Hodgkin Lymphoma Treatment & Management

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

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

Classical Hodgkin lymphoma stages

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

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

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

The EORTC definition uses the following patient criteria ^[39] :

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

The GHSG definition uses the following criteria ^[40] :

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

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

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

Treatment toxicity

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

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

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

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

Treatment goals

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

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

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

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

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

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

See also Hodgkin Lymphoma Treatment Protocols.

Clinical trials and consultations

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

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

Hodgkin lymphoma has gone from an incurable disease to one with a cure rate of almost 75%. ^[41] In general, the goal of therapy is to obtain complete remission (CR). Even in patients who fail to achieve CR, however, there are effective salvage regimens available that can result in long-term survival or cure.

Treatment response criteria are defined as follows:

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

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

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

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

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

Mid-treatment PET or combined PET/CT scans are increasingly used to help guide therapy. The current literature supports the use of interim PET or PET/CT scanning to provide prognostic information at any stage and to adapt therapy in advanced Hodgkin lymphoma. ^{[42, 43, 44]}

Guidelines recommend obtaining PET scans at least 6-8 weeks after completion of therapy. Some expert societies recommend waiting 8-12 weeks ^[36] because of the high-rate of false-positive scans. ^[45] If a scan is obtained, any positive result should lead to performance of a biopsy to confirm residual disease prior to altering therapy. ^{[46, 36]}

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

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

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

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

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

• Involved-node radiation (INRT): Radiation field that includes pre- and post-chemotherapy nodal volumes plus a 1-cm margin of healthy tissue; there are increasing data to support this, but it is still considered experimental ^[47]

ISRT is largely replacing IFRT. Current NCCN and international guidelines recommend ISRT for Hodgkin lymphoma. ^{[4, 48]}

In addition to the field used, the dose of radiation is also changing. The standard is typically 30-40 Gy (administered in single, daily fractions of 1.8-2 Gy, 5 times/wk), with the option of a boost of 6 Gy to sites of concern. ^{[49, 50, 51]}

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

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

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

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

The ABVD regimen is the standard of care for the treatment of classical Hodgkin lymphoma, particularly in the United States. ABVD is superior to MOPP in terms of disease-free survival (DFS) and has a lower incidence of sterility and secondary leukemia. ^[52]

The A+AVD regimen is a modification of the ABVD regimen, with brentuximab vedotin added and bleomycin omitted. It is the newest FDA-approved regimen for patients with stage III or IV classic Hodgkin lymphoma. Approval was based on a phase III trial that showed improved modified progression-free survival (PFS) compared with ABVD. ^[53] However, this trial has received criticism over its use of modified PFS as opposed to standard PFS, and long-term outcomes are awaited.

The Stanford V regimen is a multidrug regimen with irradiation included as part of standard therapy. ^[54] The drugs are administered weekly, alternating myelosuppressive and nonmyelosuppressive agents, for 12 weeks. Involved-field radiation (IFRT) at the conclusion of the 12-week treatment is an important part of this regimen. A potential advantage of the Stanford V regimen is that its use of a broad spectrum of chemotherapy drugs can limit the exposure (and potential side effects) of any single drug. However, several studies have failed to show superiority over ABVD, and the latter regimen remains the standard. ^[55]

The BEACOPP regimen was developed in Germany and is the default standard regimen there. ^[56] A dose-intensified version of BEACOPP (escalated BEACOPP), with higher doses of etoposide, doxorubicin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (G-CSF) for neutrophil support, has also been developed and may be useful for unfavorable, advanced-stage Hodgkin lymphoma. However, escalated BEACOPP is associated with greater hematologic toxicity and a higher incidence of secondary malignancies, including acute myelogenous leukemia (AML).

A study by Viviani et al demonstrated that BEACOPP produced better initial outcomes in patients with advanced Hodgkin lymphoma than treatment with ABVD but found no significant long-term differences between the regimens. ^[57] A meta-analysis by Bauer et al found that patients aged 16-60 years with early unfavorable or advanced stage disease benefited from escalated BEACOPP in terms of progression-free survival; however, no significant difference was noted in overall survival. ^[58]

More recently, a randomized comparison study by Mounier et al, in 150 low-risk patients with an International Prognostic Score (IPS) of 0-2, found that progression or relapses were more frequent with ABVD than BEACOPP (17 versus 5 patients, respectively). ^[59] In contrast, a randomized comparison study by Carde et al in 549 patients with high-risk stage III-IV Hodgkin lymphoma reported similar rates of event-free and overall survival with ABVD and BEACOPP; these authors stressed the importance of considering treatment burden, immediate and late toxicities, and associated costs when selecting a regimen. ^[60]

Induction chemotherapy schedules

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

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

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

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

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

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

The Stanford V regimen is given as follows ^[61] :

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

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

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

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

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

Salvage chemotherapy schedules

Single-agent therapy is given as follows:

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

The ICE regimen is given as follows:

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

The DHAP regimen is given as follows:

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

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

Historically, hematopoietic stem cells have been obtained from bone marrow, but they are now typically obtained by pheresis of peripheral blood lymphocytes. A validated and relatively safe conditioning regimen for autologous transplantation is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan). ^[7] In addition, Gayoso et al reported success with unmanipulated haploidentical related-donor transplant with a busulfan-based reduced conditioning regimen and post-transplant cyclophosphamide as prophylaxis against graft versus host disease. ^[62]

Myeloablative chemotherapy

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

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

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

Brentuximab vedotin is indicated as consolidation therapy following autologous hematopoietic stem cell transplantation (HSCT) in patients with classic Hodgkin lymphoma who are at at high risk of relapse or progression. Approval for this indication was based on the AETHERA clinical trial, in which median progression-free survival was 42.9 months in the brentuximab group versus 24.1 months in the placebo group, a statistically significant improvement of 18.8 months (P=0.001). ^[63]

The regimen is initiated 4-6 weeks after autologous HSCT as 1.8 mg/kg IV (not to exceed 180 mg/dose) infused over 30 minutes three times weekly for up to 16 cycles, or until disease progression or unacceptable toxicity. ^[25]

Patients with clinical stages IA or IIA classical Hodgkin lymphoma who do not have unfavorable factors (ie, bulky mediastinal or >10 cm disease, elevated erythrocyte sedimentation rate [ESR] >50 [or ESR >30 with B symptoms], more than three sites of involvement, extranodal disease) are categorized as having early-stage, low-risk disease. ^{[64, 65]}

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

In general, early-stage favorable Hodgkin lymphoma is treated with combined chemotherapy and radiation; however, there may be a role for chemotherapy alone. Randomized trials have shown that compared with radiation alone, combination chemotherapy followed by radiation is superior in terms of survival. ^[66]

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

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

The number of chemotherapy cycles and doses of radiation vary based on patient population. The German Hodgkin Study Group (GHSG) HD10 trial evaluated patients with early-stage favorable disease (defined as no more than two sites of disease, no extranodal extension, no bulky mediastinal disease, and ESR < 50 [or < 30 with B symptoms]) by looking at the following four different combinations ^[40] :

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

This study showed no difference in overall survival, freedom from treatment failure, and progression-free survival among the groups, but it did show significantly less toxicity in the lower chemotherapy and radiation arm. ^[40] The results suggested that ABVD for two cycles followed by IFRT 20 Gy is an acceptable treatment for patients with early-stage disease.

The question as to whether radiation therapy is needed after combination chemotherapy in the treatment of early-stage disease is a matter of debate. When the largest trial to date (NCIC/Eastern Cooperative Oncology Group [ECOG] HD6 trial) examined ABVD alone versus ABVD followed by radiation in patients with early-stage Hodgkin lymphoma, the investigators reported that the chemotherapy alone arm had superior overall survival based on less late toxicity. ^[67] However, whether these results are applicable to patients treated on modern protocols with ISRT is unknown.

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

However, although it is clear that such scans have prognostic value, it remains unclear whether altering therapy based on PET scan results improves treatment outcomes in early-stage disease. ^{[68, 69]} The current data support the monitoring of patients with history and physical examination prior to administering each cycle or modality of treatment and prior to obtaining laboratory studies and CT scans. Some experts suggest that PET scans should not be used to alter therapy outside of a clinical trial.

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

The preferred regimen is ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine), although other regimens are acceptable, including Stanford V and dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). It should be noted that these regimens are chosen not because they have been proven to be superior in managing early-stage disease; rather, they are an extrapolation from treatment of advanced disease, in which ABVD has been shown to have superior outcomes. ^[70]

At least two trials have compared therapy with escalated-BEACOPP versus ABVD in early-stage, unfavorable Hodgkin lymphoma. ^[58] These trials have shown that there does not appear to be a benefit to the use of dose-escalated BEACOPP relative to four cycles of ABVD. In addition, the toxicity was greater with BEACOPP therapy. ^[58] The results of these studies suggest that ABVD for four cycles followed by 30 Gy of IFRT is the current standard of care.

Similarly, in another study that examined alternating dose-escalated BEACOPP with ABVD versus ABVD alone with both regimens followed by IFRT, the escalated-BEACOPP regimen failed not only to show a survival advantage to the dose-intense regimen but also showed increased toxicity. ^[71]

It is a matter of debate as to whether chemotherapy alone can be used in patients with unfavorable disease. As noted, the only trial completed to date, the HD6 trial, did include patients with unfavorable Hodgkin lymphoma. ^[67] Given the flaws in design, particularly the use of outdated radiation therapy, the conclusions are limited. Regardless, chemotherapy alone may be an option for early-stage unfavorable patients without bulky disease.

Patients with early-stage disease with bulky mediastinal disease are treated differently than those with early-stage unfavorable disease without bulky mediastinal disease. In the United States, these individuals are usually treated with ABVD for 4-6 cycles, followed by ISRT at 36 Gy. ^[72]

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

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

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

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

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

Investigational regimens

The randomized phase II NIVAHL trial demonstrated the benefit of combining nivolumab with chemotherapy in early-stage unfavorable classical Hodgkin lymphoma. In NIVAHL, patients were randomly assigned to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. ^[73] On median follow-up of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival (PFS) rate was 98% in the sequential treatment group and 100% in the concomitant treatment group. ^[74]

The BREACH trial, a phase II study by the LYSA-FIL-EORTC Intergroup, demonstrated the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma. After two cycles, the primary end point of the study was met: 93 (82.3%) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%) of 57 patients in the ABVD arm. The 2-year PFS in the BV-AVD and ABVD arms was 97.3% versus 92.6%, respectively. ^[75]

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

The most commonly used regimen, and one endorsed by the National Comprehensive Cancer Network (NCCN), is ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine). ^{[4, 76, 77]} The drugs are administered every 14 days, with one cycle consisting of two administrations. This regimen is most commonly given for up to six cycles (12 doses of chemotherapy), although, occasionally, eight cycles are used. It is important to give the doses as planned (maintenance of dose intensity), and it should be noted that afebrile neutropenia is not a reason to withhold therapy. ^[78]

There is some suggestion in the literature that granulocyte colony-stimulating factor (G-CSF) may increase rates of bleomycin lung injury, but this has not been confirmed. ^[79] In fact, the largest series in patients with germ-cell tumors did not show an increased risk of bleomycin lung injury with G-CSF use. ^[80]

ABVD will result in complete remission (CR) in approximately 80% of patients treated, and up to one quarter of patients will have progressive disease-requiring salvage therapy (see below). ^[52]

An alternative regimen, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), is recommended by the NCCN for patients with a poor prognosis, as indicated by an International Prognostic Score (IPS) of 4 or higher. ^[56] Four cycles of escalated BEACOPP are given, with slow responders receiving four additional cycles. ^[4]

Escalated BEACOPP has CR rates of up to 95% in some trials, ^[81] but whether this is superior to ABVD therapy in an era with effective salvage is not known. ^{[57, 58]} However, adjustments in the delivery of BEACOPP including a reduced number of cycles has proven to be equally effective as the original schedule but with less toxicity. ^[82] Again, these modifications have not been compared to ABVD.

For patients with an IPS score of less than 3, the NCCN suggests use of the Stanford V regimen. ^[4] This regimen is used by some clinicians because of its decreased length of treatment and decreased doses of agents. Initial single-institution studies showed impressive results, ^[83] but subsequent randomized trials have not shown superiority over ABVD. ^[84]

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

A+AVD is the most recently approved regimen for advanced disease and has been shown to improve modified progression-free survival (time to disease progression, death, or evidence of non-complete response after completion of frontline therapy) compared with ABVD. ^[53] A higher incidence of febrile neutropenia in the brentuximab vedotin arm identified before the trial was complete led to the use of G-CSF as primary prophylaxis in subsequent patients in that arm of the trial. Peripheral neuropathy was also seen more commonly in patients who received brentuximab vedotin, but pulmonary toxicity less commonly.

Beyond chemotherapy, there is even more controversy regarding the role of radiation in advanced Hodgkin lymphoma. The majority of data to date suggest that radiation improves progression-free survival but without improving overall survival. ^{[85, 86]} When administered after ABVD or BEACOPP, radiation probably adds little benefit to the majority of patients. ^{[18, 87]} One exception may be those patients with bulky mediastinal disease—which is known to be a poor prognostic marker—whose outcomes may be improved with radiation. ^[88] It must be noted that if the Stanford V regimen is used, then radiation is an integral part of the regimen and must be given.

The role of interim PET-CT scans in the treatment of advanced Hodgkin lymphoma has become more established. A phase III trial showed that if interim PET-CT is negative after two cycles of ABVD, bleomycin can be stopped (ie, de-escalation to AVD) without compromising efficacy. ^[44] Notably, in the same trial, patients with a positive PET-CT went on to receive BEACOPP, but there was no randomized comparison of BEACOPP versus ABVD in the PET-positive patients. The NCCN guidelines support this approach, ^[4]  which avoids the pulmonary toxicity associated with bleomycin.

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

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

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

Early-stage NLPHL can be treated with local excision, involved-field radiation therapy (IFRT), or expectant management (close observation). ^[89] Advanced-stage disease may represent histologic transformation to T-cell-rich B-cell lymphoma (TCR-BCL) or diffuse large cell B-cell lymphoma (DLBCL), both of which should be treated with a typical non-Hodgkin regimen such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab is a humanized monoclonal antibody that is specific for CD20, a cell-surface antigen expressed by the malignant lymphocytic and histiocytic (L&H) cells in NLPHL. It is a promising agent that has shown activity in NLPHL. On long-term follow-up, the German Hodgkin Lymphoma Study Group observed a 94% overall response rate, with 8 complete remissions, from their population of 15 patients treated with rituximab for relapsed/refractory NLPHL. ^[90] The use of rituximab in NLPHL, especially in early-stage disease, should ideally be pursued in the context of a clinical trial.

A phase 2 study by Eichenauer et al found that results with rituximab appear inferior when compared with radiotherapy and combined-modality treatment in patients with early-stage NLPHL. However, the authors concluded that investigation of anti-CD20 antibody–based combinations in patients with NLPHL is indicated. ^[91]

An era-to-era comparison between ABVD treatment and radiotherapy alone found that treating limited-stage NLPHL similar to classical Hodgkin lymphoma may improve outcome compared with the use of radiation alone. ^[92]

In patients with advanced Hodgkin lymphoma and HIV infection, the results with standard chemotherapy can be dramatically improved by simultaneous treatment with effective antiretroviral therapy (ART). ^[3] For more information on ART regimens, see HIV Infection and AIDS.

Patients with Hodgkin lymphoma who have never entered complete remission (CR), or whose disease has relapsed after the attainment of CR, have a very poor prognosis when treated with standard chemotherapy and radiation. Therefore, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) is recommended for these patients. ^[93]

In this procedure, salvage chemotherapy is first administered to help reduce the size of the persistent disease and obtain CR, if possible. The number of cycles to be administered depends on how well the disease is responding to therapy. An optimal situation is one in which the disease enters CR with negative positron emission tomography (PET) scan findings, although one study demonstrated that patients may achieve long-term disease-free survival even if their condition has little or no response. ^[94]

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

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

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

In some cases in which HDC fails, allogeneic HSCT may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes radiation therapy) is followed by the infusion of hematopoietic stem cells from a genetically matched donor. ^[95] This offers the potential for an immunologic antitumor effect from T cells provided by the hematopoietic stem cell donor, which may improve the chances for cure of the disease.

Historically, allogeneic HSCT for Hodgkin lymphoma has been considered too high-risk for most patients, due to high transplant-related mortality. However, new transplant protocols use less toxic conditioning regimens and may be safer and more effective for patients with refractory Hodgkin lymphoma. ^[96]

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in 2011 for treatment of patients with Hodgkin lymphoma after failure of autologous HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for HSCT. This agent is a CD30-directed antibody-drug conjugate consisting of IgG1 antibody cAC10, specific for human CD30, and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin). ^[97]

Results from a study of patients with Hodgkin lymphoma in whom autologous HSCT and a median of four chemotherapy regimens had failed (n = 102) showed that 73% (95% confidence interval [CI], 65-83%) achieved an objective response to brentuximab vedotin therapy, including 32% with complete remission (95% CI, 23-42%) and 40% with partial remission (95% CI, 32-49%). Response duration averaged 6.7 months (range, 1.3-21.9 months). ^[98]

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

In 2016, the FDA approved the monoclonal antibody nivolumab for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous HSCT and posttransplantation brentuximab vedotin. Approval was based on a combination of the phase 2 CheckMate 205 and phase 1 CheckMate 039 trials with an efficacy analysis conducted on data from 95 patients. Treatment with nivolumab showed an objective response rate (ORR) of 65% (CI 95%: 55-75; 62/95), a complete response rate (CRR) of 7% (CI 95%: 3-15; 7/95), and a partial response rate (PRR) of 58% (CI 95%: 47-68; 55/95). Among responders, the median duration of response was 8.7 months (CI 95%: 6.8-NE; range 0.0+, 23.1+). ^{[99, 100]} Extended follow-up of the CheckMate 205 trial confirmed that responses to nivolumab were frequent and durable. ^[101]

In 2017, pembrolizumab, another monoclonal antibody to programmed cell death-1 protein (PD-1) gained accelerated approval from the FDA for classical Hodgkin lymphoma. It is indicated in adults and pediatric patients who have refractory disease or have relapsed after 3 or more prior lines of therapy. Approval was based on data from the KEYNOTE-087 trial (n=210), which demonstrated an ORR with pembrolizumab averaging ~67% (95% CI: 62, 75), a CRR of 22%, and a PRR of 47%. The median follow-up time was 9.4 months. In the 145 patients who responded to treatment, the median duration of response was 11.1 months. ^[102]

In the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who were ineligible for or had relapsed after autologous HSCT, interim analysis showed median progression-free survival (PFS) of 13.2 months with pembrolizumab versus 8.3 months with brentuximab vedotin (P = 0.0027). Pneumonitis occurred more frequently in the pembrolizumab arm, but generally responded well to management. ^[103]

Cardiac disease

Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease, and defects in the conduction system. ^{[104, 105]} Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac death.

A study of patients who had previously undergone mediastinal irradiation for Hodgkin lymphoma but who had no clinical evidence of heart disease demonstrated a significant incidence of silent coronary artery obstruction and previous ventricular damage. ^[106] Based on these results, it is reasonable to initiate functional screening 5 years after radiation therapy in patients with Hodgkin lymphoma.

Pulmonary disease

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

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

Secondary cancers

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

The most common secondary malignancy following treatment for Hodgkin lymphoma is lung cancer. Both chemotherapy with alkylating agents and irradiation are associated with a 10-fold increased relative risk of lung cancer. Smoking can further increase the risk. In addition, retrospective data have suggested that survival is worse in Hodgkin lymphoma survivors who develop lung cancer compared with matched cohorts with de novo lung cancer. ^[107]

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

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

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

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

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

A study by Swerdlow et al found that the risk of second malignancy from chemotherapy alone is lower and affects fewer anatomic sites than combined treatment modalities. The authors concluded the risk of second malignancy was slight after 15 years. ^[108]

Taken in aggregate, these trial results suggest that altering the treatment paradigms of Hodgkin lymphoma to maximize curability while preventing long-term complications should be a focus of ongoing research. Using the least amount of therapy required to cure the disease and minimize complications should be the goal. Early results have suggested that modification of treatment is feasible and have shown some decreased rates of secondary cancers. ^[109]

Infertility

The degree of infertility varies widely with the regimen used. MOPP chemotherapy causes permanent infertility in at least 80% of males and approximately 50% of females. ^[108] The escalated BEACOPP regimen results in infertility in nearly 100% of patients treated. ^[109] The ABVD and Stanford V regimens pose a lower risk of permanent sterility than regimens that contain an alkylating agent (eg, MOPP chemotherapy). ^[110]

The EORTC Lymphoma Group reported an 82% rate of recovery of fertility in male patients who were treated without alkylating agents. ^[111] Given the overall excellent prognosis of Hodgkin lymphoma and the early age of onset, it is important to keep fertility preservation in mind when designing treatment plans for these patients. Options include sperm banking for men and various pharmacologic treatments for women including gonadotropin-releasing hormone agonists, ovarian stimulation, and egg preservation.

Infectious complications

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

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

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

Other complications

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

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

Survivors of Hodgkin lymphoma have an increased incidence of fatigue, psychiatric distress (anxiety, depression), employment problems, family issues, and sexual functioning problems, as compared to individuals without this disease or relative to survivors of acute leukemia. ^{[112, 113]}

Peripheral neuropathy occurred in 29% of patients receiving brentuximab vedotin as part of the A+AVD regimen as opposed to 17% of those who received ABVD. ^[53] The neuropathy resolved in 43%of the patients and improved in another 23%.

Complications of Immunotherapy

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

Both the National Comprehensive Cancer Network ^[4] and the European Society for Medical Oncology (ESMO) ^[5] guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission. ^{[4, 5]} Most relapses occur in the first 3 years after therapy, and Hodgkin lymphoma is the main cause of mortality in the first 10-15 years of follow-up. ^[114] Follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.

Follow-up examinations include the following ^[114] :

• History and physical examination

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

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

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

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

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

• Annual history and physical examination
• Annual blood pressure
• Aggressive management of cardiovascular risk factors
• Pneumococcal, meningococcal, and Haemophilus influenzae revaccination after 5–7 y, if the patient received splenic irradiation or splenectomy
• Annual influenza vaccine
• Consider stress test/echocardiogram at 10-y intervals after treatment completion
• Consider carotid ultrasound at 10-y intervals if the patient underwent neck irradiation
• Annual CBC, platelets, and chemistry profile
• TSH at least annually if the patient underwent neck irradiation
• Biannual lipid levels
• Annual fasting glucose study
• Low-dose chest CT scans may be considered in patients at increased risk for lung cancer
• Female patients who have received chest irradiation should be screened annually with mammography, starting at age 40 years or 5-8 years following the radiation therapy; however, the American Cancer Society also recommends breast magnetic resonance imaging (MRI) for patients who received chest radiation therapy between the ages of 10 and 30 years ^[115]

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

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

Prominent goals in the follow-up of survivors of Hodgkin lymphoma include the following ^[114] :

• Identify secondary cancers in a timely manner

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

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

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

ACCRU, a single-arm phase 2 trial of brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma, failed to meet the prespecified activity criteria but found that brentuximab vedotin plus nivolumab is active and generally well tolerated in older patients with previously untreated Hodgkin lymphoma with comorbidities. ^[116] On the other hand, interim results of the ongoing phase 1/2 CheckMate 812 trial showed that the combination of brentuximab vedotin and nivolumab was active and well tolerated as initial salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma; the complete response rate was 61% (82% objective response rate), and patients were able to undergo subsequent autologous hematopoietic stem cell transplantation without adverse impact. ^[117]

Other current studies are exploring the use of various combinations of brentuximab vedotin and chemotherapy for relapsed or refractory cases. ^{[118, 119, 120, 121]} Preliminary data show high response rates. To date, however, there are no randomized trials to establish a standard pre-transplant regimen.

In the frontline setting, a phase 3 trial involving patients with previously untreated stage III or IV classical Hodgkin lymphoma found that brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (AVD) had superior efficacy compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years was 4.9% lower with brentuximab vedotin plus AVD compared with ABVD. ^[122] A phase 2 study demonstrated the safety and efficacy of nivolumab followed by nivolumab plus AVD in patients with newly diagnosed, untreated, advanced-stage Hodgkin lymphoma. ^[123]

Finally, an emerging area of research is the use of chimeric antigen receptor (CAR) T-cells to treat Hodgkin lymphoma. A set of 2 parallel phase I/II studies of anti-CD30 CAR T-cell therapy in 41 heavily pretreated patients with relapsed or refractory Hodgkin lymphoma demonstrated a high rate of durable responses with an excellent safety profile; for all evaluable patients, the 1-year progression-free survival was 36% and overall survival was 94%. ^[124] CAR T-cell therapy for Hodgkin lymphoma will be an ongoing area of investigation. ^[125]