Pediatric Hodgkin Lymphoma 

Updated: Mar 20, 2017
Author: Pedro A de Alarcon, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP 

Overview

Background

Formally known as Hodgkin disease, Hodgkin lymphoma (HL) is a highly curable malignancy. It is a unique neoplasm in which the malignant cell, the Reed-Sternberg cell (RSC), represents only a small proportion of cells constituting the bulk of the tumor. It also has very particular clinical characteristics and distinct biological behavior.

Hodgkin lymphoma is a rather rare malignancy in the pediatric population, however, it constitutes approximately 40% of all lymphomas that present during childhood and is the most common malignancy in adolescents and young adults. In all age groups, Hodgkin lymphoma is highly sensitive to chemotherapy and irradiation. In fact, Hodgkin lymphoma was the first cancer to be cured with radiation therapy alone or with a combination of several chemotherapeutic agents.

The cure rate for children and adolescents with Hodgkin lymphoma has steadily improved over the years, particularly with the introduction of combined radiation and multiagent chemotherapy.[1]

This therapeutic success has come at the price of serious long-term toxicities, such that a 30-year survivor of Hodgkin lymphoma is more likely to die of therapy-related complications than from Hodgkin lymphoma. Therefore, the therapeutic paradigm has shifted toward reducing treatment-associated toxicity while maintaining high cure rates. This new paradigm has led to the current risk-adapted, response-based approach to the treatment of Hodgkin lymphoma (see Treatment).

See also the Medscape Reference topic Hodgkin Disease.

Pathophysiology

Hodgkin lymphoma (HL) is a malignancy of the germinal-center B cells that affects the reticuloendothelial and lymphatic systems.[2] The origin of the HL Reed-Sternberg cells (HL-RSC) became clear with the introduction of microdissection and single-PCR methods. HL-RSC carry clonal immunoglobulin gene rearrangements, which establishes their clonality and their B cell origin. Germinal-center B-cells undergo clonal expansion and activate the process of somatic hypermutation that introduces mutations at a high rate into rearranged immunoglobulin variable genes. Germinal-center B-cells with unfavorable mutations are functionally crippled and undergo programmed cell death (apoptosis). The reason for the apoptosis resistance of HL-RSC precursors is unclear but may involve several distinct transforming events, such as Epstein-Barr Virus (EBV) infection.

Epidemiologic data suggest that environmental, genetic, and immunologic factors are involved in the development of Hodgkin lymphoma. Clusterings of cases in families or racial groups supports the theory of a genetic predisposition or a common environmental factor.

In identical twins of patients with Hodgkin lymphoma, the risk of developing Hodgkin lymphoma is higher than that of other first-degree relatives. Subjects with acquired or congenital immunodeficiency disorders also have an increased risk of developing Hodgkin lymphoma.

Findings from several epidemiologic studies have suggested links between HL and certain viral illnesses. The strongest case to date is a relationship to EBV, in that EBV viral DNA can be found in HL-RSC. Infants and children aged 0-14 years with Hodgkin lymphoma have EBV DNA in their HL-RSC cells more often than young adults aged 15-39 years with HL.

In EBV-positive Hodgkin lymphoma, EBV-encoding genes play a role in preventing apoptosis. Latent membrane protein-1 (LMP-1) expressed in EBV-positive Hodgkin lymphoma RSCs mimics an activated CD40 receptor, activating the antiapoptotic nuclear factor–kappa-B (NF-κB) pathway.

Up-regulation of NF-κB in HL is observed in both Hodgkin lymphoma RSCs and the surrounding supporting cells. This up-regulation is due to gene amplification of c-rel and activation of cell-surface receptors such as CD30, CD40, RANK, and Notch1.

The production of the ligand for these receptors is responsible for the phosphorylation and translocation to the nucleus of NF-κB. The constitutive translocation of NF-κB to the nucleus of Hodgkin lymphoma RSCs is essential for the malignant transformation of the RSCs. It leads to inhibition of apoptosis, proliferation, and secretion of proinflammatory cytokines.[3]

Epidemiology

Hodgkin lymphoma (HL) generally occurs in all age groups but young adults are most often affected. The distinguishing epidemiologic feature of Hodgkin lymphoma is its bimodal age incidence, which is commonly seen in populations living in economically advanced, Westernized countries such as the United States. There is a rapid increase in incidence rates among teenagers, which peaks at about age 25 years, and another peak occurs in patients aged approximately 50–60 years.

The age-adjusted standardized rate of Hodgkin lymphoma in North America, Western Europe, and Oceania is usually just below 7 cases per million. For children and adolescents younger than 15 years, the incidence is 5.5 cases per million. For individuals aged 15-20 years, the incidence is 12.1 cases per million population. These rates are in contrast to those in western Asia (from the Mediterranean to northwest India), where the age-adjusted standardized rate is consistently higher than 7 cases per million.

A different age pattern is evident among economically disadvantaged populations in which there is an initial peak in childhood, particularly for boys.

In the United States and in Western Europe, the childhood rate is lower than the young-adult rate. In Eastern Europe, the young-adult rate is similar to that observed in the United States and Western Europe, but the childhood rate is higher. Latin American countries have patterns of incidence approaching those of the United States.

The incidence is relatively low in Asia, with the exception of South Asia, where the incidence is relatively high.

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

In the United States, the incidence of Hodgkin lymphoma among whites and blacks is essentially the same. However, the ratio is 1.4:1 in children older than 10 years.[4] A significant male-to-female ratio of 3:1 is observed in children younger than 10 years. In older children and adults, the male-to-female ratio is about 1:1.

The incidence of Hodgkin lymphoma by age show a bimodal distribution. In developed nations, the first peak occurs at approximately age 20 years and the second peak is observed in patients aged 55 years or older. Hodgkin lymphoma is uncommon before age 5 years. However, in developing countries, the first peak is shifted into childhood, usually before adolescence.

Prognosis

With the development of an integrated treatment approach, the cure rate and survival of patients with Hodgkin lymphoma (HL) is now high. In developed countries, the 5-year overall survival for Hodgkin lymphoma of all stages is very high, usually greater than 80%. Patients with stage I or II disease have overall survival rates greater than 90%, whereas those with stage III or IV disease have overall survival rates as low as 70%. The survival rate in children, adolescents, and young adults with Hodgkin lymphoma is similarly good as that in adult patients.

Survival in developing countries may be lower, depending on availability of care and medications, distance to the treating centers, and number of patients who abandon therapy before completion.

A prognostic score for advanced Hodgkin lymphoma based on presenting clinical parameters (international prognostic factors for advanced Hodgkin lymphoma) is used for risk stratification for adults. The score system includes the following findings:

  • Erythrocyte sedimentation rate (ESR) of more than 50 mm/h

  • Hemoglobin concentration less than 10.5 g/dL

  • WBC count of 15,000/μL or less

  • Absolute lymphocyte count less than 600/μL

  • Albumin level less than 4 g/dL

However, the system is not applicable to pediatric patients. More recently, the data from the Children’s Oncology group reported by Dr. Schwartz described the Childhood Hodgkin International Prognostic score (CHIPS) to predict event free survival in pediatric and adolescent HL. The CHIPS score found that 4 factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever. The CHIPS score identified a subset of patients accounting for 22% of an intermediate risk population who are predicted to have an event-free survival (EFS) rate of less than 80%. Early augmentation of therapy may improve outcome for this cohort.[5]

Furthermore, this score system identified low albumin as an excellent predictor of decreased EFS in mixed cellularity Hodgkin lymphoma, allowing the identification of a cohort of intermediate risk patient with mixed cellularity histology that may benefit from augmented therapy.[6]

Patient Education

Before the initiation of treatment, patients with Hodgkin lymphoma (HL) should be counseled about the potential complications of Hodgkin lymphoma. Depending on the therapeutic modality, this may include the risk of cardiac disease, lung toxicity, infertility, infection, and secondary cancers. 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.

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 to manage some of these issues.

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma.

 

Presentation

History

Most patients with Hodgkin lymphoma (HL) present with persistent painless adenopathy, usually cervical and/or mediastinal, unresponsive to antibiotic therapy. More than 70% of patients present with cervical lymphadenopathy. Patients with mediastinal adenopathy may present with respiratory symptoms such as shortness of breath, chest pain, or cough. These patients are at risk for respiratory failure, especially if they undergo sedation or anesthesia for diagnostic procedures. A large mediastinal mass may also cause superior vena cava syndrome. Approximately 25% of patients present with one or more systemic symptoms that are associated with advanced disease and an adverse prognosis.

The Ann Arbor staging system recognizes the following 3 symptoms, known as B symptoms, as having prognostic significance (see Staging):

  • Unexplained fever with temperatures above 38°C for 3 consecutive days

  • Unexplained weight loss of 10% or more in the previous 6 months

  • Drenching night sweats

Patients may have other symptoms that relate to the cytokines produced by Hodgkin lymphoma Reed-Sternberg cells (RSCs) or the supporting environment within the affected lymph nodes, such as pruritus, urticaria, and fatigue.

The clinical manifestations of Hodgkin lymphoma result from the mass effect that is mostly due to the reactive tissue surrounding RSCs, as well as cytokine production by RSCs. Systemic symptoms have been attributed to the production of interleukin (IL)–6, whereas some of the histopathological characteristics, such as eosinophilia and collagen sclerosis, have been attributed to cytokine production, such as IL-4, IL-5 exotoxin, IL-6, IL-7, tumor necrosis factor (TNF), lymphotoxin, transforming growth factor β (TGF-β), and basic fibroblast growth factor.

Several immune-mediated paraneoplastic syndromes, such as immune thrombocytopenic purpura, autoimmune hemolytic anemia, and nephrotic syndrome, can be associated with Hodgkin lymphoma. These paraneoplastic syndromes can present before, after, or at the time of presentation of HL.

Physical Examination

Physical examination is important in the evaluation of patients with Hodgkin lymphoma (HL) because it allows the clinician to monitor the response to treatment. Careful evaluation of all lymph node stations, hepatosplenomegaly, and involvement of Waldeyer or tonsillar tissues should always be performed, and the findings should be documented.

Patients may have firm, nontender lymphadenopathy. This lymphadenopathy is cervical in 70-80% of patients and axillary in 25%. Other sites are supraclavicular, inguinal, and, less often, epitrochlear or popliteal. A mediastinal mass may cause superior vena cava obstruction, respiratory symptoms, or both. Splenomegaly, hepatomegaly, or both may be present.

Disease extension is predictable, is contagious, and can affect other organs and systems. Organs that are predominantly affected include the lungs, bone, bone marrow, liver parenchyma, and, rarely, the central nervous system.

 

DDx

 

Workup

Approach Considerations

The evaluation of the patient with Hodgkin lymphoma includes physical examination of all lymph node regions, chest radiography, CT scan of the chest/abdomen/pelvis, and nuclear imaging with gallium scan or, preferably, positive emission tomography (PET). In the past, patients with bone pain and elevated alkaline phosphatase or extensive disease also received bone scans. Nowadays PET detects more disease sites when combined with CT scans. Also, bilateral bone marrow biopsies were common practice for the staging of Hodgkin disease. Their use now is restricted to patients with advanced disease and or B symptoms. The need for bone marrow biopsies for staging is controversial, considering that a PET-CT scan can detect bone marrow involvement; however, additional studies are needed to confirm this.

Hematological and blood chemistry evaluation may reveal nonspecific findings in patients with Hodgkin lymphoma. Some usual findings include the presence of neutrophilia or eosinophilia. Some patients may have hypoalbuminemia. Some patients may have marked anemia or thrombocytopenia, and, occasionally, those may be related to an autoimmune dysregulation caused by a paraneoplastic related disorder. However, several of these findings have been used as prognostic factors.

Lymph node biopsy is mandatory to make the definitive diagnosis of Hodgkin lymphoma. Staging laparotomy is no longer advocated in pediatric Hodgkin lymphoma.

Staging

After a tissue diagnosis is made, Hodgkin lymphoma (HL) is staged by using imaging studies, evaluating the bone marrow, and assessing for B symptoms.

The most widely used staging system is the Ann Arbor staging system, as follows:

  • Stage I - Single lymph node region or single extranodal site

  • Stage II - Two or more lymph node regions on the same side of the diaphragm

  • Stage III - Lymph node regions on both sides of the diaphragm

  • Stage IV - Diffuse or disseminated involvement of one or more extralymphatic organs (liver, bone marrow, lung) or tissues with or without associated lymph node involvement (The spleen is considered a nodal site.)

A or B designations are also used. B includes the presence of at least one of the following symptoms:

  • Drenching night sweats

  • Unexplained fevers with temperature more than 38°C for 3 consecutive days

  • More than 10% loss of body weight in the past 6 months

The A designation involves the absence of symptoms described above. The E designation is extension or contiguous involvement of extranodal sites by large mediastinal masses that are not considered metastatic or stage IV.

Bulky disease defined as a 10 cm or larger mass (=6-cm mass for many pediatric trials) or large mediastinal adenopathy (mass greater than one third maximum thoracic diameter by chest radiography) is an adverse outcome factor.

In addition to the staging for pediatric patient with Hodgkin lymphoma, patients tend to be grouped according to their risk for relapse.

Table 1. Risk According to Stage (Open Table in a new window)

Risk Groups

Children’s Oncology Group

German Multicenter Studies

Stanford/Dana Farber/St. Jude

Low risk

I A no bulk or E II A no bulk or E

I A /B II A

I A II A no bulk

Intermediate risk

I A with bulk or E, I B II A with bulk or E II B III A IV A E

II B III A – E III B

I A bulk I B II A with bulk IIB III IV

High risk

III B IV B

II B – E III A / B - E IV A / B

 

 

The risk assignment allows the intensification of treatment according to the risk for relapse in such a way that low stages required less therapy than those with advanced stages. Risk assignment varies among the pediatric cancer cooperative groups, and, therefore, assignment of treatment varies. The risk stratification in one cooperative should not be mixed with therapy regimen of another cooperative group. The cooperative cancer groups strive to improve the outcome of children with Hodgkin lymphoma; however, the risk assignment may change with newer regimens.

CBC Count, Chemistry Panel, and Other Tests

The CBC count may reveal the following:

  • Hemolytic anemia (Coombs positive), anemia of chronic disease, or anemia secondary to involvement of the bone marrow

  • Leukocytosis, lymphopenia, eosinophilia, monocytosis

  • Thrombocytopenia due to marrow infiltration or idiopathic thrombocytopenia purpura

Assessment of acute-phase reactants may show elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein, serum copper, and ferritin levels.

A full serum chemistry panel may aid in evaluating levels of serum electrolytes; lactate dehydrogenase (LDH) levels, which reflect bulk of disease; alkaline phosphatase, which indicates bony metastasis; and liver and kidney function.

Urinalysis may reveal proteinuria. Nephrotic syndrome may be associated with Hodgkin lymphoma.

Radiography and Other Imaging Studies

Chest radiography is performed with anteroposterior and lateral projections to assess the bulk of the mediastinal mass. Mediastinal mass with a thoracic ratio of 33% or greater is of prognostic importance.

CT or MRI of the neck, chest, abdomen, and/or pelvis is indicated to assess sites of disease (nodal and extranodal), as well as to assess liver and spleen involvement. Ultrasonography can be used to assess the abdominal and pelvic structures in centers with limited resources in which CT scanning or MRI is not available. The minimal feasible amount of ionizing radiation should be used for diagnostic imaging in order to limit the future incidence of secondary malignancy.

Positron Emission Tomography

On (PET) scanning, uptake of the radioactive glucose analog 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is correlated with proliferative activity in tumors undergoing anaerobic glycolysis. PET scanning is used with increasing frequency to identify the extent of disease at diagnosis and for follow-up. After 2 cycles of therapy with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a positive PET scan finding may be predictive of poor outcome. However, confirmation of its utility with other regimens is pending.

PET scanning is becoming an important modality to guide involved-field radiation therapy in adult Hodgkin lymphoma,[7] and its role in guiding involved-field radiation therapy in pediatrics is being explored.

Gallium scanning is rarely used and has been replaced by PET scanning. Bone scanning has been used when bony metastases are suspected because of an elevated alkaline phosphatase level, but the same information may be obtained with PET scanning.

Biopsy

Histological diagnosis of Hodgkin lymphoma is always required. Ideally, the largest abnormal lymph node should be excised intact (excisional biopsy). Appropriate tissue handling is of essence to allow adequate evaluation of tissue architecture. When a formal lymph node excisional biopsy specinmen cannot be obtained, particularly from sites not easily accessible to the surgeon, such as the mediastinum fine-needle aspiration biopsy may be used. Although the diagnosis of HL can be made with very small samples by expert pathologists, a definitive diagnosis may be challenging for the less experienced specialist. Fine-needle aspiration biopsies are more reliable in the diagnosis of recurrent Hodgkin lymphoma.

Fine-needle aspiration is not recommended due to the lack of stromal tissue and the difficulty of classifying Hodgkin lymphoma into one of the classic subtypes versus nodular lymphocyte–predominant (NLP) subtype.

Bone marrow biopsy previously was common practice for the staging of Hodgkin lymphoma. Its use is now restricted to patients with advance disease (stage III and IV) or any other stage with B symptoms. Some controversy exists with regard to the need for bone marrow biopsy for staging, as it is thought that the PET scanning can detect bone marrow involvement. However, additional studies are needed to confirm these findings.

Histopathologic studies consist of hematoxylin and eosin staining and special immuno histochemical staining for surface markers such as CD15, CD20, CD30, and CD45. Consider other immuno histochemical staining to ensure that they are negative and to rule out non-Hodgkin lymphoma, such as CD3 and anaplastic lymphoma kinase (ALK).[#Workup Histologic Findings]

Histologic Findings

Hodgkin lymphoma (HL) is a unique malignant neoplasm in which the malignant cell represents only a small proportion of the cells making up the tumor. The majority of the cells are small lymphocytes, histiocytes, neutrophils, plasma cells, and fibroblasts in different proportions depending on the histological subtypes.

Hodgkin lymphoma is the Reed-Sternberg cells (RSCs). The RSCs generally are binucleated or multinucleated giant cells. The typical RSC has a bilobed nucleus with 2 large nucleoli that produces the characteristic "owl’s eye" appearance. The typical RSC is characterized by CD30 positivity, absence of J chains, and frequent expression of CD15, which is consistent with classic Hodgkin lymphoma.[8] . A variant of the RSC is the so called "popcorn cell" and is formally known as the lymphocyte and histiocytic (L&H) cell, typical of nodular lymphocyte-predominant Hodgkin lymphoma. L&H cells are small with a very lobulated nucleolus and small nucleoli. Their immunophenotype is characterized by CD20 positivity, J-chain rearrangements, and, in general, CD30 and CD15 negativity.

Classification

It has been recognized that Hodgkin lymphoma can be subdivided in 2 clinical, pathological, and biologic disease entities: classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin Lymphoma. The 1999 World Health Organization classification is presented below:[9]

  • Nodular lymphocyte-predominant Hodgkin Lymphoma (NLPHL)

  • Classical Hodgkin lymphoma

    • Nodular sclerosis

    • Mixed cellularity

    • Lymphocyte depleted

    • Lymphocyte rich

Nodular sclerosing Hodgkin lymphoma is notable for fibrous bands that result in a nodular pattern and lacunar-type RSCs, wherein the cytoplasm in formalin-fixed specimens retracts, forming a lacuna around the nucleus. This is the most common type in all age groups (77% of adolescents and 72% of adults), although it affects only 44% of younger children.

Mixed-cellularity Hodgkin lymphoma may have interstitial fibrosis, but fibrous bands are not observed. RSCs are classic in appearance or mononuclear. Lymphocytes may predominate in the cellular background (see the image below). This subtype is more common in young children (33%) than in adolescents (11%) or adults (17%).

Mixed cellularity Hodgkin lymphoma showing both mo Mixed cellularity Hodgkin lymphoma showing both mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells (hematoxylin and eosin, original magnification X200).

Lymphocyte-rich Hodgkin lymphoma has classic or lacunar-type H-RSC with rare or absent eosinophils on a cellular background. This type is extremely rare.

Lymphocyte-depleted Hodgkin lymphoma has large numbers of RSCs with sarcomatous variants and a hypocellular background because of fibrosis and necrosis. This type is also extremely rare.

Nodular lymphocyte-predominant Hodgkin lymphoma may be nodular, but fibrosis is unusual. The RSC variants are known as L&H cells (popcorn cells, because their nuclei resemble an exploded kernel of corn). The nuclei are multilobed and vesicular with small nucleoli. The characteristic halo of the classic RSC is absent. The background consists of histiocytes and lymphocytes with a B-cell predominance, in contrast to the cellular background in classic Hodgkin lymphoma, which has T-cell predominance.

Nodular sclerosis Hodgkin lymphoma is the most common type in developed countries, whereas in some developing countries, mixed-cellularity Hodgkin lymphoma is the most common histologic type.

 

Treatment

Approach Considerations

(HL) is one of the most curable malignancies of childhood and adolescence. The treatment of pediatric Hodgkin lymphoma is based on the experience of adult Hodgkin lymphoma treatment regimens. In general, the treatment of Hodgkin lymphoma is tailored to the subtype, staging, and response to therapy, and, as such, an accurate histopathological diagnosis is required.

Hodgkin lymphoma can be cured with radiation therapy and/or chemotherapy. Combined-modality therapy, including radiation and chemotherapy, is the preferred approach for most pediatric patients. Because most pediatric patients with Hodgkin lymphoma are successfully treated, an important consideration in the treatment approach of children and adolescents is the selection of a treatment regimen, particularly in reference to the anticipated late toxicities associated with cancer-directed therapy. Late toxicities vary substantially according to the treatment modality used.

Most modern pediatric treatment strategies focus on reducing late effects of therapy while maintaining excellent cure rates with risk-adapted chemotherapy alone or response-adjusted combined-modality regimens.[8]

The optimum treatment for adolescents and young adults (18-25 y) is not well defined. Pediatric and adult regimens are used depending on center-specific policies and referral patterns. Adult regimens have been shown to be safe and effective; however, the cumulative doses of chemotherapy used on those regimens have a significant impact on the growing child or adolescent.

The authors believe that children and adolescents (≤18 y) with Hodgkin lymphoma should be treated at a pediatric oncology center where a multidisciplinary team of pediatric specialists is familiar with the treatment and the acute and long-term complications of pediatric malignancies. Whether patients older than 18 years should be treated with adult or pediatric approaches should be tested prospectively in future trials. Currently, retrospective reviews seem to suggest that pediatric approaches may be better for these patients.

Hospital admission is sometimes indicated for supportive medical care.

Goals of therapy

Although pediatric Hodgkin lymphoma is highly sensitive to the treatment regimens devised for adults, long-term toxicity is enhanced in the developing individual. As a result, there have been dual goals in the design of clinical trials for pediatric Hodgkin lymphoma: (1) to reduce long-term organ injury and (2) increase efficacy. Radiation doses and fields have been reduced by enhanced reliance on chemotherapy, thus limiting the risk of hypothyroidism, secondary cancers, and cardiac disease. Multiagent chemotherapeutic regimens have been developed to reduce the cumulative doses of alkylating agents and anthracyclines to avoid the risk of sterility, leukemia, and cardiopulmonary toxicity. Most pediatric approaches use the response to therapy to limit the number of chemotherapy cycles for patients with good responses to therapy.

Assessment of treatment response

Response-based protocols for low stage and advanced stage are the standard of care in pediatric patients. There is evidence that response to therapy after induction chemotherapy is a predictor of event-free survival. Early response to therapy is a measure of chemosensitivity and a reflexion of the complex interplay between tumor biology and host factors, and for that reason it is used to tailor individual treatment and can serve as a basis for reduction of therapy.

Overall response is measured by the presence of a significant reduction, in general (>50–70%) of measurable disease from diagnosis, as measured by a CT scan. Evaluation of response with functional images is becoming the standard of care. Evidence of a negative FGD-PET activity of the positive areas at the time of diagnosis early in the treatment is utilized to tailor intensity of subsequent therapy.

As the use of functional imaging to assess response to therapy has increased, the level of uptake is now more standardized. A scoring system of London-Deuville is now used.

Radiation Therapy

Sequential nodal spread of disease, usually from neck to pelvis, allows for cure with radiation therapy to the involved and contiguous nodal regions but requires accurate staging of the disease. Radiation therapy was the first curative modality used for Hodgkin lymphoma (HL) in the early 1960s. However, the doses and fields used for the treatment of adult Hodgkin lymphoma caused profound musculoskeletal retardation, cardiac toxicity, and increased incidence of secondary malignancies in the radiation field (eg, breast cancer in female survivors).

The use of mantle field (cervical, mediastinal, and axillary nodes) and the inverted-Y field (para-aortic, pelvic, and inguinal nodes) are only used in exceptional situations.

Radiation protocols are used as an adjuvant treatment after chemotherapy. To reduce complications, risk-adapted or response-based, low-dose, involved-field, or extended-field radiation is administered. In current pediatric trials, the use of nodal conformal radiation is being evaluated to further decrease the burden of radiation to other tissues. In addition, in some protocols the field for radiation has changed, from the involved areas at the time of diagnosis to the residual disease present at the time of response to therapy evaluation. For example, radiation is limited to the areas of bulky disease at the time of diagnosis and/or persistent positron-emission tomography (PET)–positive areas after induction therapy.

Clinical trials incorporating radiation-sparing therapy protocols for pediatric Hodgkin lymphoma have recently been implemented. Preliminary data suggest that a subset of patients with good response to therapy may have good outcomes without radiation therapy.

PET scanning is becoming an important modality to guide involved-field radiation therapy in adult Hodgkin lymphoma,[7] and its role in guiding involved-field radiation therapy in pediatrics is being explored.

New guidelines on treatment of pediatric lymphoma with radiation therapy by the International Lymphoma Radiation Oncology Group[10, 11] include the following:

  • In children with Hodgkin lymphoma, treatment is more effective when 3-dimension imaging results are considered during the planning of radiation therapy (RT) and the calculation of the RT volume to be administered.

  • CT and FDG-PET scans before chemotherapy are critical in the calculation of RT gross tumor volume because they indicate the extent of tissue involvement. Gross tumor volumes should be considered when defining the "volume we need to treat" or when planning the volume of RT to deliver in children.

  • When planning RT volume, it is important to determine internal target volume, which takes into account variations in shape and motion in each patient, and the need for immobilization procedures.

  • Postchemotherapy imaging provides information on sites that remain abnormal.

  • A boost in radiation dose might be appropriate in cases of bulky residual disease or when responses are poor.

Chemotherapy Regimens

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.

Combined-modality therapy is preferred to avoid the high cumulative doses of alkylating agents, bleomycin, and anthracyclines used in chemotherapy-only protocols.

Although the treatment of pediatric patients with Hodgkin lymphoma started with regimens devised for adults, over the past 30 years those approaches have evolved to yield produce pediatric-focused protocols, which although more dense and intense, tend to reduce the cumulative doses of chemotherapy, below the threshold for known long-term toxicities. Multi agent chemotherapeutic regimens for children have been developed to avoid or reduce the risk of sterility, leukemia, and cardiopulmonary toxicity.

Chemotherapy alone may be effective in low-stage disease with a good response to therapy or in patients with limited-stage nodular lymphocyte-predominant Hodgkin lymphoma. This approach is recommended, especially in centers where pediatric radiation therapy is not feasible but where chemotherapy can be reliably administered.

The most common pediatric regimens used for the treatment of Hodgkin lymphoma are:

Europeans Regimens:

  • OPPA: Vincristine (Oncovin), procarbazine, prednisone, and doxorubicin (Adriamycin)

  • OEPA: Vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin)

  • COPP: Cyclophosphamide, vincristine, procarbazine, and prednisone

  • COPDAC: Cyclophosphamide, vincristine, prednisone and dacarbazine

  • VBVP: Vinblastine, bleomycin, etoposide, and prednisone

American Regimen (Children’s Oncology Group)

  • ABVE: Doxorubicin, bleomycin, vincristine, and etoposide

  • ABVE-PC: Doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide

  • BEACOPPesc: Bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone

  • COPP/ABV: Cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, and vinblastine

  • VAMP/COP: Vincristine, doxorubicin (Adriamycin), methotrexate, and prednisone alternating with cyclophosphamide, vincristine, and prednisone

  • Stanford V: Doxorubicin (Adriamycin), vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone

Other combinations of chemotherapeutic agents, as well as novel therapies, have been studied and found effective in front-line and salvage therapy for Hodgkin lymphoma.[12, 13]

Treatment for favorable-risk pediatric Hodgkin lymphoma

For early or favorable disease (stage IA or IIA with < 3 nodal sites, and some IIIA without bulky disease) standard treatment includes 2-4 chemotherapy cycles of ABVE, OEPA, or VAMP plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles of COPP alternating with ABVD and no irradiation. 2-4 cycles of the adult regimen ABVD is also comparable in terms of survival and cumulative doses of chemotherapy. Other regimens are feasible, effective, and safe but expose patients to unnecessary doses of chemotherapy.

Table 2. Survival Rates Associated With Chemotherapy and Radiation Therapy (Open Table in a new window)

Regimen

Involved-Field Radiation Dose

Five-Year Survival Rate

2-4 ABVD

20-40 Gy

90%

2-4 ABVE

21 Gy

88.3%

2 OEPA/OPPA

20-35 Gy

94%

4 VAMP

15-25.5 Gy

93%

4 COPP/ABV

21 Gy

100%

3 MOPP/3 ABVD

15-25.5 Gy

100%

2 MOPP/2 ABVD

20-40 Gy

87%

Treatment of advanced or unfavorable pediatric Hodgkin lymphoma

For intermediate-risk disease (stage IIA bulky disease with extension or 3 nodal sites, stage IIB, stage III, stage IV), standard treatment includes 3-5 cycles (depending on response to induction treatment) with ABVE-PC plus 21 Gy of involved-field radiation. The regimen delivers effective chemotherapy with a dose-dense regimen while reducing cumulative chemotherapy exposure for all patients.

For advanced or unfavorable disease (stages IIB, IIIB, or IV), one of the following 3 approaches is used:

  • The OEPA regimen spares the use of procarbazine by replacing it with etoposide and therefore reduces gonado-toxicity. It is also combined with COPP or COPDAC and is well tolerated and effective in the pediatric population.

  • The BEACOPP regimen is highly effective, but the cumulative doses of chemotherapy are problematic. The most benefit with this regimen is seen in patients with stage IVB disease.

  • Eliminating radiation therapy from the treatment of patients in this category has reduced event-free survival.[14]

Table 3. Survival Rates Associated With Chemotherapy and Radiation Therapy in Advanced or Unfavorable-Risk Disease (Open Table in a new window)

Regimen

Involved-Field Radiation Dose

Five-Year Survival Rate

4-8 ABVD

 

80%

3-5 ABVE-PC

21 Gy

84%

OPPA/OEPA

20-25 Gy

91%

COPP/ABV

21 Gy

72%

4 MOPP/4 ABVD

10-21 Gy

78%

6 VAMP/COP

15-25 Gy

68%

BEACOPPesc

21 Gy

94%

 

The treatment of Hodgkin lymphoma is a moving target. All cooperative groups are aiming to find the best strategy that will produce the best results with minimal toxicity. In this effort, the introduction of novel therapies such as Brentuximab-Vedotin, an anti-CD30 antibody conjugated and antitubulin agent, is being introduced in combination of standard chemotherapy agents, within the context of clinical trials.

Retrieval therapies for relapsed Hodgkin lymphoma

In patients with relapsing or unresponsive disease, autologous stem cell transplantation significantly prolongs disease-free survival. Various drug combinations have been used with stem cell rescue.

In the United States, (ICE) is the most widely used reinduction treatment option in children with Hodgkin lymphoma. Although, the use of ICE can put patients in second remission, it is not optimal, since it is associated with myelosuppression and increased risk of treatment-related secondary malignant neoplasms associated with the use of alkylating agents and epipodophyllotoxins.

Other retrieval regimens, such as the combination of ifosfamide with vinorelbine (IV), or Gemcitabine in combination with Vinorelbine (GV) have shown to be safe and effective as a reinduction regimen for relapsed pediatric Hodgkin lymphoma.[15] They have the advantage of eliminating the use of etoposide and reducing the increased incidence of treatment-related secondary myelodysplasia and acute myelocytic leukemia associated with this medication.

Other novel approaches for relapsed Hodgkin lymphoma in children include the combination of bortezomib, a proteasome inhibitor, to ifosfamide/vinorelbine (IV). Methotrexate, ifosfamide, etoposide, and dexamethasone has also been studied.[16]

In March 2017, pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1) gained accelerated approval from the FDA for cHL. It is indicated in adults and pediatrics patients with refractory cHL or who 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. Among the 145 responding patients, the median duration of response was 11.1 months.[17] Efficacy for pediatric patients is extrapolated from the results in the adult cHL population.

Although all of the salvage regimens produce remission rates in the range of 50–65% for relapsed Hodgkin lymphoma, when used alone, they are not curative and the disease-free survival (DFS) remains low. Addition of more intensive chemotherapy regimens followed by stem cell rescue has been shown to improve DFS compared with salvage chemotherapy alone.[18, 19]

High-dose therapy followed by autologous stem cell transplantation, after reinduction or salvage chemotherapy, is the current standard treatment for relapse disease. The most commonly used regimen is called BEAM (carmustine, etoposide, cytarabine and melphalan), which is given in the same fashion as given for adult patients.

One of the defining features of HL is CD30 expression by Reed-Sternberg cells. The use of an anti-CD30 molecule has been an attractive target in the treatment for HL.[6] Several anti CD30 antibodies have been engineered: MDX-060 (Medarex) a fully humanized antibody to CD30 (SGN-30), an ad chimeric monoclonal anti-CD30 antibody, both have shown to inhibit cell proliferation and to induce cell death in CD30 positive lymphomas. However, when used alone they were not effective as single agents, showing response rates much lower than traditional cytotoxic chemotherapy.

Newer generations of anti-CD30 antibodies with enhanced Fc receptor-antibody activity (Medarex, MDX-1401) and with antibody-drug conjugates are currently under study. The recent introduction of a conjugated anti-CD30 antibody conjugated to the antitubulin agent (brentuximab vedotin) has shown excellent results in CD30 positive lymphomas.

In a phase I, open label, multicenter dose-escalation study, 42 evaluable patients with refractory CD30 lymphomas demonstrated tumor regression of 86%.[20] An additional phase II clinical trial used Brentuximab Vedotin intravenously, at a dose of 1.8 mg/kg every 3 weeks with a response of 75% (76 out of 102) in patient with Hodgkin lymphoma, with complete remission in 34% of them. The average duration of response was 6.7 months. The excellent results of these studies resulted in the recent FDA approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma whose disease has progressed after autologous stem cell transplant, or after 2 prior multiagent chemotherapy treatments among patients ineligible to receive a transplant. Prospective studies in the pediatric population are warranted.

Other novel pharmacological approaches include inhibition of NF-kB pathway. NF-kB is a transcription factor that is constitutively activated in Hodgkin lymphoma, and that is thought to be responsible for cell proliferation and antiapoptosis in Hodgkin lymphoma.[21]

Bortezomib (Velcade) is a proteasome inhibitor that also inhibits NF-kB pathway. Bortezomib has shown some limited efficacy when used as a single agent or in combination with dexamethasone.[22] Inhibition of the antiapoptotic molecule XIAP has shown some encouraging results in preclinical studies.[23] M-TOR inhibitors, particularly everolimus, have also shown some promising results, with as much as a 42% overall response rate in patients with RR-Hodgkin lymphoma.[24]

Supportive Medication

A variety of medications may be used to counter the toxicities of treatment, such as the following:

  • Antiemetics (eg, ondansetron, diphenhydramine [Benadryl])

  • Pain relievers (eg, codeine, gabapentin) for neuropathic pain secondary to vinca alkaloids

  • H2 blockers or proton pump inhibitors to protect the gastric mucosa in patients receiving steroids

  • Pneumocystis prophylaxis and granulocyte colony-stimulating factor are also considered.

Long-Term Monitoring

The effects of therapy in the developing child/adolescent is significant. Most acute and late complications are due to treatment-related toxicities. Hypothyroidism after neck and chest irradiation is prevalent and affects as many as 50% of patients who survive pediatric Hodgkin lymphoma (HL) 10 years after treatment. In particular, white female patients are at greater risk than male patients and black patients.

Cardiac and pulmonary complications after radiotherapy depend on the cumulative doses of anthracyclines (cardiac effects) and bleomycin (pulmonary effects) and on the radiation dose.

Girls, and especially boys, are at high risk for infertility after they receive regimens containing high doses of alkylating agents. Therefore, male patients should receive counseling about storing their sperm in a sperm bank, when appropriate, before such a regimen is started.

As many as 30% of patients who survive pediatric Hodgkin lymphoma develop a secondary malignancy up to 30 years after their Hodgkin lymphoma is diagnosed. The most common secondary malignancies are thyroid cancer, breast cancer, no melanoma skin cancer, non-Hodgkin lymphoma, and acute leukemia.

Long-term survivors of Hodgkin lymphoma are more likely to die from treatment-related complications 30 years after diagnosis than from Hodgkin lymphoma.[25]

Patients require regular monitoring to assess their response to therapy and to check for adverse effects of treatment. During periods of decreased blood cell counts due to bone marrow suppressive effects of treatment, neutropenic and thrombocytopenic precautions should be observed.

In patients who achieve remission, 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. Most relapses occur in the first 3 years after therapy.

 

Medication

Medication Summary

Several chemotherapeutic agents in various combinations are used to treat Hodgkin lymphoma (HL). The combinations vary by the stage of disease and by the treating institution. In patients with relapsing or unresponsive disease, autologous 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 non overlapping 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.

Antineoplastic Agents

Class Summary

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 cancers grow quickly and undergo cell division more often compared with normal tissues, and the growth rate may be decreased in large tumors. This difference makes cancer more susceptible to chemotherapy.

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.

Mechlorethamine (Mustargen)

This alkylating agent is a component of the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen.

Bleomycin

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

Vinblastine

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

Dacarbazine

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

Etoposide (Toposar)

Etoposide is an epipodophyllotoxin that induces DNA strand breaks by disrupting topoisomerase II activity.

Vincristine ( Vincasar PFS)

Vincristine is a vinca alkaloid with a mechanism of action similar to that of vinblastine.

Procarbazine (Matulane)

Procarbazine is an alkylating agent with mechanism of action similar to that of dacarbazine.

Prednisone

Prednisone is a corticosteroid used to treat leukemias and lymphomas because of its lympholytic activity.

Cyclophosphamide

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.

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.

Methotrexate (Rheumatrex, Trexall)

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

Antineoplastics, Antimetabolite

Class Summary

These agents inhibit cell growth and proliferation.

Gemcitabine (Gemzar)

Gemcitabine is a cytidine analog. It is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is cell-cycle specific for the S phase and inhibits DNA synthesis by inhibiting DNA polymerase.

Antineoplastics, Monoclonal Antibody

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Brentuximab vedotin (Adcetris)

Brentuximab vedotin is an antibody genetically engineered antibody drug conjugate directed at DC30 consisting of a CD30-specific chimeric IgG1 antibody cAC10, a microtubule-disrupting agent, and a protease-cleavable dipeptide that conjugates MMAE to cAC10. The antibody internalizes MMAE within the cells, which then disrupts the microtubule network, causing cell cycle arrest and apoptosis.

PD-1/PD-L1 Inhibitors

Class Summary

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.

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. Efficacy for pediatric patients is extrapolated from the results in the adult cHL population.