Lymphoma

Continuing Education Activity

Lymphoma comprises heterogeneous malignancies that arise from the clonal proliferation of lymphocytes. It represents approximately 5% of malignancies. Overall survival is estimated to be 72%. This activity outlines the evaluation and management of lymphoma and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the etiology of the common types of lymphoma.
• Describe the clinical presentation of the common types of lymphoma.
• Outline the treatment plan of the common types of lymphoma.

Introduction

Lymphomas are a heterogeneous group of malignancies that arise from the clonal proliferation of B- cell, T- cell and natural killer (NK) cell subsets of lymphocytes at different stages of maturation.[1][2] Lymphoma comprises heterogeneous malignancies that arise from the clonal proliferation of lymphocytes. It represents approximately 5% of malignancies. Overall survival is estimated to be 72%.

Etiology

Different environmental, infectious, and genetic factors have been identified, which predispose to lymphoma.

Occupational exposure: herbicides, pesticides

Infectious organisms: These include Helicobacter pylori (MALT lymphoma), Borrelia burgdorferi, Chlamydia psittaci, Campylobacter jejuni, human T- cell lymphotropic virus (adult T- cell leukemia/lymphoma), hepatitis C ( lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma and marginal zone lymphoma), human herpesvirus 8 (primary effusion lymphoma and Castleman disease). Chronic stimulation of lymphoid tissue also increases the risk of lymphoma development. Persistent infection with viruses like Epstein Barr virus and cytomegalovirus also predisposes to the development of lymphoma.[3][4]

Immunodeficiency: HIV infection, transplant recipients, and those with genetic immunodeficiency disorders (severe combined immunodeficiency and common variable immunodeficiency).[5]

Drugs: Tumour necrosis factor-alpha inhibitors are associated in particular with T- cell lymphoma. Chronic immunosuppression in post-transplant patients (both solid organ transplant and bone marrow transplant recipients) increases the risk of lymphoma.

Autoimmune diseases: Inflammatory bowel disease (enteropathy associated lymphoma), rheumatoid arthritis and, Sjögren’s syndrome (diffuse large B-cell lymphoma)

Geographic location: Extranodal NK/T- cell lymphoma incidence is high in Southern Asia and some parts of Latin America.[1][2]

Epidemiology

The incidence of lymphoma in the United States from 2009 to 2013 was 22/ 100,000, representing approximately 5% of malignancies, it doubled in the time period 1970-1990, and it has been stable since. The median age of diagnosis is 63. Overall survival is estimated to be 72% at five years, and it is improving.[1]

Lymphomas are broadly classified into Hodgkin lymphoma (HL), 10% and Non- Hodgkin lymphoma (NHL), 90%.

HL is further classified into classical and non-classical types and NHL into B- cell, T- cell and natural killer (NK) cell types.

For clinical purposes, lymphoma is termed as aggressive (high grade) and indolent (low grade).[6]

Below is the revised 2016 revised WHO classification of lymphomas.[7]

Mature B-cell neoplasms

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
•  Monoclonal B-cell lymphocytosis
•  B-cell prolymphocytic leukemia
•  Splenic marginal zone lymphoma
•  Hairy cell leukemia
•  Splenic B-cell lymphoma/leukemia, unclassifiable

  • Splenic diffuse red pulp small B-cell lymphoma
  • Hairy cell leukemia-variant
•  Lymphoplasmacytic lymphoma

  • Waldenström macroglobulinemia
•  Monoclonal gammopathy of undetermined significance (MGUS), IgM
•  μ heavy-chain disease
•  γ heavy-chain disease
•  α heavy-chain disease
•  Monoclonal gammopathy of undetermined significance (MGUS), IgG/A
•  Plasma cell myeloma
•  Solitary plasmacytoma of bone
•  Extraosseous plasmacytoma
•  Monoclonal immunoglobulin deposition diseases
•  Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
•  Nodal marginal zone lymphoma

  • Pediatric nodal marginal zone lymphoma
•  Follicular lymphoma

  • In situ follicular neoplasia
•  Duodenal-type follicular lymphoma
•  Pediatric-type follicular lymphoma
•  Large B-cell lymphoma with IRF4 rearrangement
•  Primary cutaneous follicle center lymphoma
•  Mantle cell lymphoma

  • In situ mantle cell neoplasia
•  Diffuse large B-cell lymphoma (DLBCL), NOS

  • Germinal center B-cell type
  • Activated B-cell type
•  T-cell/histiocyte-rich large B-cell lymphoma
•  Primary DLBCL of the central nervous system (CNS)
•  Primary cutaneous DLBCL, leg type
•  EBV+ DLBCL, NOS
•  EBV+mucocutaneous ulcer
•  DLBCL associated with chronic inflammation
•  Lymphomatoid granulomatosis
•  Primary mediastinal (thymic) large B-cell lymphoma
•  Intravascular large B-cell lymphoma
•  ALK+ large B-cell lymphoma
•  Plasmablastic lymphoma
•  Primary effusion lymphoma
•  HHV8+DLBCL, NOS
•  Burkitt lymphoma
•  Burkitt-like lymphoma with 11q aberration
•  High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
•  High-grade B-cell lymphoma, NOS
•  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T and NK neoplasms

•    T-cell prolymphocytic leukemia
•  T-cell large granular lymphocytic leukemia
•  Chronic lymphoproliferative disorder of NK cells
•  Aggressive NK-cell leukemia
•  Systemic EBV+ T-cell lymphoma of childhood
•  Hydroa vacciniforme–like lymphoproliferative disorder
•  Adult T-cell leukemia/lymphoma
•  Extranodal NK-/T-cell lymphoma, nasal type
•  Enteropathy-associated T-cell lymphoma
•  Monomorphic epitheliotropic intestinal T-cell lymphoma
•  Indolent T-cell lymphoproliferative disorder of the GI tract
•  Hepatosplenic T-cell lymphoma
•  Subcutaneous panniculitis-like T-cell lymphoma
•  Mycosis fungoides
•  Sézary syndrome
•  Primary cutaneous CD30+ T-cell lymphoproliferative disorders

  • Lymphomatoid papulosis
  • Primary cutaneous anaplastic large cell lymphoma
•  Primary cutaneous γδ T-cell lymphoma
•  Primary cutaneous CD8+aggressive epidermotropic cytotoxic T-cell lymphoma
•  Primary cutaneous acral CD8+T-cell lymphoma
•  Primary cutaneous CD4+small/medium T-cell lymphoproliferative disorder
•  Peripheral T-cell lymphoma, NOS
•  Angioimmunoblastic T-cell lymphoma
•  Follicular T-cell lymphoma
•  Nodal peripheral T-cell lymphoma with TFH phenotype
•  Anaplastic large-cell lymphoma, ALK+
•  Anaplastic large-cell lymphoma, ALK−
•  Breast implant-associated anaplastic large-cell lymphoma

Hodgkin lymphoma

 Nodular lymphocyte-predominant Hodgkin lymphoma

 Classical Hodgkin lymphoma

•   Nodular sclerosis classical Hodgkin lymphoma
•   Lymphocyte-rich classical Hodgkin lymphoma
•   Mixed cellularity classical Hodgkin lymphoma
•   Lymphocyte-depleted classical Hodgkin lymphoma

Posttransplant lymphoproliferative disorders (PTLD)

•  Plasmacytic hyperplasia PTLD
•  Infectious mononucleosis PTLD
•  Florid follicular hyperplasia PTLD
•  Polymorphic PTLD
•  Monomorphic PTLD (B- and T-/NK-cell types)
•  Classical Hodgkin lymphoma PTLD

Pathophysiology

Different stressors in the form of infectious, inflammatory, and toxic factors interact with the genetic makeup of the human host in a complex manner to result in lymphomagenesis.[1][2] One of the widely accepted principles of lymphomagenesis is being on long term immunosuppressive therapies, which makes the innate immune system less able to detect and destroy cancer cells or ward off infections that could result in cancers.

Histopathology

A diagnosis of lymphoma is confirmed by tissue biopsy, and commonly used methods include fine-needle aspiration, core biopsy, incision/wedge biopsy, and excisional biopsy. Excisional biopsy is considered the "gold standard" as it allows for the assessment of whole lymph node architecture. The different pathologic characteristics and histologic patterns of common lymphomas are as below.

Hodgkin Lymphoma (HL)

HL is defined by the presence of pathological Hodgkin Reed-Sternberg (HRS) cells, which are of B-cell origin on the background of nodular sclerosis, lymphocyte-predominant, or depleted stroma. Classical HL is divided into four different types, which in decreasing order of frequency are: nodular sclerosing, mixed cellularity, lymphocyte rich, and lymphocyte depleted. Non -classical HL is of an only single type, nodular lymphocyte-predominant.

HL presentation is bimodal with one age peak in the early 20s and second in the mid-60s.  For most cases, no underlying cause is found, but for some subtypes of classical HL, a significant number of patients test positive for EBV. The causative relationship between EBV and HL been investigated extensively. Other risk factors are genetic predisposition (high incidence among patient's relatives), immunodeficiency states, and environmental factors (high incidence in farmers, woodworkers, and meat processors).

Histologic features of HL: are HRS cells, which are odd-looking large, bilobed cells with two nuclei, appearing within a background of non-malignant inflammatory cells. Immunohistochemical staining of HL shows positive markers for CD30, CD15, but negative for CD20, making it difficult to determine the B-cell lineage.[1][2][7]

Non-Hodgkin Lymphoma (NHL)

Diffuse large B Cell lymphoma (DLBCL)

It is the most common NHL, accounting for 25% to 30% of cases.  It is a clinically aggressive lymphoma. DLBCL often arises in the lymph nodes but can also present anywhere else in the body, and the gastrointestinal tract is the most common system outside the lymphatic system. Other common involvement sites are testes, eyes, and central nervous system.

When an extranodal disease is present with minimal or no lymph node involvement, the disease is considered primary extranodal DLBCL, whereas when both nodal and extranodal disease is present, the disease is considered nodal lymphoma.

It is classified based on gene expression into three categories according to the cell of origin: germinal center B cell-like, activated B cell-like, and type 3; the last two have unfavorable prognosis.

Low-grade lymphomas like follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma can develop into high-grade through a transformation of disease into DLBCL, which is triggered by accumulation of additional transforming mutations.

Histologic features: include areas of diffuse involvement by large lymphoid cells that stain positive for B-cell markers CD20 and CD19. The proliferation index, determined by staining with Ki67 antibody is moderate to high.[1][2][7]

Follicular Lymphoma (FL)

It is an indolent lymphoma and accounts for about 20% of lymphoma diagnoses, making it the second most common lymphoma. Overall survival ranges from 8-15 years. It originates from the follicular cells in the germinal center of the lymph node. The tumor cells have overexpression of the anti-apoptotic protein BCL-2, due to translocation of the BCL-2 gene on chromosome 14 to the immunoglobulin or B-cell receptor gene on chromosome 18, t(14:18). It can transform into more aggressive DLBCL in some cases.[1][2]

Histologic features: histologic diagnosis requires areas of considerable follicular proliferation and expansion within the lymph node. Within the expanded lymph node follicles,  small and large cells proliferate (similar to reactive lymph node), but instead of a  combination of B cells (CD20+) and some T cells (CD3+), the follicles are composed mostly of B cells positive for BCL-2 in FL. However, in FL, as in a reactive node, there is a difference in the size of follicle B cells, small cells, which are called centrocytes and large cells called centroblasts. The proportion of large cells, centroblasts, is measured as being either greater than or less than 15 cells per high-power field (HPF). The larger the number of centroblasts, the higher the grade; in grades I and II, there are 0 to 15 centroblasts/HPF, whereas, in grade III, there are more than 15 centroblasts/HPF. The difference between grade IIIA and grade IIIB is the presence of a mixture of centrocytes and centroblasts in all follicles in grade IIIA, whereas, in grade IIIB, follicles consist exclusively of centroblasts, immunoblasts (activated lymphocytes), or both. Of note, FL grade IIIB is managed the same way as DLBCL.[1][2][7]

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

Normal mucosal tissue contains non-continuously spread collections of lymphocytes called mucosa-associated lymphoid tissue (MALT). Lymphoma that originates from the marginal zone of such collection is called MALT lymphoma and constitutes 7% of all lymphomas. It is a slow-growing B-cell lymphoma. Repeated antigen stimulation in the setting of infection, autoimmune disease, or other inflammatory condition predisposes to the pathogenesis. Some well-known associations are H.pylori (gastric), C. psitacci (ocular), C. jejuni (small intestine),  B. burgdorferi (skin), Hashimoto thyroiditis (thyroid) and Sjögren syndrome (salivary gland). It originates from a marginal zone cell, a B-cell.[1][2][7][2]

Histologic features: Aggregates of small lymphocytes with IHC staining positive for CD20 and negative CD5 and CD10.[1][2][7]

Mantle Cell Lymphoma

It comprises 6% of lymphomas. It has the worst prognosis among all lymphoma subtypes with a median overall survival of 5 years. Despite that, it has a wide range of presentations, and in some older patients, it has a very slowly progressive course where close surveillance without immediate treatment initiation has been used. It has a male predominance. It usually presents as a widespread disease; bone marrow and gastrointestinal tract are the most common sites of involvement. In the gastrointestinal tract, it can cause obstruction due to the formation of multiple polyps, a condition called lymphomatous polyposis.

Histologic features: lt arises from the mantle zone cell of the lymph node, which is a post–GC (germinal center) B-cell. Histologic diagnosis is made by visualizing areas of small lymphoid cells, arising from mantle zone directly in some cases, with characteristic IHC staining and being always positive for cyclin D1, a protein involved in cell cycle regulation. It results from a translocation of the gene encoding for cyclinD1 on chromosome 11 and the one encoding for Ig (immunoglobulin) on chromosome 14, t(11;14).[1][2][7]

Burkitt Lymphoma (BL)

It was first described by the Irish surgeon Denis Burkitt in 1958 and is a very aggressive B-cell lymphoma. It is divided into three types: endemic, spontaneous, and immunodeficiency associated. The endemic form of BL is a pediatric tumor in Africa, usually presenting as a mandibular mass and is strongly associated with chronic EBV infection. In the United States, spontaneous BL is the most common form and usually presents as an abdominal mass or lymphadenopathy. Immunodeficiency associated BL is seen in HIV infection, and its presence can be an AIDS-defining condition. The pathogenesis is caused by translocation of the cell proliferation proto-oncogene, C-Myc to one of the sites encoding Ig expression, either the heavy chain t(8;14) or one of the two light chains, t(2;8) or t( 8;22).

Histologic features: histologic diagnosis is made by recognizing medium to large B-cells with a very high proliferation rate (Ki67 of almost 100%), with the classic starry sky appearance due to tingible body macrophages with surrounding clearing.[1][2][7]

Peripheral T Cell lymphomas  

The peripheral T-cell lymphomas (PTCLs) are a diverse group of diseases that constitute approximately 5% to 10% of NHL.

The PTCLs are classified into three main categories with predominantly leukemic, nodal, or extranodal involvement. The first subset of the peripheral T-cell lymphomas frequently presents with a leukemic phase. It includes T-cell prolymphocytic leukemia, T-cell large granular lymphocytic (LGL) leukemia, natural killer/T (NK/T)-cell leukemia, and adult T cell leukemia/ lymphoma. The second set presents with adenopathy, and it includes angioimmunoblastic T- cell lymphoma (AITL), systemic anaplastic large cell lymphoma (ALCL), and peripheral T- cell lymphoma (PTCL).

The extranodal PTCLs include mycosis fungoides (MF) and cutaneous ALCL.  These have chronic and slow progression with long term remission. Sezary syndrome represents the leukemic transformation of MF, presenting with abnormal circulating lymphocytes (Sezary cells), adenopathy, and erythroderma and has a worse prognosis.

Extranodal NK/T-cell lymphoma, nasal type (nasal NK/T lymphoma) is an aggressive lymphoma that is the most common cause of the "lethal midline granuloma" syndrome. It is strongly associated with EBV infection and is frequently seen in East Asia and among the indigenous population in Peru. It affects both children and adults and presents as a locally invasive disease presenting with nasal obstruction and destruction of nasal passages, hard palate, and sinuses[1][2][7][8]

History and Physical

Hodgkin Lymphoma

Usually presents with painless, superficial enlarged lymphadenopathy, which involves contiguous lymph node chains in a predictable manner with the spread of the disease. Later in the disease course, hematogenous spread occurs with vascular invasion. The majority of patients present with supradiaphragmatic disease and isolated infra-diaphragmatic disease occurs in only 3-7% of patients. Approximately 60 to 70% of patients present with cervical and/or supraclavicular lymphadenopathy, 30% with the axillary disease, 50 to 60% with mediastinal involvement seen on radiology in the absence of symptoms. Infra diaphragmatic disease involves para-aortic lymph nodes, but the involvement of abdominal organs is uncommon. Only 10-15 % of patients with HL have extranodal disease, and the commonly affected organs are bone, bone marrow, lung, and liver. CNS involvement is very rare, but extension from para-aortic adenopathy into epidural space can result in neurological symptoms.[1][2][9]

Approximately 25% of patients with previously undiagnosed HL develop systemic symptoms before the development of lymphadenopathy called B symptoms (fevers, drenching night sweats, and unintentional weight loss). The presence of these symptoms carries a worse prognosis in both early and advanced-stage disease.  Other symptoms include severe pruritis and alcohol-induced pain occurring minutes after alcohol intake and localized to regions of lymphadenopathy. Some rare neurological syndromes, including cerebellar degeneration and stiff-person syndrome, also have been reported.[1][2]

Non-Hodgkin Lymphoma

DLBCL

The most common complaint is symptomatic, enlarging lymph nodal mass either located centrally or peripherally. 20% of patients present with stage I disease, approximately 40% with disease limited to one side of the diaphragm (stage II), and another 20% with involvement above and below the diaphragm and 40% with the widespread disease with extranodal involvement. Common sites of extranodal spread are lung, liver, kidney, and bone marrow. This is in contrast to primary extranodal sites of origin of DLBCL, which are the gastrointestinal tract, thyroid, bone, brain, testis, kidney, liver, breast, and skin.

Approximately 30% of patients will report B symptoms as well as less specific symptoms of malaise and fatigue.

Follicular Lymphoma

The most common presentation is subacute, or chronic asymptomatic peripheral lymphadenopathy, which sometimes persists or waxes and wanes over a period of years. Abdominal, pelvic, or retroperitoneal lymphadenopathy can be bulky without causing gastrointestinal or genitourinary symptoms, and nodal masses are not locally invasive and destructive. The lymph node involvement is not in an orderly manner, and early hematogenous dissemination is common.  B-symptoms are seen in less than 20% of patients and should prompt consideration for transformation into DLBCL.[10]

Marginal Zone Lymphoma

Presenting symptoms related to the sites of involvement (stomach, lung, ocular adnexa, breast, thyroid, bowel, skin, and soft tissue) and B-symptoms are rare and should raise suspicion for transformed lymphoma.

Mantle Cell Lymphoma

70% to 90% of patients present with detectable stage 4 disease. Bone marrow involvement is common, and a leukemic phase is seen as frequently as 75% in some series. The gastrointestinal tract is frequently involved and can present from diffuse lymphomatous polyposis to a normal lumen with microscopic disease seen on biopsy. Other common sites of involvement are the spleen and Waldyer’s ring.

Burkitt Lymphoma

Endemic BL presents in children as a tumor of the jaw or facial bones and spreads hematogenously early in the course to extranodal sites, including kidney, testis or ovary, CNS, or meninges. Sporadic BL presents as a bulky abdominal disease involving stomach, caecum, or small intestine with associated ascites. The involvement of kidneys, ovarian or testicular organs, CNS, or meninges is common as well. Immunodeficiency related BL usually presents with lymph node involvement, but can also involve the bone marrow, CNS, or meninges and rarely may present with leukemic phase.[1][2]

Evaluation

After confirming the diagnosis of lymphoma by tissue biopsy, further evaluation involves the determination of tissue where disease activity is the greatest. PET/CT scans by measuring uptake of radiolabeled fluorodeoxyglucose (FDG) are used to measure the biological activity of lymphoma.[11][1][2] Staging is performed before the initiation of therapy for lymphoma.

The clinical staging of both HL and NHL is derived from the Ann Arbor staging system. The presence or absence of B symptoms (persistent fever, weight loss in excess of 10% of body weight over six months, or night sweats) is included in the staging for lymphoma. Blood work includes lactate dehydrogenase along with complete blood counts with differential, comprehensive metabolic panel, and uric acid.

Whole-body PET/CT imaging is preferred over CT of the chest, abdomen, and pelvis. Bone marrow biopsy is often performed for staging but may be omitted for stage III DLBCL and HL because detection of stage IV disease over stage III does not change the treatment.[12] In some cases where the lymphoma is judged to be high risk, standard staging is supplemented by cerebrospinal fluid testing. For aggressive lymphomas like DLBCL, CNS-IPI (CNS Internal Prognostic Index) tool can be used to predict CNS relapse or progression.[13]

Antigen-specificity for B and T-cells is defined by the cell-surface receptor, B-cell receptor, or T-cell receptor, respectively. T-cells are programmed for antigen recognition in the thymus. B-cells mature in the marrow and encounter foreign antigen for the first time within the lymph node germinal center (GC). As such, B-cells may be divided into GC or post-GC. Post-GC, some B-cells develop eventually into plasma cells, which secrete the soluble form of B-cell receptor, that is, immunoglobulin (Ig) or antibody. The method used for determining malignancy or clonality in B-cell lymphomas is by immunohistochemical staining for light chains to show that the sample has lymphocytes expressing all kappa or lambda light chains. It is called light chain restriction and shows the presence of lymphocytic clone.[1][2]

Treatment / Management

Hodgkin Lymphoma[14]

Combined modality therapy, including chemotherapy with antibody-drug conjugates and radiotherapy, is the usual standard of care. Most cases of HL are chemosensitive and overall survival is 86%.

Standard treatment in the United States (US) consists of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). In Germany, the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) is more popular. A third regimen that is used is Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone). All these regimens have similar response rates with BEACOPP carrying slightly better cure rates than the other two but at the cost of greater toxicity, including the development of secondary acute myeloid leukemia/myelodysplastic syndrome and sterility. In 2018, the FDA approved brentuximab vedotin (CD30 targeted antibody-drug conjugate) in combination with AVD chemotherapy for first-line treatment of stage III or IV classical HL.[15]

Systemic chemotherapy is supplemented by local radiation either because of bulky disease or persistent PET/CT positivity after chemotherapy.[1][2][16]

Repeat imaging is done to assess the response to treatment, which consists of a PET/CT scan. PET/CT results are evaluated by Deavullie criteria whereby signal less than or equal to the physiologic signal from the liver is negative (1-3) and signal greater than the liver (4-5) is positive. A new strategy evolving in both the United States and Europe is to start the initial treatment with ABVD, monitor response to chemotherapy with repeat PET/CT after two cycles, then escalate the treatment to BEACOPP only for those patients with an incomplete response.[17] Recent indications are that if PET/CT response to ABVD is good, then bleomycin may be omitted from later cycles without compromising response, and avoiding unnecessary pulmonary toxicity.

Upon completion of therapy, patients are evaluated as part of surveillance at regular intervals to exclude disease recurrence, with history & physical and basic laboratory tests, but without routine repeat imaging. Because many patients with HL are young and cured, they will live for a long time after treatment and must be monitored for the sequelae of the treatment especially the development of secondary cancers within previous radiation fields, such as lung, breast, or thyroid, as well as coronary artery disease.

For patients with resistant or relapsed HL, several salvage regimens are available. Brentuximab vedotin is also approved by the FDA as a second-line agent. Salvage therapy, if successful, is followed by consolidation with high dose chemotherapy and autologous stem cell rescue. In cases where the disease is fully resistant or relapses again after autologous stem cell rescue, experimental agents within the context of a clinical trial are indicated, or, in selected cases, allogeneic stem cell transplantation.[1][2][18]

Diffuse Large B- Cell Lymphoma

Many patients with DLBCL achieve a long term disease-free status with aggressive combination chemotherapy.

The gold standard for DLBCL treatment is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).[1][2][19]

For localized disease, combination chemoradiation therapy can be used, with three cycles of systemic chemotherapy supplemented by involved field radiation therapy (IFRT) with the purpose of limiting overall exposure to the chemotherapy. For patients with poor performance status, milder treatment options include R-mini CHOP (reduced doses of all drugs except rituximab), R-CHOP minus doxorubicin (R–CVP), or single-agent rituximab.[1][2][20][21]

Special consideration should be given to cardiac comorbidities due to the cardiac toxicity of doxorubicin, an anthracycline. Baseline echocardiography or multi gated acquisition (MUGA) scan should be performed before initiation of chemotherapy.

For a subgroup of DLBCL, categorized as double hit or triple hit lymphomas (based on rearrangements of two or three genes: c-MYC, BCL-2, and BCL-6), the prognosis is poor, and they tend to carry morphologic, biologic and cytogenetic properties similar to both DLBCL and much aggressive BL. There is a lack of data regarding the optimal chemotherapy regimen for such lymphomas but are usually treated with more intense chemotherapy regimens, similar to those used in the management of BL.

Reimaging by PET/CT is recommended to assess for treatment response at the end of the treatment. Interval assessment is also done during treatment, after 2 to 4 cycles of chemotherapy, with the purpose of identifying those cases not responding to initial chemotherapy. Patients who complete successful therapy should be followed at regular intervals as part of surveillance. Follow-up consists of history and physical examination, with basic laboratory tests (complete blood counts, metabolic panel, liver function tests, and lactate dehydrogenase). Repeat imaging is not needed routinely, in the absence of specific concerns. Most disease relapse occurs within two years, such that the follow-up interval is spaced out if the disease remains in remission beyond five years.

Clinical trials are currently underway to assess the efficacy and safety of adding immunomodulatory agents (lenalidomide) or Bruton’s tyrosine kinase inhibitors (ibrutinib) to R-CHOP in previously untreated DLBCL.[22][23]

For those cases which do not respond or relapse after first-line chemotherapy, several higher-intensity chemotherapy regimens are used as salvage therapy. Common second-line regimens include R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)  which are more intense than R- CHOP and require inpatient administration of chemotherapy drugs. Survival after successful salvage therapy for resistant/relapsed DLBCL is improved significantly if salvage therapy is followed by high dose chemotherapy with autologous stem cell rescue (HD-SCT) consolidation.

The benefit of HD-SCT lies in the use of high doses of chemotherapy. A harvest of autologous peripheral blood stem cells before administration of high-dose chemotherapy allows for the use of chemotherapy doses, which are so bone marrow toxic that they would otherwise kill the patient, were it not for rescue by stem cell reinfusion. In cases where second-line therapies fail, clinical trials or allogeneic stem cell transplantation may be considered.[24]

The latest advance in the management of relapsed/refractory DLBCL is the utilization of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.[25][26]

Follicular Lymphoma

As an indolent slow-growing lymphoma, the clinical behavior of FL is variable. While some cases of FL remain asymptomatic, even being untreated, or wax and wane on their own, others progress and cause significant symptoms. Asymptomatic FL can be managed by close observation, that is, monitoring for appearance of signs of progression or significant symptoms before any intervention is planned. Treatment is usually not considered to be curative, so it must be chosen judiciously, weighing benefits against toxicities and the fact that after multiple therapies, toxicity will be cumulative.[27]

For localized FL confined to 1 lymph node area, radiotherapy may be chosen as the single modality of therapy. More commonly, several areas within the body are involved in FL, and systemic therapy is needed. Usually, a less aggressive approach such as single-agent rituximab may be chosen as first-line therapy, even for patients with good performance status, thus reserving the option of escalation in therapy for future needs. For higher disease burden FL, systemic cytotoxic chemotherapy is used. In FL, a number of different regimens have been used over the years.

Since overall survival in FL is measured in decades, it is difficult to show the superiority of 1 regimen over another. Recently, rituximab-bendamustine (R- Benda) has emerged as the most popular treatment, being superior to R-CHOP in terms of progression-free survival.[28]

Maintenance rituximab after completion of frontline systemic chemotherapy, usually once every two months for two years, has been shown to prolong progression-free survival but not overall survival.[29]

As an incurable disease, relapse of FL is anticipated at some point in clinical course and can be treated with the other regimens at frontline treatment. Upon recurrence of all indolent lymphomas, the possibility of transformation to aggressive lymphoma should be excluded. In cases where FL relapses early or show aggressive features, HD-SCT or allogeneic transplantation can be considered.

Marginal Zone Lymphoma

In many circumstances, the treatment of marginal zone lymphomas (MZL) is similar to FL, but it differs in certain specific scenarios. For early-stage gastric MALT lymphoma, eradication of H.pylori in patients with favorable cytogenetics results in tumor regression or remission in 50-80% of patients.

Patients with limited disease in whom H.pylori eradication is ineffective, are also cured usually with definitive radiotherapy.

Another important divergence from routine management of FL exists for splenic MZL. For patients with symptomatic splenomegaly and associated cytopenias, surgical splenectomy results in normalization of cell counts and helps to achieve disease stabilization and systemic regression. Single-agent rituximab therapy is also an approved non-surgical treatment alternative. 

Mantle Cell Lymphoma

Treatment of the less aggressive disease is with either R- CHOP or R- Benda, followed by maintenance rituximab. Most patients also need more intensive treatment regimens. One agent cytarabine is included in most regimens due to its activity in mantle cell lymphoma. The front line chemotherapy is followed in the first remission by consolidation with high dose chemotherapy and autologous stem cell transplantation. One such approach is the Nordic protocol (a maxi R–CHOP regimen alternating with rituximab and high-dose cytarabine). Another regimen is alternating hyper CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with methotrexate/cytarabine. Lenalidomide and bortezomib have single-agent activity in relapsed MCL. The Bruton’s tyrosine kinase inhibitor, Ibrutinib, is approved by the FDA for use in relapsed MCL as it has good activity in MCL.[14]

Burkitt Lymphoma

BL should be approached as an oncologic emergency due to a high proliferation rate of the tumor. This high proliferation rate requires immediate treatment with aggressive chemotherapy regimens in which the intensity of delivery is meant to outpace the capacity for the cellular division to prevent the development of tumor resistance. Failure to do so can result in rapid tumor proliferation, end-organ damage, and death. If treatment is initiated in a timely manner, results are favorable. Treatment options for BL include R-hyper CVAD-methotrexate/cytarabine and R-CODOX-M/IVAC (rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/ ifosfamide, etoposide, cytarabine). Recently, DA-R-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) a more intense and easier to tolerate regimen has shown good results. These intense regimens are associated with complete remission rates of approximately 80 to 90% and disease-free survival rates of 50-75%.[30]

With BL, obtaining a good response with the first attempt of treatment is of particular importance.

Peripheral T- Cell Lymphoma (PTCL)

For different types of PTCL, there is no consensus on the treatment. Indolent slow-growing cutaneous T-cell lymphomas, including early-stage MF and cutaneous ALCL, can usually be monitored or treated with skin-directed treatments (topical medications, prednisone, ultraviolet therapy, involved-field radiotherapy) or mild systemic treatments such as retinoids. 18-FDG PET scanning is utilized in selected cases, mainly in the evaluation of cutaneous T-cell lymphoma, to identify the extracutaneous disease as it can change both prognosis and therapeutic approach. For the aggressive PTCLs, chemotherapy with multiple agents is used, such as CHOP, although with the exception of ALK-1 positive ALCL, where it is commonly associated with brief progression-free durations.

For nasal NK/T-cell lymphoma, early incorporation of radiation therapy in a combined modality therapy results in better outcomes.

For CD30 positive lymphomas, the antibody-drug conjugate brentuximab vedotin is effective. Histone deacetylase inhibitors such as romidepsin and belinostat have moderate activity in T- cell lymphoma.[1][2][11][31]

Differential Diagnosis

1. Tuberculosis
2. Sarcoidosis
3. Behçet disease[2][32]

Radiation Oncology

For classic HL, radiation therapy (RT) is often used after chemotherapy for a residual, limited area of lymphadenopathy that is FDG avid on restaging PET/CT. RT by itself can be used to treat some cases of nodular lymphocyte-predominant HL.

In NHL, RT can be used in various scenarios;

• For early-stage (Ann Arbor stage I or II) indolent NHL with a limited amount of disease burden, RT can be used as a single modality treatment. 
• For more advanced and/or aggressive NHL, RT is used after chemotherapy as consolidation.

Consensus recommendations/guidelines from the International Lymphoma Radiation Oncology Group (ILROG):

• Positron emission tomography (PET)/computed tomography (CT) is recommended as the standard modality for staging and response assessment in fluorodeoxyglucose (FDG)-avid lymphomas, in line with the international Lugano guidelines. An accurate definition of sites of involvement before any systemic therapy is important for radiation therapy (RT) planning. Baseline pretreatment PET/CT is recommended as best practice.
• Radiation oncologists should familiarize themselves with the limitations of FDG imaging and recognize conditions that mimic lymphoma, such as brown fat; physiologic uptake in tonsils, nasopharynx, or salivary glands; inflammatory uptake; benign tumors of parotids; sarcoidosis; thymic hyperplasia; and physiologic bone marrow uptake.
• Magnetic resonance imaging (MRI) is indicated in certain anatomic areas: central nervous system, head (orbits, nose/paranasal sinuses, and skull base), and skeletal sites.
• The use of a 5-point score (known as Deauville criteria) is recommended for response assessment, in line with the international Lugano guidelines.
• Deauville score 3 requires cautious interpretation, with consideration given to clinical context, histological type, disease stage, bulk, and estimated prognosis, as well as the results of clinical trials. In some clinical trials using a de-escalation strategy with the omission of RT, Deauville score three was not considered a complete metabolic response.
• When defining RT targets based on PET/CT, the clinician should carefully consider the anatomical information from the CT part of the scan because some small involved nodes with low FDG uptake may be below the PET detection limit.
• Smaller nodes that are not FDG-avid but seen on CT adjacent to (or between) FDG-avid nodes, and judged to be involved, should be included in the target volume. For CT masses with partial FDG uptake, the entire mass should be included in the target volume.
• Residual FDG-avid areas can be treated to higher doses using an integrated boost technique.
• Thin-slice CT should be performed in the chosen treatment position, using immobilization devices if required, and should include relevant organs at risk as a whole. Intravenous contrast is recommended to help identify blood vessels and enhance soft-tissue definition.
• Breathing-control techniques (e.g., deep inspiration breath-hold) are recommended as best practice for mediastinal treatment to help reduce organ-at-risk doses.
• PET/CT is highly recommended as best practice for planning modern radiation volumes, according to the involved node or involved site RT concepts.
• If RT is the sole modality of treatment, a dedicated planning PET/CT can be performed in the treatment position, with the use of immobilization devices if required.
• If chemotherapy is given before RT, it is recommended that the prechemotherapy PET/CT be performed in a position similar to RT position to enable accurate coregistration with the planning CT and outlining of involved node RT volumes.
• If the prechemotherapy PET/CT cannot be obtained in the treatment position and accurate coregistration is not possible, the concept of involved site RT as described in other International Lymphoma Radiation Oncology Group guidelines should be used to account for the lack of optimal prechemotherapy imaging.
• In sites where MRI is useful, both PET/CT and MRI scans should be coregistered with planning CT scans to guide target volume definition.
• Image-guided radiotherapy, particularly using cone-beam CT, is recommended with modern RT techniques, which use small target volumes and steep dose gradients, to ensure accuracy of treatment delivery.
• The frequency of imaging has not been studied carefully in the context of lymphoma, and individual departments should decide on the frequency of imaging based on local setup accuracy data, margins used to create the planning target volume, specific treatment site, and use of immobilization devices.[33]

Staging

The clinical staging of both HL and NHL derive from the Ann Arbor (AA) staging system, which was subsequently modified at the Cotswolds meeting in 1989. The modification kept the previous four-stage system, with the addition of the modifier ‘‘X’’ for bulk, defined as greater than 10 cm in long-axis or for a mediastinal mass as measuring greater than one-third of the internal transverse thoracic diameter of a standard PA chest X-ray at the level of the fifth or sixth thoracic vertebral body. It is based on the extent of involvement of lymph node groups. The ‘‘E’’ modifier presents a direct extension of the tumor to an extranodal site, or for stage IE disease, isolated involvement of a single extranodal site without evidence of lymph node disease (e.g., primary lymphoma of bone or thyroid). The ‘‘B’’ modifier refers to the presence of one or more of a set of symptoms that are associated with more aggressive disease and worse prognosis, and these include unexplained recurring or persistent fever, drenching night sweats, or unexplained weight loss of 10% of body weight (B symptoms).

Cotswolds modification of the Ann Arbor staging system:

Stage I

Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring) or involvement of a single extra lymphatic site (IE)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized contiguous involvement of only one extranodal organ or side and its regional lymph-nodes with or without other lymph node regions on the same side of the diaphragm (IIE)Note: The number of anatomic regions involved may be indicated by a subscript (e.g., II3)

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ side (IIIE) or both (IIISE)

Stage IV

Disseminated (multifocal) involvement of one or more extranodal organs or tissues, with or without associated lymph-node involvement or isolated extra lymphatic organ involvement with distant (non-regional) nodal involvement

Designations Applicable to Any Disease Stage

A: No symptomsB: Fever (temperature > 38 C), drenching night sweats, unexplained loss of more than 10% of body weight during the previous six months.X: Bulky diseaseE: Involvement of an extranodal site that is contiguous or proximal to the known nodal site[1][2]

Prognosis

Due to the limited predictive power of Ann Arbor staging for both HL and NHL, clinical prognostic models are developed to help clinicians in conveying prognostic information to patients. Several models have been developed, which include HL international prognostic score, international prognostic index (IPI) for DLBCL, and FL international prognostic index (FLIPI) for follicular lymphoma. Low IPI score predicts a better outcome and high IPI a worse outcome.[2][34][35]

Complications

HL Complications

Paraneoplastic syndromes: Limbic encephalitis (anti-metabotropic glutamate receptor 5 (mGluR5) antibodies), primary CNS angiitis, cerebellar degeneration (anti-Tr antibodies), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes)[1][36][37]

NHL Complications

Transformation of indolent lymphomas such as follicular lymphoma, marginal zone lymphoma into more aggressive NHL such as diffuse large B-cell lymphoma

Chemotherapy Complications

Pancytopenias, sterility, cardiomyopathy(doxorubicin), pneumonitis (bleomycin), neuropathy (vincristine, brentuximab vedotin), and second primary malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia).

Radiotherapy Complications

Accelerated atherosclerosis, pericardial fibrosis, second primary cancers (lung, thyroid, breast, soft tissue sarcomas), and hypothyroidism[1][36]

Deterrence and Patient Education

Lymphomas are one of the common cancers of our immune system. It makes up to almost 5% of all cancers. It can affect both young and older adults. The common symptoms of this disease are persistent fevers, drenching night sweats, unintentional weight loss, and generalized or localized swelling of the lymph nodes. If any of these symptoms are observed, the primary care provider seeks a hematology consultation or opinion as soon as possible for timely diagnosis and treatment, since timely identification and treatment of lymphomas result in better survival rates with the least number of complications.

Enhancing Healthcare Team Outcomes

While a hematologist is almost always involved in the care of patients with lymphoma, it is important to consult with an interprofessional team of specialists that include a radiologist, radiation oncologist, pathologist, and a surgical oncologist. The nurses are also vital members of the interprofessional group as they monitor the patient vital signs and assist with patient and family education. Having oncology trained social workers and psychologists as part of an interdisciplinary team also plays a significant role in addressing psycho-social issues pertaining to the diagnosis and management of lymphomas, especially in young patients.

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References

1.

Mugnaini EN, Ghosh N. Lymphoma. Prim Care. 2016 Dec;43(4):661-675. [PubMed: 27866584]

2.

Matasar MJ, Zelenetz AD. Overview of lymphoma diagnosis and management. Radiol Clin North Am. 2008 Mar;46(2):175-98, vii. [PubMed: 18619375]

3.

Hjalgrim H, Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, Zhang JS, Madsen M, Rosdahl N, Konradsen HB, Storm HH, Melbye M. Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med. 2003 Oct 02;349(14):1324-32. [PubMed: 14523140]

4.

Said W, Chien K, Takeuchi S, Tasaka T, Asou H, Cho SK, de Vos S, Cesarman E, Knowles DM, Koeffler HP. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells. Blood. 1996 Jun 15;87(12):4937-43. [PubMed: 8652805]

5.

Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006 Dec 01;108(12):3786-91. [PMC free article: PMC1895473] [PubMed: 16917006]

6.

National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer. 1982 May 15;49(10):2112-35. [PubMed: 6896167]

7.

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90. [PMC free article: PMC4874220] [PubMed: 26980727]

8.

Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998 Aug;16(8):2780-95. [PubMed: 9704731]

9.

Mauch PM, Kalish LA, Kadin M, Coleman CN, Osteen R, Hellman S. Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer. 1993 Mar 15;71(6):2062-71. [PubMed: 8443755]

10.

Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, Vinnicombe S, Waters R, Rohatiner AZ, Lister TA. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007 Jun 10;25(17):2426-33. [PubMed: 17485708]

11.

Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, Jaffe ES, Ling A, Turner M, Peer CJ, Figg WD, Steinberg SM, Smith S, Joske D, Lewis I, Hutchins L, Craig M, Fojo AT, Wright JJ, Bates SE. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011 Jun 02;117(22):5827-34. [PMC free article: PMC3112033] [PubMed: 21355097]

12.

Elstrom R, Guan L, Baker G, Nakhoda K, Vergilio JA, Zhuang H, Pitsilos S, Bagg A, Downs L, Mehrotra A, Kim S, Alavi A, Schuster SJ. Utility of FDG-PET scanning in lymphoma by WHO classification. Blood. 2003 May 15;101(10):3875-6. [PubMed: 12531812]

13.

Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B, Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler M, Savage KJ. CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP. J Clin Oncol. 2016 Sep 10;34(26):3150-6. [PubMed: 27382100]

14.

Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W., Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 06;381(9873):1203-10. [PubMed: 23433739]

15.

Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J., ECHELON-1 Study Group. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2018 Jan 25;378(4):331-344. [PMC free article: PMC5819601] [PubMed: 29224502]

16.

Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. [PubMed: 25901426]

17.

Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M., German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. [PubMed: 12802024]

18.

Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993 Apr 24;341(8852):1051-4. [PubMed: 8096958]

19.

Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. [PMC free article: PMC2951853] [PubMed: 20548096]

20.

Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP., Southwest Oncology Group. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10;26(14):2258-63. [PubMed: 18413640]

21.

Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. [PubMed: 11807147]

22.

Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S, Hivert B, Westin J, Vermeulen J, Bandyopadhyay N, de Vries R, Balasubramanian S, Hellemans P, Smit JW, Fourneau N, Oki Y. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014 Aug;15(9):1019-26. [PubMed: 25042202]

23.

Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. [PMC free article: PMC8372245] [PubMed: 26193343]

24.

Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 07;333(23):1540-5. [PubMed: 7477169]

25.

Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. [PMC free article: PMC5882485] [PubMed: 29226797]

26.

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT., JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 03;380(1):45-56. [PubMed: 30501490]

27.

Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984 Dec 06;311(23):1471-5. [PubMed: 6548796]

28.

Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study. J Clin Oncol. 2019 Apr 20;37(12):984-991. [PMC free article: PMC6494265] [PubMed: 30811293]

29.

Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 01;37(31):2815-2824. [PMC free article: PMC6823890] [PubMed: 31339826]

30.

Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 01;106(7):1569-80. [PubMed: 16502413]

31.

O'Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, Bhat G, Choi MR, Walewski J, Savage K, Foss F, Allen LF, Shustov A. Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015 Aug 10;33(23):2492-9. [PMC free article: PMC5087312] [PubMed: 26101246]

32.

Göknar N, Çakır E, Çakır FB, Kasapcopur O, Yegen G, Gedik AH, Oktem F. A Difficult Case of Hodgkin Lymphoma with Differential Diagnosis of Tuberculosis and Sarcoidosis. Hematol Rep. 2015 Jun 03;7(2):5644. [PMC free article: PMC4508547] [PubMed: 26330996]

33.

Mikhaeel NG, Milgrom SA, Terezakis S, Berthelsen AK, Hodgson D, Eich HT, Dieckmann K, Qi SN, Yahalom J, Specht L. The Optimal Use of Imaging in Radiation Therapy for Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys. 2019 Jul 01;104(3):501-512. [PubMed: 30763664]

34.

Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, Loeffler M. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 May 10;28(14):2373-80. [PubMed: 20385988]

35.

International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993 Sep 30;329(14):987-94. [PubMed: 8141877]

36.

Mauermann ML. Neurologic Complications of Lymphoma, Leukemia, and Paraproteinemias. Continuum (Minneap Minn). 2017 Jun;23(3, Neurology of Systemic Disease):669-690. [PubMed: 28570324]

37.

Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology. 1992 Oct;42(10):1938-43. [PubMed: 1407576]

Disclosure: Ayesha Jamil declares no relevant financial relationships with ineligible companies.

Disclosure: Shiva Kumar Mukkamalla declares no relevant financial relationships with ineligible companies.