Treatment Outcomes of Advanced Stage Classical Hodgkin Lymphoma in the Setting of Vinblastine and Dacarbazine Shortages: A Case Series

Primary refractory Hodgkin lymphoma: Limited options and poor survival—but not always

3-year follow-up of the S1826 study confirms improved progression-free survival with nivolumab-AVD compared to brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma

Progression-Free Survival (PFS) and Toxicity with Nivolumab-AVD Compared to Brentuximab Vedotin-AVD in Pediatric Advanced Stage (AS) Classic Hodgkin Lymphoma (cHL), Results of SWOG S1826

A Phase II Study of Brentuximab Vedotin Plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma

Targeted Beacopp Variants in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Final Analysis of a Randomized Phase II Study

Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes

Introduction: Individualized, PET2-guided first-line treatment of patients with advanced-stage classical Hodgkin Lymphoma (AS-cHL) with eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). We hypothesized that remodeling the eBEACOPP regimen with brentuximab vedotin (BV) could decrease TRMB while maintaining its high efficacy. Here, we report the results of the HD21 study regarding non-inferiority of BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) as compared to eBEACOPP in terms of progression-free survival (PFS). Methods: This international open-label phase III trial included adult patients aged ≤60 with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4–6 cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. Non-inferiority of the primary efficacy endpoint PFS was defined as an absolute difference <6% at 5 years corresponding to a hazard ratio (HR) of BrECADD versus eBEACOPP <1.69. For this interim analysis at 36 months follow-up, O’Brien-Fleming method with Lan-DeMets alpha-spending function and the actual information fraction was used to calculate the significance level and HR bound for non-inferiority in the intention-to-treat (ITT) analysis set. 100 PFS events were available, resulting in a HR bound of 1.02 and a corresponding alpha level of 0.0108. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: We enrolled 1,500 patients from 9 countries and 233 trial sites between July 2016 and August 2020. The ITT population comprised 1,482 patients, 740 in the eBEACOPP arm and 742 in the BrECADD arm. 44% were female, median age was 34 y (range 18–61), 47% were at high-risk (international prognostic index ≥3), baseline characteristics were well balanced between treatment arms. 59% of patients received 4 and 41% received 6 cycles of therapy. Median follow-up was 40 months. 3-year PFS was 92.3% for eBEACOPP and 94.9% for BrECADD, the corresponding point estimate for the HR was 0.63 (99% CI 0.37–1.07) and thus below the pre-specified bound. Progression or early relapse of HL ≤1 year was documented for 37 patients in the eBEACOPP arm (5%) and 16 patients in the BrECADD arm (2.2%). 3-year overall survival was 98.5% in both groups. Conclusion: This interim analysis of the GHSG HD21 trial fully establishes non-inferiority of BrECADD compared to eBEACOPP. Importantly, we observed a relevant reduction in early PFS events with BrECADD resulting in a 3-year PFS rate of 94.9%. This mature and unparalleled PFS rate suggests that individualized treatment with PET2-directed BrECADD is currently the most effective therapy for adult patients with AS-cHL. The research was funded by: Takeda Oncology Keyword: Hodgkin lymphoma Conflicts of interests pertinent to the abstract P. Borchmann Consultant or advisory role: Takeda Oncology Research funding: Takeda Oncology Honoraria: BMS Germany, MSD Oncology Research funding: MSD Oncology (Institution); Takeda (Institution)

Targeted Beacopp Variants In Patients With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Interim Results Of a Randomized Phase II Study

Interim PET-Adapted De-Escalation Chemotherapy Regimen for Advanced Stage Classical Hodgkin Lymphoma Using Brentuximab Vedotin, Pembrolizumab, Doxorubicin, and Dacarbazine: Phase 2 Safety and Efficacy Study

The objective of this guideline is to aid clinicians in deciding which patients with primary refractory or relapsed Hodgkin lymphoma (HL) should receive salvage therapy with a view to autologous stem cell transplantation (ASCT); what response is adequate to allow ASCT and how to determine this; what is the role of radiotherapy in patient management; and what is the best management of patients unsuitable for autologous transplantation. The production of these guidelines involved the following steps: Patients with primary resistant (progression or non-response during induction treatment or within 90 days of completion) or relapsed HL represent a relatively small but increasingly challenging population. The majority have classical HL. Although patients with nodular lymphocyte predominant HL (NLPHL) may be managed according to the same algorithms, some of these patients have a chronic indolent course and may not require such aggressive treatment (their management is subject to a separate BCSH guideline, currently in preparation). Repeat biopsy is generally recommended in patients thought to have relapsed, and should be considered in those who have residual fluorodeoxyglucose (FDG)-avid lesions post-therapy. This is important in order to confirm that there is no change in histology and to ensure that abnormalities on PET/computerized tomography (CT) imaging represent active disease. In some patients lesions can be difficult to access or yield non-diagnostic material despite multiple biopsies. In such cases identification of progression on serial imaging together with the presence of symptoms will increase confidence that such abnormalities truly represent disease, although it is acknowledged that, in some cases, salvage therapy will be warranted in the absence of histological proof or radiological progression. Prognostic models for de novo HL are well established for both early and late stage HL. However, prognostic models are less well defined for relapsed or refractory disease. Furthermore, as primary therapies become more effective and the numbers of treatment failures are reduced, it is likely that the cohort identified as either resistant or relapsed will become an increasingly poor prognostic group and that the relevance of previously identified prognostic factors will require re-evaluation. For example, the intensity of first-line therapy has an important impact on the outcome of salvage therapies, with evidence that patients receiving BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) are more difficult to successfully salvage and rescue with high dose therapy than those relapsing after ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) (Josting et al, 2010). It is notable that a number of biological and pathological factors have been shown to correlate with prognosis, largely when assessed at diagnosis. (e.g. number of infiltrating CD68+ macrophages). Their independent importance has not been proven in large data sets, or specifically in the setting of relapsed or refractory disease. Primary resistance is generally considered, in itself, to be a poor prognostic marker (Longo et al, 1992; Bonfante et al, 1997; Moskowitz et al, 2001), and only limited models exist to distinguish one refractory patient from another. Clearly in this situation performance status and ability to tolerate intensive chemotherapy and ASCT will impact on survival (Josting et al, 2000; Ferme et al, 2002). Virtually no patients with primary resistant disease survive more than 8 years using conventional chemotherapy alone (0–8%)(Longo et al, 1992; Bonfante et al, 1997), whilst the projected 20-year survivals for those with early relapse (<12 months from primary therapy) or late relapse (>12 months from primary therapy) were previously estimated to be 11% and 22%, respectively, in the era of less intensive induction regimens (Longo et al, 1992). Whilst outcomes in those with primary progressive disease may appear reasonable following ASCT in some series (with a 5-year freedom from second failure (FF2F) of 42% reported by the German Hodgkin's Lymphoma study group (GHSG)), only a minority of such patients received ASCT (70/206, 33%) owing to rapidly progressive disease, therapy-related toxicity, insufficient stem cell harvest, or poor performance status (Josting et al, 2000). The 5-year FF2F for the entire cohort was only 17%. Poor performance status, age >50 years and failure to attain a temporary remission to first-line therapy were found to be poor prognostic factors in a multivariate analysis. Patients with an initial period of remission have somewhat better outcomes. In a large retrospective analysis of 422 registry patients with relapsed HL performed by the GHSG (Josting et al, 2002a) the clinical factors predictive of worse 5-year FF2F were: time to relapse (3–12 months after completion of first treatment); stage at relapse (III or IV); and anaemia at relapse (<105 g/l in females and <120 g/l in males). The FF2F were 45%, 32% and 18% for those with scores of 0–1, 2 or 3 respectively. The prognostic score was predictive for patients who relapsed after radiotherapy, chemotherapy with conventional dose salvage, and chemotherapy with ASCT. Several other studies have shown that patients relapsing within 12 months of first line therapy have a poorer prognosis (Brice et al, 1997; Wheeler et al, 1997; Sureda et al, 2001); whilst 80% of those with a late relapse will achieve a second remission (Longo et al, 1992). Further factors found to have prognostic significance in some but not all studies include extranodal disease (Brice et al, 1997; Moskowitz et al, 2001) and the presence of B symptoms (Moskowitz et al, 2001). Using a 3-point scale based on (i) early relapse or primary refractory disease, (ii) extranodal disease, and (iii) presence of B symptoms at relapse, patients could be stratified with 5-year event-free survival (EFS) of only 27% and 10% in those with a score of 2 or 3 respectively (Moskowitz et al, 2001). In summary, clinical factors prior to salvage that are most commonly identified as indicating poor prognosis include primary resistance, early relapse, disease bulk and/or stage plus allied systemic abnormalities. Performance status is also important. Response to salvage adds further discrimination in terms of prognosis, i.e., chemosensitivity, number of lines of salvage required, and status at transplant (Sureda et al, 2001). Refractoriness to salvage therapy predicts a very poor outcome. The more recent development of functional imaging modalities allows further refinement in this regard. The achievement of PET negativity following salvage therapy is a good prognostic indicator for outcome following ASCT, with 3–5 year progression-free survival (PFS) of >70% (Jabbour et al, 2007; Moskowitz et al, 2010; Smeltzer et al, 2011; Thomson et al, 2013). Residual FDG-PET-positive tumour uptake following salvage chemotherapy is associated with poor outcome following ASCT, even when ASCT is restricted to those achieving at least a partial response (PR) by conventional CT criteria (25–30% 3- to 5-year PFS) (Jabbour et al, 2007; Moskowitz et al, 2010). Thus whilst achievement of PR by CT criteria leads to recommendation for ASCT, 55–60% of such cases will have residual FDG-avid lesions following a single line of salvage (Moskowitz et al, 2010). Recent reports have indicated potential for response-adapted management using PET to identify a further subgroup with potentially good outcomes post-ASCT, employing further intensive therapy for those patients with residual metabolic activity post-first line salvage. Conversion to PET-negative status post-second line salvage chemotherapy prior to ASCT was associated with a favourable outcome (EFS of >80%), equivalent to those who were PET-negative following first line salvage in those with only nodal disease, with somewhat inferior outcomes in those who achieve PET-negative status but with extranodal disease (Moskowitz et al, 2011). Thus, although PET status post-salvage probably overrides many previously identified prognostic factors to some degree, they may still have some independent impact and this issue requires further investigation. The possible role of a PET-based response-adjusted algorithm for directing patients to more experimental therapies is discussed further in the section on allogeneic transplantation. Finally, whilst there is no a priori reason to indicate that PET responses following brentuximab vedotin will be in any way qualitatively different from those following other conventional salvage regimens, this question has yet to be addressed. There are no randomized trials to compare the efficacy of chemotherapy regimens prior to ASCT. However, many single arm phase II trials have reported on the efficacy of a wide range of different regimens (Table 1). Overall response rates are reported as 70–90% and complete response rates (usually assessed with conventional CT scanning) as 20–55%. The confidence intervals reported by the trials frequently overlap and different patient populations were treated in these studies, making comparison of efficacy very difficult. Toxicity for the majority of regimens was mainly haematological, with gastrointestinal toxicity also a common feature of some regimens. Mortality from salvage therapy is low, as expected from the young age of the patients and associated lack of co-morbidities. However, the treatment-related mortality reported for the Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarbine, melphaln) regimen was 5% in the GHSG/European Group for Blood and Marrow Transplantation (EBMT) ASCT phase III trial, although it is hard to know if this reflects an intrinsically greater toxicity for this regimen (Schmitz et al, 2002). Given that no recommendations can be made as to the most efficacious regimen, the decision should be tailored to individual patient needs (such as avoiding cisplatin in renal impairment or avoiding ifosfamide in patients at high risk of ifosfamide-induced encephalopathy) and using an established regimen which is familiar to the treating centre (Table 1). In addition to inducing remission, another important attribute of salvage regimens is a lack of toxicity to the stem cell compartment that would compromise mobilization and harvesting. Little comparative data exist on the impact of chemotherapy regimens on the success rate of stem cell collection. A retrospective comparison between collection after mini-BEAM (carmustine, etoposide, cytarabine, melphalan) and GDP (gemcitabine, dexamethasone, cisplatin) (Kuruvilla et al, 2006) appears to confirm that differences do probably exist. A collection of >5 × 106 CD34+ cells/kg was obtained in 97% of GDP-mobilized patients, but only 57% of mini-BEAM mobilized patients. A similar comparison in both HL and non-Hodgkin lymphoma (NHL) patients between IVE (ifosfamide, epirubicin, etoposide) and ICE (ifosfamide, carboplatin, etoposide) showed a collection of >5 × 106 CD34+ cells/kg was achieved in 72% and 51%, respectively, suggesting superiority for IVE (Fox et al, 2008), although it should be acknowledged that this cell dose is above that needed to support ASCT. Previous reports implicate prior exposure to agents that are toxic to stem cells as a risk factor for reduced stem/progenitor cell mobilization and subsequent engraftment. For example, a retrospective study identified, on multivariate analysis, that the number of courses of dexa-BEAM was the overriding factor affecting granulocyte-macrophage colony-forming unit (CFU-GM) collection from peripheral blood (although not from bone marrow)(Dreger et al, 1995). Two studies have identified the use of mini-BEAM as a risk factor for poor progenitor cell mobilization prior to ASCT (Watts et al, 1997; Weaver et al, 1998). Prior to stem cell collection it is therefore advised that regimens containing alkylating agents, such as melphalan and carmustine (e.g., mini-BEAM/dexa-BEAM), are avoided. A number of groups have investigated the role of intensive sequential chemotherapy regimens prior to ASCT, particularly in the higher risk cohorts, in order to try to improve outcomes (Tarella et al, 2003; Shea et al, 2009; Josting et al, 2010). To date any potential benefits have been offset by increased toxicities, with no evidence to suggest any significant overall benefits. As previously discussed, patients who are PET-positive after first line salvage chemotherapy, as a group, have relatively poor outcomes. Those achieving PET-negative status following a second line of salvage may have outcomes that are similar to those achieving this status following a single line, at least for those with exclusively nodal disease, although this finding has only been reported in a single study and requires confirmation (Moskowitz et al, 2011). Nevertheless, it is recommended that patients should receive an alternative, non-cross reacting chemotherapy regimen in an attempt to achieve PET-negative status prior to ASCT. There are no data to support the choice of any particular regimen, though similar considerations apply regarding potential impact on mobilization. Alternatively, these patients may be considered for investigational strategies in the context of clinical trials. There is no published evidence directly informing the question of how many cycles of each line of therapy should be administered before consideration of a switch to an alternative regimen. The consensus of the panel was that re-evaluation after 2 cycles of a multi-agent regimen was reasonable. Failure to demonstrate a significant improvement at this stage should prompt consideration of a switch to an alternative regimen. A third cycle should be considered in those responding well in order to try to achieve metabolic complete remission (CR). In the case of brentuximab vedotin, it is suggested that re-evaluation is undertaken after 3–4 cycles. Very little data exist to guide treatment decisions in those patients who are refractory to first line salvage regimens, as defined by the failure to reach a partial remission. A proportion of patients do appear to benefit from second line salvage regimens. For example, in a small series of patients who were refractory to DHAP (dexamethasone, cytarabine, cisplatin) as initial chemotherapy, the administration of mini-BEAM second line resulted in a 59% overall response rate with some patients proceeding to ASCT (Stewart et al, 1991). Follow up post-ASCT was too short to draw conclusions as to the curative potential of this approach. A more recent retrospective study reported on 19 patients who had not responded to GDP first line salvage and went on to receive mini-BEAM. Six patients (32%) responded and nine proceeded to ASCT. Of these nine, seven relapsed, suggesting that with current salvage regimens, the outcome for refractory disease is very poor when using an alternative standard chemotherapy regimen (Villa et al, 2012). Finally, 12/19 (63%) patients refractory to at least one line of salvage (ESHAP; etoposide, methylprednisolone, cytarabine, cisplatin) responded to mini-BEAM in another retrospective study (Moore et al, 2012). Whilst 2-year PFS following consolidation with stem cell transplantation was a more encouraging 58% in this study, the vast majority underwent allogeneic rather than autologous transplant procedures (see below). Alternative salvage agents include the anti-CD30 immunoconjugate brentuximab vedotin and bendamustine. The majority of data using brentuximab come from the pivotal phase II study in which patients were only eligible if they had relapsed following ASCT (Younes et al, 2012). The overall response rate was 75% with a 34% complete remission rate. Limited experience from small case series of up to 20 transplant-naïve patients has been published more recently. Overall response rates vary from 30 to 58% in 'refractory' patients (Forero-Torres et al, 2012; Gibb et al, 2013; Sasse et al, 2013). Two recent studies reported response rates of 53–58% in patients receiving bendamustine (Corazzelli et al, 2013; Moskowitz et al, 2013). Although most patients had received a prior ASCT, response was not by to line of suggesting this may be a second line salvage studies have specifically the efficacy of second line chemotherapy alone chemotherapy with in relapsed HL in patients not eligible for stem cell transplantation. In the randomized study, et reported a freedom from treatment failure of 34% for those patients randomized to courses of dexa-BEAM ASCT. was better for those who relapsed defined as 12 months or more after initial with of with for those who relapsed between 3 and 12 months after initial include the that the not include patients with primary refractory disease, and that patients were only eligible for if they achieved at least a PR by CT this is a relatively et reported a 10% for patients randomized to mini-BEAM alone but this was a study according to of first response is difficult. patients in this study by eligible for ASCT. Furthermore, both studies salvage regimens that have significant associated and may be by patients with co-morbidities. There are no data on the treatment of such patients who are for ASCT and would not be expected to tolerate such regimens trials of first-line for early stage disease, demonstrate the disease achieved with It therefore reasonable to radiotherapy with chemotherapy for patients at This would be particularly for those patients with limited stage disease and for those who have either not received radiotherapy as of first-line treatment or who have relapsed of the In patients to tolerate the associated with more intensive regimens, limited published experience with single such as vinblastine, or et al, et al, Little et al, et al, or multi-agent regimens with or vinblastine, such as etoposide, et al, or vinblastine, procarbazine, et al, suggest benefits may be achieved in many The role of agents, such as brentuximab vedotin, in this setting requires further The early of is The outcome of patients with relapsed or refractory disease treated with conventional of chemotherapy alone is generally poor with remission rates of between and (Longo et al, 1992; et al, et al, the higher rates outcomes only in the achieving at least a PR to initial salvage Patients relapsing years after initial treatment may do better with conventional salvage chemotherapy but PFS et al, Although no overall survival benefit has been in a randomized clinical trial, the of treatment at relapse in patients significant is to remission and to high dose therapy with ASCT. This recommendation is based on randomized which a significant benefit of ASCT conventional chemotherapy in terms of for patients with relapsed disease et al, et al, 2002). The lack of a survival benefit in either of these studies has been to patients in the arm transplant at the time of second trials the regimen prior to ASCT. In the this was to cycles of mini-BEAM et al, and in the second to cycles of Dexa-BEAM following initial induction with cycles of Dexa-BEAM (Schmitz et al, 2002). trials response to salvage therapy according to conventional CT those with less than PR from subsequent A number of other and registry series confirm similar outcomes following ASCT. the most regimen but other regimens with and outcomes have been reported in studies (Moskowitz et al, et al, et al, et al, 2007; et al, et al, 2011; et al, 2013). regimens have been largely in of regimens of a higher of and mortality with the (Sureda et al, 2001). the experience with salvage chemotherapy (see there are no data to suggest the superiority of one regimen to and the choice of regimen is therefore based on and more than years after primary therapy are but at a higher than the of HL in the suggesting that this represent a relapse of the disease et al, 2011). Although data are outcomes appear favourable in terms of response rates using either a second course of the primary treatment regimen or an alternative regimen. and mortality associated with treatment are relatively high et al, 2010; et al, and the majority of reported cases not ASCT as there is insufficient data to ASCT in those achieving a complete metabolic although it is a reasonable clinical As in other clinical agents have been investigated as possible post-ASCT therapies, but such strategies have with limited For example, an attempt to ASCT with involved radiotherapy to of disease of by cycles each of (dexamethasone, cyclophosphamide, etoposide, and (dexamethasone, administered 3 months year was notable for the that only received the post-ASCT either of early relapse or other et al, the of patients with relapsed rather than refractory disease, and with only lines of prior the PFS at years was only Further of agents that are potentially less toxic when administered as (e.g., brentuximab vedotin or are but current evidence not support A potential role for ASCT has been in a number of The a ASCT for patients with or more of risk which relapse or progression stage disease at relapse, and relapse in a previously et al, The first regimen of cyclophosphamide, carmustine, etoposide, and and the second of for patients who had received prior and Their outcomes were to those of patients who underwent a single ASCT. The outcomes for the patients inferior to those of the patients, with 5-year FF2F rates of and although it was suggested that have been to those of in series using single ASCT. will require a randomized study, and ASCT currently be recommended of clinical trials. for patients who relapse following ASCT, particularly for those with early relapse within have been in more recent the has been only months (Moskowitz et al, 2009; et al, 2012). The of treatment in these patients is to attain response to allow consideration of allogeneic transplantation in those eligible (see section In those not for allogeneic therapy should be according to patients will be most treated with a and early of is In the further to disease are that some will achieve of disease particularly those relapsing following ASCT et al, 2013). vedotin should be considered the alternative regimens at this although choice may be by prior of Although the in the pivotal study was as response rates were high and (Younes et al, 2012). The role of allogeneic in the management of this patient group Whilst has been limited by mortality in to the of strategies has re-evaluation of a possible The between relapse and the development of disease following allogeneic with responses to lymphocyte the of a activity et al, 2011; et al, 2009; et al, 2009; Sureda et al, 2012). there are no comparative data to the choice of regimen. Nevertheless, a employing a more intensive regimen may be to a based on considerations and overall of The majority of early experience was in those with relapse following ASCT, and these patients still probably represent the majority of those proceeding to allogeneic data suggest that the reduced mortality associated with reduced intensity to some degree, offset by increased relapse rates (Sureda et al, et al, 2009; et al, PFS rates in this setting range from 20 to at years in series and registry et al, Sureda et al, 2012; et al, 2011). yield outcomes to those achieved with in most series et al, 2009; et al, 2011; Sureda et al, 2012). studies, though not all et al, identify at the time of transplant as an important prognostic indicator et al, although for resistant disease Those with progressive disease have poor outcomes and be recommended for transplant et al, 2009; Sureda et al, 2012). The situation is less for those with disease that following salvage et al, Sureda et al, 2012). For those with disease, allogeneic may be the most clinical the of survival and potentially to a Two retrospective of patients who relapsed after an ASCT suggest that, for those patients with a and who responded to salvage to allogeneic to et al, et al, consolidation with a transplant a better outcome than the use of conventional with a significant in a no comparison of patients for both and A further retrospective study on of that patients who had relapsed after an ASCT showed a in the same for in those allogeneic et al, 2013). For patients relapsing very late after ASCT, a second ASCT may be a reasonable et al, comparative studies exist to recommendations regarding the most salvage In the use of an that the patient has not been to previously is vedotin has activity in the setting of relapse ASCT, although the majority of patients to achieve and the in these cases is short In these cases brentuximab vedotin may a to allogeneic with significant benefits in terms of toxicity et al, 2012). For patients achieving following brentuximab vedotin the situation is less though these patients have the best outcomes following allogeneic and experience with other salvage regimens that transplantation at the time of disease is The more recent of a response-adjusted transplantation algorithm a further potential for of allogeneic in those to be at high risk of failure of ASCT, the to those who have residual FDG-avid disease following salvage therapy et al, 2013). The PFS of in this group was with 80% PFS following may require refinement according to of number of lines of salvage, and according to the outcome of studies strategies following ASCT (e.g. the and it is recommended that they be within the context of The of HL to relapse and in previously involved et al, and the of HL a potentially important treatment in this The less use of in primary therapy also the of a greater role in relapsed or refractory patients. is well to disease in of refractory or HL et al, 1992; et al, 1997; Josting et al, treatment are to the of disease of nodal salvage is and well with to and The of late toxicity should be the associated with disease progression in this relapsed and refractory setting by in radiotherapy of within the The risk of late toxicity and second risk is on the and of as well as age and of the patient and an important role in for patients who have primary refractory disease by a as well as those who relapse after initial is generally as of therapy with salvage chemotherapy, prior to ASCT. A small group of patients with disease and no systemic symptoms with alone (Josting et al, should also be considered as a salvage in the setting of ASCT after relapse or a significant proportion of patients still achieve high response rates to salvage and a may even of whilst in it an important role in et al, 2012). failures the in this the for systemic therapy in with salvage has been for and consolidation therapy in the period in some transplant wide (Moskowitz et al, 2001), and has been reported to in numbers of ASCT failures in patients who received in single It should be considered in patients that have a of relapse at an involved are patients who have had disease with residual abnormalities following salvage chemotherapy and et al, et al, et al, 2012). For the are using guidelines et al, and are on an individual patient on the of disease at initial and at Patients who are for salvage therapy may benefit from either before or after ASCT to of In patients with complete response to salvage chemotherapy, a dose of ASCT is recommended et al, 2013). In should be as as the patient has from the of ASCT, and within following stem cell should be to and to the of and that would be the and in these guidelines is to be and at the time of to the the for the any for the of these A and have as for and/or received from There are no other of to to the the and receive from the of recommendations are made when there is confidence that the benefits do or do not and recommendations can be to most patients. as the of benefit or not is less a 2 recommendation is 2 recommendations require to individual patients. as

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Updated Efficacy and Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

CADTH recommends that Adcetris be reimbursed by public drug plans for the treatment of patients with previously untreated advanced stage Hodgkin lymphoma (HL) if certain conditions are met. Adcetris should only be covered to treat adults aged 18 years or older with advanced stage classical HL or children and adolescents aged 2 years or older with high-risk HL who are in relatively good health. Adcetris should not be covered to treat patients with nodular lymphocyte-predominant HL, severe sensory or motor peripheral neuropathy, cerebral or meningeal disease, or a neurologic disease that affects their daily activities. Adcetris should only be reimbursed if it is prescribed by a clinician with experience treating HL and its cost is reduced. In the pediatric population, the prescribing clinician should also have expertise in pediatric oncology. Brentuximab vedotin (BV) should be used in combination with doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) in adults or doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide (AVEPC) in pediatric patients.

BackgroundThe prognosis of early unfavorable and advanced stage classic Hodgkin lymphoma (cHL) remains suboptimal with the widely used ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen. Novel agents such as brentuximab vedotin (BV) and anti-PD-1 antibody have demonstrated high efficacy and good tolerance in relapsed/refractory cHL and have also shown promising results in the frontline setting. However, concurrent administration of anti-PD-1 antibody plus AVD in comparison with traditional ABVD regimen alone in untreated classic Hodgkin lymphoma (cHL) has yet to be adequately studied in real-world clinical practice.MethodsWe enrolled eligible adult patients with histologically confirmed cHL who had received initial treatment with the ABVD regimen, or the novel combination regimens of anti-PD1-AVD. The study endpoints included modified progression-free survival (mPFS) and complete response (CR) after 2 cycles of therapy. Propensity score matching (PSM) was performed to balance clinical variables between regimens prior to efficacy comparisons.ResultsOf 172 patients, 137 received the ABVD regimen and 35 received the anti-PD1-AVD regimen. With a median follow-up of 37.7 months, significantly prolonged 3-year modified PFS was reported for anti-PD1-AVD versus ABVD (PSM: 91.0 vs. 61.6%, p = 0.032). Significantly improved CR rate was observed with anti-PD1-AVD versus ABVD (PSM: 86.7 vs. 63.8%, p = 0.049).ConclusionsIn this real-world study, concurrent anti-PD1 antibody with AVD showed significantly prolonged modified PFS and improved CR rate after cycle 2 versus ABVD regimen, supporting the use of novel agents in frontline therapy.

ABSTRACTIntroduction: Second-line, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (AUTO-SCT) is the standard of care for patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Approximately 50% of patients relapse after AUTO-SCT and their prognosis is generally poor. Brentuximab Vedotin (BV) has demonstrated efficacy in this setting and allogeneic (ALLO)-SCT represents an option with curative potential in this subgroup of patients.Areas covered: A systematic review has been conducted to explore the actual knowledge on ALLO-SCT, BV and newer agents in R/R HL.Expert opinion: The introduction of BV in clinical practice has significantly improved the management of post-AUTO-SCT relapses and the drug can induce durable remissions in a subset of R/R HL. Allografting select patients has been used to improve clinical outcomes and recent case series have begun to explore BV as a potential ‘bridge’ to allo-SCT, even though the optimal timing of ALLO-SCT after BV response remains undetermined. However, reduced tumor burden at the time of ALLO-SCT is a key factor to decrease relapse risk. Based on the unique composition of the tumor, more recently new agents such as PD-1 inhibitors have been developed. The potential role of PD-1 inhibitors with ALLO-SCT remains to be explored.