Current Diagnosis

• Hodgkin lymphoma typically presents as painless lymphadenopathy in young people.

• Systemic symptoms are often absent, but may include “B” symptoms (fevers, drenching night sweats, or weight loss) or diffuse pruritus.

• Definitive diagnosis is by tissue biopsy, ideally by excisional lymph node biopsy. Fine-needle aspiration (FNA) is insensitive for the diagnosis of Hodgkin lymphoma and should be avoided.

Current Therapy

• Treatment is guided by clinical stage using the Ann Arbor staging system.

• Limited-stage disease (stages I–IIA) without adverse risk factors (also called “early favorable”) may be treated with combined- modality therapy (ABVD × 2 cycles followed by 20 Gy involved- field radiation), or 4 to 6 cycles of ABVD alone. Stanford V is an alternative option.

• Limited-stage disease (I–IIA) with adverse risk factors (also called “early unfavorable”) may be treated with combined-modality therapy (4 cycles of ABVD followed by 30 Gy involved-field radiotherapy), or with 6 cycles of ABVD alone. Patients with bulky disease at presentation should receive combined-modality therapy.

• Advanced-stage disease (Ann Arbor stage IIB–IV) should be treated with ABVD for 6 cycles. Radiation should be included for bulky stage II disease, and may be considered for consolidation of bulky presenting sites in stage III–IV disease. Escalated BEACOPP is an alternative treatment option.

• Selection of treatment should be informed by the toxicity profiles of available therapies as well as the location of disease and the age and comorbidities of the patient.


Hodgkin lymphoma is cancer of lymphoid tissue accounting for approximately 9000 new cases every year in the United States, and 1200 deaths. The median age of diagnosis is 35 years, but there is a bimodal distribution with the highest peak in the early 20s and then a rising incidence after the age of 60.


Pathologically, Hodgkin lymphoma is broadly categorized as either classical Hodgkin lymphoma (CHL) or nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (Table 1). CHL includes four histologic subtypes, which are grouped together because of a common malignant cell—the Hodgkin Reed-Sternberg (HRS) cell— and shared natural history, prognosis, and approach to therapy. These subtypes, in order of frequency, are Nodular Sclerosis (NSHL), Mixed Cellularity (MCHL), Lymphocyte Rich (LRHL), and Lymphocyte depleted (LD).

Table 1

Classification of Hodgkin Lymphoma

Classic  Hodgkin lymphoma 95%
Nodular sclerosis 75%
Mixed cellularity 15%
Lymphocyte rich 5%
Lymphocyte depleted 5%
Nodular  lymphocyte-predominant  Hodgkin lymphoma 5%

NSHL accounts for approximately 70% of new cases of HL in the United States, and occurs with a female predominance. All other subtypes of CHL occur more frequently in men. NLPHL accounts for only about 5% of new cases of HL each year, and occurs more commonly in men than in women.

Risk Factors

Most cases of Hodgkin lymphoma are sporadic, though a few risk factors have been identified. An increased risk of CHL among first- degree family members points to a heritable genetic susceptibility. Identical twins of CHL patients have a markedly increased risk of developing CHL, while other first-degree relatives are four times likelier to develop CHL than the general population. Given the low overall incidence in the population, the absolute risk of CHL among first-degree relatives remains quite low.

NSHL occurs more frequently in the Western world and is associated with a favorable socioeconomic status. MCHL, on the other hand, is the most common subtype in developing countries, and is often associated with underlying Epstein-Barr virus (EBV) infection, but the absolute risk of developing CHL after infectious mononucleosis remains low at approximately 1 in 1000. The median time to CHL diagnosis after infectious mononucleosis is 4 years. HIV infection is associated with a tenfold increased risk of developing CHL, related to the immune suppression and increased rate EBV transformation. Risk is similarly increased in other immunosuppressive states such as congenital immunodeficiency and following solid organ or hematopoietic stem cell transplantation.

Clinical Manifestations

CHL most commonly presents with painless lymphadenopathy. The most common locations are in the neck (75%) and mediastinum (60%), followed by the axillae, retroperitoneal, and inguinal lymph nodes.

Nodes are generally mobile and firm or rubbery on examination. The spleen is involved in approximately 20% of cases. Extranodal sites are uncommonly involved, including bone marrow, lungs, liver, bone, and other sites. Patients with bulky mediastinal disease may present

with dyspnea, chest pressure, or cough, though even large mediastinal masses may be asymptomatic. Superior vena cava syndrome is uncommon. Systemic “B” symptoms (fever > 38°C, unintentional weight loss of > 10% of body weight over 6 months, and drenching night sweats) occur in approximately one third of patients at diagnosis. Generalized pruritus is not considered a “B” symptom but is present in a minority of patients, in whom it may presage the diagnosis by many months. Pain at involved nodal or bony sites with alcohol ingestion is rarely present, but is unique and the mechanism is not understood. Notable laboratory findings at diagnosis are typically mediated by cytokine production associated with the lymphoma, and may include anemia, thrombocytosis, leukocytosis, eosinophilia, lymphopenia, and hypoalbuminemia. The degree of these laboratory abnormalities typically tracks with increased disease burden.

Hypercalcemia is an uncommon presenting feature, and is most commonly caused by increased production of calcitriol. Rarely, CHL can present with paraneoplastic cholestatic liver disease characterized by fevers and high conjugated bilirubin levels, but usually without frank infiltration by Hodgkin lymphoma on liver biopsy.

NLPHL presents in the majority of cases with localized painless peripheral adenopathy. Most patients are men between the ages of 30 and 50. The systemic “B” symptoms and laboratory abnormalities occasionally seen at presentation in CHL are rare in NLPHL.


Diagnosis of HL requires pathologic examination, ideally performed by excisional biopsy, which obtains the largest amount of tissue for analysis and preserves tissue architecture. Hodgkin lymphoma may be difficult to diagnose on small biopsies because the malignant cells represent only about 1% of the overall tumor cellularity, while the majority is comprised of polyclonal reactive lymphocytes, neutrophils, and eosinophils. Inadequate tissue sampling may therefore falsely suggest a reactive inflammatory process as opposed to the underlying malignancy. Core needle or mediastinoscopic biopsies may be used for deep nonpalpable lesions where excisional surgical biopsies are not possible. Fine-needle aspiration (FNA) should not be used for diagnosis when lymphoma is suspected in the differential diagnosis because of the high rate of false-negative results. On histologic examination of CHL, the involved tissue is effaced by an infiltration of malignant Hodgkin Reed-Sternberg (HRS) cells amidst a rich inflammatory background. The classic HRS cell is typically large with abundant cytoplasm and a bilobed nucleolus, each with a single large eosinophilic nucleolus giving it the classic “owl’s eye” appearance (Figure 1). Mononuclear variants also occur. By immunohistochemistry, the HRS cells usually stain positively for surface markers CD30 and CD15, and are usually negative for the pan-lymphoid marker CD45 and the B-cell marker CD20. The inflammatory microenvironment in NSHL is further characterized by dense bands of fibrosis from which its name is derived.



FIGURE 1    Classic Reed–Sternberg cell demonstrating large  size, multinucleated nucleus, and prominent eosinophilic  nucleolus.

NLPHL is similarly characterized pathologically by infrequent atypical malignant cells amidst a polyclonal inflammatory microenvironment composed primarily of small lymphocytes in large nodular meshworks of follicular dendritic cells. The malignant lymphocyte-predominant (LP) cell is quite different from the HRS cells of CHL, in that it expresses CD45 and CD20, and does not express CD30 or CD15.

Differential Diagnosis

The differential diagnosis of lymphadenopathy is quite broad, and includes a wide range of malignancies, including lymphomas and solid tumors, infections, autoimmune diseases, hypersensitivity syndromes, and others. Diagnostic evaluation is guided by the clinical presentation as well as the size, location, and examination characteristics of the adenopathy.

Staging and Risk Stratification

Following confirmation of a pathologic diagnosis, patients with Hodgkin lymphoma undergo staging studies to determine the extent of disease involvement. Unlike many other cancers, Hodgkin lymphoma is highly curable regardless of stage, but the staging does assist in treatment selection and risk stratification. Staging is based on the Cotswold modification of the Ann Arbor Staging system (Table 2). This system was developed for Hodgkin lymphoma based on the tendency for HL to spread predictably via lymphatic spread to adjacent nodal regions. Limited-stage disease is therefore confined to either a single lymph-node region (stage I) or multiple lymph-node regions on a single side of the body (stages II), whereas advanced- stage disease involves nodal regions on both sides of the diaphragm (stage III) or with extensive involvement of an extranodal site (stageIV) such as the lungs, liver, bone, or bone marrow. Additional letters may be added to the numeric stage to denote the absence or presence of “B” symptoms (“A” or “B”), bulky disease measuring greater than 10 cm (“X”) or splenic involvement (“S”). Stage IIB disease is typically categorized as advanced

Table 2

Ann Arbor Staging Sytem (Cotswold Modification)


Stage              Definition
I Confined to single lymph node region or limited involvement of a single extranodal site (IE)
II Confined to two or more lymph node regions on the same side of the diaphragm
III Lymph node regions involved on both sides of the diaphragm
IV Extensive involvement of one or more extranodal sites
E Localized focus of extranodal disease or localized extension of nodal disease into an extranodal site (e.g., hilar lymph node invading the lung)
A Absence of “B” symptoms: fever (> 38 °C), drenching night sweats, or unintentional loss of greater than 10% body weight over the previous 6 months.
B Presence of “B” symptoms
S Splenic involvement (the spleen is considered a nodal site)
X Bulky disease (greater than 10 cm or greater than 1/3 the width of the maximal intrathoracic diameter)

Staging begins with a physical examination with careful attention paid to all palpable lymph node regions, the spleen, and Waldeyer’s ring. Radiographic staging is performed with whole-body computed tomographic (CT) scans, ideally in conjunction with a Positron Emission Tomography (PET) scan as a combined PET/CT scan, which enhances the sensitivity over CT scans alone. Bone-marrow biopsy is often not performed in modern staging because of the enhanced sensitivity of PET scans in detecting bone marrow involvement in HL, which is often patchy in nature, and because of the incorporation of systemic therapy into the treatment plans of virtually all patients with either limited-stage or advanced-stage disease, ensuring that any sites of subclinical disease are still exposed to lymphoma-directed therapy. Similarly, staging laparotomy is never performed for modern staging given the sensitivity of modern radiographic techniques.

Additional pretreatment studies include routine laboratory testing with a complete blood count and differential; erythrocyte sedimentation rate; and complete metabolic panel including liver function, renal function, calcium and albumin. Given the association of HIV infection in a minority of cases, HIV antibody testing at baseline is recommended. Assessment of left ventricular function with an echocardiogram or MUGA scan as well as pulmonary evaluation with pulmonary function testing should be checked in anticipation of doxorubicin and bleomycin containing therapy, respectively. Though most chemotherapy for Hodgkin lymphoma carries only minimal risk of sterility, fertility counseling for patients in their childbearing years is recommended prior to initiation of therapy.

Risk Stratification

Though Hodgkin lymphoma is a highly curable disease, clinical and laboratory variables can stratify patients into lower and higher risk groups. The cure rate for limited-stage CHL with modern therapy is greater than 85%. Identified risk factors can place patients into an “early favorable” or “early unfavorable” category, though, importantly, the vast majority of patients in both groups will be cured of their disease with initial therapy. Adverse risk factors denoting early unfavorable disease include age greater than 50 years, bulky mediastinal mass, involvement of more than three nodal areas, extranodal disease, presence of systemic “B” symptoms, and an elevated erythrocyte sedimentation rate.

Within advanced-stage CHL, multivariable analysis identified seven adverse risk factors that are summed to generate the International Prognostic Score (IPS). These adverse risk factors at the time of diagnosis are male gender, age greater than 45 years, stage IV disease, serum albumin less than 4.0 g/dL, hemoglobin concentration less than 10.5 g/dL, white cell count greater than 15,000/mm3, and lymphopenia (< 600 cells/mL or < 8% of white cells). Data in the modern era with ABVD (doxorubicin [Adriamycin], bleomycin [Bleoxane], vinblastine [Velban] and dacarbazine [DTIC-Dome]) show 5-year freedom from progression ranging from 62% in the highest risk patients to 88% in the lowest risk patients, and 5-year overall survival ranging from 67% to 98%.

Prognosis in NLPHL is generally more favorable than that in classical HL, owing to a significantly more indolent natural history and higher likelihood of presenting as localized disease. Although late relapses may occur, very few patients die from NLPHL.


Limited-Stage Classical Hodgkin Lymphoma

Standard therapy for limited-stage (stage I-IIA) CHL has most commonly included combined-modality therapy with systemic chemotherapy followed by involved-field radiation. This standard evolved over many years, during which time randomized clinical trials demonstrated improved overall survival favoring combined- modality therapy compared to radiation alone, and showed no benefit to extended-field radiation over narrower radiation fields.

Patients with nonbulky limited-stage disease and absence of adverse risk factors (“early favorable”) may receive only 2 cycles of chemotherapy with ABVD followed by 20 Gy of radiation therapy to all involved fields. Bulk is defined as greater than one third of the maximum thoracic diameter greater than or equal to 10 cm in maximal diameter. Among patients with limited-stage disease with presenting bulk or presence of adverse risk factors (“early unfavorable”), combined-modality therapy is intensified to consist of 4 cycles of ABVD followed by 30 Gy of involved-field radiotherapy. Similar excellent results have been obtained with the Stanford V regimen, which is an 8- to 12-week chemotherapy program including mechlorethamine (Mustargen), doxorubicin, vinblastine, prednisone, vincristine (Oncovin, Vincasar PFS), bleomycin, and etoposide (Toposar),1 along with involved-field radiation therapy. Treatment intensification with the escalated BEACOPP regimen (bleomycin, etoposide,1 doxorubicin [Adriamycin], cyclophosphamide (Cytoxan), vincristine [Oncovin], procarbazine [Matulane] and prednisone) has been compared to ABVD in early unfavorable disease, each followed by involved-field radiation therapy, and found no difference in overall survival to favor the intensified approach. ABVD remains the most commonly employed chemotherapy backbone for limited-stage

Hodgkin lymphoma given the tolerability of the regimen and reduced reliance on alkylating agents.

Radiation therapy in young patients with Hodgkin lymphoma has prompted safety concerns given the increased incidence of late toxicities from mediastinal radiotherapy, including increased risk of secondary malignancies such as breast cancer, thyroid cancer, and lung cancer, as well as heart disease and lung disease. A large randomized trial comparing chemotherapy alone to combined- modality therapy showed a small increased risk of recurrence in patients who receive chemotherapy alone, but an improved overall survival 10 years after completion of therapy favoring chemotherapy alone, due to an excess of nonlymphoma deaths in the irradiated patients. Notably, the radiation employed in this trial was more extensive than modern involved-field radiotherapy, which may have overestimated the rate of late radiation events, but 94% of patients receiving ABVD alone remained alive and well 12 years later, demonstrating outstanding results from the radiation-sparing approach. These data support consideration of ABVD chemotherapy alone for 4 to 6 cycles in patients with nonbulky limited-stage Hodgkin lymphoma. Patients with bulky disease have not been included in a randomized trial sparing radiation, and so combined- modality therapy remains the standard of care for such patients.

Ongoing clinical trials in limited-stage disease are evaluating the role of early interim PET scanning in guiding intensity of chemotherapy and inclusion of radiation therapy.

Advanced-Stage Classical Hodgkin Lymphoma

Advanced-stage CHL (Ann Arbor stages IIB-IV) had been a nearly uniformly fatal disease prior to the development of effective combination chemotherapy with the introduction of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, and prednisone) at the National Cancer Institute in 1964. ABVD subsequently emerged as an alternative to MOPP, and was confirmed to have improved efficacy and reduced toxicity in a randomized trial that defined it as the standard of care. Modern outcomes with ABVD for advanced-stage disease produce 5-year freedom from progression and overall survival of 78% and 90%, respectively. ABVD is administered on days 1 and 15 of a 28-day cycle for 6 total cycles.

Consolidative radiation therapy is not routinely administered in advanced-stage disease, except in the setting of an incomplete response to chemotherapy alone, or to bulky sites of disease at presentation.

The escalated BEACOPP regimen has been extensively explored as an alternative to ABVD, and does modestly decrease the rate of recurrence, but without a clear impact on overall survival. Stanford V has also been evaluated in several randomized trials of advanced- stage disease without evidence of superiority over ABVD. In the absence of an overall survival benefit favoring escalated BEACOPP or Stanford V, and the increased treatment-associated toxicity associated with intensified therapy, most practitioners in North America continue to favor ABVD as the standard of care for advanced-stage disease, though this remains a subject of worldwide debate.

Treatment of Relapsed Hodgkin Lymphoma

Though the majority of patients with CHL will be cured with initial treatment, approximately 15% of patients will relapse and require additional therapy. Patients who relapse with localized disease greater than 1 year after completion of initial therapy and without systemic “B” symptoms may be treated with conventional-dose second-line chemotherapy followed by involved-field radiation. The majority of patients, however, will relapse in less than 12 months or with more advanced disease, for which conventional-dose chemotherapy offers a disappointingly low chance of cure. In such patients, second-line chemotherapy followed by high-dose chemotherapy with autologous stem cell support offers a cure rate approaching 50% and is the modern treatment of choice. Patients who relapse after high-dose chemotherapy may be candidates for allogeneic stem cell transplantation with curative intent, but success rates are low, and risks of treatment-associated morbidity and mortality are significant.

For patients who are not candidates for intensive therapy, or who relapse after stem cell transplantation, multiple chemotherapy options are available that may offer palliative disease control. An appealing option at relapse is the antibody drug conjugate brentuximab vedotin (Adcetris), which is a monoclonal antibody against CD30 bound to the microtubule toxin monomethyl auristatin E (MMAE). This targeted therapy is FDA approved for relapsed Hodgkin lymphoma based on an overall response rate of 75% and complete response rate of 34% in patients relapsing after high-dose chemotherapy and autologous stem cell transplantation. Current efforts are evaluating earlier use of brentuximab vedotin. The phase III double blind placebo-controlled AETHERA trial studied brentuximab consolidation therapy for patients in remission immediately following autologous stem cell transplantation for high risk relapsed Hodgkin lymphoma. Patients randomized to receive brentuximab consolidation had a significantly improved progression-free survival of 43 months, compared to 24 months in placebo-treated patients. No difference in overall survival has yet been observed in this trial, but patients progressing on the placebo arm did cross over and receive brentuximab at that time.

These results led to FDA-approval of brentuximab vedotin in this setting. Clinical trials incorporating brentuximab vedotin into upfront therapy in both limited- and advanced-stage Hodgkin lymphoma are ongoing. Most recently, immune checkpoint inhibitors have emerged as highly active agents in relapsed classical Hodgkin lymphoma.

Hodgkin Reed-Sternberg cells carry frequent genomic amplifications of chromosome 9p24.1, leading to constitutive expression of programmed death 1 (PD-1) ligands, which interact with PD-1 on the surface of T-cells in the microenvironment promoting immune evasion. This led to a phase I study of the PD-1 inhibitor nivolumab (Opdivo)1 in relapsed/refractory Hodgkin lymphoma, and found an overall response rate of 87%, some of which were durable. Similarly encouraging activity has been observed with an additional PD-1 inhibitor, pembrolizumab (Keytruda)1. Further investigation of these agents as monotherapy and in combination is ongoing.

Treatment of Nodular Lymphocyte- Predominant Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) follows a unique natural history from CHL, and is typically treated with less-intensive therapy. Limited-stage NLPHL usually presents at peripheral locations rather than the mediastinum, and may be treated with involved-field radiation alone (without chemotherapy), which produces a 10-year overall survival in excess of 95%. Advanced-stage NLPHL is uncommon, but may be treated with rituximab (Rituxan)1 because of the CD20 positivity of the malignant LP cells, with encouraging single-agent activity. Combination chemotherapy with either ABVD or with alkylator-based regimens is also effective.


Patients on therapy for Hodgkin lymphoma are evaluated for response using PET and CT scans, ideally as a combined-modality PET/CT scan. A complete response on PET/CT following 2 cycles of chemotherapy predicts for an extremely favorable prognosis, while a persistent positive PET scan is associated with a high rate of treatment failure. Clinical trials evaluating treatment intensification for patients with positive PET scans after 2 cycles of chemotherapy are ongoing, but presently there is no evidence that intensified therapy overcomes the negative prognostic effect of interim PET positivity, and so treatment modification based on interim PET results is not recommended outside of a clinical trial. Patients undergoing therapy for Hodgkin lymphoma are also evaluated with routine blood counts and chemistries to assess for treatment-associated marrow and organ toxicity. Patients receiving bleomycin are typically evaluated every 2 cycles with repeat pulmonary function tests in order to detect early evidence of bleomycin lung injury, though the predictive value of pulmonary function testing is controversial. Following completion of therapy, PET/CT scans should also be employed for end-of-treatment restaging, where it increases sensitivity over CT scans alone, particularly in the assessment of residual masses, which often represent residual scar tissue and debris of successfully treated disease.

Once patients achieve remission, they are followed by their oncologist in cooperation with their primary care physician to assess for relapse as well as late treatment-associated toxicities. Patients are monitored with periodic history and physical examination. CT scans are typically performed every 6 months for 2 to 3 years after completion of therapy, and thereafter only if prompted by concerning signs, symptoms, or physical findings. There is no role for PET scans in the routine follow-up of Hodgkin lymphoma after remission has been achieved. Following completion of radiographic surveillance, periodic history and physical examination continue, as does laboratory evaluation, to monitor for the development of uncommon late toxicities, including secondary malignancies, heart disease, and lung disease. Specific monitoring is dependent in part on the precise treatment the patient received.


Combination chemotherapy may be associated with fatigue, bone marrow suppression, increased susceptibility to infection, gastrointestinal upset, constipation, peripheral neuropathy, and mouth sores, among other complications. Doxorubicin carries a low risk of myocardial injury and congestive heart failure, and bleomycin carries a risk of lung injury, which may be life threatening. The risk of bleomycin lung injury persists lifelong, and may be precipitated by exposure to high inspired fractions of oxygen or other pulmonary insults. Risks of myelodysplasia and secondary leukemia as well as impaired fertility are rare after ABVD, but occur with increased frequency following MOPP, escalated BEACOPP, and high-dose chemotherapy.

Radiation-associated toxicities may occur decades following completion of therapy, and are a function of dose and volume of tissue exposure. Secondary malignancies steadily increase beginning approximately a decade after completion of therapy, and include breast cancer, lung cancer, thyroid cancer, gastrointestinal cancers, urogenital cancers, melanoma, and non-Hodgkin lymphomas, among others. Age-appropriate cancer screening is recommended as well as consideration of breast MRI for women who received mediastinal radiation as children or young adults.

Mediastinal radiation, particularly in combination with doxorubicin-containing chemotherapy, confers multiple cardiac risks to be aware of in long-term follow-up, including premature coronary artery disease, cardiomyopathy, valvular heart disease, and restrictive pericarditis. Lung exposure to radiation, particularly in concert with bleomycin, also confers a risk of radiation pneumonitis or late radiation fibrosis. Radiation to the neck may be associated with dental caries, dry mouth, thyroid dysfunction, and cerebrovascular disease.

Long-term care of the Hodgkin lymphoma patient requires attention to risk not only of relapse, but of the many late complications of therapy that may have substantial impact on long-term morbidity and mortality in Hodgkin lymphoma survivors.


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2.    Ansell S.M., Lesokhin A.M., Borrello I., et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–319 Jan 22.

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5.     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. J Clin Oncol. 1999;17:776–783.

6.      Eichenauer D.A., Fuchs M., Pluetschow A., et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2011;118:4363–4365.

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16.     Moskowitz C.H., Nademanee A., Masszi T., et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double- blind, placebo-controlled, phase 3 trial. Lancet.  2015;385(9980):1853–1862.

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1  Not FDA approved for this  indication

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