Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin s disease

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1 Symposium article Annals of Oncology 13 (Supplement 1): , 2002 DOI: /annonc/mdf626 Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin s disease A. Sureda 1 & N. Schmitz 2 * 1 Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 2 Department of Hematology, AK St. Georg, Hamburg, Germany Little information is available regarding allogeneic stem cell transplantation (allosct) and Hodgkin s disease (HD). Autologous stem cell transplantation (autosct) is usually preferred to allosct due to its widespread availability, lack of the immunological problems intrinsic to the development of graftversus-host disease (GvHD), and the infrequent bone marrow involvement present in HD patients undergoing high-dose chemotherapy/radiotherapy. AlloSCT has been associated with a high transplant-related mortality (TRM) in patients with HD due to a high incidence of GvHD and of fatal infectious events after transplantation. The poor outcome of these patients after allosct may reflect in part the advanced status of the disease at transplantation and the poor performance status of the patient population allografted. Furthermore, the high TRM present in the conventional allosct setting has never allowed a proper evaluation of a possible graft-versus-hodgkin s effect. In an effort to reduce the TRM associated with allosct, low-intensity regimens have been developed; the curative potential of these protocols would rely on the graft-versus-leukemia effect of the allogeneic infusion more than in the conditioning regimen per se. Although the number of HD patients allografted with reduced-intensity protocols is low and the follow-up still short, TRM seems lower than in the conventional allograft setting despite a similar incidence of acute GvHD (agvhd). Overall and progression-free survival seem promising, and patients developing agvhd after transplantation or donor lymphocyte infusions seem to be at a lower risk of relapse than those not presenting this complication. Key words: allogeneic stem cell transplantation, reduced-intensity conditioning regimens, relapsed or refractory Hodgkin s disease Introduction More than 80% of patients with advanced Hodgkin s disease (HD) can be cured with combination chemotherapy (CT) ± radiotherapy (RT) [1]. Despite these encouraging results, patients who fail to enter complete remission (CR) with initial CT fare poorly with conventional salvage CT. High-dose CT or CT/RT is increasingly used for patients with HD who fail to respond to first-line CT or relapse after such therapy, and may lead to long-term disease-free survival (DFS) [2 7]. It is assumed that dose intensification per se contributes to the long-term DFS that may be seen after autologous stem cell cell transplantation (autosct) and, indeed, there are two prospective randomized studies demonstrating a significant superiority of high-dose CT compared with standard salvage therapy in relapsed HD patients [8, 9]. High-dose CT/RT followed by allogeneic stem cell transplantation (allosct) has been extensively used to treat *Correspondence to: Dr N. Schmitz, Department of Hematology, AK St. Georg, Lohmuehlenstrasse 5, D Hamburg, Germany. Tel: ; Fax: ; norbert.schmitz@ak-stgeorg.lbk-hh.de patients with hematological malignancies. This procedure is largely limited to patients with a human leukocyte antigen (HLA) sibling donor available and who are in a good medical condition, because of the increased risk of regimen-related toxicity and graft-versus-host disease (GvHD) that occurs with increasing age and poor performance status [10, 11]. The curative potential of allosct is not solely due to the conditioning regimen but also to the well-documented graft-versusleukemia (GvL) effect [12]. Few studies have reported results of allosct in HD patients; autosct is preferred to allosct due to its widespread availability, lack of the immunological problems intrinsic to the development of GvHD without a clear-cut evidence of a GvL effect and the infrequent bone marrow involvement of HD patients undergoing high-dose CT. Moreover, the severe immunodeficiency present in HD patients may significantly increase the risk of severe infections after transplantation in the setting of an allogeneic graft. Conventional allogeneic transplantation and HD Little information is currently available regarding allosct and HD; in fact, the number of alloscts performed within the 2002 European Society for Medical Oncology

2 129 EBMT centers in the last 3 4 years has always been below 50, with no increase over time (Figure 1). The first published series on HD and allografting were small [13 18]. Only three published series included >20 patients; the others included <10 patients. Probabilities of survival for these patients ranged from 0 to 25%. Relapse rates after transplantation seemed to be lower than in patients undergoing autosct [15], suggesting the existence of a GvL effect [13, 14]. Two large registry-based retrospective analyses on allogeneic transplantation on HD were published in 1996: Gajewski et al. [19] analyzed the results of 100 HD patients who were allografted from an HLA-identical sibling between April 1982 and August 1992, and reported to the International Bone Marrow Transplant Registry (IBMTR). The 3-year overall survival (OS), DFS and probability of relapse rates were 21, 15 and 65%, respectively. The 100-day probability of acute GvHD (agvhd) was 35%. The two major problems after transplantation were persistent or recurrent HD and respiratory complications, which accounted for 35 and 51% of deaths, respectively. The relapse risk was lower in patients developing agvhd, suggesting a possible GvL effect, but this effect was outweighed by the increased risk of treatmentrelated mortality (TRM). The poor outcome of these patients might reflect in part the disease status at transplantation, with a vast majority of patients being transplanted in advanced resistant disease and a median time from diagnosis to transplant of 2.5 years, as well as their poor performance status pre-transplant with half of the patients presenting with a Karnofsky score 80% and about one-quarter featuring a clinically important infection in the week before transplant. Furthermore, most of the patients were conditioned with total body irradiation or busulfan plus cyclophosphamide, both of which might have contributed to the high procedure related mortality. A retrospective case-matched analysis including 45 allografts and 45 autografts reported to the European Bone Marrow Transplantation (EBMT) registry was carried out by Milpied et al. [20]. The authors did not find significant differences in actuarial probabilities of OS, progression free survival (PFS), relapse and non-relapse mortality between Figure 1. EBMT survey on auto- and allosct in the last 4 years (from the EBMT; reproduced with permission). allosct and autosct (25, 15, 61 and 48%, and 37, 24, 61 and 27%, respectively) after matching both groups for sex, age at transplantation, stage of the disease and bone marrow involvement at diagnosis and at transplant, time from diagnosis to transplant and conditioning regimen, the toxic death rate at 4 years was significantly higher for the allografts compared with the autografts (48% versus 27%; P = 0.04), even when considering only patients with chemosensitive disease at transplant. No benefit of a GvL effect could be demonstrated, although there was a decreased relapse rate when 17 allografted patients with agvhd grade 2 were compared with 17 matched autografted patients. Allogeneic transplantation after a reducedintensity conditioning regimen in HD In an effort to reduce the TRM associated with allosct, lowintensity fludarabine-based regimens have been developed [21 23]. These protocols have been designed to be immunosuppressive rather than myeloablative in order to facilitate donor engraftment and limit systemic toxicity. Thus, the curative potential of a reduced-intensity allosct would rely more on the GvL effect of the allogeneic infusion or the subsequent administration of donor lymphocytes [donor lymphocyte infusions (DLIs)] than in the conditioning regimen per se. In this sense, several lines of evidence suggest the existence of a graft-versus-hodgkin s effect (GvH). The initial studies performed by Jones et al. [17] and Anderson et al. [14] demonstrated a decreased relapse rate in allogeneic recipients compared with autologous transplants, attributed by the authors to a possible GvH effect. Major criticisms of both studies are the low number of patients included in both groups and the disparities in patient characteristics between allosct and autosct patients. In the two large retrospective registrybased studies performed [19, 20] there was a reduction in the relapse rate, although not statistically significant, in patients developing moderate to severe agvhd in the EBMT analysis [20]. A possible beneficial effect might have been obscured by the increased TRM in this subgroup of patients. A recent report indicates that when patients were allografted earlier during the course of their disease, the GvH effect can be demonstrated with a lower relapse rate and an improved event-free survival compared with autosct [24]. Several case reports of disease responses following DLIs [25] further support the existence of a GvH effect. Several small series of HD patients treated with allosct after a reduced-intensity conditioning regimen have already been reported [26 32] (Table 1). Although the number of patients included in most of them is too low to draw definitive conclusions, there are several aspects that should be pointed out. In general, the patients included in these reducedintensity allogeneic programs still were heavily pre-treated; >50% of the patients had received at least two lines of treatment before undergoing allogeneic transplantation, a signifi-

3 130 Table 1. Reported results on allogeneic stem cell transplantation after a reduced-intensity protocol in relapsed or refractory HD First author, year [reference] Anderlini, 2000 [26] (n = 6) Kottaridis, 2000 [27] (n = 10) Robinson, 2000 [28] (n = 52) Carella, 2000 [29] (n = 10) McSweeney, 2001 [30] (n = 4) Michallet, 2001 [31] (n = 3) Sureda, 2001 [32] (n = 19) Prior lines of tx [median (range)]/ previous failed autosct Donor (Sib/ URD) Disease status (sensitive/ resistant) Conditioning regimen 6 (5 9)/6 4/2 3/3 4 FC-ATG, 1 FM, 1 FLAG- IDA GvHD prophylaxis 4 (3 6)/7 8/2 10 Flu-Mel- 1 CsA/ CAMPATH-1H Mtx, 9 CsA 3 (1 6)/36 28/19 CsA ± Mtx agvhd grade 2 [number (patients evaluable)] Extensive cgvhd [number (patients evaluable)] TRM CsA/Mtx 4 (6) 2 (4) 2/6 (33%) Status at follow-up months [median (range)] 3 alive in CR: +6, +9 and (10) 0 (10) 0/10 10 alive, 9 in CR, 1 in PD [9.5 (3 26) ] PFS 17% 43% (2 year) 2 (1 5)/1 10/0 10/0 FluCy CsA/Mtx 1 (10) 1 (9) 1/10 (10%) 4 (2 5)/2 4 3/1 TBI 2 Gy CsA/ MMF 3 (4) 2 (3) 1/4 (25%) 5 alive in CR, 3 in PR, 1 in PD [11 (7 24) ] 2 alive in CR, 1 in PR: +4, +14 and +15 3/0 2/1 1 (3) 1 (3) 0/3 1 alive in CR, 1 in PR, 1 in PD 2 (1 4)/15 17/1 7/12 17 Flu-Mel, 2 Flu-Cy 2 CsA, 17 CsA/Mtx 5 (17) 3 (9) 6/19 (32%) 7 alive in CR, 1 PR, 2 PD [6.5 (2 27) ] 37%± 14% OS 72% 53%± 13% Tx, therapy; autosct, autologous stem cell transplantation; Sib/URD, HLA-compatible sibling/unrelated donor; FC-ATG, fludarabine (125 mg/m 2 i.v.) + cyclophosphamide (3 g/m 2 i.v.) + antithymocyte globulin (60 mg/kg i.v.); FM, fludarabine (125 mg/m 2 i.v.) + melphalan (180 mg/m 2 i.v.); FLAG-IDA, fludarabine (120 mg/m 2 i.v.) + cytarabine (8 g/m 2 i.v.) + idarubicin (36 mg/m 2 i.v.); FluCy, fludarabine (90 mg/m 2 i.v.) + cyclophosphamide (900 mg/m 2 i.v.); Flu-Mel, fludarabine (150 mg/m 2 i.v.) + melphalan (140 mg/m 2 i.v.); Flu-Cy, fludarabine (150 mg/m 2 i.v.) + cyclophosphamide (2.5 g/m 2 i.v.); TBI, total body irradiation; GvHD, graft-versus-host disease; CsA, cyclosporin A; Mtx, methotrexate; MMF, mycophenolate mofetil; TRM, transplant-related mortality; PFS, progression-free survival; OS, overall survival. cant proportion had been treated with RT before allosct, and progression or relapse after a previous autosct had occurred in >50% of them. In some studies [32], >50% of the patients were allografted in resistant disease, which can explain in part the somewhat high TRM in relation to other groups [27]. Conditioning regimens vary from one study to the next, but most of them include fludarabine. In the British study, CAMPATH-1H was added to the conditioning protocol in order to further prevent the development of GvHD. Acute and chronic GvHD still remain a problem with most of these protocols with incidences ranging from 0 to 75%, the lower figure probably reflecting the administration of CAMPATH- 1H. Despite the fact that the incidence of agvhd seems not to be significantly different from that of conventional allosct, TRM seems lower than in the conventional setting. TRM is impressively low in patients receiving CAMPATH-1H as part of the conditioning regimen [27, 28] because of a significant reduction of the agvhd incidence. Long-term DFS and OS are impossible to evaluate from the majority of these studies due to the low number of patients included and short followup. Nevertheless, the two larger studies [28, 32] indicate a PFS and OS between 40 and 60%, and 50 and 70%, respectively. The question of whether a significant GvH effect was observed cannot be answered definitively by these studies. However, there are some anecdotal cases reporting tumor regression after development of agvhd [30, 32] or after DLIs [27, 30, 32]. The existence of a GvH effect may also be indicated by reports from the tandem protocol of Carella et al.; patients developing agvhd after transplantation had a higher PFS than patients not developing agvhd [33]. In order to better assess the role of reduced-intensity conditioning regimens in relapsed or refractory HD patients, one could evaluate large retrospective series with the aim of demonstrating the existence of a GvH effect, coupled or not with the development of agvhd in a low TRM allogeneic protocol. In this sense, a preliminary analysis of 52 HD allo-

4 131 grafted after a reduced-intensity protocol and reported to the EBMT demonstrates an incidence of agvhd grade 2 of 30%, a still low TRM of 17.3% at 1 year, and and 2-year OS and PFS of 72, 56, 55 and 42%, respectively (unpublished data). These results seem interesting enough to initiate prospective trials including patients at high risk of relapse after autosct. The HDR-allo protocol developed by the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL/TAMO) and the German Hodgkin s Disease Study Group (GHSG) within the EBMT Lymphoma Working Party will prospectively analyze the outcome of patients treated with the combination of fludarabine (150 mg/m 2 i.v.) plus melphalan (140 mg/m 2 i.v.) and monthly escalating DLIs in cases of mixed chimerism after transplantation or disease progression. Results of this and other ongoing studies will help to redefine the role of allogeneic transplantation in HD patients. References 1. Urba WJ, Longo DL. Hodgkin s disease. 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