Advances in the treatment of Hodgkin lymphoma
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- Eichenauer, D.A. & Engert, A. Int J Hematol (2012) 96: 535. doi:10.1007/s12185-012-1199-2
In the past decades, Hodgkin lymphoma (HL) has turned from an incurable disease to one with the most favorable prognosis among adult malignancies. This is due to the introduction of effective multi-agent chemotherapy and the optimization of radiation techniques. At present, 80–90 % of patients achieve long-term remission when receiving appropriate first-line treatment. Even in case of relapse, up to 50 % can be successfully salvaged with high-dose chemotherapy and autologous stem cell transplantation. Thus, current studies do not necessarily aim at increasing treatment efficacy but rather focus on a possible reduction of acute and late toxicity by decreasing treatment intensity if possible. One promising strategy to spare therapy in good-risk patients is early response-adapted treatment stratification according to the result of interim positron emission tomography. The evaluation of novel drugs and the optimization of treatment for elderly HL patients and those with nodular lymphocyte-predominant HL are further aspects that are currently being addressed in ongoing trials. This review will give an overview on more recent clinical trials and discuss possible future strategies for the treatment of HL.
KeywordsHodgkin lymphoma Therapy Novel drugs
Definition of risk groups by the EORTC/GELA and the GHSG
CS I–II without risk factors (supradiaphragmatic)
CS I–II without risk factors
CS I–II with ≥1 risk factors (supradiaphragmatic)
CS I, CS IIA with ≥1 risk factors; CS IIB with risk factors C/D, but not A/B
CS IIB with risk factors A/B, CS III/IV
(A) Large mediastinal mass
(A) Large mediastinal mass
(B) Age ≥ 50 years
(B) Extranodal disease
(C) Elevated ESR
(C) Elevated ESR
(D) ≥4 nodal areas
(D) ≥3 nodal areas
Treatment of early favorable HL
For decades, standard treatment for patients with early favorable HL (i.e., patients with stage I/II disease without clinical risk factors) was RT alone. More than 90 % of patients achieved complete remission (CR) with this approach, but relapse rate was unacceptably high with 30 % and more. Thus, groups such as the German Hodgkin Study Group (GHSG) and the European Organisation for Research and Treatment of Cancer (EORTC) conducted randomized clinical trials comparing RT alone with combined-modality strategies with the aim to improve the clinical outcome of patients with early favorable HL.
In the GHSG HD7 trial, patients were randomly assigned to receive either 30 Gy extended-field RT (EF-RT) alone or two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) followed by the same RT . Response rates did not differ between treatment arms. However, at a median follow-up of 87 months, the 7-year freedom from treatment failure (FFTF) rate was significantly better in the combined-modality arm (88 vs. 67 %). The advantage in tumor control had not yet translated into a superior overall survival (OS) (94 vs. 92 %) at 7 years and future analyses with longer follow-up are required for a definite answer to this question.
The results of the randomized EORTC H8F trial were similar. Treatment arms consisted of three cycles of MOPP (mechlorethamine, vincristine, procarbazine, prednisone)/ABV followed by IF-RT or subtotal nodal irradiation (STNI) alone . With a median observation of 92 months, patients receiving combined-modality treatment had a significantly superior 5-year event-free survival (EFS) (98 vs. 74 %) and—in contrast to the GHSG HD7 trial—also better 10-year OS estimates (97 vs. 92 %).
On the basis of these two large controlled randomized trials, combined-modality treatment consisting of a brief chemotherapy followed by IF-RT was adopted as standard of care for the treatment of early favorable HL by most institutions worldwide.
The more recent HD13 trial aimed at detoxifying treatment by reducing the number of drugs given. Patients were randomized between two cycles of ABVD, ABV, AVD or AV chemotherapy followed by 30 Gy IF-RT . Both, the ABV and the AV arm were closed prematurely since tumor control with these regimens was significantly worse than with ABVD. The 4-year FFTF rates were 84.5 and 75.3 % with ABV and AV, respectively, compared with a 4-year FFTF beyond 90 % with ABVD; OS at 4 years did not differ between treatment arms. Thus, dacarbazine appears to be an essential component in the ABVD protocol when used in early favorable HL. The question whether AVD and ABVD are equally effective cannot be answered to date and needs further follow-up.
Ongoing trials such as the GHSG HD16 trial and the EORTC H10F study evaluate interim positron emission tomography (PET) for treatment stratification. In the randomized HD16 trial (NCT00736320), all patients initially receive two cycles of ABVD before interim PET is performed. Then, patients in the standard arm have 20 Gy IF-RT irrespective of their PET result. In the experimental arm, 20 Gy IF-RT is only applied to patients with an incomplete metabolic response while patients with a negative PET are not irradiated. In the H10F trial (NCT00433433) conducted by the EORTC and the Groupe d’Etude des Lymphomes de l’Adulte (GELA), treatment in the experimental arm is also stratified according to the result of an interim PET performed after two cycles of ABVD. While patients assigned to the standard arm receive a total of three cycles of ABVD followed by involved-node RT (IN-RT) irrespective of the PET result, patients randomized to the experimental arm received two additional cycles of ABVD without additional irradiation in case of a complete metabolic response when the trial started recruitment; patients with a positive interim PET continued treatment with two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) followed by involved-node RT (IN-RT). However, after an interim analysis revealed an increased frequency of events among patients receiving chemotherapy only, this treatment arm was closed early so that all patients with a negative PET now receive consolidating IN-RT. Although longer follow-up is required for final conclusions, the premature closure of the chemotherapy-only arm underscores the fact that treatment stratification according to interim PET in patients with early favorable HL should be restricted to clinical trials.
In summary, a brief chemotherapy with ABVD followed by IF-RT represents a safe and highly active treatment that is widely being adopted as standard of care for patients with early favorable HL. The question whether treatment can be further reduced in order to decrease the risk of adverse effects such as lung failure or RT-associated secondary solid tumors will be answered by future analyses of recently completed and ongoing randomized clinical trials.
Early unfavorable HL
Combined-modality approaches consisting of four cycles of chemotherapy followed by IF-RT represent the standard of care for patients with early unfavorable HL (i.e., those with stage I/II disease presenting with clinical risk factors). However, the optimal chemotherapy is still undefined.
In the EORTC H8U trial, three different regimens were randomly compared . Patients were assigned to receive either six cycles of MOPP/ABV plus IF-RT, four cycles of MOPP/ABV plus IF-RT or four cycles of MOPP/ABV plus STNI. There were no differences with respect to the 5-year EFS and the 10-year OS estimates. Thus, it was concluded that four courses of chemotherapy followed by IF-RT should be the standard of care for patients with early unfavorable HL.
In order to improve the tumor control in this patient group, the GHSG and the EORTC both incorporated BEACOPPbaseline into their next trial generation. In the GHSG HD11 trial, 1395 patients received either four cycles of ABVD or four cycles of BEACOPPbaseline followed by IF-RT at 20 or 30 Gy . Freedom from treatment failure with BEACOPPbaseline was superior in patients who had 20 Gy IF-RT after chemotherapy while there were no differences between BEACOPPbaseline and ABVD in patients who received 30 Gy IF-RT. Overall survival did not differ between the four treatment arms. Thus, BEACOPPbaseline was not adopted as novel standard chemotherapy regimen for patients with early unfavorable HL due to increased toxicity observed in comparison with ABVD. Preliminary results from the EORTC H9U trial were similar . Within this trial, patients were randomized between six cycles of ABVD, four cycles of ABVD and four cycles of BEACOPPbaseline. Chemotherapy was followed by 30 Gy IF-RT. Event-free survival rates were comparable for patients from all treatment arms but increased toxicity was observed with BEACOPPbaseline. Final results of this trial are pending.
The GHSG follow-up HD14 trial further intensified treatment by introducing BEACOPPescalated in this group of patients . This regimen was originally developed for patients with advanced HL and is associated with more hematotoxicity necessitating the administration of granulocyte-colony stimulating factor (G-CSF) . Patients enrolled in the HD14 trial had four cycles of ABVD followed by 30 Gy IF-RT or two cycles of BEACOPPescalated followed by two cycles of ABVD (“2 + 2”) and 30 Gy IF-RT. The final analysis at a median follow-up of 43 months revealed a better tumor control with 5-year FFTF estimates of 94.8 % for the “2 + 2” protocol as compared with 87.7 % for the standard arm. However, the advantage in terms of FFTF has not translated into a better OS so far. Thus, follow-up analyses of the HD14 trial especially addressing the question of long-term safety in the “2 + 2” arm are needed for final conclusions.
Similar to early favorable HL, current trials including patients with early unfavorable HL such as the GHSG HD17 (NCT01356680) and the EORTC/GELA H10U (NCT00433433) trial aim at tailoring treatment according to the results of an interim PET. In the HD17 trial, all patients receive chemotherapy according to the “2 + 2” regimen before a PET is performed. In the standard arm, patients receive additional 30 Gy IF-RT irrespective of the PET result. In the experimental arm, patients with a complete metabolic response do not receive further treatment while patients with residual PET-positive lymphoma have 30 Gy IN-RT. Aim of the study is to evaluate whether it is possible to spare RT in patients with a negative PET after intensive BEACOPPescalated-containing chemotherapy. The standard arm in the EORTC/GELA H10U trial consists of four cycles of ABVD followed by IN-RT irrespective of the result of an interim PET performed after the second chemotherapy cycle. In the experimental arm of the study, patients with a negative PET initially received a total of six cycles of ABVD without consolidating RT while patients with a positive PET continued treatment with two cycles of escalated BEACOPP before receiving IN-RT. However, the chemotherapy-only arm was closed on the basis of an interim analysis due to an increased number of events so that all patients with a negative PET now receive additional RT.
Long-term results from a trial conducted by the National Cancer Institute of Canada (NCIC) and the Eastern Cooperative Oncology Group (ECOG) indicate that chemotherapy-only approaches appear possible in patients with early unfavorable HL, at least in those with non-bulky disease . The 276 patients with early HL presenting with unfavorable clinical features included in this trial were randomized to receive either 4–6 cycles of ABVD alone or two cycles of ABVD followed by STNI. At a median follow-up of 11.3 years, freedom from disease progression was clearly better in the group receiving combined-modality treatment. However, this did not translate into a superior OS. In contrast, OS was better for patients treated with chemotherapy alone. This fact was mainly attributed to the increased number of deaths from secondary neoplasia among patients who had received combined-modality treatment. Nevertheless, one should keep in mind that the RT technique used in this trial is outdated and no longer used. In addition, five deaths in the combined-modality group were due to reasons very likely not associated with RT such as drowning, suicide and Alzheimer’s disease while there was no death due to such reasons in the chemotherapy-only arm. In summary, chemotherapy only might represent a treatment option in patients with non-bulky early unfavorable HL refusing radiation but combined-modality should remain standard until further data from larger randomized trials supporting chemotherapy-only approaches for this patient group are available.
Treatment of advanced stages
Treatment of advanced HL usually consists of 6–8 cycles of chemotherapy followed by localized RT. The protocols most often used are ABVD and BEACOPPescalated. The question whether one of these protocols may be more suitable for the treatment of advanced HL is an ongoing subject of debate since more than 10 years.
ABVD was shown to be equally effective and less toxic than MOPP and MOPP/ABVD in a randomized clinical trial by Cancer and Leukemia Group B (CALGB). With ABVD, MOPP and MOPP/ABVD, 5-year failure-free survival rates were 61, 50 and 65 %, and 5-year OS rates were 73, 66 and 75 %, respectively . These results were confirmed by two follow-up analyses of the trial [12, 13]. Since MOPP-containing regimens are associated with a substantially higher risk for the development of adverse late effects, secondary leukemia in particular, 6–8 cycles of ABVD have been widely adopted as standard of care for the treatment of advanced HL.
Causes of death within the HD15 trial for advanced HL according to treatment arm
8 × BEACOPPescalated (%)
6 × BEACOPPescalated (%)
8 × BEACOPP-14 (%)
Ongoing studies including patients with advanced HL aim at tailoring treatment according to early interim PET. Two different strategies are evaluated. Some groups such as the GITIL (Gruppo Italiano Terapie Innovative nei Linfomie) start with ABVD chemotherapy and intensify treatment in case of no complete metabolic response in the interim PET. Other groups such as the GHSG start with the more intensive BEACOPPescalated protocol and reduce treatment in patients with a negative interim PET. In the GITIL HD0607 trial (NCT00795613), all patients initially receive two cycles of ABVD. Then, interim PET is performed. Patients with a negative PET continue treatment with ABVD, patients with PET-positive residual disease switch to the BEACOPPescalated protocol. After four cycles of either ABVD or BEACOPPescalated, another PET is performed. Depending on the result, further treatment procedures vary between observation and allogeneic stem cell transplantation (aSCT). Within the GHSG HD18 trial (NCT00515554), patients initially receive two cycles of BEACOPPescalated. Then, interim PET is performed and patients are randomized. The standard arm consists of a total of six cycles of BEACOPPescalated irrespective of the result of the interim PET. In the experimental treatment arm, patients with a complete metabolic response receive a total of only four cycles of BEACOPPescalated. Patients with PET-positive residual disease after two cycles of chemotherapy received a total of six cycles of escalated BEACOPP supplemented by the anti-CD20 antibody rituximab in the cycles applied after the interim PET until this study arm was recently closed according to plan.
Since results with current approaches are difficult to improve, future studies will probably aim at developing more personalized treatment strategies in order to spare treatment whenever possible. In addition to interim PET, biomarkers such as the thymus and activation-regulated chemokine (TARC), the number of CD68-positive macrophages in the tumor tissue or others might be included in a score predicting the individual patient’s risk [17, 18, 19, 20]. Furthermore, treatment could be optimized by combining conventional chemotherapy with novel targeted and less toxic drugs. Ongoing phase I/II studies such as the GHSG “Targeted BEACOPP” study (NCT01569204) combining a BEACOPP backbone with the antibody–drug conjugate (ADC) brentuximab vedotin (SGN-35) currently evaluate such combinations in terms of activity, feasibility and toxicity.
Despite these recent developments, the question whether ABVD or BEACOPPescalated should be the standard of care in the first-line treatment of advanced HL is still being discussed controversially.
Treatment of relapsed HL
The standard treatment for the majority of patients with relapsed HL consists in high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Two randomized clinical trials showed the superiority of this approach in comparison with conventional chemotherapy. The first trial came from British National Lymphoma Investigation (BNLI) . Patients with relapsed HL were randomly assigned to receive high-dose BEAM (BCNU, etoposide, ara-C, melphalan) followed by autologous bone marrow transplantation (ABMT) or the same chemotherapy protocol at a lower dose without subsequent autograft. Tumor control was better among patients who received high-dose chemotherapy followed by ABMT resulting in significantly better EFS and progression-free survival (PFS) rates. However, OS did not significantly differ between study arms. The second, larger study was conducted by the GHSG and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (EBMT) . All 161 patients included initially received two cycles of Dexa-BEAM. Chemosensitive patients were then randomized between two additional cycles of the same chemotherapy or high-dose BEAM followed by ASCT. At a median follow-up of 39 months, 3-year FFTF was superior for patients receiving high-dose chemotherapy and ASCT. However, similar to the British trial, OS did not significantly differ between patient groups.
In the follow-up trial conducted by the GSHG, the EORTC, the EBMT and the Spanish Grup per l’Estudi dels Linfomes de Catalunya i Balears (GELCAB), all patients enrolled initially received two cycles of DHAP (dexamethasone, high-dose ara-C, cisplatin) . Patients responding to DHAP were randomized between high-dose BEAM followed by ASCT and a sequential high-dose program consisting of cyclophosphamide, methotrexate/vincristine, etoposide and BEAM followed by ASCT. At a median observation of 42 months, no differences between treatment arms in terms of FFTF and OS were detectable. Thus, the less toxic approach consisting of two cycles of DHAP or other salvage protocols such as IGEV (ifosphamide, gemcitabine, etoposide, vinblastine) and ICE (ifosphamide, carboplatin, etoposide) followed by high-dose chemotherapy and ASCT remains standard of care in the treatment of patients with relapsed HL [24, 25].
Ongoing trials aim at optimizing salvage therapy by combining established re-induction protocols with novel drugs such as antibodies or small molecules on the one hand and aim at identifying risk groups by the use of interim PET on the other hand. Outcome of high-risk patients may be improved by maintenance therapy, an approach that is currently evaluated.
Treatment of elderly patients with HL
HL patients aged 60 years or older are considered elderly. Treatment of this age group represents a challenge since outcome is significantly worse than in younger patients . This is mainly due to comorbidity and an increased rate of treatment-related toxic events precluding aggressive treatment in many cases. Thus, novel strategies are needed. Several groups recently evaluated approaches particularly developed for this age group. These approaches aimed at being equally or more effective and less toxic than the ABVD regimen which is considered standard of care although increased toxicity was also observed with this protocol in elderly patients . The GHSG conducted a phase II study including 59 patients with early unfavorable and advanced HL aged 60–75 years. Patients were treated with 6–8 cycles of the PVAG (prednisone, vinblastine, adriamycin, gemcitabine) regimen optionally followed by RT . Response rates were comparable to those observed with ABVD, toxicity was acceptable. At a median follow-up of 37 months, 3-year PFS and OS rates were 58 and 66 %, respectively. These results justify further evaluation of this protocol. The Scotland and Newcastle Lymphoma Group (SNLG) recently published results of a study investigating the VEPEMB (vinblastine, cyclophosphamide, prednisone, procarbazine, etoposide, mitoxantrone, bleomycin) regimen in 103 elderly HL patients. With this protocol, 3-year PFS rates for patients with early and advanced HL were 74 and 58 %, 3-year OS rates were 80.7 and 66.2 %, respectively. Thus, this regimen might also represent an option in elderly HL patients . An ongoing phase I study by the GHSG combines AVD with lenalidomide (NCT01056679). Bleomycin is not given to reduce the risk for pulmonary toxicity. However, results from this trial are pending. In case of relapse, treatment of elderly HL patients is mostly palliative since only few patients from this age group are candidates for high-dose chemotherapy followed by ASCT. In the majority of cases, single-agent chemotherapy with drugs such as gemcitabine is given . Alternatively, patients can be included in phase I/II studies evaluating novel targeted drugs.
Treatment of nodular lymphocyte-predominant HL (NLPHL)
Nodular lymphocyte-predominant HL (NLPHL) is a rare subtype representing about 5 % of HL cases . When compared with classical HL (cHL), NLPHL is characterized by a more indolent clinical course often resembling indolent B cell non-Hodgkin lymphoma (NHL) and a substantially different immunophenotype with consistent positivity for CD20 [31, 32]. Due to its mostly indolent clinical course, the standard treatment for early favorable NLPHL recommended by most cooperative groups consists of RT alone [33, 34]. Results with this approach are excellent with remission rates close to 100 % and long-term survival in about 95 % . A recent GHSG study evaluated the anti-CD20 antibody rituximab in the treatment of stage IA NLPHL patients with the aim to reduce the risk of long-term toxicity such as RT-associated secondary solid tumors . Patients received four weekly standard doses (375 mg/m2) of the antibody. All 28 patients included in the study responded to treatment. However, relapse rate at a median follow-up of 43 months was 25 % and thus significantly higher than with RT only so that this approach cannot be recommended for the majority of patients with early favorable NLPHL. Early unfavorable and advanced NLPHL are usually treated very similar to cHL since no mature data on alternative treatment approaches for NLPHL are available to date. In relapsed NLPHL, the standard of care for cHL consisting of high-dose chemotherapy followed by ASCT appears to be less effective resulting in higher relapse rates . Thus, anti-CD20 antibody treatment represents an alternative in this situation. A study including 15 patients with relapsed NLPHL reported a response rate of 94 % and durable remissions in a relevant proportion of patients after treatment with rituximab . Given the low toxicity of the antibody, rituximab can therefore be considered treatment of choice in relapsed NLPHL, at least in patients with more localized disease. An ongoing trial by the GHSG evaluates the tolerability and efficacy of the fully human second-generation anti-CD20 antibody ofatumumab in relapsed NLPHL (NCT01187303).