Hodgkin Lymphoma

Hodgkin lymphoma (formerly, Hodgkin disease) is a potentially curable lymphoma with distinct histology, biologic behavior, and clinical characteristics. The disease is defined in terms of its microscopic appearance (histology) (see the image below) and the expression of cell surface markers (immunophenotype). (See Pathophysiology.)

Micrograph of Hodgkin lymphoma in a fine-needle aspiration lymph node specimen (field stain). Eosinophils, Reed-Sternberg cells, plasma cells, and histocytes can be seen.

To diagnose Hodgkin lymphoma a histologic evaluation is always required, and an excisional lymph node biopsy is recommended for this purpose (see Workup). Various imaging studies are used to stage the patient.

Treatment for Hodgkin lymphoma is with multiagent chemotherapy, with or without radiation therapy. Treatment seeks to balance the risk of treatment failure with the risk of treatment side effects (see Treatment).

See also the Medscape article Pediatric Hodgkin Disease.

The World Health Organization (WHO) classifies Hodgkin lymphoma into five types.[1] Nodular sclerosing, mixed cellularity, lymphocyte depleted, and lymphocyte rich are the four types referred to as classical Hodgkin lymphoma. The fifth type, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), is a distinct entity with unique clinical features and a different treatment paradigm.

In classical Hodgkin lymphoma, the neoplastic cell is the Reed-Sternberg cell (see the image below).[8, 9] Reed-Sternberg cells comprise only 1-2% of the total tumor cell mass. The remainder is composed of a variety of reactive, mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes.

A Reed-Sternberg cell in Hodgkin lymphoma. Reed-Sternberg cells are large, abnormal lymphocytes that may contain more than one nucleus. Image courtesy of National Cancer Institute.

Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers but no longer able to produce antibodies. Hodgkin lymphoma cases in which the Reed-Sternberg cell is of T-cell origin are rare, accounting for 1-2% of classical Hodgkin lymphoma.

The Reed-Sternberg cells consistently express the CD30 (Ki-1) and CD15 (Leu-M1) antigens. CD30 is a marker of lymphocyte activation that is expressed by reactive and malignant lymphoid cells and was originally identified as a cell surface antigen on Reed-Sternberg cells. CD15 is a marker of late granulocytes, monocytes, and activated T-cells that is not normally expressed by cells of B lineage.

Classical Hodgkin lymphoma

Classical Hodgkin lymphoma is classified into the following 4 types:

• Nodular sclerosing Hodgkin lymphoma (NSHL)
• Mixed-cellularity Hodgkin lymphoma (MCHL)
• Lymphocyte-depleted Hodgkin lymphoma (LDHL)
• Lymphocyte-rich classical Hodgkin lymphoma (LRHL)

Nodular sclerosing Hodgkin lymphoma

In NSHL, which constitutes 60-80% of all cases of Hodgkin lymphoma, the morphology shows a nodular pattern. Broad bands of fibrosis divide the node into nodules. The capsule is thickened. The characteristic cell is the lacunar-type Reed-Sternberg cell, which has a monolobated or multilobated nucleus, a small nucleolus, and abundant pale cytoplasm.

NSHL is frequently observed in adolescents and young adults. It usually involves the mediastinum (see the image below) and other supradiaphragmatic sites.

Nodular sclerosing Hodgkin lymphoma of the mediastinum. The diagnosis is strongly suggested by the presence of distinct nodules on the cut surface of this lymph node.

Mixed-cellularity Hodgkin lymphoma

In MCHL, which constitutes 15-30% of cases, the infiltrate is usually diffuse. Reed-Sternberg cells are of the classical type (large, with bilobate, double or multiple nuclei, and a large, eosinophilic nucleolus). MCHL commonly affects the abdominal lymph nodes and spleen. Patients with this histology typically have advanced-stage disease with systemic symptoms. MCHL is the histologic type most commonly observed in patients with human immunodeficiency virus (HIV) infection.

Lymphocyte-depleted Hodgkin lymphoma

LDHL constitutes less than 1% of cases. The infiltrate in LDHL is diffuse and often appears hypocellular. Large numbers of Reed-Sternberg cells and bizarre sarcomatous variants are present.

LDHL is associated with older age and HIV-positive status. Patients usually present with advanced-stage disease. Epstein-Barr virus (EBV) proteins are expressed in many of these tumors. Many cases of LDHL diagnosed in the past were actually non-Hodgkin lymphomas, often of the anaplastic large-cell type.

Lymphocyte-rich classical Hodgkin lymphoma

LRHL constitutes 5% of cases. In LRHL, Reed-Sternberg cells of the classical or lacunar type are observed, with a background infiltrate of lymphocytes. It requires immunohistochemical diagnosis. Some cases may have a nodular pattern. Clinically, the presentation and survival patterns are similar to those for MCHL.

Nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) constitutes 5% of cases. It is a distinct clinical entity and is not considered part of the classical Hodgkin lymphoma type. Typical Reed-Sternberg cells are either infrequent or absent in NLPHL. Instead, lymphocytic and histiocytic (L&H) cells, or "popcorn cells" (their nuclei resemble an exploded kernel of corn), are seen within a background of inflammatory cells, which are predominantly benign lymphocytes (see the image below). Unlike Reed-Sternberg cells, L&H cells are positive for B-cell antigens, such as CD20, and are negative for CD15 and CD30.

Very high magnification micrograph of nodular lymphoctye predominant Hodgkin lymphoma (NLPHL), with a popcorn-shaped Reed-Sternberg cell (hematoxylin and eosin).

A diagnosis of NLPHL needs to be supported by immunohistochemical studies, because it can appear similar to LRHL or even some non-Hodgkin lymphomas.

The etiology of Hodgkin lymphoma is unknown. Infectious agents, particularly Epstein-Barr virus (EBV), may be involved in the pathogenesis.[10, 11] Depending on the study, data show that up to 30% of cases of classical Hodgkin lymphoma may be positive for EBV proteins.[12] In addition, a case control study supports an increased risk of classical Hodgkin lymphoma after EBV infection, with a risk of approximately 1 in 1000 cases.[13]

The incidence of EBV positivity varies with subtype. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) rarely expresses EBV proteins,[14] whereas in classical Hodgkin lymphoma, EBV positivity is most common in the mixed-cellularity variant.[15] However, the exact mechanism by which EBV can lead to Hodgkin lymphoma is not known.

HIV-positive patients also have a higher incidence of Hodgkin lymphoma compared with HIV-negative patients. However, Hodgkin lymphoma is not considered an AIDS-defining neoplasm.

Genetic predisposition plays a role in the pathogenesis of Hodgkin lymphoma. Approximately 1% of patients with Hodgkin lymphoma have a family history of the disease, and siblings of an affected individual have a 3- to 7-fold increased risk of developing the disease.[16] Most evidence for a genetic etiology has been established in the distinct subtype of nonsclerosing Hodgkin lymphoma (NSHL). NSHL has been shown to be one of the most heritable types of neoplasm, with a 100-fold increased risk in identical twins.[17, 18]

There is evidence that NSHL may result from an atypical immune response to a virus or other trigger, in an individual with a genetic predisposition to such a response.[19] For decades, specific human leukocyte antigen (HLA) class II genotypes, including HLA-DRB1 and HLA-DQB1, have been known to be associated with NSHL, and this has been confirmed by genome-wide association studies.[20] Several single-nucleotide polymorphisms in the 6p21.32 region, which is rich in genes associated with immune function, have also been associated with NSHL risk.[21]

United States statistics

Information regarding the incidence and mortality of Hodgkin lymphoma in the United States can be found at the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) database Website. The NCI reports that age-adjusted rates for new Hodgkin lymphoma cases have been falling on average 2.3% each year over the last 10 years. As of 2014-2018, the age-adjusted incidence is 2.6 cases per 100,000 population. Death rates have decreased slowly but steadily in recent decades, but were stable at 0.3 per 100,000 population per year over 2014-2018.[22]

Data are also collected by the American Cancer Society (ACS). The ACS estimates that 8830 new cases of Hodgkin lymphoma will be diagnosed in 2021, and 960 deaths will occur.[23]

International statistics

In Europe and other developed countries, the incidence parallels US data.[24, 25] United Kingdom data from 2016-2018 show a crude incidence rate of 3.2 cases per 100,000 population (3.8 cases per 100,000 males and 2.7 cases per 100,000 females). Since the early 1990s, incidence rates of Hodgkin lymphoma in the UK have risen 37%.[26]

Race-, sex-, and age-related differences in incidence

Hodgkin lymphoma incidence rates in the United States vary by race and sex. In general, incidence is higher in males than in females. The sex predilection is most pronounced in children, with 85% of cases affecting boys.[22] The lowest incidence rates are in American Indians/Alaska Natives and Asians/Pacific Islanders.[22]

The incidence of Hodgkin lymphoma varies with age, with a clear bimodal distribution that is consistent across most countries and studies. The initial peak is in young adults (15-34 years); Hodgkin lymphoma is the most commonly diagnosed cancer in teens ages 15 to 19. The second peak is in older adults (> 55 years).[27] There is also a difference in subtype based on age, with young adults having nodular sclerosing Hodgkin lymphoma (NSHL) and older adults tending to have mixed cellularity Hodgkin lymphoma (MCHL). 

Patient prognosis is largely based on the stage of the disease and various prognostic factors, which may be defined differently across various major cooperative groups (eg, German Hodgkin's Study Group [GHSG] vs European Organisation for Research and Treatment of Cancer [EORTC] and others).[28] (See also Staging.)

The SEER data report an 86.2% overall 5-year survival rate from 2006-2012.[22] Table 1 summarizes the stage distribution and 5-year relative survival at diagnosis for the same period for all races and both sexes.[22] In addition to the stage of the disease, many factors contribute to the likelihood of survival from Hodgkin lymphoma (see Staging). Factors that influence prognosis include patient age, presence or absence of B symptoms, stage of disease, and elevation of erythrocyte sedimentation rate.[29]

Table 1. Stage Distribution and 5-Year Relative Survival by Stage at Diagnosis for All Races and Both Sexes: 2011-2015 (Open Table in a new window)

The most commonly used prognostic system is the International Prognostic System (IPS), which uses the following variables to The most commonly used prognostic system is the International Prognostic System (IPS), which uses the following variables to determine prognosis[30] :

• Serum albumin less than 4 g/dL

• Hemoglobin less than 10.5 g/dL

• Male sex

• Age of 45 years or older

• Stage IV disease (Ann Arbor classification)

• White blood cell (WBC) count greater than 15,000/mm3

• Absolute lymphocyte count less than 600/mm3, less than 8% of the total WBC count, or both

Each of the above variables is assigned 1 point. The total number of points for prognostic factors is used to determine risk. When applied to a group of 5141 patients with Hodgkin lymphoma the IPS produced the following groups of 5-year survival rates[30] :

• 0 prognostic factors: 84%

• 1 prognostic factor: 77%

• 2 prognostic factors: 67%

• 3 prognostic factors: 60%

• 4 prognostic factors: 51%

• 5 or more prognostic factors: 42%

These results have been validated in other populations as well, including in patients undergoing stem cell transplant.[31, 32] However this scoring system is most applicable to patients with advanced-stage disease (stages III and IV).

Before beginning treatment, patients with Hodgkin lymphoma should be counseled about the potential complications of therapy, including the risk of cardiac disease, lung toxicity, and secondary cancers. Patients should also be apprised of the potential loss of fertility that may arise from treatments such as MOPP (mechlorethamine, vincristine, procarbazine, prednisone) chemotherapy, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy, and pelvic irradiation, so that they may explore fertility-preserving options such as sperm banking, oral contraceptive use, or oophoropexy. Although less likely, infertility can also occur with ABVD therapy (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine).

Female patients who have received chest radiation therapy should be encouraged to perform regular breast self-examinations. All patients should be counseled on health habits that may help reduce the risk of cancer and cardiovascular disease, including avoidance of smoking, control of lipids, and the use of sunscreen.

Although splenectomy is uncommon with modern therapy, any patient who has undergone this procedure needs to be counseled about vaccination needs and their long-term risk of infection.

Patients should understand the risk of psychosocial problems that may affect survivors of Hodgkin lymphoma. Consultations with social workers, psychologists, and psychiatrists may be helpful.

For patient education information, see Understanding Hodgkin Lymphoma -- the Basics.

Features of Hodgkin lymphoma include the following:

• Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients)

• Constitutional symptoms (unexplained weight loss [>10% of total body weight] within the past 6 months, unexplained fever >38º C, or drenching night sweats) are present in 40% of patients; collectively, these are known as "B symptoms"

• Intermittent fever is observed in approximately 35% of cases; infrequently, the classic Pel-Ebstein fever is observed (high fever for 1-2 wk, followed by an afebrile period of 1-2 wk)

• Chest pain, cough, shortness of breath, or a combination of those may be present due to a large mediastinal mass or lung involvement; rarely, hemoptysis occurs

• Pruritus may be present

• Pain at sites of nodal disease, precipitated by drinking alcohol, occurs in fewer than 10% of patients but is specific for Hodgkin lymphoma

• Back or bone pain may rarely occur

• A family history is also helpful; in particular, nodular sclerosis Hodgkin lymphoma (NSHL) has a strong genetic component and has often previously been diagnosed in the family

Physical examination findings in Hodgkin lymphoma include the following:

• Palpable, painless lymphadenopathy can be seen in the cervical area (neck, 60-80%), axilla (armpit, 6-20%), and, less commonly, in the inguinal area (groin, 6-20%)

• Involvement of the Waldeyer ring (back of the throat, including the tonsils) or occipital (lower rear of the head) or epitrochlear (inside the upper arm near the elbow) areas is infrequently observed

• Splenomegaly and/or hepatomegaly may be present

• Superior vena cava syndrome may develop in patients with massive mediastinal lymphadenopathy

• Central nervous system (CNS) symptoms or signs may be due to paraneoplastic syndromes, including cerebellar degeneration, neuropathy, Guillain-Barre syndrome, or multifocal leukoencephalopathy

The patient’s history and physical examination are important for diagnosis, but the foundation for determining the ideal Hodgkin lymphoma treatment is accurate staging. Imaging, sampling (biopsy), and an assessment of prognostic factors are required for staging. Hematologic (complete blood cell [CBC] count) and blood chemistry studies may reveal nonspecific findings in patients with Hodgkin lymphoma that may be associated with disease extent. Several of these findings have been used as prognostic factors.

Formerly, staging laparotomy and laparoscopy were the standard of care in Hodgkin lymphoma, but with modern imaging and treatment paradigms these procedures are no longer needed.

Complete blood cell (CBC) count studies for anemia (low red blood cell [RBC] count), lymphopenia (low white blood cell [WBC] count), excess neutrophils (neutrophilia), or eosinophils (eosinophilia) should be performed. Some of these factors have prognostic implications, as noted under Prognosis. Hodgkin lymphoma–associated anemia is most commonly the anemia of chronic disease. However, it may result from bone marrow involvement by tumor or, rarely, from the presence of an autoantibody (as indicated by a positive warm-agglutinin on a Coombs test). Platelet counts may be increased or decreased.

The erythrocyte sedimentation rate (ESR)—a general marker of inflammation—may be elevated in Hodgkin lymphoma. An elevated ESR has been associated with worse prognosis. However, the ESR is a nonspecific test that should not be used for Hodgkin lymphoma screening.

Lactate dehydrogenase (LDH) may be increased. LDH levels may correlate with the bulk of disease.

Serum creatinine may be elevated in the rare cases of nephrotic syndrome associated with Hodgkin lymphoma. Levels of alkaline phosphatase (ALP) may be increased due to the presence of liver or bone involvement. Other uncommon laboratory findings include hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies).

A test for human immunodeficiency virus (HIV) is important in the workup of Hodgkin lymphoma, because antiretroviral therapies can improve disease outcomes in HIV-positive patients.[3] Screening for hepatitis B and C should also be considered.

Serum levels of cytokines (interleukin [IL]-6, IL-10) and soluble CD25 (IL-2 receptor) correlate with tumor burden, systemic symptoms, and prognosis, but these studies are generally obtained only in special situations or in the context of a clinical trial.

Imaging studies are important for accurate staging of Hodgkin lymphoma. These studies include plain x-rays, computed tomography (CT) scans, and positron emission tomography (PET) scans. In addition, imaging studies can help to define disease bulk, which has prognostic implications. The definition of bulky disease varies, but in general is defined as any nodal mass greater than 10 cm (>5 cm in some studies) and a mediastinal mass greater than one third the thoracic diameter as measured at T5/6.

Historically, posteroanterior (PA) and lateral chest x-rays have been used to measure mediastinal mass in relationship to thoracic diameter. This approach remains the gold standard, but with the availability of cross-sectional imaging in CT scanning, chest radiography has been largely replaced by CT. See the image below.

A computed tomography (CT) scan showing bulk disease in a patient with Hodgkin lymphoma.

On CT scans of the chest, abdomen, and pelvis, possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly (with or without focal parenchymal abnormalities), lung nodules or infiltrates, and pleural effusions (see the image below).

This computed tomography scan is from a 46-year patient with Hodgkin lymphoma at the level of the neck. Enlarged lymph nodes are visible on the left side of the neck (red-shaded region).

PET scanning is now considered essential to the initial staging of Hodgkin lymphoma, because of its ability to distinguish between viable tumor and necrosis or fibrosis in residual masses that are often present after treatment in patients who have no other clinical or biochemical evidence of disease.[35] This imaging study is often performed in conjunction with CT scanning (see the images below).[36] A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding in classical Hodgkin lymphoma, although it is uncommon in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

The American College of Radiology does not recommend changing chemotherapy or omitting radiation therapy based on PET scan response for early-stage patients.[28, 29]

A positron emission tomography (PET) scan obtained with fluorodeoxyglucose (FDG) that shows increased FDG uptake in a mediastinal lymph node.

This image depicts a computed tomography (CT) scan, positron-emission tomography (PET) scan, and maximum intensity projection (MIP) PET scan from a patient with histologically proven Hodgkin lymphoma.

A histologic diagnosis of Hodgkin lymphoma is always required. An excisional lymph node biopsy is recommended because the lymph node architecture is important for histologic classification (see the image below). When a patient presents with neck lymphadenopathy and risk factors for a head and neck cancer, a fine-needle aspiration is usually advised as the initial diagnostic step, followed by excisional biopsy if squamous cell histology is excluded.

Mixed cellularity Hodgkin lymphoma showing both mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells (hematoxylin and eosin, original magnification x200).

Bone marrow biopsies are indicated in some cases. Bone marrow involvement is more common in elderly patients and those with advanced-stage disease, systemic symptoms, or a high-risk histology. However, given the low incidence of bone marrow involvement, some experts and expert groups feel that bone marrow biopsy can be omitted, particularly in early-stage disease. There is a bone marrow risk calculator available to help determine need for bone marrow biopsy.[37]

Sampling of a pleural effusion by thoracentesis and examination of the cells obtained may be useful in the evaluation of Hodgkin lymphoma. The pleural fluid may be an exudate or transudate, or it may be chylous.

Central nervous system (CNS) evaluation by lumbar puncture and magnetic resonance imaging (MRI) should be performed if symptoms or signs of CNS involvement are present. CNS involvement with Hodgkin lymphoma is exceedingly rare, but it has been reported.

Clinical staging involves assessment of disease extent by clinical examination, history, and imaging techniques. The Ann Arbor classification (1971) is used most often for Hodgkin lymphoma. It classifies cases into the following four stages, principally on the basis of lymph node involvement:

• Stage I - A single lymph node area or single extranodal site
• Stage II - Two or more lymph node areas on the same side of the diaphragm
• Stage III - Lymph node areas on both sides of the diaphragm
• Stage IV - Disseminated or multiple involvement of the extranodal organs

Involvement of the liver or the bone marrow is considered stage IV disease. For staging classifications, the spleen is considered to be a lymph node area. Involvement of the spleen is denoted with the S suffix (ie, IIBS).

A or B designations denote the absence or presence of B symptoms. A "B" designation includes the presence of one or more of the following:

• Fever (temperature >38°C)
• Drenching night sweats
• Unexplained loss of more than 10% of body weight within the preceding 6 months

An "A" designation is the absence of the above.

An "X" designation is sometimes used to indicate the presence of bulky disease (ie, bulk >10 cm).

Spread of Hodgkin lymphoma takes place via the lymphatics, hematogenous routes, and direct extension. Contiguous involvement of extranodal sites (eg, involvement of the lung parenchyma due to direct extension of large mediastinal lymphadenopathy) is not considered stage IV disease. Rather, it is designated with the E suffix (ie, IIBE).

Unfavorable factors in Hodgkin lymphoma are discussed in Overview/Prognosis.

See also Hodgkin Lymphoma Staging.

Treatment of Hodgkin lymphoma is tailored to disease type, disease stage, and an assessment of the risk of resistant disease. Hodgkin lymphoma is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. General treatment modalities include radiation therapy, induction chemotherapy, salvage chemotherapy, and hematopoietic stem cell transplantation.

The current treatment of Hodgkin lymphoma seeks to maximize the risk-benefit ratio of treatment. Thus, treatment focuses on tailoring therapy to each patient according to age, risk of short-term and long-term toxicity, and risk of relapse.

Classical Hodgkin lymphoma stages

In general, the management of Hodgkin lymphoma depends on the subtype. Most clinicians divide classical Hodgkin lymphoma into the following three general groups:

• Early-stage favorable
• Early-stage unfavorable
• Advanced-stage disease

However, favorable disease is defined differently by different groups. The two most commonly used definitions are that of the European Organization for the Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group (GHSG).

The EORTC definition uses the following patient criteria[38] :

• Limited-stage disease
• Age younger than 50 years
• No bulky mediastinal adenopathy
• Erythrocyte sedimentation rate (ESR) less than 50 mm/h
• No B symptoms (or an ESR < 30 mm/h with B symptoms)
• Three or fewer sites of involvement

The GHSG definition uses the following criteria[39] :

• No more than two sites of disease
• No extranodal extension
• No bulky mediastinal disease
• ESR < 50 mm/h (or < 30 mm/h if B symptoms present)

With either definition, any patient with early-stage disease who does not meet the above criteria is considered to have early-stage unfavorable disease. In general, patients with early-stage favorable disease are treated with less intense chemotherapy and radiation regimens than those that are used for early-stage unfavorable disease.

Advanced-stage disease is generally treated with chemotherapy alone, with radiation therapy reserved for selected patients.

Treatment toxicity

Short-term toxicity varies based on the regimen and modalities used (chemotherapy, radiation, combination of both, and stem cell transplantation) and include:

• Hematologic toxicity: Anemia (need for transfusion), thrombocytopenia, increased risk of infection (febrile neutropenia)
• Pulmonary toxicity, particularly if bleomycin or thoracic radiation are used
• Cardiac toxicity from anthracycline therapy
• Treatment-related toxicity that can lead to death

Long-term toxicities vary based on patient age and treatment regimen. In general, the older the patient, the less the concern for long-term toxicity. Long-term toxicities and monitoring are described in detail later, but include the following:

• Hematologic: Development of treatment-related myelodyplasia or acute leukemia
• Pulmonary: Increased risk of lung cancer or fibrotic lung disease, particularly in smokers
• Cardiac: Congestive heart failure from treatment, increased risk of coronary artery disease
• Infectious: Long-term increased risk of infection from splenectomy (rarely done in current practice), long-term immunodeficiency from treatment effects
• Cancer: Increased risk of secondary cancers, particularly breast cancer in young women treated with mediastinal radiation; increased risk of sarcomas in radiation fields; increased risk of lung cancer in smokers
• Neurologic: Chemotherapy-induced neuropathy, muscular atrophy
• Psychiatric: Depression and anxiety related to diagnosis and complications from treatment

Treatment goals

Given the curable nature of this disease and patients’ long-term survival, goals for treatment are the following:

• Maximize cure for all stages
• Minimize both short-term and long-term complications, assuming this does not have an impact on cure
• Weigh the risks of toxicity (eg, elderly patients might not tolerate acute toxicities as well as younger patients, and given their prognosis from other conditions, aggressive treatment in seniors might not be indicated)

The overarching theme is assessing patients individually for their extent of disease, disease-related prognosis, associated conditions, risk of relapse, and long-term survival. By taking these factors into account, treatment can be tailored to each patient.

There are several examples of changes to treatment over the last several decades that illustrate these goals, such as the following:

• Minimizing the number of cycles of chemotherapy used
• Changing radiation fields to include only involved-field radiation
• Enhancing surveillance for toxicity
• Realizing that even relapsed disease can often be salvaged with stem cell transplantation, allowing for less intense treatments upfront

The above considerations apply mainly to classical Hodgkin lymphoma, but many of these principles can be applied to nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) as well. In general, NLPHL is clinically distinct from classical Hodgkin lymphoma in that NLPHL generally presents as early-stage disease that can be treated with local measures (surgery, radiation) or followed expectantly. However, some cases of NLPHL can transform to aggressive non-Hodgkin lymphomas that are treated using standard protocols. It is important to note the differences in immunophenotype; for example, NLPHL being CD20-positive allows for successful treatment with rituximab either alone or in combinations.

See also Hodgkin Lymphoma Treatment Protocols.

Clinical trials and consultations

Because of the limited number of patients with Hodgkin lymphoma and the importance of the clinical questions that remain about optimal disease management, patient involvement in clinical trials is strongly encouraged. It is also recommended that clinicians seek the following consultations in cases of Hodgkin lymphoma:

• Hematologist/oncologist
• Radiation oncologist
• Social worker
• Tertiary care center for consideration of clinical trial enrollment

Hodgkin lymphoma has gone from an incurable disease to one with a cure rate of almost 75%.[40] In general, the goal of therapy is to obtain complete remission (CR). Even in patients who fail to achieve CR, however, there are effective salvage regimens available that can result in long-term survival or cure.

Treatment response criteria are defined as follows:

• CR: Disappearance of all evidence of disease as assessed by computed tomography (CT) scanning, positron-emission tomography (PET) scanning, history and physical examination, and bone marrow biopsy (if appropriate)

• Partial response: Achievement of at least a 50% regression in sites of measurable disease and no new sites of disease

• Stable disease: Failure to achieve either of the above criteria, but not meeting criteria for progressive disease

• Progressive disease: Any new lesion or an increase from a nadir of at least 50% in a measurable lesion; if this occurs after a prior CR, it is called relapsed disease

Patients are assessed for response in various ways. Prior to each cycle of therapy, the patient is evaluated by a clinician who performs a history and physical examination. In addition, laboratory studies are usually obtained. In general, a CT scan is performed midway through the planned treatment to assess for response (particularly if there are no peripheral lesions that are assessable by physical examination).

Mid-treatment PET or combined PET/CT scans are increasingly used to help guide therapy. The current literature supports the use of interim PET or PET/CT scanning to provide prognostic information at any stage and to adapt therapy in advanced Hodgkin lymphoma.[41, 42, 43]

Guidelines recommend obtaining PET scans at least 6-8 weeks after completion of therapy. Some expert societies recommend waiting 8-12 weeks[35] because of the high-rate of false-positive scans.[44] If a scan is obtained, any positive result should lead to performance of a biopsy to confirm residual disease prior to altering therapy.[45, 35]

For treatment of classical Hodgkin lymphoma, radiation therapy is often administered in combination with chemotherapy. However, such treatment is dependent on the disease stage and bulk as well as where the patient is being treated. Although the role of radiation is becoming increasingly controversial in the treatment of Hodgkin lymphoma, it is still used in many patients.

The radiation fields used in the treatment of Hodgkin lymphoma have evolved to maximize response while minimizing toxicity. Although there are several definitions of radiation fields, the following are generally used:

• Extended-field radiation (EFRT): Radiation that includes not only the clinically involved nodes but also the adjacent, clinically uninvolved nodes; this is called mantle-field or inverted-Y field; EFRT is not used in modern treatment of Hodgkin lymphoma

• Involved-field radiation (IFRT): Radiation field that encompasses all of the clinically involved regions (eg, the mediastinum and the low-supraclavicular fields)

• Involved-site radiation (ISRT): Radiation field that includes pre- and post-chemotherapy nodal volumes plus a 1.5-cm margin of healthy tissue

• Involved-node radiation (INRT): Radiation field that includes pre- and post-chemotherapy nodal volumes plus a 1-cm margin of healthy tissue; there are increasing data to support this, but it is still considered experimental[46]

ISRT is largely replacing IFRT. Current NCCN and international guidelines recommend ISRT for Hodgkin lymphoma.[4, 47]

In addition to the field used, the dose of radiation is also changing. The standard is typically 30-40 Gy (administered in single, daily fractions of 1.8-2 Gy, 5 times/wk), with the option of a boost of 6 Gy to sites of concern.[48, 49, 50]

The following induction regimens are given as initial treatment for Hodgkin lymphoma:

• MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone)
• ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine)
• A+AVD (brentuximab vedotin [Adcetris], doxorubicin, vinblastine, dacarbazine)
• Stanford V (doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, prednisone)
• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

All the medications in these regimens are given intravenously, except for prednisone and procarbazine, which are given orally.

The MOPP regimen was the first effective combination chemotherapy for Hodgkin lymphoma. This regimen is primarily of historical importance and is rarely used in current clinical practice, as it is less effective and more toxic than modern regimens.

The ABVD regimen is the standard of care for the treatment of classical Hodgkin lymphoma, particularly in the United States. ABVD is superior to MOPP in terms of disease-free survival (DFS) and has a lower incidence of sterility and secondary leukemia.[51]

The A+AVD regimen is a modification of the ABVD regimen, with brentuximab vedotin added and bleomycin omitted. It is the newest FDA-approved regimen for patients with stage III or IV classic Hodgkin lymphoma. Approval was based on a phase III trial that showed improved modified progression-free survival (PFS) compared with ABVD.[52] However, this trial has received criticism over its use of modified PFS as opposed to standard PFS, and long-term outcomes are awaited.

The Stanford V regimen is a multidrug regimen with irradiation included as part of standard therapy.[53] The drugs are administered weekly, alternating myelosuppressive and nonmyelosuppressive agents, for 12 weeks. Involved-field radiation (IFRT) at the conclusion of the 12-week treatment is an important part of this regimen. A potential advantage of the Stanford V regimen is that its use of a broad spectrum of chemotherapy drugs can limit the exposure (and potential side effects) of any single drug. However, several studies have failed to show superiority over ABVD, and the latter regimen remains the standard.[54]

The BEACOPP regimen was developed in Germany and is the default standard regimen there.[55] A dose-intensified version of BEACOPP (escalated BEACOPP), with higher doses of etoposide, doxorubicin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (G-CSF) for neutrophil support, has also been developed and may be useful for unfavorable, advanced-stage Hodgkin lymphoma. However, escalated BEACOPP is associated with greater hematologic toxicity and a higher incidence of secondary malignancies, including acute myelogenous leukemia (AML).

A study by Viviani et al demonstrated that BEACOPP produced better initial outcomes in patients with advanced Hodgkin lymphoma than treatment with ABVD but found no significant long-term differences between the regimens.[56] A meta-analysis by Bauer et al found that patients aged 16-60 years with early unfavorable or advanced stage disease benefited from escalated BEACOPP in terms of progression-free survival; however, no significant difference was noted in overall survival.[57]

More recently, a randomized comparison study by Mounier et al, in 150 low-risk patients with an International Prognostic Score (IPS) of 0-2, found that progression or relapses were more frequent with ABVD than BEACOPP (17 versus 5 patients, respectively).[58] In contrast, a randomized comparison study by Carde et al in 549 patients with high-risk stage III-IV Hodgkin lymphoma reported similar rates of event-free and overall survival with ABVD and BEACOPP; these authors stressed the importance of considering treatment burden, immediate and late toxicities, and associated costs when selecting a regimen.[59]

Induction chemotherapy schedules

The MOPP regimen is given every 28 days for six or more cycles, as follows:

• Mechlorethamine: 6 mg/m ², days 1 and 8
• Vincristine: 1.4 mg/m ², days 1 and 8
• Procarbazine: 100 mg/m ², days 1-14
• Prednisone: 40 mg/m ², days 1-14, cycles 1 and 4 only

The ABVD regimen is given every 28 days for six or more cycles, as follows:

• Doxorubicin: 25 mg/m ², days 1, 15
• Bleomycin: 10 mg/m ², days 1, 15
• Vinblastine: 6 mg/m ², days 1, 15
• Dacarbazine: 375 mg/m ², days 1, 15

The A+AVD regimen is given every 28 days for six cycles, as follows:

• Brentuximab vedotin: 1.2 mg/kg, days 1, 15
• Adriamycin: 25 mg/m ², days 1, 15
• Vinblastine: 6 mg/m ², days 1, 15
• Dacarbazine: 375 mg/m ², days 1, 15

The Stanford V regimen is given as follows[60] :

• Vinblastine: 6 mg/m ², weeks 1, 3, 5, 7, 9, 11
• Doxorubicin: 25 mg/m ², weeks 1, 3, 5, 9, 11
• Vincristine: 1.4 mg/m ², weeks 2, 4, 6, 8, 10, 12
• Bleomycin: 5 units/m ², weeks 2, 4, 8, 10, 12
• Mechlorethamine: 6 mg/m ², weeks 1, 5, 9
• Etoposide: 60 mg/m ² twice daily, weeks 3, 7, 11
• Prednisone: 40 mg/m ², every other day, weeks 1-10, tapered weeks 11, 12
• Radiation therapy to bulky sites 2-4 weeks following the end of chemotherapy

The escalated BEACOPP regimen is given every 3 weeks for eight cycles, as follows:

• Bleomycin: 10 mg/m ², day 8
• Etoposide: 200 mg/m ², days 1-3
• Doxorubicin: 35 mg/m ², day 1
• Cyclophosphamide: 1,250 mg/m ², day 1
• Vincristine: 1.4 mg/m ², day 8
• Procarbazine: 100 mg/m ², days 1-7
• Prednisone: 40 mg/m ², days 1-14

When induction chemotherapy fails, or patients experience relapse, salvage chemotherapy is generally given. Salvage regimens incorporate drugs that are complementary to those that failed during induction therapy. Commonly used salvage regimens include the following:

• ICE (ifosfamide, carboplatin, etoposide)
• DHAP (cisplatin, cytarabine, prednisone)
• ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)

Salvage chemotherapy schedules

Single-agent therapy is given as follows:

• Brentuximab vedotin, 1.8 mg/kg once every 3 weeks for up to 16 cycles
• Nivolumab, 3 mg/kg once every  2 weeks until disease progression or unacceptable toxicity
• Pembrolizumab, 200 mg every 3 weeks until disease progression or excessive adverse effects, for a maximum of 24 months

The ICE regimen is given as follows:

• Ifosfamide: 5 g/m ², day 2
• Mesna: g/m ², day 2
• Carboplatin: AUC 5, day 2
• Etoposide: 100 mg/m ², days 1-3

The DHAP regimen is given as follows:

• Cisplatin: 100 mg/m ², day 1
• Cytarabine: 2 g/m ², given twice on day 2
• Dexamethasone: 40 mg, days 1-4

High-dose chemotherapy (HDC) at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous transplantation) or infusion of stem cells from a donor source (allogeneic transplantation). Patients with refractory or relapsed Hodgkin lymphoma should be promptly referred to centers capable of HDC with hematopoietic stem cell support.

Historically, hematopoietic stem cells have been obtained from bone marrow, but they are now typically obtained by pheresis of peripheral blood lymphocytes. A validated and relatively safe conditioning regimen for autologous transplantation is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan).[7] In addition, Gayoso et al reported success with unmanipulated haploidentical related-donor transplant with a busulfan-based reduced conditioning regimen and post-transplant cyclophosphamide as prophylaxis against graft versus host disease.[61]

Myeloablative chemotherapy

High-dose therapy, which requires hematopoietic stem cell support for recovery, is given according to the BEAM regimen. Different schedules for BEAM exist that vary primarily in the dose of etoposide administered. The following is the version used by Schmitz et al in a key randomized, prospective clinical trial[7] :

• BCNU 300 mg/m ², day –7
• Etoposide 150 mg/m ², every 12 hours, total of 8 doses, days –7 to –4
• Cytarabine 200 mg/m ², every 12 hours, total of 8 doses, days –7 to –4
• Melphalan 140 mg/m ², day –3

Following this chemotherapy regimen, autologous hematopoietic stem cells are administered on day 0.

Brentuximab vedotin is indicated as consolidation therapy following autologous hematopoietic stem cell transplantation (HSCT) in patients with classic Hodgkin lymphoma who are at at high risk of relapse or progression. Approval for this indication was based on the AETHERA clinical trial, in which median progression-free survival was 42.9 months in the brentuximab group versus 24.1 months in the placebo group, a statistically significant improvement of 18.8 months (P=0.001).[62]

The regimen is initiated 4-6 weeks after autologous HSCT as 1.8 mg/kg IV (not to exceed 180 mg/dose) infused over 30 minutes three times weekly for up to 16 cycles, or until disease progression or unacceptable toxicity.[24]

Patients with clinical stages IA or IIA classical Hodgkin lymphoma who do not have unfavorable factors (ie, bulky mediastinal or >10 cm disease, elevated erythrocyte sedimentation rate [ESR] >50 [or ESR >30 with B symptoms], more than three sites of involvement, extranodal disease) are categorized as having early-stage, low-risk disease.[63, 64]

The treatment of these patients requires an individualized approach that provides enough therapy to eradicate the disease and avoid the long-term toxicity of treatment. Despite the existence of guidelines for the treatment, there must be room for individualized treatment, based on weighing of the benefits of therapy versus long-term toxicity.

In general, early-stage favorable Hodgkin lymphoma is treated with combined chemotherapy and radiation; however, there may be a role for chemotherapy alone. Randomized trials have shown that compared with radiation alone, combination chemotherapy followed by radiation is superior in terms of survival.[65]

The most commonly used regimen is ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) for 2-4 cycles followed by involved-site radiation therapy (ISRT) (usually to 30 Gy). This regimen is the default regimen in the United States.

Current National Comprehensive Cancer Network (NCCN) guidelines give two cycles of the ABVD regimen a category 1 rating (ie, the recommendation is based on high-level evidence and uniform NCCN consensus that the intervention is appropriate), but list the Stanford V regimen as an alternative.[4] Direct comparisons of ABVD with the Stanford V regimen in early-stage favorable disease have not been reported to date.

The number of chemotherapy cycles and doses of radiation vary based on patient population. The German Hodgkin Study Group (GHSG) HD10 trial evaluated patients with early-stage favorable disease (defined as no more than two sites of disease, no extranodal extension, no bulky mediastinal disease, and ESR < 50 [or < 30 with B symptoms]) by looking at the following four different combinations[39] :

• ABVD x four cycles, followed by IFRT 30 Gy
• ABVD x four cycles, followed by IFRT 20 Gy
• ABVD x two cycles, followed by IFRT 30 Gy
• ABVD x two cycles, followed by IFRT 20 Gy

This study showed no difference in overall survival, freedom from treatment failure, and progression-free survival among the groups, but it did show significantly less toxicity in the lower chemotherapy and radiation arm.[39] The results suggested that ABVD for two cycles followed by IFRT 20 Gy is an acceptable treatment for patients with early-stage disease.

The question as to whether radiation therapy is needed after combination chemotherapy in the treatment of early-stage disease is a matter of debate. When the largest trial to date (NCIC/Eastern Cooperative Oncology Group [ECOG] HD6 trial) examined ABVD alone versus ABVD followed by radiation in patients with early-stage Hodgkin lymphoma, the investigators reported that the chemotherapy alone arm had superior overall survival based on less late toxicity.[66] However, whether these results are applicable to patients treated on modern protocols with ISRT is unknown.

As discussed under Goals of Therapy and Response Assessment, there is increasing use of mid-treatment positron-emission tomography (PET) scans to guide therapy. Current NCCN guidelines recommend the use of interim PET-CT scans to guide therapy when ABVD is chosen as the initial regimen, regardless of the initial stage of disease.[4]

However, although it is clear that such scans have prognostic value, it remains unclear whether altering therapy based on PET scan results improves treatment outcomes in early-stage disease.[67, 68] The current data support the monitoring of patients with history and physical examination prior to administering each cycle or modality of treatment and prior to obtaining laboratory studies and CT scans. Some experts suggest that PET scans should not be used to alter therapy outside of a clinical trial.

Patients with early-stage disease and unfavorable prognostic factors (eg, more than three sites of disease, bulky mediastinal disease, elevated erythrocyte sedimentation rate [ESR], extranodal extension) are classified as having early-stage unfavorable Hodgkin lymphoma. These individuals are treated differently than early-stage favorable patients. In general, four to six cycles of chemotherapy are given followed by involved-site radiation therapy (ISRT).

The preferred regimen is ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine), although other regimens are acceptable, including Stanford V and dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). It should be noted that these regimens are chosen not because they have been proven to be superior in managing early-stage disease; rather, they are an extrapolation from treatment of advanced disease, in which ABVD has been shown to have superior outcomes.[69]

At least two trials have compared therapy with escalated-BEACOPP versus ABVD in early-stage, unfavorable Hodgkin lymphoma.[57] These trials have shown that there does not appear to be a benefit to the use of dose-escalated BEACOPP relative to four cycles of ABVD. In addition, the toxicity was greater with BEACOPP therapy.[57] The results of these studies suggest that ABVD for four cycles followed by 30 Gy of IFRT is the current standard of care.

Similarly, in another study that examined alternating dose-escalated BEACOPP with ABVD versus ABVD alone with both regimens followed by IFRT, the escalated-BEACOPP regimen failed not only to show a survival advantage to the dose-intense regimen but also showed increased toxicity.[70]

It is a matter of debate as to whether chemotherapy alone can be used in patients with unfavorable disease. As noted, the only trial completed to date, the HD6 trial, did include patients with unfavorable Hodgkin lymphoma.[66] Given the flaws in design, particularly the use of outdated radiation therapy, the conclusions are limited. Regardless, chemotherapy alone may be an option for early-stage unfavorable patients without bulky disease.

Patients with early-stage disease with bulky mediastinal disease are treated differently than those with early-stage unfavorable disease without bulky mediastinal disease. In the United States, these individuals are usually treated with ABVD for 4-6 cycles, followed by ISRT at 36 Gy.[71]

Currently, the National Comprehensive Cancer Network (NCCN) supports the following treatments[4] :

• Early-stage unfavorable, no bulky mediastinal disease: ABVD regimen for two cycles (initially with staging and additional ABVD cycles as warranted) or Stanford V regimen or escalated BEACOPP for two cycles + ABVD for two cycles +ISRT

• Early-stage unfavorable, with bulky mediastinal disease: ABVD for four cycles followed by ISRT (category 1 recommendation) or Stanford V regimen for three cycles (12 weeks) + ISRT or escalated BEACOPP for two cycles + ABVD for two cycles +ISRT

Ongoing trials will determine if irradiation is needed. Currently, radiation is an important part of therapy, and it is mandatory with the Stanford V regimen.

In addition, as with early-stage favorable Hodgkin lymphoma, there is controversy regarding the role of interim positron emission tomography (PET) scanning. As with early-stage favorable disease, the NCCN endorses the use of PET scanning for restaging. How this impacts survival is not known, but mid-treatment PET scanning remains an option. If this imaging modality is performed, biopsy of positive sites is mandatory before changing treatment.

Patients are considered to have advanced Hodgkin lymphoma if they demonstrate stage III or IV disease. Chemotherapy is the mainstay of therapy, with radiation reserved for initial bulky sites or residual activity on positron emission tomography (PET) scans, but even in these situations, the role of radiation remains an area of debate. When patients present with advanced disease, they are staged as outlined in Staging, and their prognosis is determined by calculation of the International Prognostic System (IPS) (see Prognosis).

The most commonly used regimen, and one endorsed by the National Comprehensive Cancer Network (NCCN), is ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine).[4, 72, 73] The drugs are administered every 14 days, with one cycle consisting of two administrations. This regimen is most commonly given for up to six cycles (12 doses of chemotherapy), although, occasionally, eight cycles are used. It is important to give the doses as planned (maintenance of dose intensity), and it should be noted that afebrile neutropenia is not a reason to withhold therapy.[74]

There is some suggestion in the literature that granulocyte colony-stimulating factor (G-CSF) may increase rates of bleomycin lung injury, but this has not been confirmed.[75] In fact, the largest series in patients with germ-cell tumors did not show an increased risk of bleomycin lung injury with G-CSF use.[76]

ABVD will result in complete remission (CR) in approximately 80% of patients treated, and up to one quarter of patients will have progressive disease-requiring salvage therapy (see below).[51]

An alternative regimen, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), is recommended by the NCCN for patients with a poor prognosis, as indicated by an International Prognostic Score (IPS) of 4 or higher.[55] Four cycles of escalated BEACOPP are given, with slow responders receiving four additional cycles.[4]

Escalated BEACOPP has CR rates of up to 95% in some trials,[77] but whether this is superior to ABVD therapy in an era with effective salvage is not known.[56, 57] However, adjustments in the delivery of BEACOPP including a reduced number of cycles has proven to be equally effective as the original schedule but with less toxicity.[78] Again, these modifications have not been compared to ABVD.

For patients with an IPS score of less than 3, the NCCN suggests use of the Stanford V regimen.[4] This regimen is used by some clinicians because of its decreased length of treatment and decreased doses of agents. Initial single-institution studies showed impressive results,[79] but subsequent randomized trials have not shown superiority over ABVD.[80]

Although these data suggest that ABVD remain the standard treatment for most patients, the Stanford V regimen may be appropriate for those patients in whom lower doses of bleomycin and doxorubicin are desired, or in those in whom radiation is going to be administered regardless of therapy response. For patients who cannot receive bleomycin, A+AVD is an appropriate option.

A+AVD is the most recently approved regimen for advanced disease and has been shown to improve modified progression-free survival (time to disease progression, death, or evidence of non-complete response after completion of frontline therapy) compared with ABVD.[52] A higher incidence of febrile neutropenia in the brentuximab vedotin arm identified before the trial was complete led to the use of G-CSF as primary prophylaxis in subsequent patients in that arm of the trial. Peripheral neuropathy was also seen more commonly in patients who received brentuximab vedotin, but pulmonary toxicity less commonly.

Beyond chemotherapy, there is even more controversy regarding the role of radiation in advanced Hodgkin lymphoma. The majority of data to date suggest that radiation improves progression-free survival but without improving overall survival.[81, 82] When administered after ABVD or BEACOPP, radiation probably adds little benefit to the majority of patients.[17, 83] One exception may be those patients with bulky mediastinal disease—which is known to be a poor prognostic marker—whose outcomes may be improved with radiation.[84] It must be noted that if the Stanford V regimen is used, then radiation is an integral part of the regimen and must be given.

The role of interim PET-CT scans in the treatment of advanced Hodgkin lymphoma has become more established. A phase III trial showed that if interim PET-CT is negative after two cycles of ABVD, bleomycin can be stopped (ie, de-escalation to AVD) without compromising efficacy.[43] Notably, in the same trial, patients with a positive PET-CT went on to receive BEACOPP, but there was no randomized comparison of BEACOPP versus ABVD in the PET-positive patients. The NCCN guidelines support this approach,[4]  which avoids the pulmonary toxicity associated with bleomycin.

In general, the following guidelines may be helpful when treating advanced-stage Hodgkin lymphoma:

• Advanced stage without bulky disease: ABVD for six (occasionally eight) cycles, no routine radiation therapy. Acceptable alternatives would be BEACOPP or Stanford V

• Advanced stage bulky disease: ABVD for six cycles with involved-field radiation therapy to original sites of bulky disease (generally 30-36 Gy). Acceptable alternatives would be BEACOPP or Stanford V

Early-stage NLPHL can be treated with local excision, involved-field radiation therapy (IFRT), or expectant management (close observation).[85] Advanced-stage disease may represent histologic transformation to T-cell-rich B-cell lymphoma (TCR-BCL) or diffuse large cell B-cell lymphoma (DLBCL), both of which should be treated with a typical non-Hodgkin regimen such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab is a humanized monoclonal antibody that is specific for CD20, a cell-surface antigen expressed by the malignant lymphocytic and histiocytic (L&H) cells in NLPHL. It is a promising agent that has shown activity in NLPHL. On long-term follow-up, the German Hodgkin Lymphoma Study Group observed a 94% overall response rate, with 8 complete remissions, from their population of 15 patients treated with rituximab for relapsed/refractory NLPHL.[86] The use of rituximab in NLPHL, especially in early-stage disease, should ideally be pursued in the context of a clinical trial.

A phase 2 study by Eichenauer et al found that results with rituximab appear inferior when compared with radiotherapy and combined-modality treatment in patients with early-stage NLPHL. However, the authors concluded that investigation of anti-CD20 antibody–based combinations in patients with NLPHL is indicated.[87]

An era-to-era comparison between ABVD treatment and radiotherapy alone found that treating limited-stage NLPHL similar to classical Hodgkin lymphoma may improve outcome compared with the use of radiation alone.[88]

In patients with advanced Hodgkin lymphoma and HIV infection, the results with standard chemotherapy can be dramatically improved by simultaneous treatment with highly active antiretroviral therapy (HAART). Such therapy generally involves three drugs: two nucleoside reverse transcriptase inhibitors (NRTIs) combined with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor (non-NRTI), or a viral fusion inhibitor.

Patients with Hodgkin lymphoma who have never entered complete remission (CR), or whose disease has relapsed after the attainment of CR, have a very poor prognosis when treated with standard chemotherapy and radiation. Therefore, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) is recommended for these patients.[89]

In this procedure, salvage chemotherapy is first administered to help reduce the size of the persistent disease and obtain CR, if possible. The number of cycles to be administered depends on how well the disease is responding to therapy. An optimal situation is one in which the disease enters CR with negative positron emission tomography (PET) scan findings, although one study demonstrated that patients may achieve long-term disease-free survival even if their condition has little or no response.[90]

Following one of the cycles of salvage chemotherapy, hematopoietic stem cells are collected from the peripheral blood by leukapheresis and are stored frozen. Following the administration of myeloablative chemotherapy (eg, BEAM), the stored hematopoietic stem cells are thawed and reinfused into the patient to facilitate hematopoietic recovery. High-dose chemotherapy (HDC) with autologous HSCT can provide better than 50% long-term, progression-free survival for patients with relapses, although specific predicted outcomes vary widely depending on patient-specific risk factors.

Many questions relating to salvage and HDC therapy for patients with Hodgkin lymphoma need to be addressed and are the subject of ongoing clinical trials. These include the following:

• The optimal salvage regimen or regimens
• The ideal conditioning regimen or regimens
• The potential benefits of twin transplants compared with single transplants
• How to prospectively identify those patients who are unlikely to benefit from HDC and how to best manage their disease

In some cases in which HDC fails, allogeneic HSCT may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes radiation therapy) is followed by the infusion of hematopoietic stem cells from a genetically matched donor.[91] This offers the potential for an immunologic antitumor effect from T cells provided by the hematopoietic stem cell donor, which may improve the chances for cure of the disease.

Historically, allogeneic HSCT for Hodgkin lymphoma has been considered too high-risk for most patients, due to high transplant-related mortality. However, new transplant protocols use less toxic conditioning regimens and may be safer and more effective for patients with refractory Hodgkin lymphoma.[92]

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in 2011 for treatment of patients with Hodgkin lymphoma after failure of autologous HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for HSCT. This agent is a CD30-directed antibody-drug conjugate consisting of IgG1 antibody cAC10, specific for human CD30, and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin).[93]

Results from a study of patients with Hodgkin lymphoma in whom autologous HSCT and a median of four chemotherapy regimens had failed (n = 102) showed that 73% (95% confidence interval [CI], 65-83%) achieved an objective response to brentuximab vedotin therapy, including 32% with complete remission (95% CI, 23-42%) and 40% with partial remission (95% CI, 32-49%). Response duration averaged 6.7 months (range, 1.3-21.9 months).[94]

Current NCCN guidelines recommend brentuximab vedotin as maintenance therapy for 1 year after high-dose therapy with autologous stem cell rescue (HDT/ASCR). In addition, in selected patients, brentuximab vedotin can be used as second-line therapy prior to HDT/ASCR to minimize the use of more intensive chemotherapy.[4]

In 2016, the FDA approved the monoclonal antibody nivolumab for the treatment of classic Hodgkin lymphoma that has relapsed or progressed after autologous HSCT and posttransplantation brentuximab vedotin. Approval was based on a combination of the phase 2 CheckMate 205 and phase 1 CheckMate 039 trials with an efficacy analysis conducted on data from 95 patients. Treatment with nivolumab showed an objective response rate (ORR) of 65% (CI 95%: 55-75; 62/95), a complete response rate (CRR) of 7% (CI 95%: 3-15; 7/95), and a partial response rate (PRR) of 58% (CI 95%: 47-68; 55/95). Among responders, the median duration of response was 8.7 months (CI 95%: 6.8-NE; range 0.0+, 23.1+).[95, 96] Extended follow-up of the CheckMate 205 trial confirmed that responses to nivolumab were frequent and durable.[97]

In 2017, pembrolizumab, another monoclonal antibody to programmed cell death-1 protein (PD-1) gained accelerated approval from the FDA for classic Hodgkin lymphoma. It is indicated in adults and pediatric patients who have refractory disease or have relapsed after 3 or more prior lines of therapy. Approval was based on data from the KEYNOTE-087 trial (n=210), which demonstrated an ORR with pembrolizumab averaging ~67% (95% CI: 62, 75), a CRR of 22%, and a PRR of 47%. The median follow-up time was 9.4 months. In the 145 patients who responded to treatment, the median duration of response was 11.1 months.[98]

In the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who were ineligible for or had relapsed after autologous HSCT, interim analysis showed median progression-free survival (PFS) of 13.2 months with pembrolizumab versus 8.3 months with brentuximab vedotin (P = 0.0027). Pneumonitis occurred more frequently in the pembrolizumab arm, but generally responded well to management.[99]

Cardiac disease

Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease, and defects in the conduction system.[100, 101] Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac death.

A study of patients who had previously undergone mediastinal irradiation for Hodgkin lymphoma but who had no clinical evidence of heart disease demonstrated a significant incidence of silent coronary artery obstruction and previous ventricular damage.[102] Based on these results, it is reasonable to initiate functional screening 5 years after radiation therapy in patients with Hodgkin lymphoma.

Pulmonary disease

The ABVD regimen contains bleomycin, a drug associated with dose-related pulmonary toxicity, mainly interstitial pneumonitis, which may lead to fibrosis. The addition of mantle irradiation enhances lung injury. Pulmonary symptoms, such as cough or dyspnea on exertion, are observed in 50% of patients. Declining pulmonary function is observed in approximately one third of patients during ABVD chemotherapy, with or without radiation therapy. This may necessitate dose reductions or even discontinuation of bleomycin.

Although acute toxicity is common, the incidence of severe long-term pulmonary toxicity is low. Fatal pulmonary toxicity has been reported in up to 2-3% of patients treated with the ABVD regimen.

Secondary cancers

Secondary leukemias and solid tumors are significant causes of morbidity and mortality for patients who have received early therapies, including the MOPP regimen and mantle radiation therapy. With modern therapies that emphasize the widespread use of the ABVD and Stanford V regimens and the application of radiation to involved fields only, the incidence of secondary cancers is expected to be much lower.

The most common secondary malignancy following treatment for Hodgkin lymphoma is lung cancer. Both chemotherapy with alkylating agents and irradiation are associated with a 10-fold increased relative risk of lung cancer. Smoking can further increase the risk. In addition, retrospective data have suggested that survival is worse in Hodgkin lymphoma survivors who develop lung cancer compared with matched cohorts with de novo lung cancer.[103]

Myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML) is a particular concern. In the Stanford case series, the projected risk for developing MDS/AML over a follow-up period of 35 years was 2%, and the relative risk compared with matched controls was 38%. The MOPP regimen is associated with an approximately 5% incidence of MDS/AML. With the ABVD regimen the risk is lower, less than 1%.

MDS/AML is usually seen in the first 3-8 years following treatment for Hodgkin lymphoma; subsequently, the risk appears to decline. These findings are consistent with the biology of secondary leukemias following alkylator therapy. MDS/AML usually develops in the context of an MDS with cytogenetic abnormalities in chromosomes 5 and/or 7. Exposure to alkylating agents (eg, the mechlorethamine used in the MOPP regimen) has been implicated.

Exposure to epipodophyllotoxins (etoposide and teniposide) may also result in AML, which generally develops within 3 years and is associated with chromosomal abnormalities at band 11q23.

Breast cancer is 19 times more likely to occur in patients treated with mantle radiation therapy when they are younger than 30 years. If female patients are exposed to chest radiation therapy when they are younger than 15 years, this relative risk increases to 136. MOPP chemotherapy also produces an increased risk for breast cancer when combined with XRT.

Patients in the Stanford case series were also found to have increased risks of developing a variety of other cancers. These include melanoma, non-Hodgkin lymphoma, soft-tissue sarcoma, salivary gland cancers, pancreatic cancers, and thyroid cancers.

A study by Swerdlow et al found that the risk of second malignancy from chemotherapy alone is lower and affects fewer anatomic sites than combined treatment modalities. The authors concluded the risk of second malignancy was slight after 15 years.[104]

Taken in aggregate, these trial results suggest that altering the treatment paradigms of Hodgkin lymphoma to maximize curability while preventing long-term complications should be a focus of ongoing research. Using the least amount of therapy required to cure the disease and minimize complications should be the goal. Early results have suggested that modification of treatment is feasible and have shown some decreased rates of secondary cancers.[105]

Infertility

The degree of infertility varies widely with the regimen used. MOPP chemotherapy causes permanent infertility in at least 80% of males and approximately 50% of females.[104] The escalated BEACOPP regimen results in infertility in nearly 100% of patients treated.[105] The ABVD and Stanford V regimens pose a lower risk of permanent sterility than regimens that contain an alkylating agent (eg, MOPP chemotherapy).[106]

The EORTC Lymphoma Group reported an 82% rate of recovery of fertility in male patients who were treated without alkylating agents.[107] Given the overall excellent prognosis of Hodgkin lymphoma and the early age of onset, it is important to keep fertility preservation in mind when designing treatment plans for these patients. Options include sperm banking for men and various pharmacologic treatments for women including gonadotropin-releasing hormone agonists, ovarian stimulation, and egg preservation.

Infectious complications

Although not commonly performed, patients who have undergone splenectomy are predisposed to bacterial sepsis secondary to encapsulated microorganisms (especially Streptococcus pneumoniae). Empiric antibiotic therapy should be instituted promptly in patients who have undergone splenectomy and present with fever.

Influenza vaccination annually may help to reduce the incidence and/or complications of influenza in patients who have received bleomycin or chest radiation therapy.

Herpes zoster usually appears in previously irradiated dermatomes, but this condition may also occur in patients who have not been irradiated.

Other complications

Lhermitte syndrome (an electric-shock sensation that radiates along the back and legs upon flexion of the neck) can occur in approximately 15% of patients after mantle irradiation. Lhermitte syndrome is not associated with the development of radiation myelitis, and it does not require treatment. This syndrome may last for many months, but it will eventually resolve without long-term sequelae.

Elevation of thyroid stimulating hormone (TSH) occurs in one-third of adult patients after neck/mediastinal radiation therapy.

Survivors of Hodgkin lymphoma have an increased incidence of fatigue, psychiatric distress (anxiety, depression), employment problems, family issues, and sexual functioning problems, as compared to individuals without this disease or relative to survivors of acute leukemia.[108, 109]

Peripheral neuropathy occurred in 29% of patients receiving brentuximab vedotin as part of the A+AVD regimen as opposed to 17% of those who received ABVD.[52] The neuropathy resolved in 43%of the patients and improved in another 23%.

Complications of Immunotherapy

Nivolumab and pembrolizumab are used as salvage therapy in Hodgkin lymphoma and can have numerous autoimmune side effects as a result of immune checkpoint inhibition. This can include pneumonitis, colitis, nephritis, hypothyroidism, hypopituitarism, and adrenalitis. High-dose corticosteroids may be required to treat these side effects. Hypothyroidism requires thyroid hormone replacement and adrenal insuffiency requires physiologic replacement of corticosteroids and mineralocorticoids.

Both the National Comprehensive Cancer Network[4] and the European Society for Medical Oncology (ESMO)[5] guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission.[4, 5] Most relapses occur in the first 3 years after therapy, and Hodgkin lymphoma is the main cause of mortality in the first 10-15 years of follow-up.[110] Follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.

Follow-up examinations include the following[110] :

• History and physical examination

• Complete blood cell count and chemistry panel, including lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), glucose, and lipid levels

• Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck radiation therapy)

• Chest x-ray or CT scans of the chest every 6-12 months in the first 2-5 years

• Abdominal and pelvic CT scans may be added every 6-12 months in the first 2-3 years, especially if the disease originally occurred below the diaphragm

After 5 years, the NCCN recommends the following surveillance schedule[4] :

• Annual history and physical examination
• Annual blood pressure
• Aggressive management of cardiovascular risk factors
• Pneumococcal, meningococcal, and Haemophilus influenzae revaccination after 5–7 y, if the patient received splenic irradiation or splenectomy
• Annual influenza vaccine
• Consider stress test/echocardiogram at 10-y intervals after treatment completion
• Consider carotid ultrasound at 10-y intervals if the patient underwent neck irradiation
• Annual CBC, platelets, and chemistry profile
• TSH at least annually if the patient underwent neck irradiation
• Biannual lipid levels
• Annual fasting glucose study
• Low-dose chest CT scans may be considered in patients at increased risk for lung cancer
• Female patients who have received chest irradiation should be screened annually with mammography, starting at age 40 years or 5-8 years following the radiation therapy; however, the American Cancer Society also recommends breast magnetic resonance imaging (MRI) for patients who received chest radiation therapy between the ages of 10 and 30 years ^[111]

Use of PET scans for surveillance in patients with complete remission is specifically not encouraged by the NCCN, due to the possibility of false-positive results.

Lung injury may result from mantle irradiation or ABVD chemotherapy. Baseline tests and follow-up evaluation with pulmonary function tests are recommended. The best parameter to follow is the carbon monoxide diffusion capacity.

Prominent goals in the follow-up of survivors of Hodgkin lymphoma include the following[110] :

• Identify secondary cancers in a timely manner

• Consider sepsis as a possible cause for fever in a splenectomized patient

• Diagnose and treat predictable complications of Hodgkin lymphoma treatment, such as coronary artery, pulmonary, or thyroid disease

As discussed earlier, single-agent brentuximab vedotin, nivolumab, and pembrolizumab may be used in the relapsed/refractory setting either post-transplant or in transplant-ineligible patients. Combination therapy with those agents is under investigation.

ACCRU, a single-arm phase 2 trial of brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma, failed to meet the prespecified activity criteria but found that brentuximab vedotin plus nivolumab is active and generally well tolerated in older patients with previously untreated Hodgkin lymphoma with comorbidities.[112] On the other hand, interim results of the ongoing phase 1/2 CheckMate 812 trial showed that the combination of brentuximab vedotin and nivolumab was active and well tolerated as initial salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma; the complete response rate was 61% (82% objective response rate), and patients were able to undergo subsequent autologous hematopoietic stem cell transplantation without adverse impact.[113]

Other current studies are exploring the use of various combinations of brentuximab vedotin and chemotherapy for relapsed or refractory cases.[114, 115, 116, 117] Preliminary data show high response rates. To date, however, there are no randomized trials to establish a standard pre-transplant regimen.

In the frontline setting, a phase 3 trial involving patients with previously untreated stage III or IV classical Hodgkin lymphoma found that brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (AVD) had superior efficacy compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years was 4.9% lower with brentuximab vedotin plus AVD compared with ABVD.[118] A phase 2 study demonstrated the safety and efficacy of nivolumab followed by nivolumab plus AVD in patients with newly diagnosed, untreated, advanced-stage Hodgkin lymphoma.[119]

Finally, an emerging area of research is the use of chimeric antigen receptor (CAR) T-cells to treat Hodgkin lymphoma. A set of 2 parallel phase I/II studies of anti-CD30 CAR T-cell therapy in 41 heavily pretreated patients with relapsed or refractory Hodgkin lymphoma demonstrated a high rate of durable responses with an excellent safety profile; for all evaluable patients, the 1-year progression-free survival was 36% and overall survival was 94%.[120] CAR T-cell therapy for Hodgkin lymphoma will be an ongoing area of investigation.[121]

Guidelines contributor: Priyank P Patel, MD Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo

Diagnosis

Updated guidelines on the management of Hodgkin lymphoma have been issued by the National Comprehensive Cancer Network (NCCN)[4] and the European Society for Medical Oncology (ESMO).[5] The NCCN and ESMO guidelines have very similar recommendations for the diagnostic evaluation.[4, 5] Histological evaluation is required for diagnosis according to the World Health Organization (WHO) classification of either nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or one of four classical Hodgkin lymphoma (CHL) subtypes, as follows:

• Nodular sclerosis CHL (NSCHL)
• Mixed cellularity CHL (MCCHL)
• Lymphocyte-depleted CHL (LDCHL)
• Lymphocyte-rich CHL (LRCHL)

The presence of Hodgkin and Reed-Sternberg (HRS) cells is disease defining for CHL. Detection of lymphocyte-predominant (LP) cells is required for the diagnosis of NLPHL

Biopsy recommendations are as follows:

• Excisional biopsy is preferred
• Core needle biopsy can be considered if excisional biopsy is not possible
• Fine needle aspiration should be avoided

Other recommendations for diagnosis are as follows:

• History and physical examination to determine presence of B symptoms (unexplained weight loss >10%, fever, drenching night sweats)
• Fatigue, pruritus, and alcohol intolerance should also be noted

Both the National Comprehensive Cancer Network (NCCN)[4]  and the European Society for Medical Oncology (ESMO)[5] recommend the Cotswold modified Ann Arbor classification for staging Hodgkin lymphoma.[122] See Table 1, below.

Table 1. Cotswold Modification of Ann Arbor Staging System (Open Table in a new window)

The ESMO guidelines for staging and risk assessment include the following recommendations[5] :

• Chest x-ray and a contrast-enhanced CT scan of neck, chest, and abdomen are mandatory

• A baseline PET should be conducted, if this is available

• A bone marrow biopsy is not indicated in patients undergoing PET-CT evaluation but must be carried out if PET-CT is not available.

• Full blood cell count, erythrocyte sedimentation rate (ESR), and blood chemistry analysis are obligatory. Screening for hepatitis B and C viruses and HIV is compulsory.

• After staging examinations are completed, HL patients are allocated to distinct risk groups depending on their clinical stage and the presence of clinical risk factors

• Cardiac and pulmonary function tests should be performed out before the start of treatment

• Reproductive counselling and consideration of sperm banking, oocyte collection, or ovarian tissue cryopreservation should be offered to patients of reproductive age before treatment.

In 2014, the International Conference on Malignant Lymphomas, a multi-disciplinary team of researchers, representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan and Australasia, published guidelines for the evaluation, staging, and response assessment. These guidelines were intended to be an update to the 2007 revised guidelines of the International Harmonization Project.[6] The revised recommendations for staging are as follows[123] :

• PET-CT is preferred for pretreatment assessment and routine staging

• Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning

• Chest x-ray is not required

• PET-CT is preferred for determining splenic involvement with cutoff for splenomegaly of more than 13 cm

• Liver size is not a reliable measure of hepatic involvement; diffusely increased or focal uptake, with or without focal or disseminated nodules, supports liver involvement

• Bone marrow aspirate/biopsy is not required for early-stage HL (stage I-IIA) if PET-CT was performed (an exception noted by NCCN is if PET-CT is negative but the patient has unexplained cytopenias[4] )

• Bone marrow biopsy and aspirate is required for patients with advanced-stage HL (stage IIB-IV)

In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification. See Table 2, below.[123]

Table 2. International Conference on Malignant Lymphomas Modification of Ann Arbor Staging (Open Table in a new window)

Based on the clinical scenario, staging, and degree of end-organ damage, patients with Hodgkin lymphoma are further categorized into the following three groups:

• Early-stage favorable
• Early-stage unfavorable
• Advanced-stage

National Comprehensive Cancer Network (NCCN) guidelines define unfavorable factors for stage I-II as follows[4] :

• Bulky mediastinal disease (mediastinal mass ratio [MMR; maximum width of mass/maximum intrathoracic diameter] greater than 0.33) or bulky disease greater than 10 cm
• B symptoms
• Erythrocyte sedimentation rate (ESR) >50 mm/hr
• More than two-three nodal sites of disease

The European Society for Medical Oncology (ESMO) guidelines recommend the slightly different definitions of risk factors from the European Organization for Research and Treatment of Cancer /Lymphoma Study Association (EORTC/LSA) and the German Hodgkin Study Group (GSHG), as outlined in Table 3, below.[5]

Table 3. Unfavorable Risk Factors for Stages I and II Hodgkin Lymphoma (Open Table in a new window)

Patients with advanced disease are further risk stratified using the International Prognostic Score (IPS), which includes the following risk factors (for scoring, each factor receives 1 point)[30] :

• Albumin < 4 g/dL
• Hemoglobin < 0.5 g/dL
• Male
• Age ≥45 y
• Stage IV disease
• Leukocytosis: white blood cell count (WBC) >15,000/μL
• Lymphopenia: Lymphocyte count < 8% of WBC and/or absolute lymphocyte count < 600 cells/μL

Based on the IPS score, patients with advanced disease can be categorized as follows[123] :

• Good risk (IPS 0-1)
• Fair risk (IPS 2-3)
• Poor risk (IPS 4-7)

Recommendations for primary treatment of classical Hodgkin lymphoma (cHL) vary by stage and risk stratification. Chemotherapy is followed by restaging with PET-CT.

On the basis of fluorodeoxyglucose (FDG) PET findings, a Deauville score can be assigned. The Deauville score is based on visual interpretation of FDG uptake by FDG-avid (or previously FDG-avid) lesions, compared with two reference points: the mediastinum (which represents the blood pool) and the liver.[124] Scores are as follows:

1. No uptake or no residual uptake (when used interim) 
2. Slight uptake, but equal to or less than that of blood pool (mediastinum) 
3. Uptake above mediastinal, but below or equal to uptake in the liver
4. Uptake slightly to moderately higher than liver
5. Markedly increased uptake or any new lesion (on response evaluation)

Early-stage favorable disease

Combined modality is the treatment of choice in patients with early-stage cHL. The National Comprehensive Cancer Network (NCCN) guidelines give the ABVD (doxorubicin [Adriamycin]/bleomycin/vinblastine/dacarbazine) regimen a category 1 rating (ie, the recommendation is based on high-level evidence and uniform NCCN consensus that the intervention is appropriate), but also list an 8-week Stanford V regimen (doxorubicin, vinblastine, mechlorethamine [or cyclophosphamide], etoposide, vincristine, bleomycin, and prednisone) as an alternative.[4]

ABVD is administered in four cycles. However, two cycles are suggested in highly selected patients with very favorable disease characterized by the following[4] :

• No bulky disease
• No extralymphatic involvement
• Fewer than three sites of disease
• Erythrocyte sedimentation rate (ESR) < 30 mm/hr, or < 50 mm/hr in patients without B symptoms

After initial ABVD and interim restaging with PET, the NCCN recommends subsequent management according to the patient’s Deauville score, as follows[125] :

• Deauville score of 1 to 3: A planned course of involved-site radiation therapy (ISRT) (20 Gy) is recommended.
• Deauville score of 4: Two additional cycles of ABVD followed by interim PET/CT may be considered prior to ISRT (30 Gy).
• Deauville score of 5: Biopsy is recommended. If the biopsy is negative, patients may be treated with two additional cycles of ABVD and ISRT (30 Gy). A repeat PET/CT could be considered before initiation of RT. If the biopsy is positive, patients should be managed as described for refractory disease.
• Alternatively, patients with a Deauville score of 1 to 2 can be treated with an additional cycle of ABVD and ISRT (30 Gy). Patients with a Deauville score of 3 can be treated with two additional cycles of ABVD and ISRT (30 Gy).

If there is a preference to use chemotherapy alone, recommended options for subsequent management depend on the patient’s Deauville score, as follows[125] :

• Deauville score of 1 or 2: An additional one to two cycles of ABVD or four cycles of AVD (for initial stage IIB or ≥3 sites)
• Deauville score of 3: An additional two cycles of ABVD or 4 cycles of AVD (for initial stage IIB or ≥3 sites).
• Deauville score of 4: Two additional cycles of ABVD or two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine [Oncovin], procarbazine, prednisone) followed by restaging with PET. If the restaging Deauville score is 1 to 3, the treatment options include an additional two cycles of ABVD (if previously given), or an additional 2 cycles of escalated BEACOPP (if previously given).
• Deauville score of 5: Biopsy is warranted; patients with a negative biopsy should be managed as for Deauville 1 to 3. Those with a positive biopsy should be managed as for refractory disease.

The European Society for Medical Oncology (ESMO) guidelines recommend two to three cycles of ABVD followed by ISRT. Alternatively, patients may undergo PET-CT scanning after two cycles of ABVD: PET-postive patients then receive two cycles of BEACOPPesc (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone in escalated dose) followed by 30Gy ISRT; PET-negative patients undergo one cycle of BEACOPPesc followed by 20Gy ISRT.[5]  

ESMO notes that whether RT can be omitted in selected patients with complete metabolic response at interim PET is a matter of debate. However, this approach may be offered to individual patients in whom the late risk of RT is thought to outweigh the short-term benefit of improved disease control.[5]

Early-stage unfavorable disease

Stage I-II unfavorable, non-bulky disease

According to NCCN guidelines, if the preference is to treat with combined-modality therapy, the preferred regimen, recommended options for subsequent management depend on the patient’s Deauville score, as follows[125] :

• Deauville score of 1 to 2: Two additional cycles of ABVD and ISRT
• Deauville score of 3 to 4: Either two additional cycles of ABVD alone (preferred if Deauville 3) or two cycles of escalated BEACOPP (preferred for Deauville 4 or 5). PET restaging may be considered at this point and patients are followed up with ISRT (30 Gy).
• Deauville score of 5: Biopsy is recommended. If the biopsy is negative, patients are treated as described for a Deauville score of 3 to 4. All patients with a positive biopsy should be managed as described for refractory disease.

If there is a preference to treat patients with chemotherapy alone, the treatment recommendations are the same as for stage I–II favorable, non-bulky disease.

The ESMO guidelines recommend four cycles of ABVD with involved-field radiation therapy (IFRT). In younger patients (≤60 years) a more intensive treatment can be considered, consisting of two cycles of escalated BEACOPP followed by two cycles of ABVD with IFRT.[5]

Stage I-II unfavorable, bulky mediastinal disease or adenopathy >10 cm

According to NCCN guidelines, after initial ABVD and interim restaging with PET, subsequent management by the patient’s Deauville score is as follows[125] :

• Deauville score of 1 to 3: Two additional cycles of ABVD plus ISRT or four cycles of AVD with or without ISRT
• Deauville score of 4: Two additional cycles of ABVD or two to three cycles of escalated BEACOPP followed by PET and ISRT or an additional cycle of escalated BEACOPP, if they were previously treated with three cycles of escalated BEACOPP.
• Deauville score of 5: Biopsy is recommended. If the biopsy is negative, management is as described for patients with a Deauville score of 4. Patients with a positive biopsy should be managed as described for refractory disease. Alternatively, two cycles of escalated BEACOPP may be given, followed by PET and ISRT.

Advanced-stage disease

NCCN guidelines advise that chemotherapy is always used for patients with advanced-stage disease (stage III-IV), but combined-modality therapy is used in some treatment regimens, especially for patients with bulky disease and in those who show a poor response to chemotherapy in other treatment regimens.[125]

After initial ABVD and interim restaging with PET, subsequent management by the patient’s Deauville score is as follows:

• Deauville score of 1 to 3: Four cycles of AVD, then observation or ISRT to initially bulky or selected PET-positive sites.
• Deauville score of 4: Two additional cycles of ABVD or two cycles of escalated BEACOPP followed by reassessment of response with PET.
• Deauville score of 5: Two cycles of BEACOPP may be considered in select cases, but biopsy is recommended. If a biopsy is negative, treatment is as for a Deauville score of 4; if it is positive, management is as described for refractory disease.

The addition of brentuximab vedotin to AVD is a category 2A option in select patients with no known neuropathy, if the International Prognostic Score (IPS) ≥4 or bleomycin is contraindicated.

The ESMO guidelines recommend the following[5] :

• ABVD for six to eight cycles, followed by localized radiotherapy of residual lymphoma larger than 1.5 cm

• Escalated BEACOPP for six cycles, followed by localized radiotherapy of residual lymphoma larger than 2.5 cm

Older patients

The NCCN recommends enrollment in a clinical trial, when available, for patients older than 60 years with classical HL.[125] Otherwise, the NCCN recommends considering the regimens listed below in order to lessen or minimize toxicity, although they have not been proven to improve disease outcomes in older patients.

Stage I-II favorable disease options are as follows:

• ABVD (preferred) or AVD, followed by ISRT
• CHOP (cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin], prednisolone) with ISRT
• VEPEMB (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin) with or without ISRT

Stage I–II unfavorable or stage III–IV disease options are as follows:

• ABVD plus brentuximab vedotin lead in followed by AVD and brentuximab vedotin maintenance
• Brentuximab vedotin plus dacarbazine (DTIC)
• CHOP
• PVAG (prednisone, vinblastine, doxorubicin, gemcitabine)
• VEPEMB with or without ISRT

Refractory or relapsed disease

NCCN guidelines recommend second-line systemic therapy followed by response assessment with PET for all patients with refractory or relapsed disease.[125] Other options include the following:

• Further cytoreduction and high-dose therapy with autologous stem cell rescue (HDT/ASCR), with RT if not previously given
• RT or systemic therapy with or without RT
• Conventional-dose second-line systemic therapy may precede HDT/ASCR
• RT should be strongly considered for selected sites of relapse that have not been previously irradiated. In radiation-naïve patients, total lymphoid irradiation may be an appropriate component of HDT/ASCR.

ESMO guidelines recommend high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for refractory or relapsed disease. The selection of second-line chemotherapy is determined by comparison with the agents previously used.[5] Brentuximab vedotin is recommended for patients who have a failure of ASCT or failure of at least two prior multi-agent chemotherapy regimens.[5]

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct entity with unique clinical features and a different treatment paradigm. The National Comprehensive Cancer Network (NCCN) prefers involved-site radiation therapy (ISRT) over involved-field radiation therapy (IFRT) for treatment of early-stage favorable NLPHL. (Involved-site fields are generally smaller than classic involved fields.) For early-stage unfavorable or advanced-stage NLPHL, an ABVD regimen (doxorubicin [Adriamycin]/bleomycin/vinblastine/dacarbazine) plus ISRT is recommended. CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) may also be used.[4]

Rituximab may be considered in combination with ABVD or CHOP. For refractory disease, maintenance rituximab may be considered. Individualized treatment is recommended. At relapse, patients biopsy should be performed due to the high rate of conversion to aggressive B-cell lymphoma.[4]

ESMO recommends IFRT for treatment of patients with stage IA NLPHL who have no risk factors. For early-stage unfavorable or advanced stage disease, the treatment recommendation is identical to that for CHL.[5]

Both the National Comprehensive Cancer Network (NCCN)[4] and the European Society for Medical Oncology (ESMO)[5] guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission. The NCCN recommends interim physical exams and blood tests every 3 to 6 months for 1 to 2 years and then every 6 to 12 months for the next 3 years and then annually.[4] ESMO suggests follow-up every 3 months for the first 6 months, and every 6 months until year 4, then annually.[5]

Follow-up examination recommendations are similar for both guidelines, but those from the NCCN are more detailed. NCCN recommendation for follow-up in the first 5 years include the following[4] :

• History and physical examination

• Complete blood cell count (CBC), serum chemistry panel, and erythrocyte sedimentation rate (ESR)

• Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck radiation therapy)

• Annual influenza vaccine

• Neck/chest/abdomen/pelvis CT scan with contrast, at 6, 12, and 24 mo following completion of therapy, or as clinically indicated, is acceptable

• PET/CT is recommended only if last PET was Deauville 4-5, to confirm complete response

Recommendations for annual monitoring for late complications after 5 years include the following[5] :

• CBC, serum chemistry panel, and erythrocyte sedimentation rate (ESR)

• TSH levels (at least annually if the patient had neck radiation therapy)

• Biannual lipids assay

• Annual fasting glucose

• Blood pressure monitoring

• Management of cardiovascular risk factors; stress test/echocardiogram and carotid ultrasound (if the patient has had neck radiation therapy) every 10 years

• Vaccinations against pneumococcus, Haemophilus influenzae, and meningococcus (especially in patients who have had splenectomy), with revaccination every 5-7 years

• Annual influenza vaccine

• Chest x-ray or low-dose CT scans of the chest in patients with increased risk of lung cancer

• In women who have received chest irradiation¸ annual screening with mammography, starting at age 40 years or 8-10 years after radiation therapy; breast magnetic resonance imaging (MRI) in addition to mammography is indicated for patients who received chest radiation therapy between the ages of 10 and 30 years

Several chemotherapeutic agents in various combinations are used to treat Hodgkin lymphoma. The combinations vary by the stage of disease and by the treating institution. In patients with relapsing or unresponsive disease, hematopoietic stem-cell transplantation significantly prolongs disease-free survival. Various drug combinations have been used with stem-cell rescue.

Although the intended target is the malignant cells of Hodgkin lymphoma, the effects of chemotherapy on normal cells of the body are considerable and account for the adverse effects observed with these agents. Because most patients with Hodgkin lymphoma are long-term survivors, one of the goals of current therapy is to decrease the long-term adverse effects while maintaining excellent cure rates. The use of different therapeutic agents with nonoverlapping toxicities is one way to achieve this goal. Various combinations of the drugs presented below are used to treat Hodgkin lymphoma .

Although adverse effects vary with each drug, some are common to many drugs. These adverse effects include nausea, vomiting, alopecia, bone marrow suppression, and, less commonly, secondary malignancies.

Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell-division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the growth rate may be decreased in large tumors. This difference allows normal cells to recover more quickly than malignant ones after chemotherapy and is the rationale behind current cyclic dosage schedules.

Class Summary

Antineoplastic agents interfere with cell reproduction. Some agents are specific to phases of the cell cycle, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Alkylating antineoplastic agents elicit their effects through the formation of covalent bonds with DNA, which disturbs protein synthesis and cellular division. They are able to form bonds with DNA of all cells, especially those which reproduce rapidly. Because of their nonspecific action on cells, toxicities to normal cells are an issue.

Mechlorethamine (Mustargen)

Mechloroethamine is a component of the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen. It exerts cytotoxic effect by inhibiting rapid proliferation of cancer cells.

Class Summary

Antibiotic antineoplastic agents are produced by microorganisms and inhibit or prevent the proliferation of neoplasms.

Bleomycin (Blenoxane)

Classified as an antibiotic, bleomycin induces free radical-mediated breaks in strands of DNA. This agent is part of the ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) regimen.

Class Summary

The vinca alkaloid agents are naturally occurring or semisynthetic nitrogenous bases that elicit their cytotoxic effects through tubulin-binding properties and disruption of microtubule function, which lead to metaphase arrest.

Vinblastine (Velban)

Vinblastine is a vinca alkaloid that inhibits mitosis because of interactions with tubulin.

Dacarbazine (DTIC-Dome)

Dacarbazine is an alkylating agent that inhibits DNA, RNA, and protein synthesis. It inhibits cell replication in all phases of the cell cycle.

Vincristine (Vincasar PFS, Oncovin)

Vincristine is a vinca alkaloid with a mechanism of action similar to that of vinblastine. It is presumed to stop the metaphase stage therefore preventing microtubule formation in the mitotic spindle.

Class Summary

Podophyllotoxin derivative antineoplastic agents have cytotoxic effects on cell growth.

Etoposide (Toposar)

Etoposide is an epipodophyllotoxin that induces DNA strand breaks by disrupting topoisomerase II activity. This causes cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

Procarbazine (Matulane)

Procarbazine is an alkylating agent with a mechanism of action similar to that of dacarbazine: inhibition of DNA, RNA, and protein synthesis. It inhibits cell replication in all phases of the cell cycle. It is part of COPP, BEACOPP and MOPP regimens.

Class Summary

Cyclophosphamide is a synthetic agent similar to nitrogen mustard. This agent requires activation in the liver to form its active intermediaries, which in turn modify and cross-link DNA, thereby inhibiting DNA, RNA, and protein synthesis. Eventually, apoptosis occurs.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is an alkylating agent that is chemically related to nitrogen mustards. The mechanism of action of its active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Class Summary

Antimetabolite antineoplastic agents interfere with cell functions by competing for its receptors or enzymes involved in the synthesis of DNA. Tissues that have a high rate of cellular metabolism are most sensitive to the effects.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, which is necessary for conversion of folate to biologically active tetrahydrofolate.

Class Summary

Anthracycline antineoplastic agents elicit their cytotoxic effects through nucleotide base intercalation and cell membrane lipid-binding. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases.

Doxorubicin (Adriamycin)

An anthracycline that functions as a DNA intercalator, doxorubicin inhibits topoisomerase II and produces free radicals, which may destroy DNA. The combination of these 2 events can inhibit the growth of neoplastic cells. Doxorubicin is administered intravenously and distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. It does not cross the blood-brain barrier and is excreted primarily in bile.

Class Summary

Antimicrotubular antineoplastics disrupt the microtubular network in cells by promoting stabilization and assembly. In addition, these agents block the disassembly of microtubules, thereby preventing cell division, leading to cell death.

Brentuximab vedotin (Adcetris)

Brentuximab is a CD30-directed antibody-drug conjugate (ADC) that consists of chimeric IgG1 antibody cAC10, which is specific for human CD30, bound to the microtubule-disrupting agent monomethyl auristatin E (MMAE, or vedotin). This agent is indicated for treatment of classic Hodgkin lymphoma (cHL) after failure of autologous stem cell transplant (ASCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates. It is also indicated as consolidation treatment post-auto-HSCT in patients with high risk for relapse or disease progression. Additionally, brentuximab vedotin is indicated as first-line therapy for previously untreated stage III-IV cHL in combination with chemotherapy.

Class Summary

Immunotherapy is emerging for use in hematologic malignancies.

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.

This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation.

Nivolumab (Opdivo)

Monoclonal antibody which inhibits suppression of T-cells by blocking the interaction between programmed cell death-1 protein and its ligands. Nivolumab is indicated for the treatment of classical Hodgkin lymphoma in patients who have relapsed or shown progression after autologous hematopoietic stem cell transplantation (HSCT) and post transplantation brentuximab vedotin.

Pembrolizumab (Keytruda)

Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated for adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL) or who have relapsed after 3 or more prior lines of therapy.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone)

Prednisone is a corticosteroid used to treat leukemias and lymphomas because of its lympholytic activity. Prednisone acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.

Prednisone is readily absorbed via the gastrointestinal tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose dependent or duration dependent.