Symposium article
© 2002 European Society for Medical Oncology
Role of allogeneic stem cell transplantation in relapsed or
refractory Hodgkin’s disease
A. Sureda
1& N. Schmitz
2*
1Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 2Department of Hematology, AK St. Georg, Hamburg, Germany
*Correspondence to: Dr N. Schmitz, Department of Hematology, AK St. Georg, Lohmuehlenstrasse 5, D-20099 Hamburg, Germany. Tel: +49-40-2890-2023; Fax: +49-40-2890-4226;
E-mail: norbert.schmitz@ak-stgeorg.lbk-hh.de
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 graft-versus-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 trans-plant-related mortality (TRM) in patients with HD due to a high incidence of GvHD and of fatal infec-tious 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 popu-lation 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 con-ditioning regimen per se. Although the number of HD patients allografted with reduced-intensity proto-cols 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 promis-ing, 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 pro-spective randomized studies demonstrating a significant superi-ority of high-dose CT compared with standard salvage therapy in relapsed HD patients [8, 9].
High-dose CT/RT followed by allogeneic stem cell trans-plantation (alloSCT) has been extensively used to treat
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 condi-tioning regimen but also to the well-documented graft-versus-leukemia (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 infec-tions 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
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], suggest-ing the existence of a GvL effect [13, 14].
Two large registry-based retrospective analyses on allo-geneic transplantation on HD were published in 1996: Gajew-ski 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 respira-tory 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 treatment-related 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 trans-plant 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 differ-ences in actuarial probabilities of OS, progression free sur-vival (PFS), relapse and non-relapse mortality between
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 involve-ment 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 allo-grafted patients with aGvHD grade ≥2 were compared with 17 matched autografted patients.
Allogeneic transplantation after a
reduced-intensity conditioning regimen in HD
In an effort to reduce the TRM associated with alloSCT, low-intensity fludarabine-based regimens have been developed [21–23]. These protocols have been designed to be immuno-suppressive rather than myeloablative in order to facilitate donor engraftment and limit systemic toxicity. Thus, the cura-tive 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 per-formed by Jones et al. [17] and Anderson et al. [14] demon-strated 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 registry-based 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 sup-port 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 reduced-intensity allogeneic programs still were heavily pre-treated; >50% of the patients had received at least two lines of treat-ment before undergoing allogeneic transplantation, a
signifi-Figure 1. EBMT survey on auto- and alloSCT in the last 4 years (from
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 follow-up. Nevertheless, the two larger studies [28, 32] indicate a 1-year 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 stu-dies. 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 indi-cated 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 con-ditioning 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-Table 1. Reported results on allogeneic stem cell transplantation after a reduced-intensity protocol in relapsed or refractory HD
Tx, therapy; autoSCT, autologous stem cell transplantation; Sib/URD, HLA-compatible sibling/unrelated donor; FC-ATG, fludarabine (125 mg/m2
i.v.) + cyclophosphamide (3 g/m2
i.v.) + antithymocyte globulin (60 mg/kg i.v.); FM, fludarabine (125 mg/m2
i.v.) + melphalan (180 mg/m2
i.v.); FLAG-IDA, fludarabine (120 mg/m2
i.v.) + cytarabine (8 g/m2
i.v.) + idarubicin (36 mg/m2
i.v.); FluCy, fludarabine (90 mg/m2
i.v.) + cyclophosphamide (900 mg/m2
i.v.); Flu-Mel, fludarabine (150 mg/m2
i.v.) + melphalan (140 mg/m2
i.v.); Flu-Cy, fludarabine (150 mg/m2
i.v.) + cyclophosphamide (2.5 g/m2
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.
First author, year [reference] Prior lines of tx [median (range)]/ previous failed autoSCT Donor (Sib/ URD) Disease status (sensitive/ resistant) Conditioning regimen GvHD prophyl-axis aGvHD grade ≥2 [number (patients evaluable)] Extensive cGvHD [number (patients evaluable)] 1-year TRM Status at follow-up months [median (range)] 1-year PFS 1-year OS Anderlini, 2000 [26] (n = 6) 6 (5–9)/6 4/2 3/3 4 FC-ATG, 1 FM, 1 FLAG-IDA CsA/Mtx 4 (6) 2 (4) 2/6 (33%) 3 alive in CR: +6, +9 and +26 NA NA Kottaridis, 2000 [27] (n = 10) 4 (3–6)/7 NA 8/2 10 Flu-Mel-CAMPATH-1H 1 CsA/ Mtx, 9 CsA 0 (10) 0 (10) 0/10 10 alive, 9 in CR, 1 in PD [9.5 (3–26) ] NA NA Robinson, 2000 [28] (n = 52) 3 (1–6)/36 NA 28/19 NA CsA ± Mtx NA NA 17% NA 43% (2 year) 72% Carella, 2000 [29] (n = 10) 2 (1–5)/1 10/0 10/0 FluCy CsA/Mtx 1 (10) 1 (9) 1/10 (10%) 5 alive in CR, 3 in PR, 1 in PD [11 (7–24) ] NA NA McSweeney, 2001 [30] (n = 4) 4 (2–5)/2 4 3/1 TBI 2 Gy CsA/ MMF 3 (4) 2 (3) 1/4 (25%) 2 alive in CR, 1 in PR: +4, +14 and +15 NA NA Michallet, 2001 [31] (n = 3) NA 3/0 2/1 NA NA 1 (3) 1 (3) 0/3 1 alive in CR, 1 in PR, 1 in PD NA NA Sureda, 2001 [32] (n = 19) 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% 53%± 13%
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 1-year 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 Dis-ease Study Group (GHSG) within the EBMT Lymphoma Working Party will prospectively analyze the outcome of patients treated with the combination of fludarabine (150 mg/m2
i.v.) plus melphalan (140 mg/m2 i.v.) and monthly escalating
DLIs in cases of mixed chimerism after transplantation or dis-ease 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. N Engl J Med 1992; 326: 678–677.
2. Chopra R, McLimman AK, Linch DC et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in high risk Hodgkin’s disease. A single-center eight-year study of 155 patients. Blood 1993; 81: 1137–1145.
3. Nademanee A, O’Donnell MR, Snyder DS et al. High dose chemo-therapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin’s disease: results in 85 patients with analysis of prognostic factors. Blood 1995; 85: 1381– 1390.
4. Reece DE, Connors JM, Spinelli JJ 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. 5. Sweetenham JW, Carella AM, Taghipour G et al. High dose therapy
and autologous stem cell transplantation for adult patients with Hodg-kin’s disease who fail to enter remission after induction chemotherapy: Results in 175 patients reported to the EBMT. J Clin Oncol 1999; 17: 3101–3109.
6. Lazarus HM, Rowlings PA, Zhang M-J et al. Autotransplants for Hodgkin’s disease in patients never achieving a complete remission: a report from the Autologous Blood and Marrow Transplant Registry (ABMTR). J Clin Oncol 1999; 17: 534–545.
7. Sureda A, Arranz R, Iriondo A et al. Autologous stem cell transplant-ation for Hodgkin’s disease: Results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea Spanish Cooperative Group. J Clin Oncol 2001; 19: 1393–1404.
8. Linch DC, Winfield D, Goldstone AH et al. Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 1993; 341: 1051–1053.
9. Schmitz N, Sextro M, Pfistner B et al. High dose therapy followed by hematopoietic stem cell transplantation for relapsed chemosensitive Hodgkin’s disease. Results of a randomized GHSG and EBMT trial: HD-R1. Lancet 2002; In press.
10. Ringden O, Horowitz MM, Gale RP et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 1993; 270: 57–60.
11. Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older. Blood 1986; 67: 770–776. 12. Weiden PL, Flournoy N, Thomas ED et al. Anti-leukemic effect of
graft-versus-host-disease in recipients of allogeneic marrow grafts. N Engl J Med 1979; 300: 1068–1073.
13. Jones RJ, Ambinder RF, Piantadosi S et al. Evidence of a graft versus lymphoma effect associated with allogeneic bone marrow transplant-ation. Blood 1991; 77: 649–653.
14. Anderson JE, Litzow MR, Appelbaum FR et al. Allogeneic, syn-geneic, and autologous marrow transplantation for Hodgkin’s disease: the 21-year Seattle experience. J Clin Oncol 1993; 11: 2342–2350. 15. Appelbaum FR, Sullivan KM, Thomas DE et al. Allogeneic marrow
transplantation in the treatment of MOPP resistant Hodgkin’s dis-ease. J Clin Oncol 1985; 3: 1490–1494.
16. Phillips GL, Reece DE, Barnett MJ et al. Allogeneic marrow trans-plantation for refractory Hodgkin’s disease. J Clin Oncol 1989; 7: 1039–1045.
17. Jones RJ, Piantadosi S, Mann RB et al. High dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol 1990; 8: 527–537.
18. Phillips GL, Herzig RH, Lazarus HM et al. High-dose chemotherapy, fractionated total body irradiation and allogeneic marrow transplant-ation for malignant lymphoma. J Clin Oncol 1986; 4: 480–488. 19. Gajewski JL, Phillips GL, Sobocinski KA et al. Bone marrow
trans-plantation from HLA-identical siblings in advanced Hodgkin’s dis-ease. J Clin Oncol 1996; 14: 572–578.
20. Milpied N, Fielding AK, Pierce RM et al. Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin’s disease. J Clin Oncol 1996; 14: 1291–1296. 21. Khouri IF, Keating M, Körbling M et al. Transplant-lite: induction of
graft-versus-malignancy using fludarabine-based nonablative chemo-therapy and allogeneic blood progenitor-cell transplantation as treat-ment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824. 22. Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hemato-poietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.
23. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.
24. Akpek G, Ambinder RF, Piantadosi S et al. Long-term results of blood and marrow transplantation for Hodgkin’s lymphoma. J Clin Oncol 2001; 19: 4314–4321.
25. Porter DL, Connors JM, Van Deerlin VMD et al. Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol 1999; 17: 1234–1243. 26. Anderlini P, Giralt S, Anderson B et al. Allogeneic stem cell
trans-plantation with fludarabine-based, less intensive conditioning regi-mens as adoptive immunotherapy in advanced Hodgkin’s disease. Bone Marrow Transplant 2000; 26: 615–620.
27. Kottaridis PD, Milligan DW, Chopra R et al. In vivo CAMPATH-1H prevents graft-versus-host-disease following non-myeloablative stem cell transplantation. Blood 2000; 96: 2419–2425.
28. Robinson SP, Mackinnon S, Goldstone AH et al. Higher than expected transplant-related mortality and relapse following
non-myeloablative stem cell transplantation for lymphoma adversely effects progression free survival. Blood 2000; 96: 554a (Abstr 2380). 29. Carella AM, Cavaliere M, Lerma E et al. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol 2000; 18: 3918–3924.
30. McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.
31. Michallet M, Bilger K, Garban F et al. Allogeneic hematopoietic stem cell transplantation after nonmyeloablative preparative regi-mens: impact of pretransplantation and posttransplantation factors on outcome. J Clin Oncol 2001; 19: 3340–3349.
32. Sureda A, Schmitz N, Canals C et al. Allogeneic peripheral blood stem cell transplantation after a reduced conditioning regimen in refractory or relapsed Hodgkin’s disease. Leuk Lymphoma 2001; 42 (Suppl 2): 75 (Abst 150).
33. Carella AM, Beltrami G, Carella M Jr et al. Immunosuppressive non-myeloablative allografting as salvage therapy in advanced Hodgkin’s disease. Haematologica 2001; 86: 1121–1123.
