Santoro

Current Role of Autologous and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Luca Castagna1, Carmelo Carlo-Stella1,2, Rita Mazza1 and Armando Santoro1

1 Department of Hematology and Oncology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano (Milano), Italy
2 Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy

L.C. and C.C.-S. contributed equally to this manuscript.

Corresponding author: Armando Santoro, M.D. Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center. Via Manzoni, 56 - Rozzano 20089, Italy. Tel: +39 02 8224 4080, Fax: +39 02 8224 4590. E-mail: armando.santoro@cancercenter.humanitas.it           

Published: February 15, 2015
Received: November 11, 2014
Accepted: January 19, 2015
Mediterr J Hematol Infect Dis 2015, 7(1): e2015015, DOI 10.4084/MJHID.2015.015
This article is available on PDF format at:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States. First-line chemo-radiotherapy leads to cure rates approaching 80% in patients with advanced-stage disease. However, 25 to 30% of these patients are not cured with chemotherapy alone (i.e., the ABVD regimen) and show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have an established role in the management of refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients. However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early relapsed patients, their treatment represents an unmet medical need. Allogeneic SCT represents, by far, the only strategy with a curative potential for these patients; however, as discussed in this review, it’s role in cHL remains controversial. Despite a general consensus that early relapsed and primary refractory patients represent a clinical challenge requiring effective treatments to achieve long-term disease control, there has been no consensus on the optimal therapy that should be offered to these patients. This review will briefly discuss the clinical results and the main issues regarding autologous SCT as well as the current role of allogeneic SCT.

Introduction

Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States.[1] First-line chemo-radiotherapy yields cure rates approaching 80% in patients with advanced-stage disease.[2,3] However, 25 to 30% of these patients are not cured with modern chemo-radiotherapy and show either primary refractoriness to chemotherapy, as defined by disease progression during or within 3 months of doxorubicin-based chemotherapy, early disease relapse (i.e., within 12 months after the end of first-line treatment) or late disease relapse.[4] Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have become the standard of care for refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients.[5-12] However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early-relapsed patients, their treatment represents an unmet medical need. Despite a general consensus that these patients represent a clinical challenge requiring effective treatments, there remains no consensus on the optimal therapy to be offered to early relapsed and primary refractory patients.[13,14] Disease recurrence or progression after autologous SCT is associated with a very poor prognosis and the median survival time from transplantation failure ranges from 12 to 29 months in different series.[15-18] Various therapeutic options are currently available for relapsed/refractory cHL patients who fail autologous SCT.[19] Among these, brentuximab vedotin (BV), nivolumab and bendamustine have demonstrated extraordinary efficacy.[20-24] However, both drugs are limited in terms of long-term disease control, and by far, allogeneic SCT represents the only strategy with a curative potential for multirelapsed and refractory patients.[25-27] Nevertheless, among patients who receive allogeneic SCT, long-term progression-free survival (PFS) does not exceed 25% to 35% in most series, and disease relapse is associated with an exceedingly poor outcome, with less than half of patients surviving for 3 years.[25,26,28-31] This review will briefly discuss the clinical results and the main issues regarding autologous SCT and the current role of allogeneic SCT.            

Autologous SCT

According to retrospective and prospective, as well as randomized studies, HDC followed by autologous SCT can rescue 30 to 80% of relapsed/refractory cHL patients. On average, 50% of patients who receive autologous SCT relapse or progress within 12 months after transplant. Randomized studies (Table 1) have failed to report significantly improved overall survival (OS), likely due to the “cross-over” to autologous SCT of patients failing conventional therapy.[5,8,32] The treatment-related mortality (TRM) in 3 randomized studies was similar between HDC and conventional chemotherapy, likely due to the relatively high toxicity of chemotherapy used in the conventional arm.[33] Although initial studies reported an average TRM of 10% (range, 3 - 17%), randomized studies (Table 1) reported a lower TRM (3 - 4%), likely due to better supportive care, the use of peripheral blood stem cells (PBSC) instead of bone marrow (BM), and earlier referral of patients to autografting. Long-term toxicity, including heart, lung and endocrine toxicities, as well as infections, infertility, and secondary malignancies should also be considered during counseling. A consensus study from several cooperative groups suggested that as early as 6 months after the start of HDC, patients should receive a specific follow-up for the early detection of complications.[34] An analysis involving more than 800 patients autografted for hematological malignancies who survived more than 2 years after transplant showed that their risk of late death was 13-fold higher than in the general population, particularly in the first 2-5 years after HDC. For cHL patients, the standardized mortality ratio (SMR) was 28, meaning that these patients had a 28-fold increased risk of dying compared with the general population. Furthermore, the most frequent specific causes of death were secondary cancers and lung disease (SMR 30 and 29, respectively).[34]

Table 1 Table 1. Randomized studies of autologous SCT in cHL.

Prognostic Factors and Risk-Adapted Strategies. Factors shown to influence the outcome of relapsed/refractory patients have led to the generation of prognostic scores for the risk stratification of patients undergoing HDC and autologous SCT (summarized in Table 2). The most popular scoring system is the German Score (GS), which incorporates 3 variables, including anemia, stage III-IV, and time to relapse less than 12 months.[35,36] The GS was validated by the randomized HDR2 study, which showed a 3-year PFS of 81%, 70%, 50%, and 14% in patients with adverse factors ranging from 1 to 4, respectively.[32] Majhail et al.[10] analyzed 141 patients and identified the 3 following variables as being predictive of outcome: chemoresistance, B symptoms at relapse, and persistence of disease at transplant. According to this score, the figures for 5-year PFS were 67%, 37% and 9% for patients with 0-1, 2, and 3 factors, respectively. Similarly, the 5-year OS was significantly different among the 3 groups, with respective values of 71%, 49%, and 13%.[10

Table 2 Table 2. Prognostic scores for relapsed/refractory cHL.

Prognostic scores have also been used prospectively to evaluate the clinical impact of risk-adapted therapeutic programs. Moskowitz et al.[37] used standard-dose ICE for low-risk patients, intensified-ICE for intermediate-risk patients, and ICE plus autologous SCT for high-risk patients and showed that risk-adapted augmentation of salvage treatment improved event-free survival in higher risk patients.
Morschhauser et al.[38] subsequently tested the prognostic score proposed by Brice et al.[39] This score included advanced stage disease, duration of first response shorter than 12 months, disease relapse in irradiated fields, and refractoriness to first-line chemotherapy. Intermediate-risk patients received conventional salvage chemotherapy followed by BEAM, whereas high-risk patients (chemorefractory or bearing more than 2 risk factors) were treated with intensified salvage chemotherapy and double autologous SCT (CBV-Mx or BEAM and TAM or BAM).[38] The 5-year freedom from second failure (FF2F) and OS rates were 46% and 57% in the high-risk group and 73% and 85% in the intermediate-risk group. The overall efficacy of salvage chemotherapy was not optimal, as the objective response rate (ORR) was 63%, and this value was even lower among high-risk patients (ORR 54%, CR/Cru 23%).[38] Although the results obtained with tandem autologous SCT in the poor prognosis group were better than those reported in other trials (Table 3), they are still unsatisfactory, further supporting the requirement for new therapeutic strategies. A study from the Royal Marsden involving patients with relapsed or refractory disease and a 10-year follow-up reported PFS and OS figures of 49% and 37%, respectively. Chemosensitive disease and a Hasenclever index <3 at SCT were the two prognostic factors for OS and PFS.[40]
Primary Refractory cHL. Chemorefractoriness to first-line therapy represents the strongest factor predicting a poor outcome after autologous SCT. These patients were not included in randomized trials, and autografting resulted in 30% to 40% durable PFS, once again supporting the general concept of poorer outcome in chemorefractory patients compared with chemosensitive patients (Table 3). In a study from the German group, 206 primary progressive patients were analyzed and 153 received salvage chemotherapy, of which only 70 (34%) were autografted, whereas 47 received salvage radiotherapy.[36] The 5-year FF2F and OS for all patients were 17% and 26%, respectively; the same figures for patients treated with HDC were 31% and 43%, respectively. The identification of three prognostic factors, including an age >50 years, failure to obtain temporary remission after first-line chemotherapy, and poor performance status, enabled the design of a prognostic score. Combining these factors, the 5-year OS ranged from 56% (absence of adverse factors) to 0% (presence of all 3 factors).[36] Uncontrolled disease prior to autologous SCT, either stable or progressive, was included for a small group of very high-risk patients and generated an OS ranging from 11% to 37% (Table 4). Furthermore, in most of the studies dealing with mixed cohorts of patients with relapsed or refractory disease, the absence of chemosensitivity before autografting negatively influenced the outcome. Therefore, biomarkers enabling the early identification of chemorefractory patients (such as CD68 expression on macrophages,[41] PD-1/PD-L1 expression on Hodgkin Reed-Sternberg cells or microenvironment cells,[42] etc.), novel agents specifically targeting tumor cells along with the tumor microenvironment at the genetic or epigenetic level, as well as innovative therapeutic strategies are urgently needed for chemorefractory patients.

Table 3 Table 3. Clinical results in patients with relapsed/refractory disease after first-line chemotherapy.

Table 4 Table 4. Clinical outcome of patients with chemorefractory disease after receiving autologous SCT.

Conditioning Regimens. The potential benefit of a conditioning regimen has not been adequately explored in the autologous setting. Two randomized studies applied the BEAM conditioning regimen,[5,8] which was introduced several years ago but not previously tested in randomized trials. Nevertheless, this regimen is considered the gold standard for autologous transplantation. When salvage chemotherapy followed by BEAM was compared with a more intensive high-dose sequential therapy (HDS-CT), the outcomes were not different, although the toxicities were higher in the HDS-CT arm.[32] Evidence emerging from several recent studies also supports the concept that alternative conditioning regimens are not more effective and/or less toxic than BEAM. In the event that a randomized study comparing BEAM with newer regimens is not performed, the BEAM regimen may be considered the gold standard. However, due to drug constraints on carmustine, this drug is often replaced by a variety of agents, including fotemustine,[43] bendamustine,[44] and thiotepa.[45]
Role of PET Imaging. The extensive use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) over the past 10 years has resulted in significant changes in the outcomes of relapsed/refractory patients, as some patients classified as PR or SD, or rarely PD after salvage chemotherapy, may in fact be in metabolic CR. The bottom line is that FDG-PET segregates patients into 2 groups: positive and negative. The available data show that a positive FDG-PET before autografting identifies patients with poorer outcome than those with negative FDG-PET.[37] However, the outcome of the FDG-PET positive group (OS 40-58%, PFS 23-40%) is often unsatisfactory, and newer approaches should be tested for their ability to obtain FDG-PET negativity. However, the early application of allogeneic SCT in FDG-PET positive patients was reported by the English group, with encouraging results (3-year PFS 68% and OS 88%).[46] Interestingly, the use of FDG-PET overcame the impact of prognostic factors (B symptoms, early relapse/refractoriness), with the exception of extra-nodal localization.[47] Castagna et al. also showed that in the context of salvage therapy, interim FDG-PET could predict PFS.[48] Prospective studies are currently ongoing, in which the treatment strategy is changed based on the FDG-PET results, after first-line or second-line chemotherapy. Devillier et al.[49] recently published a retrospective study on 111 patients, confirming the predictive value of the response by FDG-PET at autografting (5-year PFS and OS, 79% vs. 23% and 90% vs. 55% in FDG-PET negative and positive patients, respectively). Furthermore, in FDG-PET positive patients, the outcome was better if they received a double transplant.[49] Therefore, defining the therapeutic response with FDG-PET represents the most relevant improvement in the treatment of advanced cHL, challenging most of the data generated in recent years.[47]
The prognosis of patients who fail autologous SCT is poor.15 A joint EBMT and GITMO retrospective analysis on 462 patients who relapsed or progressed after autologous SCT showed a median time from SCT to relapse of 7 months (range, 1 - 78) and a 5-year OS for the entire cohort of 32%.[16] In multivariate analysis, early relapse, stage IV, bulky disease, poor performance status, and age ≥50 years were significantly associated with survival, and 3 groups (0, 1, ≥2 factors) showed different OS rates (62%, 37%, and 12%, respectively).[16] Thus, patients with refractory disease and patients failing autologous SCT represent an unmet medical need requiring innovative treatment.[50]


Allogeneic SCT

Clinical results from retrospective trials of allogeneic SCT reported in the early nineties were disappointing, likely due to the inclusion of heavily pretreated patients, who had received extended radiotherapy and were allografted in the presence of active disease after myeloablative conditioning with bone marrow stem cells (reviewed in Sureda et al.[51]). Allogeneic SCT has been associated with a high TRM due to the high incidence of graft versus host disease (GVHD) and fatal infections post-transplantation. The poor outcome of cHL patients after allogeneic SCT may reflect, in part, the advanced status of the disease at transplantation and the poor performance status of the patient population that was allografted. Furthermore, the high TRM present in the conventional allogeneic SCT setting has never allowed proper evaluation of a possible graft-versus-Hodgkin's effect. In the late nineties, this scenario changed substantially with the introduction of reduced intensity conditioning (RIC) and non-myeloablative conditioning (NMAC) regimens (Table 5). As a matter of fact, a clinically significant reduction of TRM below 30% was reported by several investigators and resulted in a renewed interest in allogeneic SCT. On average, PFS ranged from 20% to 42% and OS from 25% to 57%. Such a wide variability is mainly due to the heterogeneity of patients included in these retrospective trials. Despite representing an increasingly used procedure, allogeneic SCT remains a matter of discussion, and several controversial issues are currently under investigation. 

Table 5 Table 5. Results of allogeneic SCT in cHL using reduced intensity conditioning (RIC) or non-myeloablative conditioning (NMAC).

One general question that needs to be addressed is how allogeneic SCT compares with other therapies. In the absence of randomized trials, figures extrapolated from retrospective studies have to be considered with caution. An EBMT/GITMO study retrospectively analyzed the risk factors predicting the outcome of cHL patients relapsing after autologous SCT.[16] A total of 462 patients were treated with either conventional chemotherapy eventually supplemented by radiotherapy (64%), a second autologous SCT (9%) or allogeneic SCT (29%). At a median follow-up of 49 months, 2-year and 5-year OS rates were 55% and 32%. In multivariate analysis, allogeneic SCT was associated with a trend towards improved survival (P = 0.08).[16] In fact, the OS at 5 years was 48% for patients receiving allogeneic SCT (RIC) and 32% for those treated with conventional chemotherapy/radiotherapy, with a median survival time of 45 and 19 months, respectively. Independent risk factors predicting a poor OS were early relapse within the first 6 months after HDC, stage IV disease, bulky disease, presence of B symptoms, a Karnofsky performance status under 80% and age of 50 years or older. Patients presenting with none of these risk factors had a 5-year OS rate of 62%, whereas among patients presenting with one risk factor, the 5-year OS rate was 37%. In contrast, patients with two or more risk factors had a poor clinical outcome, with a 5-year OS rate of only 12%.
Novel Agents and Allogeneic SCT. Several retrospective studies have suggested that allogeneic SCT should be considered a therapeutic option in patients relapsing or progressing after autografting.[25,46,52] The current availability of active, although non-curative drugs, such as BV,[20,21] nivolumab,[22] bendamustine,[23,24,53] histone deacetylase inhibitors,[54,55] mTOR inhibitors,[56] kinase inhibitors,[57,58] and immunomodulatory drugs,[59] has allowed substantially high rates of objective responses in patients who previously failed autologous SCT, thus resulting in significant improvements of the quality and quantity of clinical responses achieved by patients who became eligible for allogeneic SCT after having failed autografting. Recently, Chen et al.[60] compared a small cohort of patients (n = 21) receiving BV before allogeneic SCT with historical controls (n= 23). The BV cohort showed better 2-year PFS (59% vs. 26%) and OS (71% vs. 56%), with a lower relapse rate (24% vs. 57%) and 1-year NRM of 9.5% vs. 17%. Interestingly, these treatments shared a good toxicity profile, thus allowing patients to achieve a good performance status at the time of allografting.
Allogeneic SCT could also be a viable option for patients who are refractory to salvage chemotherapy, especially because better results are obtained when this treatment is applied earlier.[61] Indeed, the survival of these patients is poor, and most of them die from disease progression.[62] The availability of novel agents resulting in objective responses may eventually result in increased eligibility for allogeneic SCT (Figures 1, 2). 

Figure 1
Figure 1. Treatment algorithm for relapsed/refractory cHL
Figure 2
Figure 1. Treatment algorithm for cHL relapsing or progressing following Auto-SCT

Recently, the UK group reported interesting results in patients who were FDG-PET positive after salvage chemotherapy and treated with allogeneic SCT. For most of these patients, the conditioning regimen consisted of BEAM plus Campath, and the results were encouraging because the 3-year NRM, PFS, and OS rates were 24%, 68%, and 80%, respectively.[46] In general, for patients refractory to salvage CT, allogeneic SCT should be considered, provided that good disease control is achieved prior to transplantation.[63]
Conditioning Regimens. The type of conditioning regimen to be used prior to allogeneic SCT represents another matter of discussion. There is a consensus that RIC should be preferred to MAC regimens. Indeed, in a retrospective registry-based study, Sureda et al. reported that patients receiving MAC had lower OS rates than those treated with RIC.[26] However, it should be noted that after MAC, even though NRM was higher, the relapse rate was lower, meaning that new and less toxic myeloablative regimens should be prospectively evaluated.
Prognostic Factors. Several prognostic factors associated with different outcomes after allogeneic SCT have been reported. In a large retrospective study from EBMT, Robinson et al.[28] reported that prognostic factors may help to define different patient populations with significantly different outcomes (Table 6); the most important and recurrent factor was the disease status before allogeneic SCT, as patients not achieving CR at the time of transplantation experienced shorter survival, increased toxicity and relapse. Furthermore, in patients allografted after autologous SCT, the interval between relapse and autografting (cut-off 6 months) was a protective prognostic factor. In contrast with other studies, which demonstrated a reduction of relapse in patients experiencing chronic GVHD (cGVHD),[26,63] the EBMT study failed to show a link between the development of cGVHD and survival.[28]  

Table 6 Table 6. Prognostic factors at allogeneic SCT (adapted from Robinson et al.[28]). 

Donor Source. The vast majority of allografting in cHL stemmed from studies using either an HLA-identical sibling or a matched unrelated donor (MUD). With a median NRM of 10% (range, 3-25%), the use of HLA-identical siblings is considered a standard option due to its good toxicity profile. Because only 25-30% of patients have an HLA-identical sibling, searching for a MUD is mandatory, despite the consistent increase in median NRM to 28% (range 16-34). In recent years, great interest has been focused on haploidentical family donors (HLA-haplo). Encouraging results have been obtained using the Baltimore approach, combining NMAC regimens, T cell-replete BM and post-transplant cyclophosphamide (Cy).[64] This scheme is well tolerated and has shown a remarkably low NRM, with good OS in a variety of hematological malignancies.[65,66] Two retrospective studies have reported the activity of transplantation from haploidentical family donors. Burroughs et al. compared the results obtained in patients receiving transplantation from a matched related donor (MRD), MUD, or haploidentical family donor.[67] The PFS, NRM, and relapse rates were significantly lower after haploidentical transplantation than transplantation using other stem cell sources. Furthermore, the incidence of acute and chronic GVHD was equally lower in the haploidentical group.[67] More recently, Raiola et al. reported [26] cHL patients grafted from haploidentical family donors with rates of PFS, OS, relapse, and NRM of 63%, 77%, 31%, and 4%, respectively.[65] Additionally, this study confirmed the low incidence of both acute GVHD (grade 2-4, 24%) and cGVHD (9%).[65] Altough preliminary and based on a limited number of patients, the extraordinary efficacy of this strategy of haploidentical transplant suggests a peculiar role of the conditioning regimen in eliciting an HL-specific immune activity.   
Management of Disease Relapse after Allogeneic SCT. Notwithstanding the reduction of NRM and GVHD, disease relapse following allogeneic SCT ranges from 31% to 81% in different series and still represents a major issue that needs to be addressed. In particular, the survival of relapsing patients is dismal. Ram et al. analyzed the outcome of 26 cHL patients and reported that the 3-year OS was 47%, with a median time from allografting to relapse of 6 months (range, 0.5-29 months). Different therapies were administered, including withdrawal of immunosuppressive therapy, standard chemotherapy eventually combined with radiotherapy, donor lymphocyte infusion (DLI), or a second allogeneic transplantation. This translated to an ORR of 78%, which was, however, associated with a high risk of further progression.[31] A second retrospective study in 28 cHL patients reported a survival rate of 49% and identified late relapse (cut off 100 days), achievement of CR/PR, and localized nodal or extra-nodal relapse as significant predictive factors.[68] We reported a series of 97 HL patients receiving allogeneic SCT at either Humanitas Cancer Center (Rozzano, Italy) or Institut Paoli Calmettes (Marseille, France). Thirty-three (34%) patients relapsed after a median time from allografting of 4.5 months (range, 0.3-17 months). In this series, the median follow-up time was 46 months (range, 1-160 months), and the 2-y PFS and OS were 17% and 33%. We also confirmed that patients with late relapse showed a better prognosis (Castagna L. et al., manuscript in preparation).
Survival data from the EBMT/GITMO study, as well as other series, strongly suggest that allogeneic SCT is feasible and appears to be active in at least one third of multi-relapsed patients. However, this treatment modality cannot be considered a standard procedure and should be offered to carefully selected chemosensitive patients included in clinical studies. However, the availability of new active drugs to be used alone or in combination, and eventually associated with DLI, could substantially change this scenario.
The implementation of novel agents, such as BV, nivolumab, and bendamustine, for the treatment of multi-relapsed cHL patients has improved the outcome of these patients and will significantly impact the history of multi-relapsed cHL in the near future when the results of combination studies become available. Two studies have reported similar efficacy data of BV used as single agent in patients with recurrent disease after allogeneic SCT.[69,70] The largest study of BV after allografting failure involved 24 patients who received a median of 8 cycles (range, 1-16) of BV at a median of 42 months (range, 6-116) after allografting. After a median follow-up time of 34 weeks, these patients showed ORR and CR rates of 50% and 38%, respectively, with a median PFS of 7.8 months, whereas the median OS was not reached.[69] The toxicity profile was good, without any impact on GVHD or CMV reactivation.[69] The largest cohort study of bendamustine in cHL patients with recurrent disease after allogeneic SCT was recently reported.[23] In a multicenter retrospective study, 45 and 22 patients received bendamustine for disease recurrence after autologous and allogeneic SCT, respectively; most of these patients received 90 mg/m2 x 2 days (73%). The CR+PR rates for patients treated with bendamustine due to recurrence after autologous or allogeneic SCT were 56% and 59%, respectively, whereas the same figures for patients achieving SD+PD were 44% and 41%, respectively. After a median follow-up time of 13 months, the PFS was 49%, and OS was 70% at 1 year. The median PFS was 10 months, whereas the median OS was not established. Toxicities were manageable, with grade 3-4 hematological toxicity being evident in less than 20% of patients. The most common extra-hematological toxicities were fever and febrile neutropenia.[23]
DLI has been used frequently, resulting in an average ORR ranging from 40% to 80%. However, in most cases, the duration of the response was short and almost all patients relapsed.[71] Of special interest are the data from the English group, showing that disease relapse was extremely rare in patients receiving DLI when in CR after allogeneic SCT and with mixed chimerism. Overall, the 4-year OS was 59%. This result may confirm the immunological effect of donor lymphocytes in the situation of minimal residual disease.[72] DLI has also been combined with other drugs. In a proof-of-principle study, Teurich et al. treated 4 patients with the combination of BV plus DLI and demonstrated an immunological effect on HL cell lines mediated by heterogeneous CD161-positive lymphocytes.[73] In addition, all patients showed a metabolic response. In a multicenter retrospective study, Sala et al. assessed 18 patients receiving bendamustine, 9 of them in association with DLI, and the 1-year OS and PFS rates were 59% and 30%, respectively.[74]


Conclusions

Autologous SCT have become the standard of care for refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients (Figure 1). Furthermore, the current availability of active, yet non-curative, drugs has significantly improved the management of autografting failures, allowing for substantially increased rates of objective responses. In particular, these treatments have resulted in significant quantitative and qualitative improvements in the clinical responses of patients who have subsequently become eligible for allogeneic SCT after having failed autografting (Figure 2). Patients achieving PET-negativity after a second salvage regimen may do well with autologous SCT even though they were PET-positive after the first salvage regimen.[47] However, retrospective data in the setting of haploidentical SCT report a low TRM and suggest the existence of clinically relevant, graft-induced immune effects, thus suggesting that allogeneic SCT can be offered to chemorefractory cHL patients, as well as to those patients who fail autologous SCT and achieve CR or PR using novel agents.[61] Despite the reduction of NRM and GVHD, disease relapse still represents the major issue in the setting of allogeneic SCT failure. Novel biomarkers for the early identification of relapsing and refractory patients, as well as novel agents specifically targeting genetic or epigenetic changes in both tumor cells and the tumor microenvironment, are needed for refractory patients. Together, the integration of novel prognostic biomarkers, novel agents and allogeneic SCT will significantly impact the history of multi-relapsed and refractory patients, overcoming the issues of chemorefractoriness as well as disease relapse. Finally, the long-term toxicities of such treatments should be carefully evaluated, and specific follow-up, which ideally would be given in specialized clinics, should become part of global care. 


Acknowledgments

This work was supported in part by funding from the Ministry of Health (RF #2010-2313979 to C.C.-S.) and the Italian Association for Cancer Research (AIRC, grant #15835 to C.C.-S.).

References


  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.http://dx.doi.org/10.3322/caac.21208  PMid:24399786  
  2. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987;5:27-37. PMid:2433409  
  3. Engert A, Plutschow A, Eich HT, Lohri A, Dorken B, Borchmann P, Berger B, Greil R, Willborn KC, Wilhelm M, Debus J, Eble MJ, Sokler M, Ho A, Rank A, Ganser A, Trumper L, Bokemeyer C, Kirchner H, Schubert J, Kral Z, Fuchs M, Muller-Hermelink HK, Muller RP, Diehl V. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med. 2010;363:640-652. http://dx.doi.org/10.1056/NEJMoa1000067 PMid:20818855  
  4. Canellos GP, Rosenberg SA, Friedberg JW, Lister TA, Devita VT. Treatment of Hodgkin lymphoma: a 50-year perspective. J Clin Oncol. 2014;32:163-168. http://dx.doi.org/10.1200/JCO.2013.53.1194  PMid:24441526  
  5. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993;341:1051-1054. http://dx.doi.org/10.1016/0140-6736(93)92411-L  
  6. Brice P, Divine M, Simon D, Coiffier B, Leblond V, Simon M, Voilat L, Devidas A, Morschhauser F, Rohrlich P, Andre M, Lepage E, Ferme C. Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin's disease (HD). SFGM/GELA Study Group. Ann Oncol. 1999;10:1485-1488. http://dx.doi.org/10.1023/A:1008343823292  PMid:10643540  
  7. Moskowitz CH, Nimer SD, Zelenetz AD, Trippett T, Hedrick EE, Filippa DA, Louie D, Gonzales M, Walits J, Coady-Lyons N, Qin J, Frank R, Bertino JR, Goy A, Noy A, O'Brien JP, Straus D, Portlock CS, Yahalom J. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97:616-623. http://dx.doi.org/10.1182/blood.V97.3.616  PMid:11157476  
  8. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Muller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359:2065-2071. http://dx.doi.org/10.1016/S0140-6736(02)08938-9   
  9. Moskowitz CH, Kewalramani T, Nimer SD, Gonzalez M, Zelenetz AD, Yahalom J. Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin's disease. Br J Haematol. 2004;124:645-652. http://dx.doi.org/10.1111/j.1365-2141.2003.04828  PMid:14871252  
  10. Majhail NS, Weisdorf DJ, Defor TE, Miller JS, McGlave PB, Slungaard A, Arora M, Ramsay NKC, Orchard PJ, MacMillan ML, Burns LJ. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin's lymphoma. Biol Blood Marrow Transplant. 2006;12:1065-1072. http://dx.doi.org/10.1016/j.bbmt.2006.06.006  PMid:17084370  
  11. Gopal AK, Metcalfe TL, Gooley TA, Pagel JM, Petersdorf SH, Bensinger WI, Holmberg L, Maloney DG, Press OW. High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience. Cancer. 2008;113:1344-1350. http://dx.doi.org/10.1002/cncr.23715  PMid:18623377 PMCid:PMC2700660  
  12. Viviani S, Di Nicola M, Bonfante V, Di Stasi A, Carlo-Stella C, Matteucci P, Magni M, Devizzi L, Valagussa P, Gianni AM. Long-term results of high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin lymphoma: a single institution experience. Leukemia & Lymphoma. 2010;51:1251-1259. http://dx.doi.org/10.3109/10428194.2010.486090  PMid:20528244  
  13. Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2009:507-519. http://dx.doi.org/10.1182/asheducation-2009.1.507  PMid:20008236  
  14. Canellos GP. Brentuximab vedotin and panobinostat: new drugs for Hodgkin's lymphoma--can they make one of medical oncology's chemotherapy success stories more successful? J Clin Oncol. 2012;30:2171-2172. http://dx.doi.org/10.1200/JCO.2011.39.6416  PMid:22547611  
  15. Moskowitz AJ, Perales M-A, Kewalramani T, Yahalom J, Castro-Malaspina H, Zhang Z, Vanak J, Zelenetz AD, Moskowitz CH. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol. 2009;146:158-163.  http://dx.doi.org/10.1111/j.1365-2141.2009.07727.x  PMid:19438504 PMCid:PMC3278667  
  16. Martinez C, Canals C, Sarina B, Alessandrino EP, Karakasis D, Pulsoni A, Sica S, Trneny M, Snowden JA, Kanfer E, Milpied N, Bosi A, Guidi S, de Souza CA, Willemze R, Arranz R, Jebavy L, Hellmann A, Sibon D, Oneto R, Luan JJ, Dreger P, Castagna L, Sureda A, for the Lymphoma Working Party of the European Group for B, Marrow T, the Gruppo Italiano Trapianto di Midollo O. Identification of prognostic factors predicting outcome in Hodgkin's lymphoma patients relapsing after autologous stem cell transplantation. Ann Oncol. 2013. http://dx.doi.org/10.1093/annonc/mdt206   
  17. Arai S, Fanale M, DeVos S, Engert A, Illidge T, Borchmann P, Younes A, Morschhauser F, McMillan A, Horning SJ. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leukemia & Lymphoma. 2013;54:2531-2533. http://dx.doi.org/10.3109/10428194.2013.798868  PMid:23617324  
  18. Crump M. Management of Hodgkin lymphoma in relapse after autologous stem cell transplant. Hematology Am Soc Hematol Educ Program. 2008:326-333.
    http://dx.doi.org/10.1182/asheducation-2008.1.326  PMid:19074105  
  19. Younes A. Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol. 2011;8:85-96. http://dx.doi.org/10.1038/nrclinonc.2011.20  PMid:21151205 PMCid:PMC3192435
  20. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821. http://dx.doi.org/10.1056/NEJMoa1002965  PMid:21047225  
  21. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30:2183-2189. http://dx.doi.org/10.1200/JCO.2011.38.1350  PMid:22454421 PMCid:PMC3646316  
  22. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. N Engl J Med. 2014;in press.  
  23. Anastasia A, Carlo-Stella C, Corradini P, Salvi F, Rusconi C, Pulsoni A, Hohaus S, Pregno P, Viviani S, Brusamolino E, Luminari S, Giordano L, Santoro A. Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi. Br J Haematol. 2014;166:140-142. http://dx.doi.org/10.1111/bjh.12821  PMid:24606548  
  24. Moskowitz AJ, Hamlin PA, Jr., Perales MA, Gerecitano J, Horwitz SM, Matasar MJ, Noy A, Palomba ML, Portlock CS, Straus DJ, Graustein T, Zelenetz AD, Moskowitz CH. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31:456-460. http://dx.doi.org/10.1200/JCO.2012.45.3308  PMid:23248254 PMCid:PMC3862960  
  25. Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, Falda M, Guidi S, Ciceri F, Bonini A, Ferrari S, Malagola M, Morello E, Milone G, Bruno B, Mordini N, Viviani S, Levis A, Giordano L, Santoro A, Corradini P. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115:3671-3677. http://dx.doi.org/10.1182/blood-2009-12-253856  PMid:20220116  
  26. Sureda A, Robinson S, Canals C, Carella AM, Boogaerts MA, Caballero D, Hunter AE, Kanz L, Slavin S, Cornelissen JJ, Gramatzki M, Niederwieser D, Russell NH, Schmitz N. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26:455-462. http://dx.doi.org/10.1200/JCO.2007.13.2415  PMid:18086796  
  27. Corradini P, Sarina B, Farina L. Allogeneic transplantation for Hodgkin's lymphoma. Br J Haematol. 2011;152:261-272. http://dx.doi.org/10.1111/j.1365-2141.2010.08492.x  PMid:21155760  
  28. Robinson SP, Sureda A, Canals C, Russell N, Caballero D, Bacigalupo A, Iriondo A, Cook G, Pettitt A, Socie G, Bonifazi F, Bosi A, Michallet M, Liakopoulou E, Maertens J, Passweg J, Clarke F, Martino R, Schmitz N, EBMT LWPot. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lymphoma: identification of prognostic factors predicting outcome. Haematologica. 2009;94:230-238.
    http://dx.doi.org/10.3324/haematol.13441  PMid:19066328 PMCid:PMC2635413  
  29. Armand P, Kim HT, Ho VT, Cutler CS, Koreth J, Antin JH, LaCasce AS, Jacobsen ED, Fisher DC, Brown JR, Canellos GP, Freedman AS, Soiffer RJ, Alyea EP. Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome. Biol Blood Marrow Transplant. 2008;14:418-425. http://dx.doi.org/10.1016/j.bbmt.2008.01.008  PMid:18342784 PMCid:PMC2364453  
  30. Corradini P, Dodero A, Farina L, Fanin R, Patriarca F, Miceli R, Matteucci P, Bregni M, Scime R, Narni F, Pogliani E, Locasciulli A, Milani R, Carniti C, Bacigalupo A, Rambaldi A, Bonifazi F, Olivieri A, Gianni AM, Tarella C, Gruppo Italiano Trapianto di Midollo O. Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome. Leukemia. 2007;21:2316-2323. http://dx.doi.org/10.1038/sj.leu.2404822  PMid:17597807  
  31. Ram R, Gooley TA, Maloney DG, Press OW, Pagel JM, Petersdorf SH, Shustov AR, Flowers ME, O'Donnell P, Sandmaier BM, Storb RF, Gopal AK. Histology and time to progression predict survival for lymphoma recurring after reduced-intensity conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:1537-1545. http://dx.doi.org/10.1016/j.bbmt.2011.03.010  PMid:21536145 PMCid:PMC3176968  
  32. Josting A, Muller H, Borchmann P, Baars JW, Metzner B, Dohner H, Aurer I, Smardova L, Fischer T, Niederwieser D, Schafer-Eckart K, Schmitz N, Sureda A, Glossmann J, Diehl V, DeJong D, Hansmann ML, Raemaekers J, Engert A. Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. J Clin Oncol. 2010;28:5074-5080. http://dx.doi.org/10.1200/JCO.2010.30.5771  PMid:20975066  
  33. Rancea M, Monsef I, von Tresckow B, Engert A, Skoetz N. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev. 2013;6:CD009411. PMid:23784872  
  34. Bhatia S, Robison LL, Francisco L, Carter A, Liu Y, Grant M, Baker KS, Fung H, Gurney JG, McGlave PB, Nademanee A, Ramsay NK, Stein A, Weisdorf DJ, Forman SJ. Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood. 2005;105:4215-4222. http://dx.doi.org/10.1182/blood-2005-01-0035  PMid:15701723 PMCid:PMC1895040  
  35. Josting A, Franklin J, May M, Koch P, Beykirch MK, Heinz J, Rudolph C, Diehl V, Engert A. New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol. 2002;20:221-230. http://dx.doi.org/10.1200/JCO.20.1.221  PMid:11773173  
  36. Josting A, Rueffer U, Franklin J, Sieber M, Diehl V, Engert A. Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood. 2000;96:1280-1286. PMid:10942369  
  37. Moskowitz CH, Yahalom J, Zelenetz AD, Zhang Z, Filippa D, Teruya-Feldstein J, Kewalramani T, Moskowitz AJ, Rice RD, Maragulia J, Vanak J, Trippett T, Hamlin P, Horowitz S, Noy A, O'Connor OA, Portlock C, Straus D, Nimer SD. High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol. 2010;148:890-897. http://dx.doi.org/10.1111/j.1365-2141.2009.08037.x  PMid:20085577 PMCid:PMC3920913  
  38. Morschhauser F, Brice P, Ferme C, Divine M, Salles G, Bouabdallah R, Sebban C, Voillat L, Casasnovas O, Stamatoullas A, Bouabdallah K, Andre M, Jais JP, Cazals-Hatem D, Gisselbrecht C, Group GSS. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol. 2008;26:5980-5987. http://dx.doi.org/10.1200/JCO.2007.15.5887  PMid:19018090  
  39. Brice P, Bouabdallah R, Moreau P, Divine M, Andre M, Aoudjane M, Fleury J, Anglaret B, Baruchel A, Sensebe L, Colombat P. Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin's disease: analysis of 280 patients from the French registry. Societe Francaise de Greffe de Moelle. Bone Marrow Transplant. 1997;20:21-26.
    http://dx.doi.org/10.1038/sj.bmt.1700838  PMid:9232251  
  40. Sirohi B, Cunningham D, Powles R, Murphy F, Arkenau T, Norman A, Oates J, Wotherspoon A, Horwich A. Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma. Ann Oncol. 2008;19:1312-1319. http://dx.doi.org/10.1093/annonc/mdn052  PMid:18356139  
  41. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, Gascoyne RD. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362:875-885.  http://dx.doi.org/10.1056/NEJMoa0905680  PMid:20220182 PMCid:PMC2897174  
  42. Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6:74. http://dx.doi.org/10.1186/1756-8722-6-74  PMid:24283718 PMCid:PMC3851976  
  43. Musso M, Scalone R, Marcacci G, Lanza F, Di Renzo N, Cascavilla N, Di Bartolomeo P, Crescimanno A, Perrone T, Pinto A. Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. Bone Marrow Transplant. 2010;45:1147-1153. http://dx.doi.org/10.1038/bmt.2009.318  PMid:19898504  
  44. Visani G, Malerba L, Stefani PM, Capria S, Galieni P, Gaudio F, Specchia G, Meloni G, Gherlinzoni F, Giardini C, Falcioni S, Cuberli F, Gobbi M, Sarina B, Santoro A, Ferrara F, Rocchi M, Ocio EM, Caballero MD, Isidori A. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011;118:3419-3425. http://dx.doi.org/10.1182/blood-2011-04-351924  PMid:21816830  
  45. Tombleson RL, Green MR, Fancher KM. Putting caution in TEAM: high-dose chemotherapy with autologous HSCT for primary central nervous system lymphoma. Bone Marrow Transplant. 2012;47:1383-1384.
    http://dx.doi.org/10.1038/bmt.2012.48  PMid:22426753  
  46. Thomson KJ, Kayani I, Ardeshna K, Morris EC, Hough R, Virchis A, Goldstone AH, Linch DC, Peggs KS. A response-adjusted PET-based transplantation strategy in primary resistant and relapsed Hodgkin Lymphoma. Leukemia. 2013;27:1419-1422. http://dx.doi.org/10.1038/leu.2012.318  PMid:23135356  
  47. Moskowitz CH, Matasar MJ, Zelenetz AD, Nimer SD, Gerecitano J, Hamlin P, Horwitz S, Moskowitz AJ, Noy A, Palomba L, Perales MA, Portlock C, Straus D, Maragulia JC, Schoder H, Yahalom J. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119:1665-1670. http://dx.doi.org/10.1182/blood-2011-10-388058  PMid:22184409 PMCid:PMC3790950  
  48. Castagna L, Bramanti S, Balzarotti M, Sarina B, Todisco E, Anastasia A, Magagnoli M, Mazza R, Nozza A, Giordano L, Rodari M, Rinifilo E, Chiti A, Santoro A. Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy. Br J Haematol. 2009;145:369-372. http://dx.doi.org/10.1111/j.1365-2141.2009.07645.x  PMid:19344403  
  49. Devillier R, Coso D, Castagna L, Brenot Rossi I, Anastasia A, Chiti A, Ivanov V, Schiano JM, Santoro A, Chabannon C, Balzarotti M, Blaise D, Bouabdallah R. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy. Haematologica. 2012;97:1073-1079.
     http://dx.doi.org/10.3324/haematol.2011.056051  PMid:22271893 PMCid:PMC3396680  
  50. Moskowitz CH, Nadamanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff PJ, Gianni AM, Carella AM, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Larsen EK, Hunder NNH, Walewski J. The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma. Blood. 2014;124:673.  
  51. Sureda A, Schmitz N. Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin's disease. Ann Oncol. 2002;13 Suppl 1:128-132. http://dx.doi.org/10.1093/annonc/13.S1.128  PMid:12078894  
  52. Castagna L, Sarina B, Todisco E, Magagnoli M, Balzarotti M, Bramanti S, Mazza R, Anastasia A, Bacigalupo A, Aversa F, Soligo D, Giordano L, Santoro A. Allogeneic stem cell transplantation compared with chemotherapy for poor-risk Hodgkin lymphoma. Biol Blood Marrow Transplant. 2009;15:432-438. http://dx.doi.org/10.1016/j.bbmt.2008.12.506  PMid:19285630  
  53. Corazzelli G, Angrilli F, D'Arco A, Ferrara F, Musto P, Guarini A, Cox MC, Stelitano C, Storti S, Iannitto E, Falorio S, Califano C, Amore A, Arcamone M, De Filippi R, Pinto A. Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma. Br J Haematol. 2013;160:207-215. http://dx.doi.org/10.1111/bjh.12120  PMid:23167437  
  54. Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S, Copeland A, Buglio D, Galal A, Besterman J, Li Z, Drouin M, Patterson T, Ward MR, Paulus JK, Ji Y, Medeiros LJ, Martell RE. Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011;12:1222-1228. http://dx.doi.org/10.1016/S1470-2045(11)70265-0   
  55. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, Harrison SJ, Kirschbaum M, Johnston P, Gallagher J, Le Corre C, Shen A, Engert A. Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30:2197-2203. http://dx.doi.org/10.1200/JCO.2011.38.1350  PMid:22547596  
  56. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, Micallef IN, Porrata LF, Ansell SM, Reeder CB, Roy V, Witzig TE. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010;85:320-324. PMid:20229590  
  57. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Mortarini R, Viviani S, Russo D, Marchiano A, Sorasio R, Dodero A, Farina L, Giordano L, Di Nicola M, Anichini A, Corradini P, Gianni AM. Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases. Clin Cancer Res. 2014;20:5641-5651. http://dx.doi.org/10.1158/1078-0432.CCR-14-0770  PMid:25239609  
  58. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Pierdominici M, Barbati C, Mortarini R, Devizzi L, Matteucci P, Marchiano A, Lanocita R, Farina L, Dodero A, Tarella C, Di Nicola M, Corradini P, Anichini A, Gianni AM. Phase II study of sorafenib in patients with relapsed or refractory lymphoma. British Journal of Haematology. 2012;158:108-119. http://dx.doi.org/10.1111/j.1365-2141.2012.09139.x  PMid:22571717  
  59. Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, Fenske TS, Hurd DD, Goy A, Schneider SE, Keppel CR, Wagner-Johnston ND, Carson KR, Bartlett NL. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118:5119-5125. http://dx.doi.org/10.1182/blood-2011-07-362475  PMid:21937701 PMCid:PMC3217400  
  60. Chen R, Palmer JM, Tsai NC, Thomas SH, Siddiqi T, Popplewell L, Farol L, Nademanee A, Forman SJ. Brentuximab vedotin is associated with improved progression-free survival after allogeneic transplantation for hodgkin lymphoma. Biol Blood Marrow Transplant. 2014;20:1864-1868. http://dx.doi.org/10.1016/j.bbmt.2014.06.037  PMid:25008328  
  61. Castagna L, Crocchiolo R, Giordano L, Bramanti S, Carlo-Stella C, Sarina B, Chiti A, Mauro E, Gandolfi S, Todisco E, Balzarotti M, Anastasia A, Magagnoli M, Brusamolino E, Santoro A. High dose melphalan with autologous stem cell support in FDG PET-refractory Hodgkin lymphoma patients as bridge to second transplant. Bone Marrow Transplant. 2014; in press.  
  62. Ardeshna KM, Kakouros N, Qian W, Powell MG, Saini N, D'Sa S, Mackinnon S, Hoskin PJ, Goldstone AH, Linch DC. Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens. Br J Haematol. 2005;130:363-372. http://dx.doi.org/10.1111/j.1365-2141.2005.05603.x  PMid:16042685  
  63. Peggs KS, Anderlini P, Sureda A. Allogeneic transplantation for Hodgkin lymphoma. Br J Haematol. 2008;143:468-480. PMid:18710379  
  64. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641-650. http://dx.doi.org/10.1016/j.bbmt.2008.03.005  PMid:18489989 PMCid:PMC2633246  
  65. Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S, Todisco E, Sarina B, Giordano L, Ibatici A, Santoro A, Clavio M, Bacigalupo A, Castagna L. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma. Bone Marrow Transplant. 2014;49:190-194. http://dx.doi.org/10.1038/bmt.2013.166  PMid:24185585  
  66. Castagna L, Bramanti S, Furst S, Giordano L, Crocchiolo R, Sarina B, Mauro E, Morabito L, Bouabdallah R, Coso D, Balzarotti M, Broussais F, Cheick JE, Stella CC, Brusamolino E, Blaise D, Santoro A. Nonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion CY for advanced lymphomas. Bone Marrow Transplant. 2014. http://dx.doi.org/10.1038/bmt.2014.197   
  67. Burroughs LM, O'Donnell PV, Sandmaier BM, Storer BE, Luznik L, Symons HJ, Jones RJ, Ambinder RF, Maris MB, Blume KG, Niederwieser DW, Bruno B, Maziarz RT, Pulsipher MA, Petersen FB, Storb R, Fuchs EJ, Maloney DG. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14:1279-1287. http://dx.doi.org/10.1016/j.bbmt.2008.08.014  PMid:18940683 PMCid:PMC2647369  
  68. Wudhikarn K, Brunstein CG, Bachanova V, Burns LJ, Cao Q, Weisdorf DJ. Relapse of lymphoma after allogeneic hematopoietic cell transplantation: management strategies and outcome. Biol Blood Marrow Transplant. 2011;17:1497-1504. http://dx.doi.org/10.1016/j.bbmt.2011.02.009  PMid:21338707 PMCid:PMC3132225  
  69. Gopal AK, Ramchandren R, O'Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012;120:560-568. http://dx.doi.org/10.1182/blood-2011-12-397893  PMid:22510871 PMCid:PMC3731651  
  70. Carlo-Stella C, Ricci F, Dalto S, Mazza R, Malagola M, Patriarca F, Viviani S, Russo D, Giordano L, Castagna L, Corradini P, Santoro A. Brentuximab Vedotin in patients with Hodgkin lymphoma and a failed allogeneic stem cell transplantation: results from a named patient programme at four Italian centers. The Oncologist. 2014; in press.  
  71. Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcarcel D, Besalduch J, Duarte R, Leon A, Pascual MJ, Garcia-Noblejas A, Lopez Corral L, Xicoy B, Sierra J, Schmitz N. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012;97:310-317. http://dx.doi.org/10.3324/haematol.2011.045757  PMid:21993674 PMCid:PMC3269494  
  72. Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005;365:1934-1941. http://dx.doi.org/10.1016/S0140-6736(05)66659-7   
  73. Theurich S, Malcher J, Wennhold K, Shimabukuro-Vornhagen A, Chemnitz J, Holtick U, Krause A, Kobe C, Kahraman D, Engert A, Scheid C, Chakupurakal G, Hallek M, von Bergwelt-Baildon M. Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustained clinical remission. J Clin Oncol. 2013;31:e59-63. http://dx.doi.org/10.1200/JCO.2012.43.6832  PMid:23269992  
  74. Sala E, Crocchiolo R, Gandolfi S, Bruno-Ventre M, Bramanti S, Peccatori J, Sarina B, Corti C, Ciceri F, Santoro A, Marktel S, Castagna L. Bendamustine Combined with Donor Lymphocytes Infusion in Hodgkin's Lymphoma Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2014. http://dx.doi.org/10.1016/j.bbmt.2014.05.024   
  75. Lohri A, Barnett M, Fairey RN, O'Reilly SE, Phillips GL, Reece D, Voss N, Connors JM. Outcome of treatment of first relapse of Hodgkin's disease after primary chemotherapy: identification of risk factors from the British Columbia experience 1970 to 1988. Blood. 1991;77:2292-2298. PMid:1709382  
  76. Reece DE, Connors JM, Spinelli JJ, Barnett MJ, Fairey RN, Klingemann HG, Nantel SH, O'Reilly S, Shepherd JD, Sutherland HJ, et al. Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy. Blood. 1994;83:1193-1199. PMid:8118023  
  77. Horning SJ, Chao NJ, Negrin RS, Hoppe RT, Long GD, Hu WW, Wong RM, Brown BW, Blume KG. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood. 1997;89:801-813. PMid:9028311  
  78. Andre M, Henry-Amar M, Pico JL, Brice P, Blaise D, Kuentz M, Coiffier B, Colombat P, Cahn JY, Attal M, Fleury J, Milpied N, Nedellec G, Biron P, Tilly H, Jouet JP, Gisselbrecht C. Comparison of high-dose therapy and autologous stem-cell transplantation with conventional therapy for Hodgkin's disease induction failure: a case-control study. Societe Francaise de Greffe de Moelle. J Clin Oncol. 1999;17:222-229. PMid:10458237  
  79. Sweetenham JW, Carella AM, Taghipour G, Cunningham D, Marcus R, Della Volpe A, Linch DC, Schmitz N, Goldstone AH. High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin's disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. Lymphoma Working Party. J Clin Oncol. 1999;17:3101-3109. PMid:10506605  
  80. Constans M, Sureda A, Terol MJ, Arranz R, Caballero MD, Iriondo A, Jarque I, Carreras E, Moraleda JM, Carrera D, Leon A, Lopez A, Albo C, Diaz-Mediavilla J, Fernandez-Abellan P, Garcia-Ruiz JC, Hernandez-Navarro F, Mataix R, Petit J, Pascual MJ, Rifon J, Garcia-Conde J, Fernandez-Ranada JM, Mateos MV, Sierra J, Conde E, Group GTC. Autologous stem cell transplantation for primary refractory Hodgkin's disease: results and clinical variables affecting outcome. Ann Oncol. 2003;14:745-751. http://dx.doi.org/10.1093/annonc/mdg206  PMid:12702529  
  81. Czyz J, Szydlo R, Knopinska-Posluszny W, Hellmann A, Gozdzik J, Hansz J, Smolewski P, Robak T, Osowiecki M, Walewski J, Avigdor A, Nagler A, Zemelka T, Pawlicki M, Sawicki Z, Wojtukiewicz M, Kachel L, Holowiecki J, Charlinski G, Jedrzejczak WW. Treatment for primary refractory Hodgkin's disease: a comparison of high-dose chemotherapy followed by ASCT with conventional therapy. Bone Marrow Transplant. 2004;33:1225-1229. http://dx.doi.org/10.1038/sj.bmt.1704508  PMid:15094747  
  82. Morabito F, Stelitano C, Luminari S, Mammi C, Marcheselli L, Callea V, Gentile M, Polimeno G, Merli F, Molica S, Gobbi P, Angrilli F, Brugiatelli M, Federico M. The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Bone Marrow Transplant. 2006;37:283-288.
    http://dx.doi.org/10.1038/sj.bmt.1705235  PMid:16327815  
  83. Akhtar S, El Weshi A, Abdelsalam M, Hussaini H, Janabi I, Rahal M, Maghfoor I. Primary refractory Hodgkin's lymphoma: outcome after high-dose chemotherapy and autologous SCT and impact of various prognostic factors on overall and event-free survival. A single institution result of 66 patients. Bone Marrow Transplant. 2007;40:651-658. http://dx.doi.org/10.1038/sj.bmt.1705792  PMid:17660837  
  84. Chopra R, McMillan AK, Linch DC, Yuklea S, Taghipour G, Pearce R, Patterson KG, Goldstone AH. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients. Blood. 1993;81:1137-1145. PMid:8443375  
  85. Rapoport AP, Rowe JM, Kouides PA, Duerst RA, Abboud CN, Liesveld JL, Packman CH, Eberly S, Sherman M, Tanner MA, et al. One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome. J Clin Oncol. 1993;11:2351-2361. PMid:8246024  
  86. Yahalom J, Gulati SC, Toia M, Maslak P, McCarron EG, O'Brien JP, Portlock CS, Straus DJ, Phillips J, Fuks Z. Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease. J Clin Oncol. 1993;11:1062-1070. PMid:8501492  
  87. Crump M, Smith AM, Brandwein J, Couture F, Sherret H, Sutton DM, Scott JG, McCrae J, Murray C, Pantalony D, et al. High-dose etoposide and melphalan, and autologous bone marrow transplantation for patients with advanced Hodgkin's disease: importance of disease status at transplant. J Clin Oncol. 1993;11:704-711. PMid:8478664  
  88. Argiris A, Seropian S, Cooper DL. High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin's disease. Ann Oncol. 2000;11:665-672. http://dx.doi.org/10.1023/A:1008396525292  PMid:10942053  
  89. Lazarus HM, Loberiza FR, Jr., Zhang MJ, Armitage JO, Ballen KK, Bashey A, Bolwell BJ, Burns LJ, Freytes CO, Gale RP, Gibson J, Herzig RH, LeMaistre CF, Marks D, Mason J, Miller AM, Milone GA, Pavlovsky S, Reece DE, Rizzo JD, van Besien K, Vose JM, Horowitz MM. Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR). Bone Marrow Transplant. 2001;27:387-396. http://dx.doi.org/10.1038/sj.bmt.1702796  PMid:11313668  
  90. Sureda A, Arranz R, Iriondo A, Carreras E, Lahuerta JJ, Garcia-Conde J, Jarque I, Caballero MD, Ferra C, Lopez A, Garcia-Larana J, Cabrera R, Carrera D, Ruiz-Romero MD, Leon A, Rifon J, Diaz-Mediavilla J, Mataix R, Morey M, Moraleda JM, Altes A, Lopez-Guillermo A, de la Serna J, Fernandez-Ranada JM, Sierra J, Conde E, Grupo Espanol de Linformas/Transplante Autologo de Medula Osea Spanish Cooperative G. Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol. 2001;19:1395-1404. PMid:11230484  
  91. Ferme C, Mounier N, Divine M, Brice P, Stamatoullas A, Reman O, Voillat L, Jaubert J, Lederlin P, Colin P, Berger F, Salles G. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial. J Clin Oncol. 2002;20:467-475. http://dx.doi.org/10.1200/JCO.20.2.467  PMid:11786576  
  92. Tarella C, Cuttica A, Vitolo U, Liberati M, Di Nicola M, Cortelazzo S, Rosato R, Rosanelli C, Di Renzo N, Musso M, Pavone E, Santini G, Pescarollo A, De Crescenzo A, Federico M, Gallamini A, Pregno P, Romano R, Coser P, Gallo E, Boccadoro M, Barbui T, Pileri A, Gianni AM, Levis A. High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence. Cancer. 2003;97:2748-2759.
    http://dx.doi.org/10.1002/cncr.11414  PMid:12767087  
  93. Robinson SP, Goldstone AH, Mackinnon S, Carella A, Russell N, de Elvira CR, Taghipour G, Schmitz N, Lymphoma Working Party of the European Group for B, Bone Marrow T. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood. 2002;100:4310-4316. http://dx.doi.org/10.1182/blood-2001-11-0107  PMid:12393626  
  94. Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006;12:172-183. http://dx.doi.org/10.1016/j.bbmt.2005.09.009  PMid:16443515  
  95. Todisco E, Castagna L, Sarina B, Mazza R, Anastasia A, Balzarotti M, Banna G, Tirelli U, Soligo D, Santoro A. Reduced-intensity allogeneic transplantation in patients with refractory or progressive Hodgkin's disease after high-dose chemotherapy and autologous stem cell infusion. Eur J Haematol. 2007;78:322-329. http://dx.doi.org/10.1111/j.1600-0609.2007.00814.x  PMid:17253967  
  96. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008;93:257-264. http://dx.doi.org/10.3324/haematol.11828  PMid:18223284 PMCid:PMC4238917  
  97. Devetten MP, Hari PN, Carreras J, Logan BR, van Besien K, Bredeson CN, Freytes CO, Gale RP, Gibson J, Giralt SA, Goldstein SC, Gupta V, Marks DI, Maziarz RT, Vose JM, Lazarus HM, Anderlini P. Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2009;15:109-117. http://dx.doi.org/10.1016/j.bbmt.2008.11.011  PMid:19135949 PMCid:PMC2929570   




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