PowerPoint Presentation

1/12/2014HAMMOUD - MOFID1

1/12/2014HAMMOUD - MOFID2ScopeThe 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 thiswhat is the role of radiotherapy in patient management what is the best management of patients unsuitable for autologous transplantation.1/12/2014HAMMOUD - MOFID3Methodology

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.1/12/2014HAMMOUD - MOFID4BackgroundPatients 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.1/12/2014HAMMOUD - MOFID5In 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.1/12/2014HAMMOUD - MOFID6Prognostic modelsThe 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.1/12/2014HAMMOUD - MOFID7Primary resistant diseasePrimary 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) 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%1/12/2014HAMMOUD - MOFID8Relapsed diseasePatients with an initial period of remission have somewhat better outcomes. the clinical factors predictive of worse 5-year FF2F were: time to relapse (312 months after completion of first treatment)stage at relapse (III or IV)and anaemia at relapse (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). 1/12/2014HAMMOUD - MOFID14Recommendations

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).1/12/2014HAMMOUD - MOFID15

1/12/2014HAMMOUD - MOFID16Salvage 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 7090% and complete response rates (usually assessed with conventional CT scanning) as 2055%. 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. 1/12/2014HAMMOUD - MOFID17Mortality 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 centre1/12/2014HAMMOUD - MOFID18In 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.1/12/2014HAMMOUD - MOFID19A 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),1/12/2014HAMMOUD - MOFID20A 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)

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.1/12/2014HAMMOUD - MOFID21

1/12/2014HAMMOUD - MOFID22Second line salvage for patients eligible for high dose therapyAs 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 ASCT1/12/2014HAMMOUD - MOFID23There 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 brentuximab vedotin, it is suggested that re-evaluation is undertaken after 34 cycles.1/12/2014HAMMOUD - MOFID24A 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 .1/12/2014HAMMOUD - MOFID2512/19 (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 procedures1/12/2014HAMMOUD - MOFID26Alternative 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-naeive 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 5358% in patients receiving bendamustine 1/12/2014HAMMOUD - MOFID27Salvage chemotherapy for patients not eligible for high dose therapyNo 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.1/12/2014HAMMOUD - MOFID28It 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.1/12/2014HAMMOUD - MOFID29In 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 brentuximab vedotin, in this setting requires further evaluation.

The early input of palliative care specialists is recommended.1/12/2014HAMMOUD - MOFID30Recommendations The choice of a first line salvage regimen in patients eligible for ASCT should be based on patient factors and familiarity of the treatment centre with 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).1/12/2014HAMMOUD - MOFID31Autologous stem cell transplantationThe 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).1/12/2014HAMMOUD - MOFID32Although 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.1/12/2014HAMMOUD - MOFID33Both trials used the BEAM conditioning regimen prior to ASCT.

In the first, this was compared to 13 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-BEAM1/12/2014HAMMOUD - MOFID34Both 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 studies1/12/2014HAMMOUD - MOFID35Total 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.1/12/2014HAMMOUD - MOFID36Although 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; Gaudio et 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 option1/12/2014HAMMOUD - MOFID37Post-ASCT maintenanceAs 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 12 lines of prior therapy, the PFS at 2.5 years was only 59%.1/12/2014HAMMOUD - MOFID38Tandem ASCTThe 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