Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: D.A. Eichenauer, B.M.P. Aleman, M. André, M. Federico, M. Hutchings, T. Illidge, A. Engert, M. Ladetto
Journal: Annals of Oncology (2018)

The crude incidence of Hodgkin lymphoma (HL) in the European Union is 2.3, the mortality 0.4 cases/100 000/year. Young adults aged 20–40 years are most often affected. Slightly more men than women are diagnosed with HL. Histologically, classical HL (cHL) accounting for ∼95% of all HL cases is distinguished from nodular lymphocyte-predominant HL (NLPHL) representing ∼5% of all HL cases. Pathological diagnosis should be made according to the World Health Organization (WHO) classification from an excisional lymph node biopsy or a sufficiently large surgical specimen to provide enough material for fresh frozen and formalin-fixed samples. In cHL, the presence of Hodgkin and Reed–Sternberg (HRS) cells is disease-defining, whereas the detection of lymphocyte predominant (LP) cells is required for the diagnosis of NLPHL. The immunophenotype of the malignant cells in cHL and NLPHL differs significantly. In contrast to HRS cells that stain consistently positive for CD30 and CD15, occasionally positive for CD20 and negative for CD45, LP cells are characterised by the expression of CD20 and CD45 but lack CD15 and CD30. The diagnostic work-up is shown in Table 1. The medical history including the presence of B symptoms (fever, drenching night sweats, unexplained weight loss > 10% over 6 months) and other disease-related symptoms such as fatigue, pruritus and alcohol-induced pain as well as the results of a physical examination should be recorded [1.Cheson B.D. Fisher R.I. Barrington S.F. et al.Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.J Clin Oncol. 2014; 32: 3059-3068Crossref PubMed Scopus (2776) Google Scholar].Table 1Diagnostic work-up in HLDiagnosisLymph node biopsy (or a biopsy from another organ with suspected affection)Staging and risk stratificationMedical history and physical examinationX-ray of the chestContrast-enhanced CT scan of the neck, chest and abdomenPETFull blood cell count and blood chemistry, ESRHBV, HCV and HIV screeningPretreatment examinationsECGEchocardiographyPulmonary function testReproductive counselling (in patients of reproductive age)Serum pregnancy test (in female patients of reproductive age)Consultation of an ear, nose and throat specialist including a fibreoptic nasolaryngoscopy (if PET–CT scan is not available at initial staging)CT, computed tomography; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; PET, positron emission tomography. Open table in a new tab CT, computed tomography; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; PET, positron emission tomography. Chest X-ray and a contrast-enhanced computed tomography (CT) scan of the neck, the chest and the abdomen are mandatory. In addition, a baseline whole-body positron emission tomography (PET) should be carried out according to the recommendations for staging and response assessment in lymphoma, if this diagnostic tool is available [1.Cheson B.D. Fisher R.I. Barrington S.F. et al.Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.J Clin Oncol. 2014; 32: 3059-3068Crossref PubMed Scopus (2776) Google Scholar, 2.Barrington S.F. Mikhaeel N.G. Kostakoglu L. et al.Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.J Clin Oncol. 2014; 32: 3048-3058Crossref PubMed Scopus (1025) Google Scholar]. Given the high sensitivity of PET–CT for bone marrow involvement, a bone marrow biopsy is no longer indicated in patients undergoing PET–CT evaluation [III, B] [1.Cheson B.D. Fisher R.I. Barrington S.F. et al.Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.J Clin Oncol. 2014; 32: 3059-3068Crossref PubMed Scopus (2776) Google Scholar, 2.Barrington S.F. Mikhaeel N.G. Kostakoglu L. et al.Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.J Clin Oncol. 2014; 32: 3048-3058Crossref PubMed Scopus (1025) Google Scholar, 3.El-Galaly T.C. d'Amore F. Mylam K.J. et al.Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma.J Clin Oncol. 2012; 30: 4508-4514Crossref PubMed Scopus (206) Google Scholar]. However, bone marrow biopsy must be carried out if PET–CT is not available. Full blood cell count, erythrocyte sedimentation rate (ESR) testing and blood chemistry analysis including C-reactive protein (CRP), alkaline phosphatase (AP), lactate dehydrogenase (LDH), liver enzymes and albumin are obligatory. Screening for hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV) is compulsory [II–III, A]. Staging is carried out according to the Ann Arbor classification in consideration of defined clinical risk factors. After completion of staging, patients are allocated to one of three categories (limited, intermediate and advanced stages) [II–III, A]. Table 2 illustrates the European Organisation for Research and Treatment of Cancer (EORTC)/Lymphoma Study Association (LYSA) and the German Hodgkin Study Group (GHSG) definitions of limited, intermediate and advanced stages.Table 2Definition of HL risk groups according to the EORTC/LYSA and the GHSGEORTC/LYSAGHSGTreatment groupLimited stagesCS I–II without risk factors (supradiaphragmatic)CS I–II without risk factorsIntermediate stagesCS I–II with ≥ 1 risk factors (supradiaphragmatic)CS I, CS IIA with ≥ 1 risk factorsCS IIB with risk factors C and/or D, but not A/BAdvanced stagesCS III–IVCS IIB with risk factors A and/or BCS III/IVRisk factorsA: Large mediastinal massaLarge mediastinal mass: mediastinum-to-thorax ratio ≥ 0.35 (EORTC/LYSA); mediastinal mass larger than one-third of the maximum thoracic width (GHSG).B: Age ≥ 50 yearsC: Elevated ESRbElevated ESR: > 50 mm/h without B symptoms, > 30 mm/h with B symptoms (B symptoms: fever, night sweat, unexplained weight loss >10 % over 6 months).D: ≥ 4 nodal areascNodal areas: involvement of ≥ 4 out of 5 supradiaphragmatic nodal areas (EORTC/LYSA); involvement of ≥ 3 out of 11 nodal areas on both sides of the diaphragm (GHSG).A: Large mediastinal massaLarge mediastinal mass: mediastinum-to-thorax ratio ≥ 0.35 (EORTC/LYSA); mediastinal mass larger than one-third of the maximum thoracic width (GHSG).B: Extranodal diseaseC: Elevated ESRbElevated ESR: > 50 mm/h without B symptoms, > 30 mm/h with B symptoms (B symptoms: fever, night sweat, unexplained weight loss >10 % over 6 months).D: ≥ 3 nodal areascNodal areas: involvement of ≥ 4 out of 5 supradiaphragmatic nodal areas (EORTC/LYSA); involvement of ≥ 3 out of 11 nodal areas on both sides of the diaphragm (GHSG).CS, clinical stage; EORTC, European Organisation for Research and Treatment of Cancer; ESR, erythrocyte sedimentation rate; GHSG, German Hodgkin Study Group; HL, Hodgkin lymphoma; LYSA, Lymphoma Study Association.a Large mediastinal mass: mediastinum-to-thorax ratio ≥ 0.35 (EORTC/LYSA); mediastinal mass larger than one-third of the maximum thoracic width (GHSG).b Elevated ESR: > 50 mm/h without B symptoms, > 30 mm/h with B symptoms (B symptoms: fever, night sweat, unexplained weight loss >10 % over 6 months).c Nodal areas: involvement of ≥ 4 out of 5 supradiaphragmatic nodal areas (EORTC/LYSA); involvement of ≥ 3 out of 11 nodal areas on both sides of the diaphragm (GHSG). Open table in a new tab CS, clinical stage; EORTC, European Organisation for Research and Treatment of Cancer; ESR, erythrocyte sedimentation rate; GHSG, German Hodgkin Study Group; HL, Hodgkin lymphoma; LYSA, Lymphoma Study Association. To identify patients at increased risk for acute and/or long-term complications and to generate baseline values for future measurements, cardiac and pulmonary function tests should be carried out before the start of treatment. As chemotherapy (ChT) and abdominal radiotherapy (RT) can cause permanent infertility, reproductive counselling and consideration of sperm banking, oocyte collection or ovarian tissue cryopreservation should be offered to patients of reproductive age before treatment. Combined-modality treatment consisting of a brief ChT followed by RT was shown to result in superior tumour control compared with RT alone [I, A] [4.Engert A. Franklin J. Eich H.T. et al.Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial.J Clin Oncol. 2007; 25: 3495-3502Crossref PubMed Scopus (200) Google Scholar, 5.Fermé C. Eghbali H. Meerwaldt J.H. et al.Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease.N Engl J Med. 2007; 357: 1916-1927Crossref PubMed Scopus (348) Google Scholar]. Two or three cycles of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) (Table 3) followed by conventionally fractionated RT represent the standard of care for limited-stage HL. A large multicentre trial in which patients were randomly assigned to either two or four cycles of ABVD followed by either 20 or 30 Gy involved-field RT (IFRT) showed similar freedom from treatment failure (FFTF) and overall survival (OS) rates for all treatment groups. Thus, the least toxic approach consisting of two cycles of ABVD followed by 20 Gy IFRT appears to be sufficient for limited-stage HL [I, A] [6.Engert A. Plütschow A. Eich H.T. et al.Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.N Engl J Med. 2010; 363: 640-652Crossref PubMed Scopus (690) Google Scholar]. Comparable disease control was also observed in a randomised trial comparing IFRT at doses of either 20 or 36 Gy in patients achieving a complete remission after six cycles of ChT with the outdated epirubicin/bleomycin/vinblastine/prednisone (EBVP) protocol [7.Thomas J. Fermé C. Noordijk E.M. et al.Comparison of 36 Gy, 20 Gy or no radiotherapy after six cycles of EBVP chemotherapy and complete remission in early stage Hodgkin lymphoma without risk factors: results of the EORTC–GELA H9-F Intergroup Randomized Trial.Int J Radiat Oncol Biol Phys. 2017; 100: 1133-1145Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. However, the current RT guidelines of the International Lymphoma Radiation Oncology Group (ILROG) recommend involved-site RT (ISRT) after ChT in limited stages. Although ISRT has not been randomly compared with IFRT in a prospective study, there is accumulating evidence of excellent disease control with these smaller RT fields [8.Specht L. Yahalom J. Illidge T. et al.Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).Int J Radiat Oncol Biol Phys. 2014; 89: 854-862Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar].Table 3The ABVD regimenDose (mg/m2)AdministrationDaysDoxorubicin25i.v.1 + 15Bleomycin10i.v.1 + 15Vinblastine6i.v.1 + 15Dacarbazine375i.v.1 + 15Recycle: day 29.ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; i.v., intravenous. Open table in a new tab Recycle: day 29. ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine; i.v., intravenous. The question of whether RT can be omitted in selected patients with complete metabolic response at interim PET is a matter of debate. Several randomised trials addressing this issue have been conducted within the last years. The available data consistently demonstrate a progression-free survival (PFS) advantage for patients treated with combined-modality approaches despite a negative interim PET (defined as a Deauville score ≤ 2 within the RAPID and H10 studies). Thus, a patient group that can be safely treated with ChT alone could not yet be defined [I, A] [9.Radford J. Illidge T. Counsell N. et al.Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma.N Engl J Med. 2015; 372: 1598-1607Crossref PubMed Scopus (494) Google Scholar, 10.André M.P.E. Girinsky T. Federico M. et al.Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial.J Clin Oncol. 2017; 35: 1786-1794Crossref PubMed Scopus (310) Google Scholar]. However, as patients treated with ChT alone still have a good overall prognosis, this approach may be offered to individual patients when the late risk of delivering RT is thought to outweigh the short-term benefit of improved disease control. Early treatment intensification appears to improve the prognosis of patients with a positive interim PET (defined as a Deauville score ≥ 3 within the H10 study). A large randomised study including patients with limited- and intermediate-stage HL revealed a significantly reduced relapse rate in those patients with a positive interim PET after two cycles of ABVD who completed ChT with two cycles of bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone in escalated dose (BEACOPPescalated) (Table 4) instead of one (limited stages) or two (intermediate stages) additional cycles of ABVD before involved-node RT (INRT) [10.André M.P.E. Girinsky T. Federico M. et al.Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial.J Clin Oncol. 2017; 35: 1786-1794Crossref PubMed Scopus (310) Google Scholar]. However, the study was not powered to analyse patients with limited- and intermediate-stage disease separately. Patients with a positive interim PET after two cycles of ABVD should be treated with two cycles of BEACOPPescalated before ISRT [I, A].Table 4The BEACOPPescalated regimenDose (mg/m2)AdministrationDaysBleomycin10i.v.8Etoposide200i.v.1–3Doxorubicin35i.v.1Cyclophosphamide1250i.v.1Vincristine1.4aThe maximum absolute dose is 2 mg of vincristine. Recycle: day 22.i.v.8Procarbazine100p.o.1–7Prednisone40p.o.1–14G-CSFs.c.From day 8BEACOPPescalated, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone in escalated dose; G-CSF, granulocyte colony-stimulating factor; i.v., intravenous; p.o., oral; s.c., subcutaneous.a The maximum absolute dose is 2 mg of vincristine. Recycle: day 22. Open table in a new tab BEACOPPescalated, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone in escalated dose; G-CSF, granulocyte colony-stimulating factor; i.v., intravenous; p.o., oral; s.c., subcutaneous. Intermediate-stage HL is usually treated with combined-modality approaches. Four cycles of ABVD followed by conventionally fractionated RT at 30 Gy are widely considered standard of care for intermediate-stage HL [I, A] [5.Fermé C. Eghbali H. Meerwaldt J.H. et al.Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease.N Engl J Med. 2007; 357: 1916-1927Crossref PubMed Scopus (348) Google Scholar]. In patients ≤ 60 years who are eligible for a more intensive treatment, this standard is challenged by a protocol consisting of two cycles of BEACOPPescalated followed by two cycles of ABVD and RT at 30 Gy. After a median follow-up of 43 months, FFTF with this protocol was superior in comparison with four cycles of ABVD followed by RT. An advantage in OS could not be shown [I, B–C] [11.von Tresckow B. Plütschow A. Fuchs M. et al.Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial.J Clin Oncol. 2012; 30: 907-913Crossref PubMed Scopus (228) Google Scholar]. Although no results of a randomised study comparing both RT fields are available to date, the ILROG guidelines recommend ISRT instead of IFRT after ChT in intermediate stages [8.Specht L. Yahalom J. Illidge T. et al.Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).Int J Radiat Oncol Biol Phys. 2014; 89: 854-862Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar]. The question of whether RT is dispensable in intermediate-stage patients with complete metabolic response at interim PET is unanswered. A large randomised study failed to demonstrate non-inferiority of ChT alone as compared with combined-modality treatment in patients with a negative interim PET (defined as a Deauville score ≤ 2 within the H10 study) [I, A] [10.André M.P.E. Girinsky T. Federico M. et al.Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial.J Clin Oncol. 2017; 35: 1786-1794Crossref PubMed Scopus (310) Google Scholar]. However, as patients treated with ChT alone still have a good overall prognosis, this approach may be offered to individual patients when the late risk of delivering RT is thought to outweigh the short-term benefit of improved disease control. Early treatment intensification appears to improve the prognosis of patients with a positive interim PET (defined as a Deauville score ≥ 3 within the H10 study). A randomised study including patients with limited- and intermediate-stage HL revealed a significantly reduced relapse rate in patients with a positive interim PET after two cycles of ABVD who completed ChT with two cycles of BEACOPPescalated instead of one (limited stages) or two (intermediate stages) additional cycles of ABVD before INRT [10.André M.P.E. Girinsky T. Federico M. et al.Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial.J Clin Oncol. 2017; 35: 1786-1794Crossref PubMed Scopus (310) Google Scholar]. Patients with a positive interim PET after two cycles of ABVD should be treated with two cycles of BEACOPPescalated before ISRT [I, A]. Due to the relevant bleomycin-induced toxicity observed in older individuals receiving more than two cycles of ABVD, bleomycin should be discontinued after the second ChT cycle in patients > 60 years [III, B–C] [12.Böll B. Goergen H. Behringer K. et al.Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials.Blood. 2016; 127: 2189-2192Crossref PubMed Scopus (64) Google Scholar]. Advanced-stage HL is usually treated with ChT alone. Additional RT is confined to patients with residual disease after ChT. Patients ≤ 60 years are treated with either ABVD (six cycles) or BEACOPPescalated (four to six cycles), optionally followed by localised RT [I, A] [13.Canellos G.P. Niedzwiecki D. Johnson J.L. Long-term follow-up of survival in Hodgkin's lymphoma.N Engl J Med. 2009; 361: 2390-2391Crossref PubMed Scopus (32) Google Scholar, 14.Engert A. Haverkamp H. Kobe C. et al.Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.Lancet. 2012; 379: 1791-1799Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar]. When ABVD is applied, the omission of bleomycin, i.e. the use of doxorubicin/vinblastine/dacarbazine (AVD) in cycles 3–6 in the case of a negative interim PET (defined as a Deauville score ≤ 3 within the RATHL study) after two cycles of ChT should be considered, especially in elderly patients and those at an increased risk for lung toxicity, although a randomised multicentre study was not able to exclude a PFS difference of > 5% at 3 years [I, A] [15.Johnson P. Federico M. Kirkwood A. et al.Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma.N Engl J Med. 2016; 374: 2419-2429Crossref PubMed Scopus (493) Google Scholar]. The question of whether consolidating RT can be safely omitted in patients who have a negative PET after two cycles of ABVD or at the end of ChT has also not yet been definitively answered. There is no randomised study evaluating the role of early treatment intensification in advanced-stage patients who have a positive interim PET after two cycles of ABVD. However, several non-randomised studies have suggested that patients with advanced HL who have a positive interim PET (defined as a Deauville score ≥ 4 within the RATHL and SWOG S0816 studies and ≥ 3 within the HD0801 study) have a better prognosis after switching from ABVD to intensified protocols than after continued treatment with ABVD [II, B] [15.Johnson P. Federico M. Kirkwood A. et al.Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma.N Engl J Med. 2016; 374: 2419-2429Crossref PubMed Scopus (493) Google Scholar, 16.Press O.W. Li H. Schöder H. et al.US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816.J Clin Oncol. 2016; 34: 2020-2027Crossref PubMed Scopus (194) Google Scholar, 17.Zinzani P.L. Broccoli A. Gioia D.M. et al.Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin lymphoma: final results of the phase II part of the HD0801 study.J Clin Oncol. 2016; 34: 1376-1385Crossref PubMed Scopus (108) Google Scholar]. A recent randomised study demonstrated an improved modified 2-year PFS after six cycles of brentuximab vedotin in combination with AVD (A-AVD) as compared with standard ABVD. However, A-AVD was associated with an increased rate of neuropathy and haematological toxicity. Thus, longer follow-up is required to draw final conclusions in terms of the A-AVD regimen [I–II, C] [18.Connors J.M. Jurczak W. Straus D.J. et al.Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma.N Engl J Med. 2018; 378: 331-344Crossref PubMed Scopus (420) Google Scholar]. In patients receiving BEACOPPescalated, treatment can be safely reduced to a total of only four cycles in the case of a negative interim PET (defined as a Deauville score ≤ 2 within the HD18 study) compared with a total of six cycles for PET-positive patients [I, A] [19.Borchmann P. Goergen H. Kobe C. et al.PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.Lancet. 2017; 390: 2790-2802Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. In addition, RT can be restricted to the patients with PET-positive (defined as a Deauville score ≥ 3 within the HD15 study and most of the HD18 study and a Deauville score ≥ 4 within a part of the HD18 study) residual lymphoma ≥ 2.5 cm after four and six cycles of BEACOPPescalated, respectively [I, A] [14.Engert A. Haverkamp H. Kobe C. et al.Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.Lancet. 2012; 379: 1791-1799Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar, 19.Borchmann P. Goergen H. Kobe C. et al.PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.Lancet. 2017; 390: 2790-2802Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. Several trials randomly comparing ABVD and BEACOPPescalated have shown a superior tumour control and a non-significant trend towards a better OS with BEACOPPescalated [20.Viviani S. Zinzani P.L. Rambaldi A. et al.ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.N Engl J Med. 2011; 365: 203-212Crossref PubMed Scopus (325) Google Scholar, 21.Mounier N. Brice P. Bologna S. et al.ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial.Ann Oncol. 2014; 25: 1622-1628Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. A network meta-analysis including 9993 patients also revealed a significantly better OS with BEACOPPescalated when compared with ABVD. The survival benefit was 10% at 5 years [I, A] [22.Skoetz N. Trelle S. Rancea M. et al.Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis.Lancet Oncol. 2013; 14: 943-952Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. However, given the relevant acute toxicity of BEACOPPescalated, appropriate surveillance and supportive care must be available when this protocol is used. In patients > 60 years, the BEACOPP regimen should not be given, as an increased rate of treatment-related mortality has been observed in this age group [II, A] [23.Ballova V. Rüffer J.U. Haverkamp H. et al.A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly).Ann Oncol. 2005; 16: 124-131Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Thus, ABVD-based ChT represents the standard of care for older HL patients who are fit enough for multi-agent ChT. However, due to the relevant bleomycin-induced toxicity observed in older individuals receiving more than two cycles of ABVD, bleomycin should be discontinued after the second ChT cycle in this patient group [III, B–C] [12.Böll B. Goergen H. Behringer K. et al.Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials.Blood. 2016; 127: 2189-2192Crossref PubMed Scopus (64) Google Scholar]. For most patients with refractory or relapsed HL, the treatment of choice consists of high-dose ChT (HDCT) followed by autologous stem cell transplantation (ASCT) [I, A] [24.Schmitz N. Pfistner B. Sextro M. et al.Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial.Lancet. 2002; 359: 2065-2071Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar]. High-risk patients may benefit from tandem ASCT [III, B] [25.Sibon D. Morschhauser F. Resche-Rigon M. et al.Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group.Haematologica. 2016; 101: 474-481Crossref PubMed Scopus (32) Google Scholar]. Consolidating treatment with the antibody-drug conjugate brentuximab vedotin following HDCT and ASCT was shown to improve the tumour control in patients presenting with at least one of the following risk factors: primary disease progression, early disease recurrence < 12 months after the end of first-line treatment and extranodal disease at the time of relapse [II, B] [26.Moskowitz C.H. Nademanee A. Masszi T. et al.Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2015; 385: 1853-1862Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar]. Salvage regimens such as dexamethasone/high-dose cytarabine/cisplatin (DHAP), ifosfamide/gemcitabine/vinorelbine (IGEV) or ifosfamide/carboplatin/etoposide (ICE) are given to reduce the tumour burden and mobilise stem cells before HDCT and ASCT [II–III, A] [27.Josting A. Rudolph C. Reiser M. et al.Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease.Ann Oncol. 2002; 13: 1628-1635Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 28.Santoro A. Magagnoli M. Spina M. et al.Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma.Haematologica. 2007; 92: 35-41Crossref PubMed Scopus (191) Google Scholar, 29.Moskowitz C.H. Nimer S.D. Zelenetz A.D. et al.A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.Blood. 2001; 97: 616-623Crossref PubMed Scopus (372) Google Scholar]. In some patients, single-agent brentuximab vedotin results in a negative PET and may therefore be sufficient as salvage therapy before HDCT and ASCT [III, B] [30.Moskowitz A.J. Schöder H. Yahalom J. et al.PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study.Lancet Oncol. 2015; 16: 284-292Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. Achieving a negative PET should be the goal of salvage therapy, irrespective of the applied protocol, because a complete metabolic response before HDCT and ASCT was shown to be associated with an improved clinical outcome [III, B] [31.Moskowitz C.H. Matasar M.J. Zelenetz A.D. et al.Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherap