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Hodgkin Lymphoma: Diagnosis and Treatment

      Abstract

      Hodgkin lymphoma is a rare B-cell malignant neoplasm affecting approximately 9000 new patients annually. This disease represents approximately 11% of all lymphomas seen in the United States and comprises 2 discrete disease entities—classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Within the subcategorization of classical Hodgkin lymphoma are defined subgroups: nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich Hodgkin lymphoma. Staging of this disease is essential for the choice of optimal therapy. Prognostic models to identify patients at high or low risk for recurrence have been developed, and these models, along with positron emission tomography, are used to provide optimal therapy. The initial treatment for patients with Hodgkin lymphoma is based on the histologic characteristics of the disease, the stage at presentation, and the presence or absence of prognostic factors associated with poor outcome. Patients with early-stage Hodgkin lymphoma commonly receive combined-modality therapies that include abbreviated courses of chemotherapy followed by involved-field radiation treatment. In contrast, patients with advanced-stage Hodgkin lymphoma commonly receive a more prolonged course of combination chemotherapy, with radiation therapy used only in selected cases. For patients with relapse or refractory disease, salvage chemotherapy followed by high-dose treatment and an autologous stem cell transplant is the standard of care. For patients who are ineligible for this therapy or those in whom high-dose therapy and autologous stem cell transplant have failed, treatment with brentuximab vedotin is a standard approach. Additional options include palliative chemotherapy, immune checkpoint inhibitors, nonmyeloablative allogeneic stem cell transplant, or participation in a clinical trial testing novel agents.

      Abbreviations and Acronyms:

      ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), FDG ([18F]-fludeoxyglucose), GHSG (German Hodgkin Study Group), MOPP (nitrogen mustard, vincristine, procarbazine, prednisone), PD-1 (programmed cell death protein 1), PET (positron emission tomography)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) identify risk factors associated with Hodgkin lymphoma, (2) define prognostic factors that are associated with patient outcome, and (3) determine the standard treatment approaches for patients with Hodgkin lymphoma.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Ansell receives research funding from Seattle Genetics, Inc, and Bristol-Myers Squibb Company.
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      In 2015, approximately 9050 new cases of Hodgkin lymphoma will be diagnosed in the United States.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2015.
      Hodgkin lymphoma has a bimodal disease distribution, with an increased incidence in patients in their teenage years or early 20s and a similar increased incidence in patients older than 55 years.
      • Glaser S.L.
      • Jarrett R.F.
      The epidemiology of Hodgkin's disease.
      The exact cause of Hodgkin lymphoma remains unknown, but factors associated with an increased risk for Hodgkin lymphoma include exposure to viral infections, familial factors, and immunosuppression. Siblings of patients with Hodgkin lymphoma have an increased risk for this disease,
      • Grufferman S.
      • Cole P.
      • Smith P.G.
      • Lukes R.J.
      Hodgkin's disease in siblings.
      • Lynch H.T.
      • Marcus J.N.
      • Lynch J.F.
      Genetics of Hodgkin's and non-Hodgkin's lymphoma: a review.
      and a twin of a patient with Hodgkin lymphoma is also at substantially increased risk.
      • Mack T.M.
      • Cozen W.
      • Shibata D.K.
      • et al.
      Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease.
      • Horwitz M.
      • Wiernik P.H.
      Pseudoautosomal linkage of Hodgkin disease.
      Although familial factors may suggest a genetic cause for Hodgkin lymphoma, multiple studies have also suggested that an abnormal immune response to infection may play a role in the pathogenesis of Hodgkin lymphoma. Epstein-Barr virus has been implicated in the etiology of Hodgkin lymphoma in multiple epidemiological and serologic studies, and the Epstein-Barr virus genome has been detected in tumor specimens in certain trials.
      • Weiss L.M.
      • Strickler J.G.
      • Warnke R.A.
      • Purtilo D.T.
      • Sklar J.
      Epstein-Barr viral DNA in tissues of Hodgkin's disease.
      Furthermore, patients with human immunodeficiency virus infection are at considerably increased risk of Hodgkin lymphoma compared with the general population.
      • Franceschi S.
      • Dal Maso L.
      • La Vecchia C.
      Advances in the epidemiology of HIV-associated non-Hodgkin's lymphoma and other lymphoid neoplasms.
      Patients with immunosuppression associated with human immunodeficiency virus commonly present with more advanced stage of the disease in unusual sites and have a poorer prognosis after initial treatment.
      • Andrieu J.M.
      • Roithmann S.
      • Tourani J.M.
      • et al.
      Hodgkin's disease during HIV1 infection: the French registry experience.
      • Tirelli U.
      • Errante D.
      • Dolcetti R.
      • et al.
      Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors.
      In contrast, studies have found that infections such as chickenpox, measles, mumps, rubella, and pertussis in childhood are in fact inversely associated with the risk of Hodgkin lymphoma and may be protective.
      • Alexander F.E.
      • Jarrett R.F.
      • Lawrence D.
      • et al.
      Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents.
      Advances in therapy have substantially increased the likelihood of cure for patients with Hodgkin lymphoma. Currently, more than 80% of patients with newly diagnosed Hodgkin lymphoma are likely to be cured of their disease. Some subsets of patients still have a poorer prognosis, however, particularly patients who are elderly when they present with Hodgkin lymphoma. Although many patients have a good outcome, approximately 1150 deaths from Hodgkin lymphoma occur annually in the United States.
      • Siegel R.
      • Ma J.
      • Zou Z.
      • Jemal A.
      Cancer statistics, 2014.

      Diagnosis of Hodgkin Lymphoma

      Most patients with Hodgkin lymphoma present with supradiaphragmatic lymphadenopathy. Retroperitoneal and inguinal lymphadenopathy occur less frequently. Approximately one-third of patients present with constitutional symptoms. These symptoms include high fevers, drenching night sweats, and profound weight loss. Patients may also present with chronic pruritus. Although it is more common for the disease to involve regional lymph nodes, Hodgkin lymphoma may also involve extranodal sites either by direct invasion or hematogenously. Common sites that may be involved include the spleen, liver, lungs, and bone marrow.
      In patients with Hodgkin lymphoma, a definitive diagnosis is critical and requires that the treating physician provide the pathologist with an adequate pathologic specimen. Fine-needle aspiration or core-needle biopsy specimens are commonly inadequate because they do not represent the architecture of the lymph node and therefore preclude an accurate diagnosis. Hodgkin lymphoma has the unique characteristic of malignant cells constituting only a minority of the intratumoral cell population, and therefore, a small biopsy specimen may not include sufficient malignant cells.
      • Stein H.
      • Delsol G.
      • Pileri S.A.
      Hodgkin Lymphoma.
      To establish a definitive diagnosis, it is necessary to identify Reed-Sternberg cells within the biopsy specimen. These cells are commonly seen within a rich cellular environment composed of reactive lymphocytes, eosinophils, and histiocytes. Two distinct disease entities have been defined in Hodgkin lymphoma, the commonly diagnosed classical Hodgkin lymphoma and the uncommon nodular lymphocyte-predominant Hodgkin lymphoma.
      • Swerdlow S.H.
      • Campo E.
      • Harris N.L.
      • et al.
      WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.
      Within the category of classical Hodgkin lymphoma, 4 subgroups have been identified: nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte depletion Hodgkin lymphoma, and lymphocyte-rich Hodgkin lymphoma.
      The pathologic hallmark of classical Hodgkin lymphoma is the presence of large malignant multinucleated Reed-Sternberg cells, which are present within a characteristic reactive cellular background. Each subtype of Hodgkin lymphoma has distinct clinical features. Nodular sclerosis subtype tends to affect adolescents and young adults. Most commonly, this subtype presents with localized disease often involving the mediastinum and supraclavicular or cervical lymph nodes. In contrast, mixed cellularity Hodgkin lymphoma is more prevalent either in children or elderly persons, commonly presents with advanced-stage disease, and sometimes has a poorer prognosis. Lymphocyte depletion Hodgkin lymphoma is reported less frequently than it was previously because many of the previously reported cases are now reclassified as non-Hodgkin lymphomas. This subtype often occurs in elderly patients and is commonly associated with AIDS. These patients often present with extensive extranodal disease without substantial lymphadenopathy. Lymphocyte-rich classical Hodgkin lymphoma has an appearance similar to nodular lymphocyte-predominant Hodgkin lymphoma (discussed in the next paragraph), but Reed-Sternberg cells are identified with a more classical immunophenotype consistent with classical Hodgkin lymphoma rather than nodular lymphocyte-predominant Hodgkin lymphoma.
      • Ekstrand B.C.
      • Horning S.J.
      Hodgkin's disease.
      Nodular lymphocyte-predominant Hodgkin lymphoma is a unique pathologic entity that is distinct from classical Hodgkin lymphoma. This entity lacks typical Reed-Sternberg cells but instead has a neoplastic population of large cells known as lymphocytic and histiocytic (L&H) cells. These cells typically express CD20 and are usually negative for CD30, in contrast with classical Hodgkin lymphoma.
      • Pinkus G.S.
      • Said J.W.
      Hodgkin's disease, lymphocyte predominance type, nodular—further evidence for a B cell derivation: L & H variants of Reed-Sternberg cells express L26, a pan B cell marker.
      Nodular lymphocyte-predominant Hodgkin lymphoma is more frequent in males and may present with limited nodal disease often involving the neck but often sparing the mediastinum. The clinical course of nodular lymphocyte-predominant Hodgkin lymphoma differs from that of classical Hodgkin lymphoma in that the disease has a more indolent course but displays a propensity for late relapses.
      • Diehl V.
      • Sextro M.
      • Franklin J.
      • et al.
      Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease.
      Transformation to a more aggressive histology such as diffuse large B-cell lymphoma may occur in a subset of patients.

      Staging and Prognostic Factors

      An accurate determination of disease stage in patients with Hodgkin lymphoma is vital to selection of the appropriate initial treatment. The staging system for Hodgkin lymphoma is based on the location of lymphadenopathy, the number and size of lymph node sites, and whether the extranodal lymph node involvement is contiguous or due to dissemination of the disease systemically. Constitutional symptoms (also called B symptoms) are also incorporated into the standard staging classification. Positron emission tomography (PET) has recently emerged as an important tool for optimizing the staging of Hodgkin lymphoma. The use of PET adds considerably to staging information that previously was obtained by more standard radiologic methods.
      • Jerusalem G.
      • Beguin Y.
      • Fassotte M.F.
      • et al.
      Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease.
      The goal of treatment for patients with Hodgkin lymphoma is to cure the disease but limit long-term complications. The use of factors that identify patients who are at high risk for relapse is critical in defining the optimal intensity and duration of treatment. This process ensures adequate treatment and avoids overtreatment for some patients or undertreatment for others. Prognostic factors are defined by whether the patients have early-stage or advanced-stage disease. Prognostic factors for patients with early-stage Hodgkin lymphoma include the presence of a bulky mediastinal mass, an increased sedimentation rate, multiple nodal site involvement, involvement of extranodal sites, age greater than 50 years, and substantial enlargement of the spleen.
      • Tubiana M.
      • Henry-Amar M.
      • Carde P.
      • et al.
      Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease: the EORTC Lymphoma Group controlled clinical trials; 1964-1987.
      • Diehl V.
      • Stein H.
      • Hummel M.
      • Zollinger R.
      • Connors J.M.
      Hodgkin's lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease.
      In contrast, prognostic factors for patients with advanced-stage disease focus less on disease bulk and more on evidence of systemic involvement. The International Prognostic Factors Project on Advanced Hodgkin's Disease
      • Hasenclever D.
      • Diehl V.
      International Prognostic Factors Project on Advanced Hodgkin's Disease. A prognostic score for advanced Hodgkin's disease.
      identified 7 variables for patients with advanced disease: (1) age greater than 45 years, (2) stage IV disease, (3) male sex, (4) white blood cell count greater than 15,000/μL (to convert to ×109/L, multiply by 0.001), (5) lymphocyte count less than 600/μL (to convert to ×109/L, multiply by 0.001), (6) albumin level less than 4.0 g/dL (to convert to g/L, multiply by 10.0), and (7) hemoglobin value less than 10.5 g/dL (to convert to g/L, multiply by 10.0). Use of these factors confirmed that they predict patient outcome in a multivariate analysis. In the high-risk category of patients with 5 or more of these prognostic factors, the 5-year freedom from progression was only 42%. In contrast, patients with no poor prognostic factors had an 84% likelihood of remaining disease free at 5 years.

      Treatment of Hodgkin Lymphoma

      In determining the optimal treatment for patients with Hodgkin lymphoma, the factors that play a major role include the histologic features of the disease (classical Hodgkin lymphoma compared with nodular lymphocyte-predominant Hodgkin lymphoma), the stage of the disease (particularly whether the patient has early- or advanced-stage disease), the presence of clinical factors that suggest a poor prognosis, the presence of systemic symptoms, and the presence or absence of a bulky mass, defined as a single site of disease greater than 10 cm in diameter.
      [18F]-Fludeoxyglucose (FDG)–PET also plays a key role in defining the initial treatment. It is particularly important in confirming the stage of the disease and is also used to determine treatment success. While treatment is being given, an interim PET scan (typically done after 2 cycles of therapy) that is positive (indicating no or suboptimal response to treatment) may result in intensification of treatment, whereas treatment may be decreased if PET is negative (indicating response to therapy). Clinical trials are currently under way to determine whether this approach impacts patient outcome. A positive PET scan at the end of therapy may result in the addition of involved-field radiation therapy to PET-positive sites of disease. An increasingly positive PET result at any point during treatment may suggest progressive disease or chemotherapy-resistant disease, and repeated biopsy of the PET-positive sites to confirm this evidence is always recommended. The use of PET to define treatment is based on previous studies documenting that FDG-positive PET on completion of treatment is associated with a higher risk of disease recurrence regardless of imaging findings.
      • Jerusalem G.
      • Beguin Y.
      • Fassotte M.F.
      • et al.
      Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging.
      • Zinzani P.L.
      • Magagnoli M.
      • Chierichetti F.
      • et al.
      The role of positron emission tomography (PET) in the management of lymphoma patients.
      Furthermore, findings on interim PET after 2 cycles of treatment have been reported to be predictive of progression-free survival and overall survival in patients with Hodgkin lymphoma. In fact, PET findings are a better predictor of outcome than other prognostic factors including stage of disease, presence of extranodal sites of disease, and other prognostic factors.
      • Hutchings M.
      • Loft A.
      • Hansen M.
      • et al.
      FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma.
      • Gallamini A.
      • Hutchings M.
      • Rigacci L.
      • et al.
      Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study.

      Initial Treatment

      Initial treatment of Hodgkin lymphoma is usually different for 3 subgroups of patients, namely, patients with early-stage disease with favorable prognostic factors, patients with limited-stage disease who have unfavorable prognostic factors, and those with advanced-stage disease. In general, patients with early-stage disease receive shorter courses of combination chemotherapy followed by involved-field radiation therapy. In contrast, patients with advanced-stage disease typically receive more prolonged courses of chemotherapy, and radiation is added only in selected cases.

      Early-Stage Hodgkin Lymphoma With Favorable Prognostic Factors

      The management of early-stage Hodgkin lymphoma (stages I-IIA) has evolved over recent years. Initially, treatment with extended-field radiation therapy was considered standard. Because of the high likelihood of relapse and increased long-term complications, extended-field radiation therapy is no longer used.
      • Brusamolino E.
      • Lazzarino M.
      • Orlandi E.
      • et al.
      Early-stage Hodgkin's disease: long-term results with radiotherapy alone or combined radiotherapy and chemotherapy.
      A randomized trial comparing subtotal nodal radiation therapy with or without ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy found that patients being treated with subtotal nodal radiation therapy had an inferior overall survival and a higher rate of causes of death other than Hodgkin lymphoma when compared with those who received ABVD chemotherapy alone.
      • Meyer R.M.
      • Gospodarowicz M.K.
      • Connors J.M.
      • et al.
      NCIC Clinical Trials GroupEastern Cooperative Oncology Group
      ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma.
      Therefore, patients are most commonly treated with chemotherapy for control of any distant areas involved by Hodgkin lymphoma, and chemotherapy is combined with involved-field radiation therapy restricted to sites of confirmed disease involvement.
      Most patients with early-stage Hodgkin lymphoma and favorable prognostic factors will commonly receive 2 to 4 cycles of combination chemotherapy and then undergo involved-field radiation therapy at a dose of approximately 20 to 35 Gy.
      • Bonadonna G.
      • Bonfante V.
      • Viviani S.
      • Di Russo A.
      • Villani F.
      • Valagussa P.
      ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results.
      Data from a 4-arm clinical trial performed by the German Hodgkin Study Group (GHSG) revealed that patients with favorable prognostic factors may in fact benefit from less therapy.
      • Engert A.
      • Plütschow A.
      • Eich H.T.
      • et al.
      Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.
      The study of 1370 patients compared 2 cycles with 4 cycles of ABVD chemotherapy and also compared 20 Gy with 30 Gy of involved-field radiation therapy. There was no difference in response to therapy, progression-free survival, or overall survival for any of the 4 treatment groups. Therefore, ABVD chemotherapy for 2 cycles followed by 20-Gy involved-field radiation therapy is the current standard for patients with early-stage Hodgkin lymphoma who have favorable prognostic factors.
      • Engert A.
      • Plütschow A.
      • Eich H.T.
      • et al.
      Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.
      However, a variety of clinical trials are currently in progress to determine whether radiation therapy is in fact required. Initial studies have suggested that patients who are PET negative after 3 cycles of treatment may in fact not require any radiation therapy at all.
      • Radford J.
      • Illidge T.
      • Counsell N.
      • et al.
      Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma.
      Further trials are also under way to consider using agents such as brentuximab vedotin instead of radiation therapy as consolidation therapy after the initial 2 to 3 cycles of ABVD chemotherapy.

      Early-Stage Hodgkin Lymphoma With Unfavorable Prognostic Factors

      In patients with unfavorable prognostic factors including multiple nodal sites, evidence of extranodal disease, or a bulky mediastinal mass, combination chemotherapy followed by involved-field radiation therapy is also the treatment of choice. In general, however, these patients will commonly receive at least 4 cycles of combination chemotherapy (often using more intensive regimens) followed by involved-field radiation therapy.
      • Engert A.
      • Schiller P.
      • Josting A.
      • et al.
      Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.
      • Eich H.T.
      • Diehl V.
      • Görgen H.
      • et al.
      Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
      Data to support this approach include the results of a clinical trial of 1395 patients with stage I/IIA Hodgkin lymphoma with unfavorable features including a large mediastinal mass, extranodal disease, or an elevated sedimentation rate.
      • Eich H.T.
      • Diehl V.
      • Görgen H.
      • et al.
      Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
      In this study, patients were randomized to receive ABVD chemotherapy for 4 cycles of treatment or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy at baseline doses for 4 cycles of treatment with a further comparison of the use of 20-Gy or 30-Gy involved-field radiation therapy. The results revealed that patients receiving ABVD chemotherapy required 30 Gy of involved-field radiation treatment, whereas the outcomes were similar when 20 Gy or 30 Gy of radiation therapy was used in combination with a more intensive regimen such as BEACOPP chemotherapy. Overall, however, the assessment from this study was that ABVD chemotherapy for 4 cycles plus 30 Gy of involved-field radiation therapy is a standard of care for patients with early-stage Hodgkin lymphoma and unfavorable prognostic factors.
      • Eich H.T.
      • Diehl V.
      • Görgen H.
      • et al.
      Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
      Further studies have investigated intensifying chemotherapy in this patient group. In a clinical trial performed by the GHSG, patients were randomized to ABVD chemotherapy for 4 cycles or escalated doses of BEACOPP for 2 cycles followed by 2 cycles of ABVD chemotherapy.
      • von Tresckow B.
      • Plütschow A.
      • Fuchs M.
      • et al.
      Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial.
      All patients were then treated with 30 Gy of involved-field radiation treatment. In this study, the freedom from treatment failure analysis favored the more aggressive chemotherapy arm, but there was no difference in overall survival and increased toxicity was seen in the aggressive chemotherapy arm. Additional studies have since examined ways to maintain the efficacy of treatment but decrease potential toxicity.
      To achieve this goal, the use of PET has played an important role. [18F]-Fludeoxyglucose–PET has been used as an interim readout of treatment efficacy, and its value has been further enhanced by the use of a 5-point scale to analyze the results.
      • Barrington S.F.
      • Qian W.
      • Somer E.J.
      • et al.
      Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma.
      Using these Deauville criteria, FDG uptake greater than that in the mediastinal blood pool is considered positive if treatment is to be decreased or abbreviated. In most other cases, FDG uptake greater than that in the liver at any site is considered positive. The findings on interim PET are now being used in clinical trials to inform decisions concerning intensification or dose reduction of chemotherapy post-PET. Two recently reported studies have illustrated this approach. The United Kingdom National Cancer Research Institute RAPID (Randomised Phase III Trial to Determine the Role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin's Disease) study randomized patients with early-stage disease who had negative PET after 3 cycles of ABVD chemotherapy to either receive 30 Gy of involved-field radiation therapy or be observed without additional treatment.
      • Radford J.
      • Illidge T.
      • Counsell N.
      • et al.
      Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma.
      This study found that the 3-year progression-free survival and overall survival were not significantly different between the 2 arms. There was, however, a trend toward less disease control in patients who did not receive radiation therapy, and in a subset analysis excluding patients who did not receive treatment as defined by the protocol, this difference became statistically significant. A similar study conducted by the European Organisation for Research and Treatment of Cancer (HD10 study) compared standard therapy with ABVD chemotherapy in combination with involved-field radiation therapy to a nonradiotherapy approach using chemotherapy only.
      • André M.P.E.
      • Reman O.
      • Federico M.
      • et al.
      Interim analysis of the randomized Eortc/Lysa/Fil Intergroup H10 trial on early PET-scan driven treatment adaptation in stage I/II Hodgkin lymphoma [abstract].
      Similar to the RAPID trial, this randomization occurred in patients with negative PET after 2 cycles of ABVD chemotherapy. The results in this study suggested poorer disease control in patients who received chemotherapy only, but a detrimental effect on overall survival has not yet been documented and will require longer follow-up.
      The evidence to date suggests that the use of combined-modality treatment results in very good disease control for patients with early-stage Hodgkin lymphoma. A notable percentage of patients managed with this approach may in fact be cured. The outcome for patients treated with chemotherapy alone in this population appears quite similar to that with the combined-modality therapy approach, and the use of PET may in the future allow us to identify patients who would benefit from less treatment and possibly avoid complications of radiation treatment.

      Advanced-Stage Hodgkin Lymphoma

      Patients with stage IIB, III, and IV disease are considered to have advanced-stage lymphoma, and patients in this category are commonly managed with combination chemotherapy alone. Initially, MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy was developed for patients who had relapse after radiation treatment, and this combination was believed to be highly effective.
      • Longo D.L.
      • Duffey P.L.
      • Young R.C.
      • et al.
      Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure.
      Subsequently, ABVD chemotherapy was developed as a combination for patients with advanced-stage disease, and comparative studies randomizing patients to ABVD chemotherapy and MOPP chemotherapy reported an advantage for patients receiving ABVD chemotherapy.
      • Canellos G.P.
      • Anderson J.R.
      • Propert K.J.
      • et al.
      Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.
      • Viviani S.
      • Bonadonna G.
      • Santoro A.
      • et al.
      Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: ten-year results.
      • Connors J.M.
      • Klimo P.
      • Adams G.
      • et al.
      Treatment of advanced Hodgkin's disease with chemotherapy—comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group [published correction appears in J Clin Oncol. 1997;15(7):2762].
      • Duggan D.B.
      • Petroni G.R.
      • Johnson J.L.
      • et al.
      Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial.
      To further decrease toxicity, the Stanford V regimen was developed that included many of the active agents from both MOPP and ABVD treatment. The regimen was a brief dose-intensive regimen combined with radiation treatment.
      • Bartlett N.L.
      • Rosenberg S.A.
      • Hoppe R.T.
      • Hancock S.L.
      • Horning S.J.
      Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: a preliminary report.
      • Horning S.J.
      • Williams J.
      • Bartlett N.L.
      • et al.
      Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492.
      Initial studies achieved good results with this combination, and numerous clinical trials have compared the Stanford V regimen to ABVD. These trials have generally reported similar response rates and similar failure-free and overall survival.
      • Chisesi T.
      • Bellei M.
      • Luminari S.
      • et al.
      Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi.
      • Hoskin P.J.
      • Lowry L.
      • Horwich A.
      • et al.
      Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244.
      • Gordon L.I.
      • Hong F.
      • Fisher R.I.
      • et al.
      A randomized phase III trial of ABVD vs. Stanford V +/– radiation therapy in locally extensive and advanced stage Hodgkin's lymphoma: an intergroup study coordinated by the Eastern Cooperatve Oncology Group (E2496) [abstract].
      The incidence of adverse events has also been similar between the 2 regimens, with patients receiving ABVD at risk for greater lung toxicity and patients receiving the Stanford V regimen having development of a greater number of other toxicities such as hematologic toxicities.
      The GHSG has developed a standard-dose and an escalated-dose BEACOPP for patients with advanced-stage Hodgkin lymphoma.
      • Diehl V.
      • Sieber M.
      • Rüffer U.
      • et al.
      German Hodgkin's Lymphoma Study Group
      BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin's disease.
      Initial trials compared cyclophosphamide, vincristine, procarbazine, and prednisone alternating with ABVD to escalated- and standard-dose BEACOPP.
      • Diehl V.
      • Franklin J.
      • Pfreundschuh M.
      • et al.
      German Hodgkin's Lymphoma Study Group
      Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease [published correction appears in N Engl J Med. 2005;353(7):744].
      These studies found better tumor control and overall survival for patients receiving dose-escalated BEACOPP.
      • Engert A.
      • Diehl V.
      • Franklin J.
      • et al.
      Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study.
      Other randomized trials comparing ABVD chemotherapy and BEACOPP chemotherapy in advanced-stage Hodgkin lymphoma have also been reported.
      • Federico M.
      • Luminari S.
      • Iannitto E.
      • et al.
      ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial.
      • Viviani S.
      • Zinzani P.L.
      • Rambaldi A.
      • et al.
      Michelangelo FoundationGruppo Italiano di Terapie Innovative nei LinfomiIntergruppo Italiano Linfomi
      ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.
      • Engert A.
      • Haverkamp H.
      • Kobe C.
      • et al.
      German Hodgkin Study GroupSwiss Group for Clinical Cancer ResearchArbeitsgemeinschaft Medikamentöse Tumortherapie
      Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.
      These studies have revealed improved progression-free survival for patients receiving escalated BEACOPP, and in a meta-analysis of ABVD and escalated BEACOPP, there appeared to be an overall survival advantage for escalated BEACOPP.
      • Skoetz N.
      • Trelle S.
      • Rancea M.
      • et al.
      Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis.
      However, severe adverse events have been more frequent in patients receiving BEACOPP than in ABVD-treated patients, and this has led physicians to question whether all patients need to receive this very intensive approach.
      • Connors J.M.
      Hodgkin's lymphoma—the great teacher [editorial].
      When a randomized comparison of ABVD chemotherapy and escalated BEACOPP was analyzed and included a secondary analysis of patients undergoing subsequent salvage treatment, the overall final outcome of patients appeared to be similar. The 7-year rate of freedom from second progression between patients who received escalated BEACOPP and ABVD chemotherapy and then a subsequent stem cell transplant if they had disease progression was the same.
      • Viviani S.
      • Zinzani P.L.
      • Rambaldi A.
      • et al.
      Michelangelo FoundationGruppo Italiano di Terapie Innovative nei LinfomiIntergruppo Italiano Linfomi
      ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.
      It may therefore be reasonable to offer less intensive therapy to all patients initially and proceed with salvage treatment and autologous stem cell transplant only for the subset of patients who have disease progression. This plan prevents all patients from receiving intensive initial treatment such as escalated BEACOPP.
      Although most of the strategies discussed thus far have focused on intensification of treatment, more recent approaches have focused on adding novel new agents to standard chemotherapy. Clinical trials incorporating the use of brentuximab vedotin in ABVD chemotherapy found that the addition of brentuximab vedotin did increase pulmonary toxicity.
      • Younes A.
      • Connors J.M.
      • Park S.I.
      • et al.
      Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study.
      When bleomycin was omitted from the combination and patients were treated with AVD chemotherapy plus brentuximab vedotin, a high response rate was seen without serious pulmonary toxicity. A randomized, controlled phase 3 trial is currently in progress comparing ABVD chemotherapy with AVD chemotherapy plus brentuximab vedotin. The GHSG is similarly exploring the use of modified BEACOPP-like regimens in combination with brentuximab vedotin. Currently, the combination of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone is being tested in a phase 2 trial to assess whether the use of brentuximab vedotin can augment the BEACOPP regimen and decrease some of the toxicity.
      • Borchmann P.
      • Eichenauer D.A.
      • Plütschow A.
      • et al.
      Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study [abstract].
      In summary, ABVD chemotherapy remains the most commonly used treatment for patients with advanced-stage Hodgkin lymphoma in the United States. However, more dose-intensive approaches such as the use of escalated BEACOPP are certainly reasonable in patients with multiple poor prognostic factors. In the future, however, the addition of novel agents including brentuximab vedotin and possibly other immunologically active agents may improve the outcome for patients with advanced-stage disease.

      Nodular Lymphocyte-Predominant Hodgkin Lymphoma

      This subtype of Hodgkin lymphoma has a very different biology and clinical course.
      • Pinkus G.S.
      • Said J.W.
      Hodgkin's disease, lymphocyte predominance type, nodular—further evidence for a B cell derivation: L & H variants of Reed-Sternberg cells express L26, a pan B cell marker.
      Management of this entity is therefore quite different from the previously described management of other subtypes. In patients with stage IA disease and no major risk factors, removal of the lymph node followed by a watchful waiting approach or the use of involved-field radiation therapy is potentially curative and is all the treatment that may be required. These patients may have prolonged disease-free intervals but are at high risk for late relapses. In patients with more advanced-stage disease, ABVD chemotherapy has commonly been used. Because these cells express CD20, rituximab has been used in combination with ABVD chemotherapy. Rituximab treatment has also been used in patients who have disease progression after initial management.
      • Ekstrand B.C.
      • Lucas J.B.
      • Horwitz S.M.
      • et al.
      Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial.
      • Rehwald U.
      • Schulz H.
      • Reiser M.
      • et al.
      German Hodgkin Lymphoma Study Group (GHSG). Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group.
      However, optimal management of this disease entity is still being explored in ongoing clinical trials.

      Management of Disease Relapse

      Despite a high likelihood of success with front-line treatment, approximately 5% to 10% of cases of Hodgkin lymphoma may be refractory to the initial chemotherapy and/or radiation therapy. Furthermore, approximately 10% to 30% of patients may experience relapse after initially having a complete response to treatment.
      • Horning S.J.
      Hodgkin's disease.
      • Diehl V.
      • Mauch P.M.
      • Harris N.L.
      Hodgkin's disease.
      The typical management of these patients is to proceed with salvage chemotherapy followed by an autologous stem cell transplant. Initial phase 2 clinical trials suggest that high-dose chemotherapy followed by an autologous stem cell transplant produces better long-term disease-free survival than conventional chemotherapy. Typically between 30% and 65% of patients have a good outcome with this approach.
      • Josting A.
      • Kàtay I.
      • Rueffer U.
      • et al.
      Favorable outcome of patients with relapsed or refractory Hodgkin's disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dex-BEAM).
      • Lazarus H.M.
      • Rowlings P.A.
      • Zhang M.J.
      • et al.
      Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.
      • Brice P.
      • Bouabdallah R.
      • Moreau P.
      • et al.
      Société Française de Greffe de Moëlle. Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin's disease: analysis of 280 patients from the French registry.
      Two randomized trials have confirmed an improved outcome for patients managed with high-dose therapy and autologous stem cell transplant when compared with salvage chemotherapy.
      • Linch D.C.
      • Winfield D.
      • Goldstone A.H.
      • et al.
      Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial.
      • Schmitz N.
      • Pfistner B.
      • Sextro M.
      • et al.
      German Hodgkin's Lymphoma Study GroupLymphoma Working Party of the European Group for Blood and Marrow Transplantation
      Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial.
      In both studies, the 3-year event-free survival for patients undergoing an autologous stem cell transplant was better than 50%. Not all patients, however, are eligible for management with an autologous stem cell transplant. In particular, elderly patients have increased treatment-related mortality when managed with an aggressive approach.
      • Kusnierz-Glaz C.R.
      • Schlegel P.G.
      • Wong R.M.
      • et al.
      Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies.
      These patients may benefit instead from the use of agents such as brentuximab vedotin or could be considered for treatment in a clinical trial testing new agents.

      Therapeutic Options for Disease Progression After Autologous Stem Cell Transplant

      Patients who have disease progression after undergoing an autologous stem cell transplant have a poor outcome.
      • Kewalramani T.
      • Nimer S.D.
      • Zelenetz A.D.
      • et al.
      Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-Hodgkin's lymphoma.
      In the past, many of these patients were treated with palliative chemotherapy including agents such as vinorelbine and gemcitabine.
      • Devizzi L.
      • Santoro A.
      • Bonfante V.
      • Viviani S.
      • Bonadonna G.
      Vinorelbine: a new promising drug in Hodgkin's disease.
      • Santoro A.
      • Bredenfeld H.
      • Devizzi L.
      • et al.
      Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study.
      Many of these patients are also considered for an allogeneic stem cell transplant.
      • Robinson S.P.
      • Goldstone A.H.
      • Mackinnon S.
      • et al.
      Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.
      The toxicity associated with a myeloablative allogeneic stem cell transplant in this population has been substantial, and therefore, reduced-intensity allogeneic transplant has been preferred.
      • Schmitz N.
      • Sureda A.
      • Robinson S.
      Allogeneic transplantation of hematopoietic stem cells after nonmyeloablative conditioning for Hodgkin's disease: indications and results.
      The treatment-related mortality at 1 year with reduced-intensity allogeneic transplant is approximately 20%, with a 2-year overall survival of approximately 50%.
      • Robinson S.P.
      • Goldstone A.H.
      • Mackinnon S.
      • et al.
      Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.
      Recent trials have utilized brentuximab vedotin, an antibody drug conjugate targeting CD30 that is expressed predominantly in Reed-Sternberg cells, and this agent has been highly effective.
      • Younes A.
      • Bartlett N.L.
      • Leonard J.P.
      • et al.
      Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.
      In the initial pivotal phase 2 trial in patients with Hodgkin lymphoma who had disease progression after an autologous stem cell transplant, the overall survival was 75%, with complete responses seen in 34%.
      • Younes A.
      • Gopal A.K.
      • Smith S.E.
      • et al.
      Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma.
      A subset of responding patients have had durable remissions with this treatment. Other agents that have shown promise have included histone deacetylase inhibitors, mTOR (mammalian target of rapamycin) inhibitors, and immunomodulatory agents.
      • Younes A.
      • Sureda A.
      • Ben-Yehuda D.
      • et al.
      Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study.
      • Fehniger T.A.
      • Larson S.
      • Trinkaus K.
      • et al.
      A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma.
      • Johnston P.B.
      • Pinter-Brown L.
      • Rogerio J.
      • Warsi G.
      • Chau Q.
      • Ramchandren R.
      Everolimus for relapsed/refractory classical Hodgkin lymphoma: multicenter, open-label, single-arm, phase 2 study [abstract].
      Recently, data has been presented from patients who had disease progression after an autologous stem cell transplant and who were treated with an antibody blocking programmed cell death protein 1 (PD-1).
      • Ansell S.M.
      • Lesokhin A.M.
      • Borrello I.
      • et al.
      PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
      Programmed cell death protein 1 is present on intratumoral T cells, and the ligand for PD-1 is highly expressed in Reed-Sternberg cells. Clinical trials utilizing nivolumab and pembrolizumab revealed very high response rates, and many of these responses have been durable.

      Conclusion

      The optimal management of patients with Hodgkin lymphoma requires that an accurate diagnosis be made and that the disease be carefully staged so that optimal treatment can be recommended. Prognostic factors allow for further risk stratification to allow for less therapy for those with good prognostic factors and more intensive treatment for those with poorer prognostic features. Patients with more extensive disease benefit from a more intensive approach, and patients with evidence of disease relapse are managed with autologous stem cell transplant. The future, however, is likely to include new agents that have activity in disease relapse. These treatments include brentuximab vedotin as well as PD-1 blockade in the salvage and front-line setting.

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