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Scope

Scope. 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)

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Scope

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  1. HAMMOUD - MOFID

  2. HAMMOUD - MOFID

  3. Scope 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 • what is the best management of patients unsuitablefor autologous transplantation. HAMMOUD - MOFID

  4. Methodology literature review to 1 Feb 2013 including Medline, Pubmed and the Cochrane reviews database, using 1970 as a start date In view of the paucity of phase III trials, all series excluding only those that were case reports were reviewed. HAMMOUD - MOFID

  5. Background • 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. • Repeat biopsy is generally recommended 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. HAMMOUD - MOFID

  6. 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. HAMMOUD - MOFID

  7. Prognostic models • The intensity of first-line therapy has an important impact on the outcome of salvage therapies • 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. HAMMOUD - MOFID

  8. Primary resistant disease • Primary resistance is generally considered, in itself, to be a poor prognostic marker • performance status and ability to tolerate intensive chemotherapy and ASCT will impact on survival • Virtually no patients with primary resistant disease survive more than 8 years using conventional chemotherapy alone • 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). • 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% • 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 performancestatus(Josting et al, 2000). • The 5-year FF2F for the entire cohort was only 17% HAMMOUD - MOFID

  9. Relapsed disease Patients with an initial period of remission have somewhat better outcomes. 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 anaemiaat 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. HAMMOUD - MOFID

  10. Several other studies have shown that patients relapsing within 12 months of first line therapy have a poorer prognosis • 80% of those with a late relapse will achieve a second remission • Further factors found to have prognostic significance in some but not all studies include extranodal disease and the presence of B symptoms 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 (Moskowitzet al, 2001). HAMMOUD - MOFID

  11. 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. HAMMOUD - MOFID

  12. Response to salvage Refractoriness to salvage therapy predicts a very poor outcome. 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% Residual FDG-PET-positive tumor 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) HAMMOUD - MOFID

  13. Thus 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). HAMMOUD - MOFID

  14. Conversion to PET-negative status post-second line salvagechemotherapy prior to ASCT was associated with a favorable 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 extranodaldisease (Moskowitzet al, 2011). HAMMOUD - MOFID

  15. Recommendations ● Repeat biopsy is generally recommended in HL patients thought to have relapsed, and should be considered in those who have residual FDG-avid lesions post-therapy (1C). ● PET-CT is the preferred restaging modality after salvage therapy (1B). ● The aim of salvage treatment should be to achieve an FDG-PET-negative remission (1B). HAMMOUD - MOFID

  16. HAMMOUD - MOFID

  17. Salvage chemotherapyFirst line salvage in patients eligible for high dose therapy There are no randomized trials to compare the efficacy of chemotherapy regimens prior to ASCT. 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. HAMMOUD - MOFID

  18. Mortality from salvage therapy is low • treatment-related mortality reported for the Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarbine, melphaln) regimen was 5% • 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 HAMMOUD - MOFID

  19. 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. 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. HAMMOUD - MOFID

  20. A collection of >5 x 10*6 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 x 10*6 CD34+ cells/kg was achieved in 72% and 51%, respectively, suggesting superiority for IVE (Fox et al, 2008), HAMMOUD - MOFID

  21. Aretrospective 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) Two studies have identified the use of mini- BEAM as a risk factor for poor progenitor cell mobilization prior to ASCT 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. HAMMOUD - MOFID

  22. HAMMOUD - MOFID

  23. Second line salvage for patients eligible for high dose therapy • As previously discussed, patients who are PET-positiveafter 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 HAMMOUD - MOFID

  24. There are no data to support the choice of any particular regimen 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 brentuximabvedotin, it is suggested that re-evaluation is undertaken after 3–4 cycles. HAMMOUD - MOFID

  25. 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 . HAMMOUD - MOFID

  26. 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). • 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 HAMMOUD - MOFID

  27. Alternative salvage agents include the anti-CD30 immunoconjugatebrentuximabvedotin 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-naeivepatients 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 HAMMOUD - MOFID

  28. Salvage chemotherapy for patients not eligible for high dose therapy No prospective studies have specifically addressed the efficacy of second line chemotherapy alone (or chemotherapy combined with radiotherapy) in relapsed HL in patients not eligible for stem cell transplantation. In the randomized GHSG/ EBMT study, Schmitz et al (2002) reported a 3-year freedom from treatment failure (FFTF) of 34% for those patients randomized to four courses of dexa-BEAM without ASCT. Outcome was better for those who relapsed late, defined as 12 months or more after initial therapy, with 3-year FFTF of 44% compared with 12% for those who relapsed between 3 and 12 months after initial treatment. Important caveats include the fact that the trial did not include patients with primary refractory disease, and that patients were only eligible for randomization if they achieved at least a PR by CT criteria, so this is a relatively highly selected group. HAMMOUD - MOFID

  29. It therefore seems reasonable to combine radiotherapy (RT) with chemotherapy for transplant ineligible patients at relapse. • This would be particularly attractive for those patients with limited stage disease and for those who have either not received radiotherapy as part of first-line treatment or who have relapsed outside of the previous radiation field. HAMMOUD - MOFID

  30. In patients unlikely to tolerate the toxicities associated with more intensive regimens, limited published experience with single agent palliative strategies, such as vinblastine, lomustine, etoposide or gemcitabine or multi-agent oral regimens with or without intravenous vinblastine, such as PECC (prednisolone, etoposide, CCNU [lomustine], chlorambucil)(Proctor et al, 2010) or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisolone) suggest therapeutic benefits may be achieved in many cases. The role of newer agents, such as brentuximabvedotin, in this setting requires further evaluation. The early input of palliative care specialists is recommended. HAMMOUD - MOFID

  31. Recommendations ● The choice of a first line salvage regimen in patients eligible for ASCT should be based on patient factors and familiarity of the treatment centrewith the regimen (2C) (Fig 1). ● Regimens containing stem cell toxic agents (such as carmustine and melphalan) should be avoided if possible until stem cells have been successfully collected and cryopreserved if ASCT is planned (1B). ● There is currently no evidence to support intensive sequential induction/consolidation strategies prior to ASCT (1B). ● Consider switching to an alternative non-cross-resistant salvage regimen if there are residual FDG-avid lesions after first line salvage treatment and the intent is to proceed to ASCT (2B). ● In patients not eligible for ASCT, combined modality therapy should be considered, especially in early stage relapse and in patients who have not received prior radiotherapy or who have relapsed outside of the initial radiotherapy field (2B). ● In patients unlikely to tolerate the toxicities associated with more intensive regimens, palliation with either a single agent or with a multi-agent oral regimen with or without intravenous vinblastine should be considered (2C). ● Early consideration of involvement of palliative care services is recommended, particularly in those not eligible for high dose therapy (1C). HAMMOUD - MOFID

  32. Autologous stem cell transplantation • The outcome of patients with relapsed or refractory disease treated with conventional doses of chemotherapy alone is generally poor with durable remission rates of between 10 and 35% (Longo et al, 1992; Linch et al, 1993; Schmitz et al, 2002), • the higher rates often reflecting long term outcomes only in the subset achieving at least a PR to initial salvage therapy. • Patients relapsing several years after initial treatment may do better with conventional salvage chemotherapy alone, but long term PFS remains below 50% (Yuen et al, 1997). HAMMOUD - MOFID

  33. Although no overall survival (OS) benefit has ever been demonstrated in a prospective, randomized clinical trial, the aim of treatment at relapse in younger patients without significant co-morbidities is to induce remission and then proceed to high dose therapy with ASCT. This recommendation is based on two randomized trials, which demonstrated a significant benefit of ASCT over conventional chemotherapy for patients with relapsed disease (Linch et al, 1993; Schmitz et al, 2002). The lack of a survival benefit in either of these two studies has been attributed to patients in the non-ASCT arm undergoing transplant at the time of second relapse. HAMMOUD - MOFID

  34. Both trials used the BEAM conditioning regimen prior to ASCT. In the first, this was compared to 1–3 cycles of mini-BEAM (Linch et al, 1993), and in the second compared to two cycles of Dexa-BEAM following initial induction with two cycles of Dexa-BEAM HAMMOUD - MOFID

  35. Both trials determined response to salvage therapy according to conventional CT criteria, excluding those with less than PR from subsequent randomization. BEAM remains the most popular regimen worldwide, but other conditioning regimens with comparable toxicities and outcomes have been reported in single-institution studies HAMMOUD - MOFID

  36. Total body irradiation (TBI)-based regimens have been largely abandoned in favour of chemotherapy-based regimens because of a higher incidence of secondary malignancies and transplant related mortality with the former (Sureda et al, 2001). • there are no prospective data to suggest the superiority of one conditioning regimen to another, and the choice of conditioning regimen is therefore usually based on institutional preference and experience. HAMMOUD - MOFID

  37. Although data are scarce, outcomes appear favorable in terms of response rates using either a second course of the primary treatment regimen or an alternative non-cross-resistant regimen. Toxicities and mortality associated with treatment complications are relatively high (Provencio et al, 2010; Gaudioet al, 2011), and the majority of reported cases did not undergo ASCT as consolidation. At present there is insufficient data to recommend routine ASCT in those achieving a complete metabolic response, although it is a reasonable clinical option HAMMOUD - MOFID

  38. Post-ASCT maintenance As in other clinical settings, cytotoxic agents have been investigated as possible post-ASCT maintenance therapies, but such strategies have met with limited success. For example, an attempt to consolidate ASCT with involved field radiotherapy (IFRT) to sites of pre-existing disease of >2 cm, followed by two cycles each of alternating DCEP-G, (dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine), and DPP (dexamethasone, cisplatin, paclitaxel), administered every 3 months until 1 year post-transplant, was notable for the fact that only 17/37 (46%) received th planned post-ASCT therapy, either because of refusal, early relapse or other complications (Rapoport et al, 2004).] Despite the inclusion of 25 (68%) patients with relapsed rather than refractory disease, and 33 (89%) with only 1–2 lines of prior therapy, the PFS at 2.5 years was only 59%. HAMMOUD - MOFID

  39. Tandem ASCT The H96 trial used a risk-adapted approach, reserving tandem ASCT for patients with two or more of three adverse risk factors, which included relapse or progression <12 months, stage III-IV disease at relapse, and relapse in a previously irradiated site (Morschhauseret al, 2008). The first conditioning regimen consisted of cyclophosphamide, carmustine, etoposide, and mitoxantrone(CBVMx) and the second of TBI (or busulphan for patients who had received prior dose-limiting radiation) and melphalan. Their outcomes were compared to those of low-risk patients who underwent a single BEAM-conditioned ASCT. The outcomes for the poor-risk patients remained inferior to those of the intermediate-risk patients, with 5-year FF2F rates of 46% and 73%, although it was suggested that results might have been superior to those of similarly high-risk cohorts in earlier series using single ASCT. Confirmationwill require a prospective randomized study, and tandem ASCT cannot currently be recommended outside of clinical trials. HAMMOUD - MOFID

  40. Relapse post ASCT Outcomes for patients who relapse following ASCT, particularly for those with early relapse within 6–12 months, have historically been poor. Even in more recent series, the median OS has been only 25–32 months (Moskowitz et al, 2009; Kaloyannidiset al, 2012). The aim of treatment in these patients is to attain sufficient response to allow consideration of allogeneic transplantation Some patients will be most appropriately treated with a palliative approach, and early involvement of specialist palliative services is recommended. In the majority, further attempts to gain disease control are warranted, recognizing that some will achieve prolonged periods of disease control, particularly those relapsing later following ASCT (Martinez et al, 2013). Brentuximabvedotin should be considered amongst the alternative regimens at this stage, although choice may be modulated by prior history of exposure. Although the median OS in the pivotal study was quoted as 22.4 months, response rates were high and toxicities modest HAMMOUD - MOFID

  41. Recommendations ● ASCT is the standard treatment for patients with relapsed disease who achieve an adequate response to salvage therapy (1A) (Fig 1). ●ASCT is also the standard treatment for patients with primary resistant disease who achieve an adequate response to salvage therapy (1B). ● ASCT is not recommended in those failing to achieve an adequate response (1B). ● An adequate response to salvage therapy is currently defined as a PR by conventional CT criteria (2B). ● Choice of conditioning regimen should be based on familiarity of the treatment centrewith the regimen (2C). ● Current evidence does not support the use of maintenance cytotoxic therapies post-ASCT (1C). ● Tandem ASCT cannot currently be recommended outside of clinical trials (1C). HAMMOUD - MOFID

  42. Allogeneic haematopoietic stem celltransplantation (HSCT) The role of allogeneic HSCT in the management of this patient group remains controversial. The inverse correlation between relapse and the development of graft versus- host disease following allogeneic HSCT, along with responses to donor lymphocyte infusions, confirms the existence of a therapeutically relevant graft-versus-lymphoma activity Currently, there are no comparative data to definitively direct the choice of preparative regimen. HAMMOUD - MOFID

  43. For patients relapsing after ASCT • PFS rates in this setting range from 20 to 40% at 2–4 years in larger series and registry datasets (Anderlini et al, 2008; Sureda et al, 2008, 2012; Peggs et al, 2011). • Appropriately (HLA)-matched unrelated donors yield comparable outcomes to those achieved with HLA-matched related donors in most series (Robinson et al, 2009; Peggs et al, 2011; Sureda et al, 2012). • Most studies, though not all (Devettenet al, 2009), identify chemo-sensitivity at the time of transplant as an important prognostic indicator HAMMOUD - MOFID

  44. Those with progressive disease have almost uniformly poor outcomes and cannot be recommended for transplant (Robinson et al, 2009; Sureda et al, 2012). For those with chemo-sensitive disease, allogeneic HSCT may be the most attractive clinical option, offering the possibility of prolonged disease-free survival (DFS) and potentially cure to a sizeable minority. Two retrospective analyses of patients who relapsed after an ASCT suggest that, for those patients with a HLA-compatible donor and who responded sufficiently to salvage to enable allogeneic HSCT to occur. HAMMOUD - MOFID

  45. consolidation with a reduced-intensity transplant offers a better long-term outcome than the use of conventional strategies, with a significant advantage for both OS and PFS. For patients relapsing very late after ASCT, a second ASCT may be a reasonable therapeutic option HAMMOUD - MOFID

  46. No prospective comparative studies exist to inform recommendations regarding the most appropriate salvage regimen (s) post-ASCT. • In general, the use of an agent(s) that the patient has not been exposed to previously is suggested. • Brentuximabvedotin clearly has impressive single-agent activity in the setting of relapse post ASCT, although the majority of patients fail to achieve CR, and the time to- progression in these cases is short (<5 months). • In these cases brentuximabvedotin may offer a useful bridge to allogeneic transplant, with significant benefits in terms of its toxicity profile (Chen et al, 2012). HAMMOUD - MOFID

  47. Recommendations ● Allogeneic transplantation using a reduced intensity conditioning regimen is the treatment of choice for younger patients with a suitable donor and chemo-sensitive disease following failure of ASCT (2B). ● An appropriately HLA-matched unrelated donor should be considered when there is no HLA-matched sibling (2B). ● A second autologous transplant is a reasonable clinical option in selected patients with late relapse following ASCT (2C). ● Investigation of the use of allogeneic transplantation earlier in the treatment pathway should be performed in the context of prospective clinical trials, but may be justified in selected patients who have required multiple lines of therapy to achieve a response (2C). HAMMOUD - MOFID

  48. Radiotherapy radiosensitivity of HL makes RT a potentially important treatment modality in this setting. The move towards less extensive use of RT in primary therapy also raises the possibility of a greater role in relapsed or refractory patients. Radiation treatment volumes are localized to encompass the known site(s) of disease recurrence, without prophylactic inclusion of adjacent lymph nodal stations. Overall, salvage RT is safe and well tolerated with mild to moderate acute reversible side effects including fatigue, anorexia, nausea, skin erythema, and dysphagia. The risk of late toxicity and second cancer risk is dependent on the site, volume and type of tissue irradiated, as well as age and sex of the patient HAMMOUD - MOFID

  49. Salvage radiotherapy • Salvage RT plays an important role in local control for patients who have primary refractory disease dominated by a local site, • as well as those who relapse after initial therapy, • RT is generally used as part of combined modality therapy along with salvage chemotherapy, prior to ASCT. HAMMOUD - MOFID

  50. A small group of patients with localized disease and no systemic symptoms enjoy prolonged DFS with RT alone (Jostinget al, 2005). RT should also be considered as a salvage option in the setting of ASCT failure, after relapse or progression, where a significant proportion of patients still achieve high response rates to salvage RT and a few may even enjoy long term DFS of over 5 years, whilst in others it plays an important role in palliation (Goda et al, 2012). HAMMOUD - MOFID

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