splenic marginal zone B-cell lymphoma

Hairy cell leukemia

Diffuse large B-cell lymphoma^b

Subtypes: mediastinal (thymic), intravascular, primary effusion lymphoma

Burkitt lymphoma

Plasmacytoma

Plasma cell myeloma

T-cell neoplasms

Precursor T-cell lymphoblastic leukemia/lymphoma^a

Mature T-cell and NK-cell neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

NK-cell leukemia

Extranodal NK/T-cell lymphoma, nasal-type (angiocentric lymphoma)

Mycosis fungoides^b

Sézary syndrome

Angioimmunoblastic T-cell lymphoma

Peripheral T-cell lymphoma (unspecified)^b

Adult T-cell leukemia/lymphoma (HTLV1⁺)^b

Systemic anaplastic large cell lymphoma (T-and null cell types)^b

Primary cutaneous anaplastic large cell lymphoma^b

Subcutaneous panniculitis-like T-cell lymphoma

Enteropathy-type intestinal T-cell lymphoma

Hepatosplenic γ/δ T-cell lymphoma

NHL, non-Hodgkin’s lymphoma; NK, natural killer.

^aThe classification of acute lymphoid leukemias will expand on the classification of precursor B-cell and T-cell malignancies, incorporating both immunophenotypic and genetic features.

^bMorphologic and/or clinical variants of these diseases are not listed, for the purpose of clarity and ease of presentation.

 Additional workup after a diagnostic biopsy includes a history and physical examination with documentation of adenopathy, hepatosplenomegaly, performance status, the presence of B symptoms, laboratory evaluations, radiographic studies, and, in most cases, a bone marrow biopsy. Necessary laboratory tests include a CBC, liver-function tests, calcium, creatinine, and lactate dehydrogenase (LDH). Cytopenias usually signify bone marrow involvement or, less commonly, hypersplenism. LDH is an important prognostic factor in the International Prognostics Index (IPI). If the LDH is elevated, a uric acid level should be obtained to evaluate for tumor lysis syndrome. Screening for HIV is indicated for patients with aggressive NHL. The Ann Arbor staging system, initially developed for Hodgkin’s lymphoma, is also used to stage NHL (Table 26-2). Alternative staging systems have been proposed but never adopted. Proper staging requires CT scans of the chest, abdomen, and pelvis, as well as bilateral bone marrow biopsies. Marrow evaluation is not always necessary in asymptomatic, older patients with indolent lymphomas if a CBC is normal, as the findings are unlikely to alter management of the disease. PET/CT scans have improved the accuracy of initial staging and response assessment, and are routinely incorporated in patients with aggressive subtypes of NHL. The role of PET/CT in indolent lymphomas remains controversial, although it can be useful in patients with equivocal CT findings and in patients who appear to have localized disease at presentation, where finding additional sites of involvement could potentially alter management. PET/CT is also helpful in identifying areas of suspected transformation, and although it should not replace the role of biopsy, it assists with directing the most appropriate site to biopsy. Patients with lymphoblastic or Burkitt lymphoma should have a lumbar puncture. If Waldeyer ring is involved, an upper gastrointestinal (GI) or upper endoscopy should be considered, given the increased incidence of gastric involvement in these patients.

TABLE 26-2

Ann Arbor Staging System

Stage	Description
Stage I	Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE)
Stage II	Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site (IIE)
Stage III	Involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE)
Stage IV	Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement

1. Therapy and prognosis
2. Indolent lymphomas. The Follicular Lymphoma International Prognostic Index (FLIPI) includes five independent poor prognostic factors, including age equal to or greater than 60, stage III or IV, greater than four involved nodal areas, elevated serum LDH, and hemoglobin less than 12 gm/dL (Blood 2004;104:1258). The 10-year OS (overall survival) rate for patients with three or more risk factors according to the FLIPI is 35% compared with 70% for patients with none or one high-risk feature. The FLIPI remains prognostic in the rituximab era (Ann Oncol 2013;24:441). Despite the marked improvement in recent outcomes for FL, there is still no plateau in the event-free survival curves with the use of chemoimmunotherapy, and “cures” remain to be achieved.
3. Stages I or II. Given the improved sensitivity of staging studies including CT scans, PET/CT scans, and the use of flow cytometry to evaluate bone marrow specimens, the diagnosis of limited-stage indolent lymphoma is uncommon. Observation, involved-field radiotherapy (IFRT), single-agent rituximab, a combination of rituximab and chemotherapy, and combined-modality therapy with rituximab plus or minus chemotherapy with IFRT are all options for patients with this unusual presentation. There are no randomized trials comparing these approaches, and treatment decisions should be based on the site and bulk of disease and patients’ age, with the more aggressive approaches being preferred for younger patients and those with bulky stage I and stage II disease.

 Gastric and other extranodal MALT lymphomas commonly present with early-stage disease. Gastric MALT lymphomas appear to occur as a direct result of antigenic stimulation from Helicobacter pylori infection. Approximately 80% of patients with gastric MALT lymphoma will have complete regression of disease with appropriate therapy for H. pylori, including antibiotics and proton-pump inhibitors. Long-term studies have demonstrated excellent durability of these remissions, with 80% to 90% of patients remaining in continuous histologic remission (J Clin Oncol 2005;23:8018; Gut 2012;61:507). For the subset of patients with gastric MALT lymphoma who do not respond to or relapse after H. pylori therapy, or are H. pylori negative, results with IFRT are excellent, with one series reporting 10-year freedom from treatment failure and OS of 88% and 70%, respectively (Ann Oncol 2013;24:1344). Other isolated extranodal presentations such as salivary gland, thyroid, breast, conjunctiva, or a unifocal skin site are also effectively treated with low-dose IFRT (30 Gy). Transformation of MALT lymphomas to aggressive, large cell lymphomas occurs in a minority of patients, but can be resistant to therapy.

1. Stage III or IV disease. Despite many effective, but to date “noncurative” therapies, there has never been any objective evidence that early intervention versus “watchful waiting” improves OS in asymptomatic patients (Lancet Oncol 2014;15:424). A subset of patients with indolent lymphomas will have no indications for therapy more than 15 years after diagnosis. Asymptomatic, older patients with low-volume disease may still be best served by close observation until progression. The current standard of care for patients with indolent lymphomas requiring therapy is a combination of rituximab and chemotherapy. The treatment approach has changed recently, following the publication of a randomized trial showing a significant improvement in remission duration and toxicity profile with bendamustine and rituximab (BR) compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (Lancet 2013;381:1203). The newly published BRIGHT trial comparing BR to R-CHOP and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) demonstrated noninferiority of the BR arm compared with the standard chemotherapy arms (ORR 97% vs. 91%) (Blood 2014;123:2944). Longer follow-up is necessary for progression-free survival (PFS) and OS comparisons.

 Maintenance rituximab following first-line chemoimmunotherapy is frequently adopted on the basis of data demonstrating improved PFS compared with observation (59% vs. 43% at 6 years); however, an OS benefit has yet to be described (Lancet 2011;377:42). Previous studies utilized a variety of maintenance schedules including one dose every 3 months for 2 years, four weekly doses every 6 months for 2 years, four weekly doses at 3 and 9 months after completion of chemoimmunotherapy, and one dose every 2 months for 8 months, although these were tested in the relapsed setting. For upfront treatment, the maintenance schedule with the most data is with rituximab administered once every two months for a duration of two years. No convincing data is available to recommend maintenance rituximab beyond 2 years. The toxicities of rituximab are mild and are limited primarily to infusion-related reactions such as fevers, chills, myalgias, transient hypotension, and, rarely, bronchospasm.

 An alternative approach for patients with low-volume disease, older patients, and patients with serious comorbid conditions is with single-agent rituximab administered for 4 weekly doses. The role of maintenance rituximab is more controversial following induction rituximab. However, the low toxicity profile as well as the implications for improved quality of life may potentially justify the role of maintenance rituximab following both chemoimmunotherapy and rituximab alone upfront approaches.

1. Relapsed disease. Multiple effective options are available for recurrent indolent lymphoma. If the first remission lasted longer than 1 to 2 years, patients often respond to the same regimen given as first-line therapy. However, remission durations are usually shorter with each subsequent treatment. All of the agents described earlier have activity in relapsed disease. Radiation can be given to patients with local, symptomatic disease. Response rates of approximately 80% have been reported with radioimmunotherapy (RIT) agents such as Zevalin, an anti-CD20 monoclonal antibody conjugated with the radioisotope [⁹⁰Y]. Despite the early promise of RIT, the approach is underutilized because of concerns about damaging stem cells as well as the risk for developing secondary leukemias.

 An exciting treatment for indolent lymphomas is with targeted agents that disrupt the B-cell receptor (BCR) pathway. Idelalisib, an oral phosphatidylinositol 3-kinase (PI3K) delta isoform inhibitor, was recently approved for the treatment of follicular lymphoma and SLL. Several other agents that target the BCR, including inhibitors of BTK (bruton’s tyrosine kinase) and SYK (spleen tyrosine kinase), are under investigation. Lenalidomide, an oral agent with unique immunomodulating properties, has significant activity in follicular lymphoma.

 Stem cell transplants are another option for relapsed indolent lymphoma. The only randomized trial of autologous transplant versus standard chemotherapy for relapsed indolent lymphoma showed both a PFS and OS advantage to transplant. Treatment-related mortality rates for allogeneic transplants have decreased significantly with the use of reduced intensity conditioning, but serious complications of both acute and chronic graft versus host disease continue to restrict this approach to patients with short remissions or refractory disease following standard approaches. In the era of having novel targeted therapies for indolent NHL, stem cell transplants are less frequently performed, and their use will likely continue to decline.

2. Aggressive lymphomas. Large cell, mantle cell, Burkitt, and lymphoblastic lymphomas compose most of the aggressive lymphomas. Peripheral T-cell lymphomas (PTCL) represent a spectrum of distinct subtypes that also usually behave aggressively. PTCL comprise approximately 10% of all the lymphomas. Standard approaches and prognosis vary for these subtypes of lymphoma and are addressed separately.
3. Stage I to II large cell lymphoma. The current standard of care for limited-stage nonbulky large cell lymphoma is three cycles of R-CHOP followed by IFRT. A phase II study of this approach showed 4-year PFS and OS rates of 88% and 92%, respectively (J Clin Oncol 2008;26:2944). Long-term follow-up of a previous trial comparing limited chemotherapy plus IFRT to eight cycles of CHOP alone showed no survival advantage to IFRT beyond 9 years because of an excess of late lymphoma relapses in the radiation arm (J Clin Oncol 2004;22:3032). These results have resulted in recommendations to consider six cycles of R-CHOP plus or minus IFRT as an alternative approach, especially in older patients and those with other high-risk features such as an elevated LDH.

 Primary mediastinal B cell lymphoma, a unique subtype of large cell lymphoma characteristically affecting young women, has not traditionally responded well to chemotherapy alone. Chemoimmunotherapy is typically followed by consolidative mediastinal radiation. Because of the rarity of this disease, randomized trials are lacking. However, a small phase 2, prospective study of infusional dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) without radiation demonstrated outstanding results with event-free and OS of 93% and 97%, respectively at a median of 5 years (N Engl J Med 2013;368:1408).

1. Stage III or IV large cell lymphoma. The standard of care for advanced-stage DLBCL remains 6 cycles of R-CHOP. Several studies are evaluating the addition of novel agents that have known activity in a particular subtype of DLBCL (germinal center vs. nongerminal center B cell) to R-CHOP. It seems likely that future treatments will vary depending on the cell of origin of DLBCL. Patients with translocations of C-Myc, and particularly patients with “double-hit” lymphomas (dual translocations of C-Myc plus either BCL2 or, less commonly, BCL6) have a significantly worse prognosis. The best treatment for these challenging cases is unknown. Studies are ongoing evaluating the role of dose-adjusted EPOCH-R.

 Prophylactic intrathecal therapy or high-dose methotrexate should be considered for patients with testicular, orbital, epidural, paranasal sinus, or extensive bone marrow involvement with an elevated LDH. These presentations carry an increased risk of CNS relapse, usually meningeal. The best treatment for prophylaxis is unknown, though cross study comparisons of retrospective studies may suggest lower CNS recurrences with high-dose methotrexate (Cancer 2010;116:4283). Patients with primary CNS lymphoma should be treated with specialized protocols using high-dose methotrexate, cytarabine, and rituximab with consideration for autologous stem cell transplant (ASCT) consolidation in eligible patients (J Clin Oncol 2013;31:3061). Treatment with high-dose methotrexate combined with whole brain radiotherapy (WBRT) increases the incidence of cognitive deficits and is avoided when possible. WBRT as a single modality is mostly reserved for elderly patients who are not eligible for chemotherapy.

 The International Prognostic Index (IPI) helps predict prognosis for individual patients with advanced-stage large cell lymphoma. The presence or absence of five independent poor prognostic features (age older than 60 years, stage III or IV disease, more than one extranodal site, performance status greater than or equal to two, and elevated serum LDH) effectively predicts an individual’s risk of relapse and death from lymphoma after standard chemotherapy. For patients treated with R-CHOP, 3-year OS rates according to the IPI are approximately 87% for patients with zero to one risk factor, 75% for patients with two risk factors, and 56% to 59% for those with three or more factors (J Clin Oncol 2010;28:2373). The nongerminal center B cell (non-GCB), also known as the activated B-cell (ABC), subtype is associated with a worse prognosis compared with GCB. Immunohistochemistry using Hans criteria (CD10, bcl-6, MUM1) as a surrogate for molecular profiling adequately discriminates the subtypes, with 5-year OS rates of 76% for the GCB group compared with 34% for the non-GCB group (Blood 2004;103:275). A revised prognostic tool driven by biomarker expression has not been adopted to date.

1. Burkitt lymphoma. Burkitt lymphomas have a poor prognosis with standard R-CHOP chemotherapy, and short-duration intensive therapies are indicated. Most current protocols prescribe four to six cycles of chemotherapy including intensive doses of alkylating agents such as cyclophosphamide or ifosfamide, vincristine, anthracyclines, and high-dose methotrexate alternating with high-dose cytarabine and etoposide. Two-year event-free survival rates of 70% to 90% are reported with this approach. CNS prophylaxis with intrathecal methotrexate and cytarabine is an essential component of therapy. Patients with an elevated LDH and bulky disease should be treated with allopurinol or rasburicase and vigorous hydration during initiation of therapy to minimize the risk of tumor lysis.
2. Lymphoblastic lymphoma. Treatment for this rare, highly aggressive lymphoma must include intensive combination chemotherapy and CNS prophylaxis. Most centers now use therapies modeled after acute lymphoblastic leukemia (ALL) regimens including induction, consolidation, and maintenance with a total treatment duration of 2 to 3 years. Five-year survival rates with this approach are approximately 60%.
3. Mantle cell lymphoma. Mantle cell lymphoma (MCL) often behaves aggressively and is characterized by multiple recurrences, yet in a subset of patients the disease follows a more indolent path. MCL occurs most frequently in men older than 60 years. Intensive approaches, such as with R-hyperCVAD (rituximab, high-dose cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and ara-C, are associated with longer remissions and survivals compared with R-CHOP and R-CVP, but plateaus in PFS have not been demonstrated. Consolidative ASCT in first remission is associated with a 5-year PFS of approximately 60% (J Clin Oncol 2009;27:6101). Treatment with the less intensive regimen of bendamustine and rituximab is associated with a median PFS of nearly 3 years. The favorable PFS and OS rates associated with novel nontransplant regimens along with the availability of several active agents in the relapsed setting have challenged the role of transplant. Maintenance rituximab administration has become standard, although its role following rituximab and bendamustine has not been published.
4. HIV-associated lymphoma. Treatment approaches have changed with the advent of highly active antiretroviral therapy (HAART). Previously, most clinicians favored low-dose chemotherapy because studies comparing low-dose and standard-dose therapy showed similar response and survival rates and more toxicity with standard-dose therapy. Such practices are no longer followed. Limited evidence suggests that R-EPOCH is the optimal regimen for HIV-associated DLBCL. Randomized data is not available, however CNS prophylaxis should be considered in all patients with HIV-related lymphomas.
5. Peripheral T-cell lymphoma. Optimal treatment for PTCL remains unknown. CHOP is associated with an approximately 30% cure rate. Multiple clinical trials are underway evaluating the role of new agents in combination with existing regimens.
6. Relapsed disease. Patients younger than 70 to 75 years without significant concurrent illnesses should be considered for high-dose therapy and autologous or allogeneic stem cell transplantation at relapse. Several effective salvage regimens are available as cytoreduction before transplant, including most commonly ICE (ifosfamide, carboplatin, and etoposide), ESHAP (etoposide, methylprednisolone [Solu-Medrol], high-dose cytarabine, cisplatin), or DHAP (dexamethasone, high-dose cytarabine, and cisplatin). Rituximab is typically added to these regimens for patients with B-cell lymphomas. Recent data suggests that R-DHAP is superior to R-ICE in patients with DLBCL of the GCB subtype (J Clin Oncol 2011;29:4079). In patients with chemosensitive relapse, the 5-year disease-free survival (DFS) rate after transplant is approximately 50%, whereas in patients with refractory relapse, it is less than 15%. Allogeneic stem cell transplant should be considered for patients with a remission duration of less than 1 year after initial therapy, refractory disease at relapse, and all patients with relapsed Burkitt or lymphoblastic lymphoma.

 Treatment options for nontransplant candidates include gemcitabine, oxaliplatin ± rituximab; lenalidomide ± rituximab (especially for non-GCB DLBCL subtype); and bendamustine ± rituximab.

1. Complications
2. Therapy related. Most first-line therapies for indolent lymphomas are well tolerated, with minimal risk of severe toxicity. Most patients experience moderate to severe infusion-related symptoms, including fevers, chills, dyspnea, and hypotension, during administration of the first dose of rituximab. These side effects are uncommon with subsequent doses. Rituximab has rarely been associated with reactivation of hepatitis B. Concurrent administration of entecavir for patients with positive antibodies is recommended (J Clin Oncol 2013;31:2765).

 Potential complications of CHOP chemotherapy include hair loss, a moderate risk of fever and neutropenia, minimal nausea and vomiting if serotonin-antagonist antiemetics are used, peripheral neuropathy secondary to vinca alkaloids, cardiomyopathy related to anthracyclines, and, rarely, hemorrhagic cystitis related to cyclophosphamide. The current American Society of Clinical Oncology (ASCO) guidelines recommend prophylactic hematopoietic colony-stimulating factors for patients older than 65 treated with CHOP (J Clin Oncol 2006;24:3187). Another clinical scenario that may justify the use of prophylactic growth factors is a patient with extensive marrow involvement and cytopenias at diagnosis.

 First-line regimens for Burkitt and lymphoblastic lymphomas, as well as most salvage regimens for relapsed aggressive NHL, have significant toxicities associated with them, most commonly, severe cytopenias and increased risk of life-threatening infection. Prophylactic growth factors should be used with these regimens. Renal insufficiency and mucositis occur frequently with regimens containing high-dose methotrexate. Cerebellar toxicity, somnolence, and, rarely, coma are reported with high-dose cytarabine, particularly in older patients. These regimens should usually be administered in a hospital setting with close monitoring of electrolytes, creatinine, and fluid balance.

 Patients with advanced-stage Burkitt or lymphoblastic lymphoma are at significant risk of acute tumor lysis during initiation of therapy. Patients with an elevated LDH or creatinine are at greatest risk. Complications of tumor lysis include hyperkalemia, hyperphosphatemia, hyperuricemia, renal failure, hypocalcemia, and death. Vigorous intravenous hydration (250 to 500 mL/hour) should be given for 2 to 3 days. Bicarbonate should be avoided. While urinary alkalinization improves uric acid excretion, systemic alkalinity increases the chance of hypocalcemia, potentially resulting in tetany and cardiac arrhythmias. Allopurinol or rasburicase should be given before initiation of chemotherapy and in the case of allopurinol continued for 10 to 14 days. If a high urine flow cannot be maintained, urgent hemodialysis may be necessary to treat and prevent life-threatening biochemical abnormalities.

 Therapy-related myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (AML) are rare, but are the devastating late complications of therapy for NHL. These complications can occur in patients with indolent lymphomas as a consequence of years of intermittent alkylator therapy. There is also an increased risk of MDS/AML after stem cell transplantation with as many as 12% of patients developing this complication, a median of 4 years after transplant. Most have complex karyotypes with deletions in chromosomes 5 and 7. The prognosis is dismal. Radioimmunotherapy drugs such as Zevalin may also be associated with an increased risk of MDS and AML, particularly in heavily pretreated patients.

2. Disease related. Most patients with indolent lymphomas are asymptomatic at presentation and have no significant complications of the disease until the terminal stages. Occasionally, lymphedema related to pelvic adenopathy or hydronephrosis related to retroperitoneal adenopathy can require urgent therapy. Both radiotherapy and chemotherapy are effective modalities in this setting.

 Patients with aggressive histologies occasionally have serious disease-related complications, particularly those with Burkitt or lymphoblastic lymphoma. Such complications include airway obstruction secondary to paratracheal adenopathy, cardiac tamponade, paraplegia secondary to spinal cord compression, gastrointestinal bleeding, bowel obstruction or perforation, SVC syndrome, ureteral obstruction, cranial neuropathies, or radiculopathies related to meningeal involvement, and very rarely hypercalcemia or uric acid nephropathy. When these complications occur at initial presentation or first relapse, rapid initiation of chemotherapy is imperative. In patients with late-stage or refractory disease, these complications are often fatal, and supportive care is appropriate.

1. Follow-up. The goals of follow-up are to provide reassurance to the patient, to detect recurrent or progressive NHL, and to monitor for long-term complications of therapy. Survivorship care plans provide treatment summaries and guidelines and can be useful when care is transitioned to the primary care physician. Anxiety and depression, often related to fear of recurrence, are common in the early period. Individual counseling, support groups, and occasionally short-term use of antidepressants may be needed.

 As described earlier, asymptomatic patients with indolent lymphoma are often observed without therapy. Appropriate follow-up for these patients includes a history and physical examination every 3 to 4 months, and a CBC, LDH, and creatinine level once or twice a year. Patients with significant intra-abdominal disease but no peripheral adenopathy may benefit from an annual abdominal and pelvic CT scan. In addition to close monitoring, patients must be educated to report potential symptoms of progression including new or enlarging lymph nodes, abdominal or back pain, bloating, lower extremity edema, or B symptoms. Because of the recurring nature of the disease, most patients with indolent lymphoma need life-long follow-up with an oncologist.

 For patients with aggressive lymphomas who achieve remission with initial therapy, recommendations regarding the optimal strategy have recently been revised to reflect the recognition that the vast majority of relapses are not detected by routine scans and that surveillance scans do not equate with earlier detection and a survival advantage. Most of the aggressive NHL recurrences occur in the first 2 years after treatment, and rarely after 5 years. Sites of recurrence include at least one previously involved site in 75% of cases and only new sites in 25% of cases. A reasonable approach for follow-up of these patients includes a history and physical examination every 3 months for 2 years and every 6 months for the next 3 years, with a CBC and LDH at each visit. Scans should probably not be performed more than annually for the first 2 years, and only to evaluate new symptoms during 3 to 5 years. Routine CT scans might not be indicated at all for patients at low risk for recurrence, including those with no high-risk features at diagnosis.

1. Background
2. Epidemiology and risk factors. In 2014, it is estimated that were will be 70,800 new cases of NHL. Between 2002 and 2011, the annual incidence rate of NHL increased by 0.5% per year, which represents a decline compared with the preceding 3 decades. Death rates have been declining on average by 2.7% each year from 2001 to 2010. The incidence of NHL is slightly higher in men than women, and increases exponentially with age. Infectious agents, including EBV, HIV, human T-cell leukemia virus (HTLV)-1, H. pylori, hepatitis C, and HHV8, are clearly linked to the pathogenesis of certain subtypes of NHL. Other infectious agents, such as chlamydia psittaci and borrelia burgdorferi, have discrepant associations, demonstrating variability with geographic location. Additional factors associated with a significant increased risk of NHL include autoimmune disorders, most commonly Sjögren syndrome and rheumatoid arthritis, although it is difficult to separate the effects of immunosuppressive drugs used to treat these diseases and the underlying autoimmune disease. Tumor necrosis factor (TNF) inhibitors have been associated with T-cell lymphomas, most commonly hepatosplenic T-cell subtype. Inconsistent associations have been reported with pesticides, hair dyes, certain occupations, smoking, consuming foods high in animal fat, and receiving blood transfusions.
3. Molecular biology. Certain lymphomas have hallmark translocations that lead to unregulated expression of genes, resulting in impaired apoptotic signaling and dysregulation of the cell cycle. Most cases of follicular lymphoma contain a t(14;18) chromosomal translocation, resulting in dysregulation of the bcl-2 gene, one of many important genes thought to play a role in apoptosis. Overexpression of bcl-2 appears to inhibit cell death. Extended cell survival may increase the opportunity of cells to acquire additional genetic defects in growth and proliferation genes. Multiple additional translocations and abnormalities of gene expression have been reported in NHL and are beyond the scope of this chapter. Examples of the better-characterized abnormalities include the t(8;14) translocation in most Burkitt’s lymphomas, resulting in dysregulation of the c-myc oncogene, and a t(11;14) translocation in most MCLs with dysregulation of bcl-1, and overexpression of cyclin D1.
4. Pathogenesis. Lymphomas represent a large collection of unique diseases that exhibit heterogeneity even within a specific subtype at the genotypic, phenotypic, morphologic, and clinical level. Advances in gene expression profiling over the past decade were key in identifying that distinct subtypes of lymphoma resemble their cell of origin. More recent expansion of sequencing technologies have been integral in our improved understanding of the genetic and epigenetic drivers in lymphomagenesis that are ultimately leading to the development of rational targeted approaches. One of the more exciting advances in lymphoma has been the recent approval of agents such as ibrutinib and idelalisib that target key upstream kinases in the B-cell receptor (BCR) pathway that is well understood to be both tonically and chronically activated, leading to tumor viability and resistance.
5. Current focus of research. Examples of ongoing research efforts aimed at improving therapy include the following:
6. Continued evaluation of targeted inhibitors of the B-cell receptor pathway (e.g., BTK, PI3K, SYK).
7. Development of adoptive gene therapy using anti-CD19 chimeric antigen receptor (CAR)-expressing T lymphocytes for patients with B-cell lymphomas.
8. Development of additional monoclonal antibodies directed at targets other than CD20.
9. Validation of new prognostic indices that build on the IPI by adding biologic factors such as the molecular classification of tumors on the basis of gene expression.
10. Clarification of the role of PET/CT in early interim restaging of aggressive NHL to determine whether outcomes improve for high-risk patients when therapy is adapted on the basis of imaging findings.

SUGGESTED READINGS

Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117(19):5019–5032.

Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014;123:2944–2952.

Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label multicenter, randomized, phase 3 non-inferiority trial. Lancet 2013;381(9873):1203–1210.

Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3 randomized controlled trial. Lancet2011;377(9759):42–51.