Approach

The management approach outlined in this topic focuses on adults with HL.

Chemotherapy and radiotherapy are typically used to treat early-stage HL. Chemotherapy alone or combined with immunotherapy is recommended for advanced HL. The goal of treatment for all patients with HL is cure while minimising risk of toxicity and long-term complications.

HL in older patients (aged >60 years) is associated with poorer outcomes and higher treatment-related toxicity and mortality compared with younger patients.[45][46][47]​​​​​​ Alternative treatment regimens may be considered for patients >60 years, or with poor performance status or substantial comorbidities. Bleomycin should be used with caution; standard regimens may be adapted to remove bleomycin or restrict its use to only two cycles.[32]​ Nivolumab plus AVD (doxorubicin plus vinblastine plus dacarbazine) may be an option for older patients (aged >60 years) with advanced disease.[32]

Early-stage (stage I to stage II) classical HL

The absence or presence of specific prognostic criteria determines whether the patient has favourable or unfavourable early-stage disease. German Hodgkin Study Group (GHSG) favourable prognosis criteria (see Diagnostic criteria) are most commonly used in the US:[42][48]

  • Mediastinal mass ratio (MMR) <0.33

  • Erythrocyte sedimentation rate (ESR) <50 mm/hour if no B symptoms; ESR <30 mm/hour if B symptoms are present

  • Involvement of ≤2 nodal sites

  • No extranodal disease

The most effective treatment for early-stage disease (favourable or unfavourable) is combined-modality therapy, which comprises combination chemotherapy (typically ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine]) followed by radiotherapy.[49][50]​​​​[51][52][53][54][55][56][57][58][59]​​​​ 

A chemotherapy-alone approach may be considered if avoiding radiotherapy is preferred (e.g., due to patient age, sex, family history of cancer or cardiac disease, comorbidities, sites of involvement).[32][60][61][62][63][64]​​ The decision to omit radiotherapy should involve expert input by a multidisciplinary team, and discussion with the patient regarding risks and benefits.

Chemotherapy alone is associated with a slightly lower rate of tumour control and higher rate of relapse compared with combined-modality therapy. Similar survival rates have been reported, but long-term data for overall survival and adverse events are lacking.[49][50]​​​​​[55][57][59][62][64][65][66][67]​​​​​​​​

Radiotherapy for early-stage HL

Involved-site radiotherapy (ISRT) is preferred to traditional involved-field radiotherapy (IFRT) due to its lower risk of adverse effects.[68][69][70][71]​​ ISRT focuses radiation only on involved lymph nodes and nearby sites, minimising radiation exposure to uninvolved structures.

Acute adverse effects of radiotherapy depend on the region treated and the dose employed.

Patients receiving treatment to the mediastinum can develop oesophagitis, clinically apparent as odynophagia that sometimes requires opioid analgesics to maintain oral intake. Infradiaphragmatic radioherapy can cause nausea and/or diarrhoea.

Fatigue is common in all patients receiving radiotherapy. Possible long-term adverse effects of radiotherapy include secondary malignancies, cardiovascular disease, and decreased pulmonary function.

PET-adapted treatment for early-stage HL

A PET-adapted treatment approach is recommended for all patients with early-stage disease (favourable or unfavourable) as it offers the opportunity to balance efficacy and toxicity of treatment.​[32][51][63][64][72][73]​​ This approach typically involves performing an interim PET/CT scan after two initial cycles of chemotherapy (e.g., ABVD) to assess metabolic response to treatment, and to inform subsequent treatment (e.g., additional chemotherapy and/or radiotherapy).

Metabolic response is determined using the Deauville criteria, which assigns a score of 1 to 5 based on fluorodeoxyglucose (FDG) uptake at involved sites.[39]​​​ Patients with a Deauville score of 1 to 3 (i.e., negative PET/CT) are considered to have a complete metabolic response. Patients with a Deauville score of 4 or 5 (i.e., positive PET/CT) are considered to have a partial metabolic response (see Diagnostic criteria). 

Treatment for favourable early-stage HL

Patients with favourable early-stage disease generally receive two initial cycles of ABVD followed by an interim PET/CT scan.[32]

Those intended for combined-modality therapy with a Deauville score 1 to 3 on interim PET/CT can receive the following subsequent treatments:

  • Deauville score 1 or 2: 20 Gy radiotherapy (favourable disease on restaging), or one additional cycle of ABVD followed by 30 Gy radiotherapy (unfavourable disease on restaging).[57][58][63][65]

  • Deauville score 3: 20 Gy radiotherapy (favourable disease on restaging), or two additional cycles of ABVD followed by 30 Gy radiotherapy (unfavourable disease on restaging).[58][63]

Those intended for chemotherapy alone with a Deauville score 1 to 3 on interim PET/CT can receive the following subsequent treatments:

  • ​Deauville score 1 to 3: two additional cycles of ABVD or four additional cycles of AVD.[57][62][64][65][66][74]​ AVD (four cycles) is preferred for Deauville score 3 treated with chemotherapy alone.[32][74]

Those with a Deauville score 4 or 5 on interim PET/CT intended for combined-modality therapy or chemotherapy alone can receive the following subsequent treatments:

  • Deauville score 4: two additional cycles of ABVD followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment.[57][62][63]​​[64][65]​ If restaging PET/CT is negative (Deauville score 1 to 3) then 30 Gy radiotherapy can be given to those having combined treatment and should be considered for those intended for chemotherapy alone. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[32] 

  • Deauville score 5: a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[32]

Treatment for unfavourable early-stage HL

Patients with unfavourable early-stage disease generally receive two initial cycles of ABVD followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment.

Those with Deauville score 1 to 3, non-bulky or bulky disease, who are intended for combined-modality therapy can receive two additional cycles of ABVD followed by 30 Gy radiotherapy.[51][57][65]

Those with Deauville score 1 to 3 intended for chemotherapy alone can receive the following subsequent treatments:

  • Deauville score 1 to 3, nonbulky: two additional cycles of ABVD or four additional cycles of AVD.

  • Deauville score 1 to 3, bulky: four additional cycles of AVD.

Those with Deauville score 4 or 5 can receive the following subsequent treatments:

  • ​Deauville score 4 or 5: two additional cycles of ABVD, or two cycles of BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) with growth factor support, followed by a restaging PET/CT scan.[32][51][57][62][64][65][75] If restaging Deauville score is 1 to 4, then 30 Gy radiotherapy can be given to those having combined treatment and should be considered for those intended for chemotherapy alone. If restaging Deauville score is 5, then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[32]

BrECADD is recommended for intensive chemotherapy due to its improved safety profile and efficacy compared with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone); however, evidence is limited in early-stage disease.[32][75]

National Comprehensive Cancer Network (NCCN) guidelines suggest consideration of the following alternative initial treatment regimens (chemoimmunotherapy or intensive chemotherapy without initial cycles of ABVD) for certain patients with unfavourable early-stage HL, although evidence in this patient group is lacking:[32]

  • Nivolumab (an anti-programmed death-1 [PD-1] monoclonal antibody) plus AVD for four cycles followed by 30 Gy radiotherapy may be considered for patients with B symptoms and/or bulky disease).[76][77]

  • Brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E) plus AVD with growth factor support for four cycles, followed by 30 Gy radiotherapy, may be considered for patients with B symptoms and bulky disease.[78]

  • BrECADD with growth factor support may be considered for patients with bulky disease with either B symptoms or extranodal disease, aged 18-61 years, using a PET-adapted treatment approach.[75] Initial treatment with two cycles is followed by an interim PET/CT scan to assess metabolic response and inform subsequent management (further cycles of BrECADD up to a total of six cycles).

Growth factor support with a granulocyte colony-stimulating factor (G-CSF) is required for patients treated with brentuximab vedotin plus AVD or BrECADD due to high risk of febrile neutropenia (>20%).[32][75][79][80]

Advanced (stage III to stage IV) classical HL

Initial treatment options for advanced-stage disease include:[32][75][81][82][83][84][85][86][87]​​​​​​​[88]​​​​​​​​

  • BrECADD

  • Nivolumab plus AVD

  • Brentuximab vedotin plus AVD

  • ABVD

BrECADD or nivolumab plus AVD are the preferred initial treatments for patients with advanced-stage disease.[32]​​[75][88]

Growth factor support with a G-CSF is required for patients treated with brentuximab vedotin plus AVD or BrECADD due to high risk of febrile neutropenia (>20%).[32][75][79]​​​[80]​​

Intensive chemotherapy for advanced HL

BrECADD is an intensive chemotherapy regimen that offers lower treatment-related morbidity and improved progression-free survival compared with escalated BEACOPP in patients with advanced-stage disease.[75] BrECADD is not recommended for older patients (aged ≥61 years).

A PET-adapted treatment approach is used in patients receiving BrECADD for advanced-stage disease to guide treatment decisions regarding escalation or de-escalation of chemotherapy.[32][33][75]​​[89]​​ Patients typically receive two initial cycles of BrECADD with growth factor support, followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment, as follows:[32][75]

  • Deauville score 1 to 3: two additional cycles of BrECADD with growth factor support followed by restaging PET/CT

  • Deauville score 4 or 5: biopsy to inform subsequent treatment. Patients with a negative biopsy can receive four additional cycles of BrECADD with growth factor support followed by a restaging PET/CT scan. Patients with a positive biopsy may require salvage therapy.

  • Consolidation radiotherapy may be considered for patients with residual PET-positive disease following completion of initial treatment with chemotherapy.

​Chemoimmunotherapy for advanced HL

Nivolumab plus AVD appears to be well-tolerated, and may be an option for older patients (aged >60 years) suitable for multi-agent chemotherapy with advanced disease.[32] Patients typically receive six cycles of nivolumab plus AVD, followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment.[32] 

Improved progression-free survival (92% vs. 83%; median follow-up 2.1 years) and lower rates of peripheral neuropathy and treatment discontinuation were demonstrated with nivolumab plus AVD compared with brentuximab vedotin plus AVD in one randomised phase 3 trial.[88] Growth factor support was optional in clinical trials.

Brentuximab vedotin plus AVD offers a survival advantage compared with ABVD in patients with advanced-stage disease.[32][90][91][92]​​ Patients typically receive six cycles of brentuximab vedotin plus AVD with growth factor support, followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment (e.g., salvage therapy). Caution is required when used in older patients (aged >60 years) and in those with baseline neuropathy. For older patients, sequential brentuximab vedotin plus AVD may be a preferred option.[87] This involves administering two cycles of brentuximab vedotin followed by 6 cycles of AVD followed by four cycles of brentuximab vedotin.[87]

Standard chemotherapy for advanced HL

ABVD may be an option for if other treatment options are not available or are contraindicated.[32] A PET-adapted treatment approach is used in patients receiving ABVD for advanced-stage disease to guide treatment decisions regarding escalation or de-escalation of chemotherapy.[32][66]​​​​​[89]

Patients typically receive two initial cycles of ABVD, followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment. Patients can receive the following subsequent treatments based on their Deauville score on interim PET/CT:[32][66]

  • Deauville score 1 to 3: four additional cycles of AVD.​​

  • Deauville score 4 or 5: three additional cycles of BrECADD with growth factor support followed by a restaging PET/CT scan. If restaging PET/CT is negative (Deauville score 1 to 3) then one additional cycle of BrECADD with growth factor support can be given. If restaging PET/CT is positive (Deauville score 4 or 5), then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy). Consolidation radiotherapy (i.e., after initial chemotherapy) may be considered for patients following completion of initial treatment with chemotherapy.

Refractory or relapsed classical HL

Refractory or relapsed HL should be confirmed with biopsy.

Treatment for refractory or relapsed HL must be individualised, taking into consideration factors such as previous first-line treatment, patient age, medical comorbidities, duration of first remission, and stage at relapse. The goal of treatment, at least initially, is cure. Referral to a centre with expertise is recommended; clinical trials should be considered, where possible.[32]

Salvage therapy, followed by high-dose chemotherapy (for conditioning) and autologous stem cell transplantation (ASCT), is the standard approach for most patients who relapse following first-line treatment.[32][93][94][95][96][97][98]​​​ Radiotherapy may be used alongside high-dose chemotherapy (as part of conditioning) in eligible patients. In selected patients, radiotherapy alone or chemotherapy alone is appropriate following salvage therapy.[99][100]

Allogeneic stem cell transplantation (AlloSCT) may be considered in select patients who relapse after ASCT, offering a potentially curative option.[101][102][103][104][105]

​Salvage therapy for refractory or relapsed classical HL

The role of salvage therapy is to reduce tumour burden and mobilise stem cells before conditioning and ASCT.[32]​ Combination chemotherapy or chemoimmunotherapy regimens can be used for salvage therapy.[32]​ The optimal salvage regimen is unclear due to the lack of head-to-head randomised trials.

The following chemoimmunotherapy regimens including a checkpoint inhibitor (nivolumab or pembrolizumab) are preferred for patients with no prior exposure to these agents:[32][106][107][108][109]

  • Nivolumab plus ICE (ifosfamide, carboplatin, etoposide)

  • Nivolumab plus brentuximab vedotin

  • Pembrolizumab plus GVD (gemcitabine, vinorelbine, pegylated liposomal doxorubicin)

  • Pembrolizumab plus ICE

The following regimens (without a checkpoint inhibitor) are commonly used for salvage therapy:[96][97][110][111][112][113][114][115][116]​​​

  • BeGEV (bendamustine, gemcitabine, vinorelbine)

  • Brentuximab vedotin

  • Brentuximab vedotin plus bendamustine

  • Brentuximab vedotin plus ICE

  • DHAP (dexamethasone, cytarabine, cisplatin)

  • GVD

  • ICE

  • IGEV (ifosfamide, gemcitabine, vinorelbine)

PET-adapted treatment for refractory or relapsed HL

A PET-adapted treatment approach is used for refractory or relapsed HL in order to optimise outcomes following stem cell transplantation. A negative pre-transplantation PET/CT (Deauville score 1 to 3) is associated with optimal outcomes following transplantation and should, therefore, be the goal of salvage therapy prior to ASCT.[117][118]​​ Patients with a positive PET/CT (Deauville score 4 or 5) following salvage therapy may be considered for a different salvage regimen to achieve a negative PET/CT.[119][120][121]

Maintenance therapy following ASCT

Brentuximab vedotin is recommended as consolidation/maintenance treatment following ASCT in patients at high risk for relapse (e.g., refractory to initial treatment; with relapse within 12 months following initial treatment; with B symptoms; PET/CT-positive at transplant; and/or with extranodal disease) with no prior brentuximab vedotin therapy.[32][122][123][124] Maintenance brentuximab vedotin is recommended for 16 cycles or until unacceptable toxicity or relapse (whichever occurs first).[123]

Early (stage I to stage II) nodular lymphocyte-predominant HL (NLPHL)

NLPHL is a rare subtype of HL. Most patients with NLPHL present with early-stage disease involving peripheral nodal regions (e.g., groin, axilla, neck). The goal of treatment is cure while minimising risk of late effects. Overall prognosis for patients with early-stage NLPHL is excellent.

Asymptomatic early (stage IA and IIA) non-bulky NLPHL

Radiotherapy alone at a dose 30 to 36 Gy is recommended for most patients with stage IA and IIA non-bulky disease.[32][68][125] ISRT is the preferred approach (although most available data are for IFRT).[68] 

Retrospective studies have reported excellent remission and survival outcomes with radiotherapy alone for early-stage NLPHL.[126][127][128][129] Randomised trials of treatments for NLPHL are lacking due to the rarity of this disease subtype.

Observation may be appropriate for patients with asymptomatic early-stage non-bulky disease, particularly if there is concern regarding toxicity related to radiotherapy.[130] Observation is also an option for selected patients with stage IA non-bulky disease who have a completely excised solitary lymph node.[32]

Asymptomatic early (stage IA and IIA) bulky NLPHL and symptomatic early (stage IB and IIB) NLPHL

Systemic treatment with rituximab plus combination chemotherapy (e.g., R-ABVD [rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine], R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone], or R-CVbP [rituximab, cyclophosphamide, vinblastine, prednisolone]) followed by radiotherapy (30 to 36 Gy) is recommended for patients with stage IA or IIA bulky disease, and those with stage IB or IIB disease.[32][125][131]

The CD20 antigen is present on most NLPHL cells; therefore, anti-CD20 treatment with rituximab is a key component of systemic treatment for NLPHL.

Observation may be appropriate for patients with asymptomatic early-stage bulky disease, particularly if there is concern regarding toxicity related to systemic treatment and radiotherapy.[130]

Advanced (stage III to stage IV) NLPHL

Observation may be appropriate for patients with asymptomatic advanced-stage disease.[32][125] Systemic treatment with rituximab plus combination chemotherapy (e.g., R-ABVD, R-CHOP, or R-CVbP) with or without radiotherapy is recommended for patients with symptomatic advanced-stage disease or rapid progression.[32][132][133]

Rituximab alone or local radiotherapy may be options for palliation in select patients.[32]

Refractory or relapsed NLPHL

Refractory or relapsed NLPHL should be confirmed by biopsy to rule out transformation to aggressive non-Hodgkin's lymphoma.

Treatment for refractory or relapsed NLPHL must be individualised, taking into consideration factors such as previous first-line treatment (e.g., R-ABVD with radiotherapy), patient age, medical comorbidities, duration of first remission, and stage at relapse.[125]

Salvage therapy with a rituximab-based chemotherapy regimen or rituximab alone is the preferred approach for most patients with refractory or relapsed NLPHL. Observation may be considered for asymptomatic patients as an initial approach.[32] ASCT may be considered for patients with aggressive disease.

The optimal regimen for salvage chemotherapy is unclear, but the following rituximab-based regimens can be considered if not previously used:[32]

  • R-ABVD

  • R-CHOP

  • R-CVbP

  • R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)

  • R-ICE (rituximab, ifosfamide, carboplatin, etoposide)

  • R-IGEV (rituximab, ifosfamide, gemcitabine, vinorelbine)

  • Rituximab plus bendamustine.

Rituximab alone can be considered for patients who relapse with limited-stage disease and low tumour volume.[32][134]

Radiotherapy may be considered in combination with systemic therapy for patients who are symptomatic or with high tumour burden disease.[32]

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