Tandem haematopoietic stem cell transplantation for High Risk
relapsed/refractory Hodgkin Lymphoma: a LYSA study
Benedicte Deau,1 Sandy Amorim,2 Aurore Perrot,3Philippe Quittet,4 Jerome Cornillon,5Driss Chaoui,6 Jean P. Marolleau,7Lucie Oberic,8 Katell Le Du,9Luc-Matthieu For-necker,10Olivier Tournilhac,11 Anne S. Veillard,12Isabelle Chaillol,12 Marie Robin,2Jer^ome Tamburini1and Pauline Brice2
1Hopital Cochin, Paris,2Hopital Saint Louis,
Paris,3CHU Nancy, Vandroeuvre,4CHU Mont-pellier, MontMont-pellier,5Institut Cancerologique de la Loire, St-Priest en Jarez,6CH Argenteuil, Argenteuil,7CH Amiens, Amiens,8CHU Tou-louse, TouTou-louse,9Clinique Victor Hugo Le Mans, Le Mans,10CHU Strasbourg, Strasbourg,11CHU
Clermont Ferrand, Clermont-Ferrand, and
12Lymphoma Academic Research Organisation
(LYSARC),Lyon, France
Received 8 November 2017; accepted for publication 21 January 2018
Correspondence: Dr Benedicte Deau, Department of Haematology, Cochin Hospital, 27 Rue du Faubourg Saint Jacques, Paris, France.
E-mail: benedicte.deau-fischer@aphp.fr
Summary
Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) fol-lowed by allogenic SCT (alloSCT) in 120 HL patients prospectively regis-tered on a French nationwide database. Median age was 26 (14–56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients under-went a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8–73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46–65%) and 71% (95% CI: 49–84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant-related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high-risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients.
Keywords: Hodgkin lymphoma, HSCT, brentuximab vedotin, positron emission tomography.
Most Hodgkin Lymphoma (HL) patients are cured after a first line of therapy. However, 10% of early-stage (Engert et al, 2010; Sieniawski et al, 2007) and 20-30% of advanced disease patients (Engert et al, 2009) have refrac-tory or relapsing (R/R) disease, with a frequently fatal
evo-lution. Previous prospective randomized trials
demonstrated that salvage chemotherapy followed by high dose therapy (HDT) and autologous stem cell transplanta-tion (ASCT) lead to 50% long-term event-free survival in these high-risk (HR) patients (Linch et al, 1993; Schmitz et al, 2002; Josting et al, 2000; Andre et al, 1999). In these patients, primary refractory disease, time to relapse/pro-gression of less than 12 months and disseminated disease at relapse are independent adverse risk factors that define the HR subgroup (Brice et al, 1996; Sureda et al, 2005). A recent large study clarified the prognostic factors of R/R HL patients (including children, adolescents and young
adults) undergoing autologous transplant: low performance status, absence of extranodal involvement and chemosensi-tive disease correlated to improved PFS while patients with a time from diagnosis to first relapse of less than 1 year had shorter survival (Satwani et al, 2015). Moreover, the absence of tumour metabolic activity, as assessed by 18fludeoxyglucose- positron emission tomography/com-puted tomography (PET/CT) scan (PET) before transplant correlates to a favourable outcome in these HR HL patients (Devillier et al, 2012; Moskowitz et al, 2012). Ret-rospective studies suggested that a double sequential ASCT (referred to as tandem ASCT) is feasible and may improve the outcome of HR R/R HL patients (Brice et al, 1999; Castagna et al, 2007; Fitoussi et al, 1999; Morschhauser et al, 2008; Fung et al, 2007). Other groups reported the potential value of allogeneic stem cell transplantation (alloSCT) after salvage chemotherapy (Sureda et al, 2012;
research paper
2008), or as a second consolidation after a first ASCT (Carella et al, 2000; Blaise et al, 2015).
We conducted a multicentre observational study on 120 prospectively registered HR R/R HL patients, to evaluate the
feasibility and efficacy of tandem auto/auto or auto/allo stem cell transplantation (SCT).
Methods Inclusion criteria
High-risk relapsed or refractory classical HL (HR R/R HL), defined in our study by primary refractory disease or stage III/IV disease with early (<12 months) relapse, aged 55 years or younger and planned tandem auto/auto or auto/allo SCT were prospectively included in our nation-wide register. A search for a human leucocyte antigen (HLA)-matched sibling or unrelated donor was mandatory, with HLA typing prior to inclusion. Exclusion criteria were the existence of serious comorbidities precluding high-dose chemotherapy and SCT and positive human immunodefi-ciency virus (HIV). All patients were prospectively included before the first ASCT. The protocol was approved by the French Institutional comittee CCTIRS (Comite consultatif
Fig 1. Flow chart for the HR2009 cohort. AlloSCT: allogeneic stem cell transplantation; ASCT, autologous stem cell transplantation; CR, complete response; HLA, human leucocyte antigen; HR, high risk; PR, partial response.
Table I. Patient characteristics, n= 120.
n % Age at relapse, years (median, range) 26 (14–56)
Male sex 68 (57%)
Ann Arbor stage at relapse
Stage III-IV 69 (58%) Bulky disease 62 (52%) Relapse modality PRD 61 (51%) Relapse 59 (49%) HLA-matched donor 61 (51%) Sibling 27 (22%)
First line salvage chemotherapy
DHAP 57 (48%) ICE 16 (13%) IVOX 24 (20%) MINE 15 (12%) Gemcitabine-based regimen 4 BEACOPP 2 ABVD 2 BV 1
Second line including BV (n= 81) 37 (46%) ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; BV: brentuximab vedotin; DHAP: dexam-ethasone, cytarabine, cisplatin; HLA: human leucocyte antigen; ICE: ifosfamide, carboplatin, etoposide; IVOX: ifosfamide, etoposide, oxaliplatin; MINE: methylguazone, ifosfamide, navelbine, etoposide; PRD: primary refractory disease.
Table II. Chemosensitivity pre-ASCT based on PET evaluation. PET status after salvage chemotherapy n= 120 (%) After first line of salvage
Complete remission 39 (33%) After 2 or more lines of salvage
Complete remission 73 (60%) Partial remission 38 (32%) Stable disease 5 (4%) Progressive disease 4 (4%) ACST, autologous stem cell transplantation; PET, positron emission tomography.
sur le traitement de l’information en matiere de recherche dans le domaine de la sante) and the study was carried out in accordance with the principles of the Decla-ration of Helsinki.
Study design
The salvage chemotherapy regimen was left to the investiga-tor choice, including the use of Brentuximab vedotin (BV) as third line therapy according to the European medicines agency (EMA) recommendations (www.ema.europa.eu/Adce tris/authorisation). PET evaluation was performed at salvage treatment onset, after 2 cycles of chemotherapy, and before SCT. Achievement of at least a stable disease was recom-mended before proceeding to ASCT. Stem cells were col-lected after the first or the second cycle of salvage chemotherapy. In case of HLA-matched (sibling or unre-lated) donor identification, alloSCT was recommended as second transplant modality; cord blood and haploidentical transplantation were not recommended. Conditioning regi-mens for first and second ASCT were BEAM (carmustine 300 mg/m2/day on day -7; etoposide 200 mg/m2/day, day -6 to day -3; cytarabine 200 mg/m2/12 h, day -6 to day -3; mel-phalan 140 mg/m2/day on day -2) and BAM (busulfan 4 mg/ kg/day, day -7 to day -5 (total dose of 12 mg/kg), cytarabine 2 g/m2/12 h day -4 through day -3 and melphalan 140 mg/ m2 on day -2), respectively. Reduced-intensity conditioning regimens based on the busulfan-fludarabine combination were used for reduced-intensity allogeneic transplant, as pre-viously reported (Sureda et al, 2008). Quarterly routine clini-cal and biologiclini-cal follow-up were reinforced by whole-body CT scan evaluations semi-annually for 2 years and then annually for 3 years.
PET evaluation
Local PET evaluations were collected and analysed using the Deauville criteria (Meignan et al, 2009), with a threshold of 1-2-3 considered as negative and 4-5 as positive, after two cycles of salvage therapy. PET before transplant was analysed as follows: Deauville 1-2-3 scores were complete response (CR), Deauville 4 was partial response (PR) and Deauville 5 was progressive disease (PD).
Statistical analysis
Progression-free survival (PFS) and overall survival (OS) were measured from the date of relapse or refractory status until progression, relapse or death from any cause, or death from any cause, respectively, and estimated with 95% confi-dence intervals (95% CI). We used the Kaplan Meier method to draw the survival curves, which were compared using the log-rank test, with P-values<005 defined as statistically sig-nificant. Hazard ratios with 95% CI were estimated using Cox proportional hazard models.
Results
One hundred and twenty HR R/R HL patients were included between 2009 and 2014 (Fig 1). Patient characteristics are summarized in Table I. The median age was 26 (14–56) years and 57% of patients were male. Sixty-nine patients (58%) had disseminated disease and 62 patients (52%) had a bulky mediastinal mass at diagnosis. Sixty-one patients (51%) had primary refractory disease and 59 (49%) had relapsing HL with a median time to relapse from the last cycle of first line chemotherapy of 6 months. A tissue sample biopsy was obtained in 48 patients (40%) at relapse. Sixty-one patients (51%) had an HLA-matched donor including 27 (22%) sib-ling donors.
The first salvage chemotherapy regimens were DHAP (dexamethasone, cytarabine, cisplatin) or a variant (DHAX [dexamethasone, cytarabine, oxaliplatin], DHAC [dexametha-sone, cytarabine, cisplatin], ESHAP [etoposide, methylpred-nisolone; cytarabine, cisplatin]) for 57 patients (48%), IVOX (ifosfamide, etoposide, oxaliplatin) for 24 (20%), ICE (ifos-famide, carboplatin, etoposide) for 16 (13%) and MINE (methylguazone, ifosfamide, navelbine, etoposide) for 15 (12%). Other regimens included gemcitabine-based (n= 4),
Table III. Comparison of baseline characteristics according to type of second transplant.
Auto-Auto Auto-Allo Test* Number
Male gender 20 (69%) 25 (59%) P= 0417 Disease stage at diagnosis
2 9 (31%) 18 (43%) P= 0328 3 1 (3%) 4 (9.5%) 4 19 (65%) 20 (47%) Bulky disease No 13 (54%) 9 (27%) P= 005 Yes 11 (45%) 24 (72%) Missing 5 9
Age at transplant (years) 25 29 P= 0146 Diagnosis to relapse 89 96 P= 0991 Disease status Relapsed 12 (42%) 23 (55%) P= 0268 Refractory 17 (58%) 19 (45%) PET2 Negative 8 (27%) 16 (40%) P= 0285 Positive 21 (72%) 24 (60%)
First line therapy
ABVD 13 (45%) 27 (65%) P= 0012 BEACOPP 15 (52%) 11 (25%)
Other 1 (3%) 4 (10%)
ABVD: doxorubicin, bleomycin, vinblastine, dacarbazin); Allo: allo-geneic; Auto: autologous; BEACOPP: bleomycin, etoposide, doxoru-bicin, cyclophosphamide, vincristine, procarbazine, prednisone; PET2; positron emission tomography after 2 cycles.
*Statistics involved chi² or Fisher’s exact test for comparing distribu-tions and Wilcoxon’s for comparing continuous variables.
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophos-phamide, vincristine, procarbazine, prednisone; n= 2), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; n= 1) and brentuximab vedotin (BV) monotherapy (n = 1) (Table I).
After the first line of salvage chemotherapy, 39 patients (33%) achieved a CR and underwent a first ASCT. The remaining 81 patients received two or more lines of salvage chemotherapy, including BV in 37 (46%), resulting in com-plete remission in 33 (40%). Overall, 73 (60%) patients
Fig 2. PFS and OS of selected cohorts. (A) Progression-free survival (PFS) and overall survival (OS) of the HR2009 cohort. (B) PFS and OS of the HR2009 tandem transplanted cohort. (C) PFS according to type of second transplant (auto/allo). 95% CI: 95% confidence interval; Allo, allogeneic; Auto, autologous; NR, not reached; black unbroken line: auto-allo; black dotted line: auto-auto. [Colour figure can be viewed at wileyonlinelibrary.com]
achieved a CR and 38 (32%) a PR before transplant, while 5 (4%) had stable disease and 4 (3%) had progressive disease (Table II).
One hundred and fifteen patients (96%) received their first SCT, including 112 auto and 3 allo. All four patients who did not receive a transplant had progressive disease; three died from progression and one was alive with progres-sive disease.
After a median interval of 28 months after the first trans-plant, 73 patients (61%) received a second SCT: 44 (37%) had a reduced intensity conditioned alloSCT and 29 (24%) a second ASCT. The baseline characteristics of the patients were similar regardless the type of second transplant, except for bulky mediastinal mass was more frequent at diagnosis in auto-allo patients (Table III). In contrast, 43 patients (35%) did not undergo a second transplant due to disease
progression in 18 of them and for various reasons in other cases, including stem cell mobilization failure (n= 5), patient decision (n= 4), altered general condition (n = 4) and investigator’s decision (n= 11). Data were missing for 1 patient. Among these 25 non-progressing patients, 96% achieved a CR after the first SCT. Half of them received radiotherapy, and three received consolidation with BV. Among 61 patients with a HLA-matched donor, 44 under-went alloSCT, while 17 (28%) were not eligible due to pro-gression (n= 2), allogenic transplant performed first (n = 3), and other reasons (n= 12, see above) (Fig 1).
The median follow-up was 43 months (48–737 months). The two-year progression-free survival (PFS) and overall sur-vival (OS) rates were 56% (95% CI: 46–65%) and 82% (95% CI: 73–88%), respectively (Fig 2A), without significant differ-ence between refractory or relapsing patients. In particular, the 2-year PFS and OS rate was 71% (95% CI 49–84%) and 85% (95% CI 75–92%), respectively, in tandem transplanted patients (n= 73) (Fig 2B), without significant difference between auto or allo SCT (Fig 2C).
We observed a striking difference in PFS between single and tandem transplanted patients (P< 0001, Fig 3A). How-ever, this difference was mostly due to early post-transplant progression, occurring in 18 patients and representing the leading cause of second transplant omission in our study. Indeed, when censoring these patients, we observed no differ-ence in the survival of patients having had one or two trans-plants (Fig 3B). For patients treated with a tandem auto/auto SCT (n= 29), 7 (24%) deaths occurred and were due to transplant-related mortality (TRM; 4 patients, 14%) and dis-ease progression (3 patients, 10%). After auto/allo SCT (n= 44), 13 (30%) deaths occurred, including 7 due to dis-ease progression (16%), 6 (135%) TRM of which 2 were due to graft-versus-host disease, 3 sepsis (n= 3) and one acute respiratory failure.
Fig 3. Progression-free survival (PFS) of single and tandem transplanted cohorts. (A) PFS according to number of transplants (2 vs. 1). (B) PFS according to number of transplants in patients without progression after first transplant (2 vs. 1). 95% CI, 95% confidence interval; NR, not reached; 1 dark unbroken line; 2 dark dotted line. [Colour figure can be viewed at wileyonlinelibrary.com]
Table IV. Univariate and multivariate analysis of selected parameters on progression-free survival.
Chi² P-value Hazard ratio Univariate analysis Age 48912 0027 1887 Stage IV 04886 04845 1216 Bulky 29493 00859 1737 Pre-transplant PET 25236 01122 2289 Multivariate analysis Age 58578 00155 2176 Pre-transplant PET 19686 01606 1239 Bulky 34614 00628 1866 Based on the literature, age (with 26 years as cut-off), stage IV (ver-sus other) and bulky disease at relapse, and pre-transplant positron emission tomography (PET) response (complete/partial response ver-sus other) were tested for correlation with progression-free survival on univariate and multivariate analysis using a Cox model.
We selected 4 broadly-used validated prognostic factors in R/R HL patients, including pre-transplant PET response assessment, age, stage 4 versus other at the time of relapse and bulky disease (Br€ockelmann et al, 2017). Univariate analysis confirmed that all these factors, except stage, had prognostic value in our cohort. Multivariate analysis found a significant correlation between older age and reduced sur-vival, and revealed a trend to decreased survival for bulky disease (Table IV).
Interestingly, neither PET positivity after 2 cycles of first salvage chemotherapy nor the use of more than one salvage line had an adverse impact on survival. In contrast, PET-defined CR and PR before transplant correlated with a longer
survival, with a two-year PFS of 62% (95% CI 49–73%) and 53% (95% CI 36–68%), respectively, as compared to 20% (95% CI 3–48%) for progressive disease (P < 0001, Fig 4). Moreover, the number of salvage lines employed to achieve a CR had no impact on PFS in transplanted patients (Fig 5).
Discussion
In our observational study, we confirmed that tandem SCT resulted in cure for a majority of HR R/R HL patients. Indeed, we observed a 2-year PFS rate of 56%, similar to the results of the prospective multicentre Lymphoma Study Association / Societe Francaise de Greffe de Moelle H96 trial
Fig 4. Progression-free survival (PFS) accord-ing to pre-transplant chemosensitivity, based on positron emission tomography pre-autolo-gous stem cell transplantation. 95% CI, 95% confidence interval; CR, complete response; NR, not reached; PR, partial response; dark dotted line: Others; CR and PR: unbroken lines. [Colour figure can be viewed at wileyon-linelibrary.com]
Fig 5. Progression-free survival (PFS) accord-ing to number of lines of salvage chemother-apy. 95% CI, 95% confidence interval; NR, not reached; 1 dark unbroken line; 2 dark dotted line. [Colour figure can be viewed at wileyonli-nelibrary.com]
involving 150 HR HL patients (Morschhauser et al, 2008). Similarly, Fung et al (2007) reported a 5-year PFS of 49% among 46 patients treated by tandem ASCT. Interestingly, a recent phase 2 study by the Southwestern Oncology Group observed a 2-year PFS rate of 63% and a 2-year OS rate of 91%, which may also reflect the recent introduction of BV in the clinical practice (Smith et al, 2017).
It has also been demonstrated that pre-transplant PET negativity by visual scale correlated to longer event-free sur-vival and OS in relapsed HL patients (Moskowitz et al, 2012, 2015a). First-line salvage with ICE induced 60% of PET CR, while second-line salvage with GVD (gemcitabine, vinorel-bine, liposomal doxorubicin) yielded an additional 52% CR, for an overall CR rate of 82%. In our study, we also observed that patients in CR/PR before transplant had a significantly longer PFS compared to those with stable or progressive dis-ease. Moreover, the use of second-line or further salvage therapy increased the CR rate from 33% after the first sal-vage therapy to up to 60%. These encouraging results may be explained by the addition of BV to chemotherapy in 50% of our patients, as previously reported (Michallet et al, 2015; Moskowitz et al, 2015a; Kalac et al, 2016).
The management of R/R HL patients remains a challenge, as only 61% of our cohort received the initially planned tan-dem transplant due, in the majority of cases, to an early pro-gression after the first transplant, suggesting that these patients are neither adequately identified as a distinct sub-group before transplant nor efficiently treated by our current approaches. The use of novel agents, such as BV or immune checkpoint inhibitors, as well as early identification of chemorefractory patients by PET or new prognostic biomark-ers might represent new routes to design early phase clinical trials in this very high-risk population.
While the survival of our patients treated by a tandem transplant appeared fairly good, this invasive approach is now widely challenged by the introduction of BV consolida-tion after a single ASCT, as encouraged by the results of the AETHERA trial (Moskowitz et al, 2015b). Indeed, tandem transplant generates early and late toxicities, as recently high-lighted by Sibon et al (2016). In fact, half of the deaths observed in our transplanted patients were toxicity-related, without significant difference between ASCT and alloSCT. We thus believe that auto-auto or auto-allo tandem trans-plant must be used with caution, particularly regarding the recent breakthrough of novel highly efficient immunothera-pies, but may represent an option for selected patients on a case-by-case basis.
Our study confirmed the efficacy of tandem SCT in R/R HL patients achieving at least a PR, but suggested that a sig-nificant minority of patients currently not adequately identi-fied by routine tests remain refractory to such strategies due to early disease progression, warranting the development of novel strategies for these patients in the near future.
Acknowledgements
The authors would like to thank all the patients for their cooperation, AMGEN for Grants, and Pr Morschhauser and Pr Ghesquieres for review.
Author contributions
BD, SA, AP, PQ, JC, DC, JPM, LO, KL, LMF, OT, MR, JT, PB performed the research study, PB designed the research study, ASV and IC analysed the data, BD, JT and PB wrote the paper.
References
Andre, M., Henry-Amar, M., Pico, J.L., Brice, P., Blaise, D., Kuentz, M., Coiffier, B., Colombat, P., Cahn, J.Y., Attal, M., Fleury, J., Milpied, N., Nedellec, G., Biron, P., Tilly, H., Jouet, J.P. & Gisselbrecht, C. (1999) 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. Journal of Clinical Oncolog, 17, 222– 229.
Blaise, D., Devillier, R., Lecoroller-Sorriano, A.-G., Boher, J.-M., Boyer-Chammard, A., Tabrizi, R., Chevallier, P., Fegueux, N., Sirvent, A., Michal-let, M., Bay, J.-O., F€urst, S., El-Cheikh, J., Vin-cent, L., Guillaume, T., Regny, C., Milpied, N., Castagna, L. & Mohty, M. (2015) Low non-relapse mortality and long-term preserved qual-ity of life in older patients undergoing matched related donor allogeneic stem cell transplanta-tion: a prospective multicenter phase II trial. Haematologica, 100, 269–274.
Brice, P., Bastion, Y., Divine, M., Nedellec, G., Fer-rant, A., Gabarre, J., Reman, O., Lepage, E. & Ferme, C. (1996) Analysis of prognostic factors after the first relapse of Hodgkin’s disease in 187 patients. Cancer, 78, 1293–1299.
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. (1999) Feasibility of tan-dem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin’s disease (HD) SFGM/GELA Study Group. Annals of Oncology, 10, 1485–1488.
Br€ockelmann, P.J., M€uller, H., Casasnovas, O., Hutchings, M., von Tresckow, B., J€urgens, M., McCall, S.J., Morschhauser, F., Fuchs, M., Borchmann, P., Moskowitz, C.H. & Engert, A. (2017) Risk factors and a prognostic score for survival after autologous stem-cell transplanta-tion for relapsed or refractory Hodgkin lym-phoma. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 28, 1352–1358.
Carella, A.M., Cavaliere, M., Lerma, E., Ferrara, R., Tedeschi, L., Romanelli, A., Vinci, M., Pinotti, G., Lambelet, P., Loni, C., Verdiani, S., De Ste-fano, F., Valbonesi, M. & Corsetti, M.T. (2000) Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allo-geneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodg-kin’s disease and non-HodgHodg-kin’s lymphoma. Journal of Clinical Oncology, 18, 3918–3924. Castagna, L., Magagnoli, M., Balzarotti, M., Sarina,
B., Siracusano, L., Nozza, A., Todisco, E., Bra-manti, S., Mazza, R., Russo, F., Timofeeva, I. & Santoro, A. (2007) Tandem high-dose chemotherapy and autologous stem cell trans-plantation in refractory/relapsed Hodgkin’s lym-phoma: a monocenter prospective study. American Journal of Hematology, 82, 122–127. Devillier, R., Coso, D., Castagna, L., Brenot Rossi,
I., Anastasia, A., Chiti, A., Ivanov, V., Schiano, J.M., Santoro, A., Chabannon, C., Balzarotti, M., Blaise, D. & Bouabdallah, R. (2012) Positron emission tomography response at the time of autologous stem cell transplantation predicts
outcome of patients with relapsed and/or refrac-tory Hodgkin’s lymphoma responding to prior salvage therapy. Haematologica, 97, 1073–1079. Engert, A., Diehl, V., Franklin, J., Lohri, A.,
D€orken, B., Ludwig, W.-D., Koch, P., H€anel, M., Pfreundschuh, M., Wilhelm, M., Tr€umper, L., Aulitzky, W.-E., Bentz, M., Rummel, M., Sezer, O., M€uller-Hermelink, H.-K., Hasenclever, D. & L€offler, M. (2009) Escalated-dose BEA-COPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. Journal of Clinical Oncology, 27, 4548–4554.
Engert, A., Pl€utschow, A., Eich, H.T., Lohri, A., D€orken, B., Borchmann, P., Berger, B., Greil, R., Willborn, K.C., Wilhelm, M., Debus, J., Eble, M.J., S€okler, M., Ho, A., Rank, A., Ganser, A., Tr€umper, L., Bokemeyer, C., Kirchner, H., Schu-bert, J., Kral, Z., Fuchs, M., M€uller-Hermelink, H.K., M€uller, R.P. & Diehl, V. (2010) Reduced treatment intensity in patients with early-stage hodgkin’s lymphoma. New England Journal of Medicine, 363, 640–652.
Fitoussi, O., Simon, D., Brice, P., Makke, J., Scrobohaci, M.L., Bibi Triki, T., Hennequin, C., Ferme, C. & Gisselbrecht, C. (1999) Tandem transplant of peripheral blood stem cells for patients with poor-prognosis Hodgkins’s disease or non-Hodgkin’s lymphoma. Bone Marrow Transplantation, 24, 747–755.
Fung, H.C., Stiff, P., Schriber, J., Toor, A., Smith, E., Rodriguez, T., Krishnan, A., Molina, A., Smith, D., Ivers, B., Kogut, N., Popplewell, L., Rodriguez, R., Somlo, G., Forman, S.J. & Nademanee, A. (2007) Tandem autologous stem cell transplanta-tion for patients with primary refractory or poor risk recurrent Hodgkin lymphoma. Biology of Blood and Marrow Transplantation, 13, 594–600. Josting, A., Rueffer, U., Franklin, J., Sieber, M.,
Diehl, V. & Engert, A. (2000) Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood, 96, 1280–1286.
Kalac, M., Lue, J.K., Lichtenstein, E., Turenne, I., Rojas, C., Amengual, J.E., Sawas, A., Deng, C., Mapara, M.Y., Connors, J.M., Kuruvilla, J. & O’ O.A. (2016) Brentuximab vedotin and ben-damustine produce high complete response rates in patients with chemotherapy refractory Hodg-kin lymphoma. British Journal of Haematology. doi: 101111/bjh.14449. [Epub ahead of print] Linch, D.C., Winfield, D., Goldstone, A.H., Moir,
D., Hancock, B., McMillan, A., Chopra, R., Mil-ligan, D. & Hudson, G.V. (1993) Dose intensifi-cation with autologous bone-marrow transplantation in relapsed and resistant Hodg-kin’s disease: results of a BNLI randomised trial. Lancet (London, England), 341, 1051–1054. Meignan, M., Gallamini, A., Meignan, M.,
Gal-lamini, A. & Haioun, C. (2009) Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leukemia & Lymphoma, 50, 1257–1260.
Michallet, A.-S., Guillermin, Y., Deau, B., Lebras, L., Harel, S., Amorin, S., Reynes, C., Salles, G., Subtil, F. & Brice, P. (2015) Sequential combi-nation of gemcitabine, vinorelbine, pegylated liposomal doxorubicin and brentuximab as a bridge regimen to transplant in relapsed or refractory Hodgkin lymphoma. Haematologica, 100, e269–e271.
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, J.-P., Cazals-Hatem, D. & Gis-selbrecht, C. for the GELA/SFGM Study Group (2008) 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. Journal of Clinical Oncology, 26, 5980–5987.
Moskowitz, C.H., Matasar, M.J., Zelenetz, A.D., Nimer, S.D., Gerecitano, J., Hamlin, P., Horwitz, S., Moskowitz, A.J., Noy, A., Palomba, L., Per-ales, M.-A., Portlock, C., Straus, D., Maragulia, J.C., Schoder, H. & Yahalom, J. (2012) Normal-ization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood, 119, 1665–1670.
Moskowitz, A.J., Sch€oder, H., Yahalom, J., McCall, S.J., Fox, S.Y., Gerecitano, J., Grewal, R., Ham-lin, P.A., Horwitz, S., Kobos, R., Kumar, A., Matasar, M., Noy, A., Palomba, M.L., Perales, M.-A., Portlock, C.S., Sauter, C., Shukla, N., Steinherz, P., Straus, D., Trippett, T., Younes, A., Zelenetz, A. & Moskowitz, C.H. (2015a) PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, sin-gle-centre, phase 2 study. The Lancet. Oncology, 16, 284–292.
Moskowitz, C.H., Nademanee, A., Masszi, T., Agura, E., Holowiecki, J., Abidi, M.H., Chen, A.I., Stiff, P., Gianni, A.M., Carella, A., Osma-nov, D., Bachanova, V., Sweetenham, J., Sureda, A., Huebner, D., Sievers, E.L., Chi, A., Larsen, E.K., Hunder, N.N. & Walewski, J., for the AETHERA Study Group. (2015b) Brentuximab vedotin as consolidation therapy after autolo-gous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or pro-gression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 385, 1853–1862.
Satwani, P., Ahn, K.W., Carreras, J., Abdel-Azim, H., Cairo, M.S., Cashen, A., Chen, A.I., Cohen, J.B., Costa, L.J., Dandoy, C., Fenske, T.S., Freytes, C.O., Ganguly, S., Gale, R.P., Ghosh, N., Hertzberg, M.S., Hayashi, R.J., Kamble, R.T., Kanate, A.S., Keating, A., Kharfan-Dabaja, M.A., Lazarus, H.M., Marks, D.I., Nishihori, T., Ols-son, R.F., Prestidge, T.D., Rolon, J.M., Savani,
B.N., Vose, J.M., Wood, W.A., Inwards, D.J., Bachanova, V., Smith, S.M., Maloney, D.G., Sur-eda, A. & Hamadani, M. (2015) A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplantation, 50, 1416–1423.
Schmitz, N., Pfistner, B., Sextro, M., Sieber, M., Carella, A.M., Haenel, M., Boissevain, F., Zsch-aber, R., M€uller, P., Kirchner, H., Lohri, A., Decker, S., Koch, B., Hasenclever, D., Goldstone, A.H. & Diehl, V. for the German Hodgkin’s Lymphoma Study Group and Lymphoma Work-ing Party of the European Group for Blood and Marrow Transplantation (2002) Aggressive con-ventional chemotherapy compared with high-dose chemotherapy with autologous haemopoi-etic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet (London, England), 359, 2065–2071. Sibon, D., Morschhauser, F., Resche-Rigon, M.,
Ghez, D., Dupuis, J., Marcßais, A., Deau-Fischer, B., Bouabdallah, R., Sebban, C., Salles, G. & Brice, P. (2016) Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/ SFGM-TC study group. Haematologica, 101, 474–481.
Sieniawski, M., Franklin, J., Nogova, L., Gloss-mann, J.-P., Schober, T., Nisters-Backes, H., Diehl, V. & Josting, A. (2007) Outcome of patients experiencing progression or relapse after primary treatment with two cycles of chemotherapy and radiotherapy for early-stage favorable Hodgkin’s lymphoma. Journal of Clini-cal Oncology, 25, 2000–2005.
Smith, E.P., Li, H., Friedberg, J.W., Constine, L.S., Rimsza, L.M., Cook, J.R., Laport, G.G., Pop-plewell, L.L., Holmberg, L.A., Smith, S.M., LeBlanc, M., Forman, S.J., Fisher, R.I. & Stiff, P.J. (2017) Tandem autologous hematopoietic cell transplantation for patients with primary progressive or recurrent hodgkin lymphoma: a SWOG and Blood & Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703). Biology of Blood and Marrow Transplantation. doi: 101016/ j.bbmt.201712798. [Epub ahead of print]. Sureda, A., Constans, M., Iriondo, A., Arranz, R.,
Caballero, M.D., Vidal, M.J., Petit, J., Lopez, A., Lahuerta, J.J., Carreras, E., Garcıa-Conde, J., Garcıa-Lara~na, J., Cabrera, R., Jarque, I., Car-rera, D., Garcıa-Ruiz, J.C., Pascual, M.J., Rifon, J., Moraleda, J.M., Perez-Equiza, K., Albo, C., Dıaz-Mediavilla, J., Torres, A., Torres, P., Besal-duch, J., Marın, J., Mateos, M.V., Fernandez-Ra~nada, J.M., Sierra, J. & Conde, E. (2005) Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lym-phoma autografted after a first relapse. Annals of Oncology, 16, 625–633.
Sureda, A., Robinson, S., Canals, C., Carella, A.M., Boogaerts, M.A., Caballero, D., Hunter,
A.E., Kanz, L., Slavin, S., Cornelissen, J.J., Gra-matzki, M., Niederwieser, D., Russell, N.H. & Schmitz, N. (2008) Reduced-intensity condi-tioning compared with conventional allogeneic stem-cell transplantation in relapsed or refrac-tory Hodgkin’s lymphoma: an analysis from the Lymphoma Working Party of the Euro-pean Group for Blood and Marrow
Transplantation. Journal of Clinical Oncology, 26, 455–462.
Sureda, A., Canals, C., Arranz, R., Caballero, D., Ribera, J.M., Brune, M., Passweg, J., Martino, R., Valcarcel, D., Besalduch, J., Duarte, R., Leon, A., Pascual, M.J., Garcıa-Noblejas, A., Lopez Corral, L., Xicoy, B., Sierra, J. & Schmitz, N. (2012) 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 Espa~nol de Linfomas/ Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica, 97, 310–317.
