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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Incidence and Mortality
Estimated new cases and deaths from HL in the United States in 2022:
More than 75% of all newly diagnosed patients with adult HL can be cured with combination chemotherapy and/or radiation therapy. Over the last five decades, U.S. national mortality has fallen more rapidly for adult HL than for any other malignancy.
Anatomy of the lymph system.
HL most frequently presents in lymph node groups above the diaphragm and/or in mediastinal lymph nodes. Involvement of Waldeyer's ring or tonsillar lymph glands is rarely seen.
Risk factors for adult HL include the following:
These and other signs and symptoms may be caused by adult HL or by other conditions:
Treatment of HL should relieve these symptoms within days. For more information, see Hot Flashes and Night Sweats, Pruritus, and Fatigue.
Diagnostic evaluation of patients with lymphoma may include the following:
All stages of adult HL can be subclassified into A and B categories: B for those with defined general symptoms (described below) and A for those without B symptoms. The B designation is given to patients with any of the following symptoms:
The most-significant B symptoms are fevers and weight loss. Night sweats alone do not confer an adverse prognosis.
The prognosis for a given patient depends on several factors. The most important factors are the following:[1,4,5]
Other important factors are:[1,4,5]
The best predictor of treatment failure is a PET-CT scan obtained after two cycles (PET2 scan) of chemotherapy.[6,7] For limited-stage disease, there are frequent false-positive tests because the relapse risk is low (low-positive predictive value). For advanced-stage disease, up to 15% of patients relapse despite a negative PET2 scan (lowering the negative predictive value).[6,7] Combining biomarkers with PET-CT scanning responses or calculating metabolic tumor volume with PET-CT scanning are methods under evaluation to improve prognostic predictions.[6,8,9,10,11]
Recommendations for posttreatment follow-up are not evidence based, but a variety of opinions have been published for high-risk patients who present with advanced-stage disease or for patients who achieve less-than-complete remission by PET-CT scans at the end of therapy.[12,13,14,15] For patients at high risk of relapse, conventional CT scans are employed for screening to avoid the increased false-positive test results and increased radiation exposure of serial PET-CT scans.
For patients with negative findings from a PET-CT scan at the end of therapy, routine scans are not advised because of the very-low risk of recurrence. Opportunistic scanning is applied when patients present with suspicious symptoms, physical findings, or laboratory test results. The 5-year risk of relapse from diagnosis is 5.6% for patients remaining event-free for 2 years after induction therapy.
Among 6,840 patients enrolled in German Hodgkin Study Group (GHSG) trials, with a median follow-up of 10.3 years, 141 patients relapsed after 5 years, compared with 466 patients who relapsed within 5 years. Treatment-related adverse effects and late relapses may occur beyond 20 years of follow-up.
Adverse Long-term Effects of Therapy
Patients who complete therapy for HL are at risk of developing long-term side effects, ranging from direct damage to organ function or the immune system to second malignancies. For the first 15 years after treatment, HL is the main cause of death. By 15 to 20 years after therapy, the cumulative mortality from a second malignancy, cardiovascular disease, or pulmonary fibrosis exceeds the cumulative mortality from HL.[20,21,22,23] This risk of developing a second malignancy is even higher for individuals with a family history of cancer.
Recommendations for screening for secondary malignancies or follow-up of long-term survivors are consensus based and not derived from randomized trials.
An increase in second solid tumors has also been observed, especially mesothelioma and cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, and head and neck.[26,30,31,32,33,34,35] These tumors occur primarily after radiation therapy or with combined-modality treatment, and approximately 75% occur within radiation ports. The risk of developing a second solid tumor (cumulative incidence of a second cancer) increases with time after treatment.
In a cohort of 18,862 5-year survivors from 13 population-based registries, the younger patients had elevated risks for breast, colon, and rectal cancers for 10 to 25 years before the ages when routine screening would be recommended in the general population. Even with involved-field doses of 15 Gy to 25 Gy, sarcomas, breast cancers, and thyroid cancers occurred with similar incidence in young patients compared with those receiving higher-dose radiation.
Lung cancer and breast cancer are among the most-common second solid tumors that develop after therapy for HL.
In two case-control studies of 479 patients who developed breast cancer after therapy for HL, cumulative absolute risks for developing breast cancer were calculated as a function of radiation therapy dose and the use of chemotherapy.[50,51] With a 30-year to 40-year follow-up, cumulative absolute risks of breast cancer with exposure to radiation range from 8.5% to 39.6%, depending on age at diagnosis. These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[50,51]
In a nested case-control study and subsequent cohort study, patients who received both chemotherapy and radiation therapy had a statistically significant lower risk of developing breast cancer than did those treated with radiation therapy alone.[44,52] Reaching early menopause with fewer than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined-modality therapy. Reduction of radiation volume also decreased the risk of breast cancer after HL.
Late effects of autologous stem cell transplantation for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.
Other adverse long-term effects
Treatment for HL also affects the endocrine, cardiac, pulmonary, skeletal, and immune systems. Chronic fatigue can be a debilitating symptom for some long-term survivors. A retrospective survey of 20,007 patients with early- and advanced-stage classical HL treated between 2000 and 2016 (i.e., the era in which ABVD became the preferred frontline chemotherapy regimen) showed 1,321 deaths not attributable to lymphoma (39% of total deaths). Heart disease (estimated excess absolute risk as follows: 6.6 per 10,000 patient-years, standardized mortality ratio, 1.7 for early-stage disease and 15.1 per 10,000 patient-years, standardized mortality ratio, 2.1 for advanced-stage disease) and infection (estimated excess absolute risk as follows: 3.1 per 10,000 patient-years, standardized mortality ratio, 2.2 for early-stage disease and 10.6 per 10,000 patient-years, standardized mortality ratio, 3.9 for advanced-stage disease) were the leading causes of death, especially in patients older than 60 years.
Infertility. A toxic effect that is primarily related to chemotherapy is infertility, usually after regimens containing MOPP or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).[56,57,58] After six to eight cycles of BEACOPP, most men had testosterone levels within normal range; however, 82% of women younger than 30 years recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses. ABVD appears to spare long-term testicular and ovarian function.[57,60,61] Increasing age and alkylator-based regimens are the two major factors increasing the risk of premature ovarian insufficiency.[59,62,63] A prospective evaluation of gonadal function embedded in the randomized Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study for patients with newly diagnosed advanced-stage HL found good recovery of anti-Müllerian hormone concentration and reduction in follicle-stimulating hormone after ABVD or AVD (doxorubicin, vinblastine, dacarbazine), but less recovery after BEACOPP and for women older than 35 years. A PET scan-adapted treatment regimen to reduce the use of BEACOPP also resulted in less infertility and gonadal dysfunction. While cryopreservation of oocytes or sperm remains the first choice for preservation of fertility, luteinizing hormone-releasing hormone agonists can be tried in this setting, although efficacy for patients with HL has not been confirmed as has been confirmed for patients with breast cancer. A national Danish registry of 793 HL survivors showed that patients who did not relapse had similar parenthood rates to the general population, but assistive reproduction methods were required more often for HL survivors (male, 21.6% vs. 6.3%; female, 13.6% vs. 5.5%; P = .001 for both comparisons).
Hypothyroidism. Hypothyroidism is a late complication primarily related to radiation therapy.[67,68,69] Long-term survivors who receive radiation therapy to the neck are followed up with annual thyroid-stimulating hormone testing.
Cardiac disease. A late complication primarily related to radiation therapy is cardiac disease, the risk of which may persist for 25 years after first treatment.[67,70,71,72,73,74,75,76,77] The AER of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient-years and is mostly attributable to fatal myocardial infarction (MI).[70,71,72,74] A retrospective survey of over 6,000 patients with HL treated on trials between 1964 and 2004 found that cardiac exposure to radiation and utilization of doxorubicin were significant predictors of ischemic heart disease, congestive heart failure, arrhythmias, and vascular disease. In a cohort of 7,033 patients with HL, MI mortality risk persisted for 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine.[74,75] A nested case-control study of 2,617 5-year survivors of HL diagnosed before age 51 years and treated between 1965 and 1995 found that the 25-year risk of heart failure (moderate to severe) increases for patients receiving anthracyclines from 11.2% for exposure to 0 Gy to 15 Gy radiation up to 32.9% for radiation equal or greater than 21 Gy. The use of subcranial blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation. Compared with a normal-matched population, HL patients treated with mediastinal radiation have been reported to be at increased risk of complications, especially during cardiac surgery.
In the U.K. RAPID trial, performed between 2003 and 2010, 183 patients with early-stage HL were PET-negative but still received involved-field radiation therapy (IFRT) (20 Gy) after receiving ABVD. The average predicted 30-year cardiovascular mortality was 5.02%, which included 3.52% expected in the general population, 0.94% absolute excess risk from the adriamycin, and 0.56% from the IFRT. Since 2010, radiation therapy techniques have advanced by using smaller target volumes, lower-dose IFRT (20 Gy), deep inspiration breath holding, intensity-modulated radiation therapy, and proton beam therapy. These techniques will need further evaluation to better assess cardiovascular risks from radiation therapy.
Pulmonary impairment. Impairment of pulmonary function may occur as a result of mantle-field radiation therapy; this impairment is not usually clinically evident, and recovery in pulmonary testing often occurs after 2 to 3 years. Pulmonary toxic effects from bleomycin as used in ABVD are seen in patients older than 40 years.
Bone necrosis. Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.
Bacterial sepsis. Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL; it is much more common in children than in adults.
Fatigue. Fatigue is a commonly reported symptom among patients who have completed chemotherapy and radiation therapy. In a case-control study design, most HL survivors reported significant fatigue lasting for more than 6 months after therapy, compared with age-matched controls. Quality-of-life questionnaires given to 5,306 patients on GHSG trials showed that 20% of patients complained of severe fatigue 5 years after therapy, and those patients had significantly increased problems with employment and financial stability.[84,85,86] For more information, see Fatigue.
Pathologists currently use the World Health Organization (WHO) modification of the Revised European-American Lymphoma (REAL) classification for the histologic classification of adult Hodgkin lymphoma (HL).[1,2]
WHO Modification of the REAL Classification
The typical immunophenotype for classic HL is CD15+, CD20-, CD30+, CD45-, while the profile for lymphocyte-predominant disease is CD15-, CD20+, CD30-, CD45+.
Clinical staging for patients with adult Hodgkin lymphoma (HL) includes the following:
Staging laparotomy is no longer recommended and should be considered only when the results will allow substantially less treatment. Staging laparotomy should not be done in patients who require chemotherapy. If the laparotomy is required for treatment decisions, the risks of potential morbidity should be considered.[3,4,5,6]
Bone marrow involvement occurs in 5% of patients; marrow involvement is more prevalent in the context of constitutional B symptoms and anemia, leukopenia, or thrombocytopenia. In a retrospective review and meta-analysis of 955 patients in nine studies, fewer than 2% of patients with positive bone marrow biopsy results had only stage I or stage II disease on PET-CT scans. Omission of the bone marrow biopsy for PET-CT–designated early-stage patients did not change treatment selection. In addition, focal skeletal bone lesions on PET-CT predicted bone marrow involvement with a 96.9% (93.0%–99.08%) sensitivity and 99.7% (98.9%–100%) specificity. For these reasons, PET-CT has replaced bone marrow biopsy in the clinical staging of newly diagnosed HL.
Massive mediastinal disease has been defined by the Cotswolds meeting as a thoracic ratio of maximum transverse mass diameter of 33% or more of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level on chest radiography. Some investigators have designated a lymph node mass measuring 10 cm or more in greatest dimension as massive disease. Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.
Staging Subclassification System
The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma. The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference, with some modifications 18 years later from the Cotswolds meeting.
The E designation is used when well-localized extranodal lymphoid malignancies arise in or extend to tissues beyond, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
Many investigators and many new clinical trials employ a clinical staging system that divides patients into three major groups that are also useful for the clinician:
The group assignment depends on:
Early-stage adverse prognostic factors:
Early favorable group: Clinical stage I or II without any of the adverse prognostic factors listed above.
Early unfavorable group: Clinical stage I or II with one or more of the adverse prognostic factors listed above.
Advanced-stage adverse prognostic factors:
For patients with advanced-stage HL, the International Prognostic Factors Project on Advanced Hodgkin's Disease developed the International Prognostic Index with a score that is based on the following seven adverse prognostic factors:
Advanced group: Clinical stage III or IV with up to three of the adverse risk factors listed above. Patients with advanced disease have a 60% to 80% freedom from progression of disease at 5 years from treatment with first-line chemotherapy.[Level of evidence: 3iiiDiii]
After initial clinical staging for Hodgkin lymphoma (HL), patients with early favorable disease or early unfavorable disease are treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy with or without involved-field or nodal radiation.
Patients with advanced-stage disease are primarily treated with chemotherapy alone, although subsequent radiation therapy may be applied for initial bulky disease (=10 cm mediastinal mass) or for residual adenopathy (>2.5 cm) with positive findings after a postchemotherapy positron emission tomography (PET) scan. Treatment regimen preferences and application, as well as relative risks, differ regionally.
Patients with HL who are older than 60 years may have more treatment-related morbidity and mortality; maintaining the dose intensity of standard chemotherapy may be difficult.[2,3] Other therapies have been proposed for elderly patients too frail to withstand conventional regimens, but no randomized trials have been conducted with these regimens. Twenty-seven previously untreated patients older than 60 years, judged by the investigator to be in poor condition and unable to undergo chemotherapy, received brentuximab vedotin. A 92% overall response rate and 73% complete remission rate were reported.[Level of evidence: 3iiiDiv] Brentuximab vedotin has been combined with dacarbazine  or sequentially with AVD (doxorubicin, vinblastine, dacarbazine) , reporting acceptable toxicities in an elderly population. A retrospective review of 287 patients aged 60 years or older with early-stage favorable HL in two German Hodgkin Study Group (GHSG) trials (HD10 and HD13) showed increased bleomycin-induced lung toxicity with more than two cycles of exposure to bleomycin.
Table 4 describes the chemotherapy regimens used in the treatment of HL.
Radiation therapy alone is almost never used to treat patients newly diagnosed with early favorable classic HL. In adult HL, the appropriate dose of radiation alone is 20 Gy to 30 Gy to clinically uninvolved sites and 30 Gy to 36 Gy to regions of initial nodal involvement.[9,10,11] When mediastinal radiation will encompass the left side of the heart or will increase breast cancer risk in young female patients, proton therapy may be considered to reduce the radiation dose to organs at risk. When used as a single modality, radiation therapy is delivered to the neck, chest, and axilla (mantle field) and then to an abdominal field to treat para-aortic nodes and the spleen (splenic pedicle). In some patients, pelvic nodes are treated with a third field. The three fields constitute total nodal radiation therapy. In some cases, the pelvic and para-aortic nodes are treated in a single field called an inverted Y.[9,10,11]
Patients are designated as having early favorable classic Hodgkin lymphoma (HL) when they have clinical stage I or stage II disease and none of the following adverse prognostic factors:
Treatment Options for Early Favorable Classic HL
Treatment options for early favorable classic HL include the following:
Chemotherapy with or without radiation therapy
Treatment options include the following:
Historically, radiation therapy alone was the primary treatment for patients with early favorable classic HL, often after confirmatory negative staging laparotomy.
The late mortality from solid tumors (especially in the lung, breast, gastrointestinal tract, and connective tissue) and cardiovascular disease makes radiation therapy a less-attractive option for the best-risk patients, who have the highest probability of cure and long-term survival.[4,5,6,7,8] Clinical trials have focused on regimens with chemotherapy and IFRT or with chemotherapy alone.
Evidence (chemotherapy and/or radiation therapy):
For patients with early favorable classic HL, the following four trials established ABVD alone for four cycles or ABVD for two cycles plus 20 Gy of IFRT.
The following results were observed for the trial:
Other trials have investigated the role of positron emission tomography (PET) scans for early favorable HL.
In the RAPID study (NCT00943423), patients with postchemotherapy PET-CT Deauville scores of 5 (uptake =3 times maximum liver uptake) had inferior 5-year PFS rates (61.9%; 95% CI, 41.1%–82.7%) and 5-year OS rates (85.2%; 95% CI, 69.7%–100%) (P = .002) when compared with patients with Deauville scores of 1 to 4 (P < .001).
Older patients with early favorable HL have also been studied.
For older patients (>60 years) with early favorable disease, when more than two cycles of ABVD are required, bleomycin may be omitted to avoid pulmonary toxicity.
Summary of early favorable classic HL:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Patients are designated as having early unfavorable classic Hodgkin lymphoma (HL) when they have clinical stage I or stage II disease and one or more of the following risk factors:
A retrospective review found that infradiaphragmatic early-stage disease appears to have an inferior outcome compared with the more frequent (>90%) supradiaphragmatic disease, with a decrement in overall survival (OS) rates of 6% (91.5% vs. 97.6%; P < .001).[Level of evidence: 3iiiD]
Treatment Options for Early Unfavorable Classic HL
Treatment options for early unfavorable classic HL include the following:
Treatment options include the following:[2,3]
See Table 4 for a description of the chemotherapy regimens used to treat HL.
Evidence (chemotherapy and radiation therapy):
The following results were observed:
Could the radiation therapy be omitted to minimize late morbidity and mortality from secondary solid tumors and from cardiovascular disease?
A Cochrane meta-analysis of 1,245 patients in five randomized clinical trials suggested improved survival for combined-modality therapy versus chemotherapy alone (HR, 0.40; 95% CI, 0.27–0.61). However, the five randomized trials that were analyzed had inadequate follow-up to account for the late toxicities and increased mortality seen with radiation therapy after 10 years.
Other trials have investigated the role of positron emission tomography?computed tomography (PET-CT) scans for patients with early unfavorable HL.
This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles.
Patients with bulky disease (=10 cm) or massive mediastinal involvement were excluded from most of the trials. On the basis of historical comparisons to chemotherapy or radiation therapy alone, these patients receive combined-modality therapy.[16,17,18][Level of evidence: 3iiiDiii] A retrospective review published in a preliminary abstract reported on 194 patients with bulky disease who had PET-CT scans at the completion of chemotherapy; 112 of them had negative PET results (Deauville score of 1 or 2). The observed 86% OS rate at 5 years suggests that radiation therapy can be excluded for patients with massive mediastinal disease who have negative PET-CT scan results after six cycles of therapy.[Level of evidence: 3iiiD]
The following adverse prognostic factors for advanced classic Hodgkin lymphoma (HL) have been combined into the International Prognostic Score for advanced-stage HL:
Even the highest-risk patients in this index have a 5-year freedom from progression rate above 60% and a 5-year overall survival (OS) rate above 70%.
Treatment Options for Advanced Classic HL
Treatment options for advanced classic HL include the following:
The chemotherapy regimen ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is administered for six cycles.
See Table 4 for a description of the chemotherapy regimens used to treat HL.
Multiple studies have addressed the role of radiation therapy consolidation after induction chemotherapy for advanced-stage HL.
A randomized prospective trial with a median follow-up of 5.9 years included 320 patients with advanced-stage HL and a large nodal mass (=5 cm). Patients were randomly assigned to receive radiation therapy or no further treatment after six cycles of ABVD. For patients with a complete metabolic response on positron emission tomography (PET)–computed tomography (CT) after six cycles of ABVD, there was no difference in the 6-year progression-free survival (PFS) rate for patients who received radiation therapy (91%; 95% confidence interval [CI], 84%–99%) versus patients who received no further treatment (95%; 95% CI, 89%–100%, P = .62).[Level of evidence: 1iiDiii]
Other trials have investigated the role of PET scans or new combinations for patients with advanced classic HL.
A+AVD does not represent a change in the standard of care (ABVD) because of the following: insufficient follow-up of long-term side effects and OS, no difference in OS at 2 years, a modest difference in modified PFS (4.9%), and mandated use of G-CSF. The avoidance of pulmonary toxicity with A+AVD is countered by the elimination of bleomycin for patients with negative PET scan results after the second treatment cycle. A+AVD can cost 50 times more than ABVD (in 2018).[19,21]
Older patients with advanced-stage HL have also been studied.
Summary of advanced-stage classic HL:
At least half of all patients with recurrent Hodgkin lymphoma (HL) can achieve long-term disease-free survival (DFS), or even cure, using conventional chemotherapeutic agents followed by stem cell/bone marrow transplantation consolidation. In this regard, the disease follows a 75% rule: 75% of patients attain a clinical complete remission with salvage therapy reinduction, and then 75% of patients who undergo autologous stem cell transplantation (SCT) are free of disease at 4 years. Poor prognostic factors include the following:[2,3,4]
Treatment Options for Recurrent Classic HL
Treatment options for recurrent classic HL:
Nivolumab or pembrolizumab
The anti-programmed cell death-1 (PD-1) monoclonal antibodies nivolumab and pembrolizumab are immune checkpoint inhibitors.
Brentuximab vedotin is a chimeric antibody directed against CD30, which is linked to the microtubule-disrupting agent monomethyl auristatin E.[12,13,14] CD30 is a target for therapy because it is expressed on malignant Reed-Sternberg cells of HL, but has limited expression on normal cells. Brentuximab vedotin is well tolerated by patients and can be used to achieve a clinical complete response before autologous or allogeneic SCT.
Evidence (brentuximab vedotin):
Brentuximab vedotin plus nivolumab
Evidence (brentuximab vedotin plus nivolumab):
Chemotherapy with stem cell transplant
Patients who relapse after initial combination chemotherapy can undergo reinduction with the same or another chemotherapy regimen followed by high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue.[1,24,25,26,27] This therapy has resulted in 3- to 4-year DFS rates of up to 50%. Patients who are responsive to reinduction therapy may have a better prognosis after subsequent autologous SCT; in one analysis, the 3-year event-free survival (EFS) rate was 80% with negative PET-CT scan results and 29% with positive PET-CT scan results.
Patients who do not respond to induction chemotherapy (about 20%?25% of all presenting patients) have survival rates lower than 10% at 8 years. For these patients, high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue [24,25,29,30,31] have resulted in 5-year DFS rates of around 25% to 30%, but selection bias clearly influences these numbers.[24,25,30,32,33]
In a retrospective review of 105 patients, those older than 60 years fared better with a combination of chemotherapy and salvage radiation therapy than with the use of intensified transplant consolidation.[Level of evidence: 3iiiDiv]
The use of HLA-matched sibling marrow (allogeneic transplantation) results in lower relapse rates, but the benefit may be offset by increased toxic effects.[24,35,36] Reduced-intensity conditioning for allogeneic SCT is also under clinical evaluation.[37,38,39]
Evidence (chemotherapy with SCT):
After completion of autologous SCT for recurrent HL, 329 patients were randomly assigned to receive brentuximab vedotin or placebo in a double-blind trial (AETHERA [NCT01100502]).[19,20]
A phase II trial reported a response rate higher than 50% for bendamustine in relapsing ABMT patients.[Level of evidence: 3iiiDiv] For patients with recurrent disease after ABMT, weekly vinblastine therapy has provided palliation with minimal toxic effects.[Level of evidence: 3iiiDiv]
For patients who experience a relapse after initial combination chemotherapy, prognosis is determined more by the duration of the first remission than by the specific induction or salvage combination chemotherapy regimen. Patients whose initial remission after chemotherapy was longer than 1 year (late relapse) have long-term survival rates of 22% to 71% with salvage chemotherapy.[2,3,4,47,48,49] Patients whose initial remission after chemotherapy was shorter than 1 year (early relapse) do much worse and have long-term survival rates of 11% to 46%.[2,3,50]
It is rare to see a patient who received only radiation therapy for initial treatment, but patients who experience a relapse after initial wide-field, high-dose radiation therapy have a good prognosis. Combination chemotherapy results in 10-year DFS rates of 57% to 81% and OS rates of 57% to 89%.[2,51,52,53]
For the small subgroup of patients with only limited nodal recurrence following initial chemotherapy, radiation therapy with or without additional chemotherapy may provide long-term survival for about 50% of these highly selected patients.[54,55]
Summary for sequencing therapies for recurrent classic HL
NLPHL (CD15-, CD20+, CD30-) has been distinguished from lymphocyte-rich classic Hodgkin lymphoma (HL) (CD15+, CD20-, CD30+) on the basis of these immunophenotypic differences.[1,2] The largest retrospective report of 426 cases showed no significant difference in clinical response or outcome to standard therapies for these two subgroups when patients present with early-stage disease (stage I or II).[Level of evidence: 3iiiA]
Patients with NLPHL have earlier-stage disease and longer survival than those with classic HL.[4,5] NLPHL is usually diagnosed in asymptomatic younger patients with cervical or inguinal lymph nodes; this usually occurs without mediastinal involvement. Bulky disease, B symptoms, and contiguous spread are also uncommon in patients with NLPHL, in contrast with patients who have classical HL.[6,7]
Treatment Options for NLPHL
Treatment options for NLPHL include the following:
Watchful waiting/active surveillance
Because of the favorable prognosis for NLPHL and a fear of long-term side effects from therapy, studies have evaluated watchful waiting or active surveillance for patients with asymptomatic, low tumor burden disease. In a retrospective comparison, 37 such patients managed with active surveillance had a 5-year progression-free survival (PFS) rate of 77%, versus 85% for patients receiving active treatment.[Level of evidence: 3iiiDiv]
Based on retrospective analyses spanning several decades and because of the rarity of this histology, limited-field radiation therapy is the most-common treatment approach for patients with early-stage disease.[5,10,11,12,13,14]
Patients with nonbulky lymphocyte–predominant disease presenting in unilateral high neck (above the thyroid notch) or epitrochlear locations require only involved-field radiation therapy (IFRT) after clinical staging. A retrospective report of 426 cases of lymphocyte-predominant HL (including the nodular lymphocyte–predominant and lymphocyte-rich classic subtypes) showed that more patients died of acute and long-term treatment-related toxicity than of recurrent HL.[Level of evidence: 3iiiA] Limitation of radiation dose and radiation fields and avoidance of leukemogenic chemotherapeutic agents, along with watchful waiting policies, should be investigated for these subgroups.[14,16]
For patients with early-stage NLPHL, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for two to three cycles has been combined with IFRT on the basis of anecdotal single-arm trials.[5,17]
For patients with advanced-stage NLPHL, chemotherapy regimens designed for patients with non-Hodgkin lymphomas, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone), may be preferred, based on two retrospective reviews and a phase II study.[7,18,19,20][Level of evidence: 3iiiDiv]
In a phase II trial of 39 patients with previously untreated and relapsed NLPHL, most of whom had advanced-stage disease, treatment with rituximab yielded a 100% response rate. With a median follow-up of 9.8 years, the median PFS was 3.0 years for patients who received rituximab induction only and 5.6 years for patients who received rituximab induction plus rituximab maintenance.[Level of evidence: 3iiiDiii] With induction only, 9 of 23 patients relapsed with an aggressive B-cell lymphoma.
Despite a usually favorable prognosis, there is a tendency for histologic transformation of NLPHL to diffuse large B-cell lymphoma or T-cell–rich large B-cell lymphoma in approximately 10% of patients by 10 years.[6,21,22] This propensity of NLPHL to transform to aggressive B-cell lymphoma underscores the importance of long-term follow-up and rebiopsy at relapse.[21,23]
With a median follow-up of 7 to 8 years, more patients died of treatment-related toxic effects (acute and long-term) than of recurrent HL. Limitation of radiation dose and fields and avoidance of leukemogenic chemotherapeutic agents, along with watchful waiting policies, should be investigated for these subgroups.[5,16,24]
Relapsing disease is handled with a paradigm similar to that for a recurrent follicular lymphoma, utilizing sequential therapies and watchful waiting for some patients and considering aggressive salvage chemoimmunotherapy (like R-ICE [rituximab, ifosfamide, carboplatin, and etoposide]) followed by stem cell transplantation for others, based on age and performance status.[7,25,26]
Hodgkin lymphoma (HL) affects primarily young women, some of whom may be pregnant. When treating a pregnant woman, an oncologist will provide therapy that minimizes risk to the fetus. Treatment choice must be individualized, taking into consideration the following:
Stage Information for HL During Pregnancy
To avoid exposing a pregnant woman to ionizing radiation, magnetic resonance imaging is the preferred method for staging evaluation. The presenting stage, clinical behavior, prognosis, and histologic subtypes of HL in pregnant women do not differ from those in nonpregnant women during their childbearing years. For more information, see the Stage Information for Adult HL section.
Treatment Options for HL During Pregnancy
Treatment options for HL during pregnancy include the following:
In one study, the 20-year survival rate of pregnant women with HL did not differ from the 20-year survival rate of nonpregnant women who were matched for similar stage of disease, age at diagnosis, and calendar year of treatment.
The long-term effects on progeny after chemotherapy in utero are unknown, although evidence tends to be promising.[3,4,5,6,7]
Based on anecdotal series, there is no evidence that a pregnancy after completion of therapy increases the relapse rate for patients in remission.[8,9]
Therapy during the first trimester
HL that is diagnosed in the first trimester of pregnancy does not constitute an absolute indication for therapeutic abortion. Treatment options for each patient must take into account disease stage, rapidity of growth of the lymphoma, and the patient's wishes.
If the HL presents in early stage above the diaphragm and appears to be growing slowly, patients can be observed carefully, with plans to induce delivery early and proceed with definitive therapy.
Alternatively, these patients can receive radiation therapy with proper shielding.[12,13,14,15] Investigators at the MD Anderson Cancer Center reported no congenital abnormalities in 16 babies delivered after the mothers had received supradiaphragmatic radiation while the uterus was shielded with five half-value layers of lead. Because of theoretical risks of the fetus developing future malignancies from even minimal scattered radiation doses outside the radiation field, postponing radiation therapy—if possible, until after delivery—should be considered.
Evidence (chemotherapy during the first trimester):
Therapy later in pregnancy
In the second half of pregnancy, patients can be observed carefully, and therapy can be postponed until induction of delivery at 32 to 36 weeks.[6,7,18]
As an alternative, a short course of radiation therapy can be used before delivery in cases of respiratory compromise caused by a rapidly enlarging mediastinal mass.
If chemotherapy is mandatory before delivery—such as for patients with symptomatic advanced-stage disease—vinblastine alone, given intravenously at 6 mg/m² every 2 weeks until induction of delivery, may be considered because it has not been associated with fetal abnormalities in the second half of pregnancy.[6,7] Combination chemotherapy with ABVD appears to be safe in the second half of pregnancy. If chemotherapy is required after the first trimester, many clinicians prefer the combination of drugs over single-agent drugs or radiation therapy. Steroids are employed both for their antitumor effect and for hastening fetal pulmonary maturity.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Adult Hodgkin Lymphoma (HL)
Added text to state that positron emission tomography (PET)–magnetic resonance imaging scans may be equivalent to PET-computed tomography (CT) in obtaining staging information at 25% of the radiation dose (cited Picardi et al. as reference 3).
Added Moskowitz et al. as reference 47.
Added Kreissl et al. as reference 54.
Added text to state that a PET scan-adapted treatment regimen to reduce the use of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) resulted in less infertility and gonadal dysfunction (cited Demeestere et al. as reference 64). Also added text about a national Danish registry of 793 HL survivors that showed that patients who did not relapse had similar parenthood rates to the general population, but assistive reproduction methods were required more often for HL survivors (cited Øvlisen et al. as reference 66).
Added Cutter et al. as reference 77.
Added text about the U.K. RAPID trial, in which 183 patients with early-stage HL who were PET-negative received involved-field radiation therapy (IFRT) after receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
Treatment of Early Unfavorable Classic HL
Added text about GHSG HD17, a randomized prospective trial of 1,100 patients with early-stage unfavorable HL that evaluated whether radiation therapy can be omitted in patients with a complete metabolic response on PET-CT scan after two cycles of escalated BEACOPP and two cycles of regular-dose BEACOPP (cited Borchmann et al. as reference 13 and level of evidence 1iiDiii).
Revised text to state that for patients with a positive PET-CT after two cycles of ABVD, adding brentuximab vedotin while eliminating bleomycin can be considered. BEACOPP or clinical trials investigating the addition of brentuximab vedotin or checkpoint inhibitors in this setting would be indicated. Radiation therapy may be omitted in patients with a negative PET-CT after two to four cycles of chemotherapy.
Treatment of Advanced Classic HL
Added text about a randomized prospective trial that included 320 patients with advanced-stage HL and a large nodal mass who were randomly assigned to receive radiation therapy or no further treatment after six cycles of ABVD (cited Gallamini et al. as reference 15 and level of evidence 1iiDiii).
Treatment of Recurrent Classic HL
Revised text to include brentuximab vedotin plus nivolumab as a treatment option for recurrent classic HL.
Added text about a prospective randomized trial that included 304 patients with relapsed or refractory disease who were ineligible for or had relapsed after autologous stem cell transplantation. Patients were assigned to receive either pembrolizumab or brentuximab vedotin (cited Kuruvilla et al. as reference 5 and level of evidence 1iiDiii).
Added Brentuximab vedotin plus nivolumab as a new subsection.
Revised text about sequencing therapies for recurrent classic HL to include starting with pembrolizumab or nivolumab alone, brentuximab vedotin alone, or the combination of a checkpoint inhibitor plus brentuximab vedotin. If clinical complete remission is achieved, proceed to autologous SCT. Chemotherapy with ICE (ifosfamide, carboplatin, etoposide) or GVD (gemcitabine, vinorelbine, liposomal doxorubicin) remain as options. If chemotherapy results in inadequate response, proceed to pembrolizumab (or nivolumab).
Treatment of Nodular Lymphocyte–Predominant HL
Added as Moskowitz as reference 8.
Added Eichenauer et al. and Binkley et al. as references 13 and 14, respectively.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Adult Hodgkin Lymphoma Treatment is:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Adult Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389473]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2022-05-26
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