Mini-review Tandem transplantation in lymphoma

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1 (2001) 28, Nature Publishing Group All rights reserved /01 $ Mini-review ation in lymphoma KP Papadopoulos, W Noguera-Irizarry and CS Hesdorffer Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA Summary: The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. There is evidence for the superiority of single high-dose chemotherapy in such patients, but many still die from recurrent disease. Strategies to improve survival in these poor-risk patients include dose-intensification with high-dose chemotherapy and PBPC support, tandem autologous HDC with PBPC support, and autologous followed by non-myeloablative allogeneic transplantation. These more aggressive strategies are feasible and tolerable. Whether tandem transplantation will prove more effective than current single high-dose therapy in appropriately selected patients remains to be determined. (2001) 28, Keywords: tandem transplantation; lymphoma; autologous; allogeneic The majority of patients with lymphoma achieve remission with standard therapy. A small percentage of patients are refractory to initial therapy, and approximately one-third of patients with stage III IV disease will relapse after achieving a complete response. Treatment of minimally responsive or refractory lymphoma patients remains a challenge. Single transplantation and the poor prognosis patient Prospective randomized trials show single HDC with autologous transplantation to be superior to standard-dose chemotherapy for relapsed and resistant Hodgkin s disease, 1 for consolidative therapy of poor-risk B cell NHL in first remission 2 and for relapsed chemo-sensitive intermediate or high-grade NHL. 3 An update of the PARMA study reports an 8-year EFS of 36% and OS of 47% for these latter patients. 4 Fewer than 5% of patients with poor-risk NHL or HD who have induction failure and receive conventional salvage chemotherapy are alive at 5 years. NHL patients with induction failure who undergo HDC and autotransplantation have an overall survival at 5 years of 37%. 5 Data from the ABMTR show HD patients with induction Correspondence: DR CS Hesdorffer, Division of Medical Oncology, MHB 6N 435, 177 Ft. Washington Avenue, New York, NY 10032, USA failure who subsequently undergo HDC have progressionfree and overall survivals at 3 years of 38% and 50%, respectively. 6 Data by Sweetenham et al 7 from the EBMT are similar, reporting an actuarial 5-year OS rate of 36% and PFS rate of 32%. Allogeneic transplantation alone does not appear to offer a survival advantage over autologous transplant for lymphoma. 8,9 Studies suggest a graft-versus-lymphoma effect, but this has not translated into increased survival due to the high treatment-related mortality associated with allogeneic transplantation. Further prospective trials, randomized on the basis of HLA-identical donor availability, may provide more reliable data on this issue. 10 While salvage rates of 45 60% are achieved with HDC in patients with relapsed NHL and HD with good prognostic factors, adverse prognostic factors, such as relapse within 1 year of initial treatment, stage III/IV relapse or chemoresistance, portend a poorer outcome, with likely cure in less than 40%. The IPI at relapse correlates with survival in aggressive NHL and only patients with IPI 1 have significantly better survival after salvage with HDC than conventional chemotherapy. 4,11 Similarly, for patients with HD undergoing HDC, the HD prognostic index applied prior to transplant appears to identify groups with distinct outcomes. Low serum albumin, hemoglobin, stage IV disease and lymphocytopenia relate significantly to EFS and outcome. 12 B symptoms at diagnosis and Karnofsky performance score at autotransplantation also correlate significantly with survival following HDC for HD. 6 Gene expression profiling can further define prognostically distinct subgroups of patients with NHL. 13 The application of these clinical prognostic indices and emerging technologies may help prospectively to identify patients who might benefit from more than single autologous HDC chemotherapy, while avoiding unnecessary morbidity in patients unlikely to profit from more aggressive strategies. The feasibility and tolerability of performing either a second autologous transplant or allogeneic transplant in patients with lymphoma who have relapsed despite autologous transplantation is confirmed in several studies. 14,15 To improve survival in patients with induction failure or highrisk or chemotherapy-resistant disease, the strategies to either increase the chemotherapy dose or the anti-lymphoma immune response include sequential HDC and autologous stem cell support, or tandem autologous transplant and non-myeloablative allogeneic transplantation.

2 530 Tandem intensive sequential chemotherapy and autologous transplantation Data from the International Prognostic Factors Project of patients with NHL treated with doxorubicin combination therapy demonstrate a 5-year survival rate of 32% for the high-risk group. 16 Patients with DLCL treated with conventional therapy have CR, DFS and 3-year survival rates of 42%, 41% and 29%, respectively. 17 The 5-year survival of patients with IPI 2 and 3 undergoing single HDC in the PARMA study was 50%. 11 Sequential intensive chemotherapy followed by HDC and autologous PBPC support has been used in patients with poor-risk disease in an attempt to improve long-term outcome. This dose-intense strategy has been applied as both first-line and salvage therapy to poor risk patients 60 years (Table 1) Two pilot studies of intensive sequential chemotherapy as first-line treatment in patients with aggressive NHL were conducted by Bouaddallah and colleagues. 23 For study ISC 92, patients received three cycles of high-dose CHOP (cyclophosphamide 3 g/m 2, doxorubicin 75 mg/m 2, vincristine 2 mg, and prednisone 60 mg/m 2 for 5 days) followed by three intensified stem cell supported cycles of high-dose CHOP with etoposide (300 mg/m 2 ) and cisplatin (100 mg/m 2 ). 18 The regimen for ISC 95 was COP and four cycles of high-dose CHOP, the last two cycles including etoposide 500 mg/m 2 and cisplatin 100 mg/m 2 and supported by PBPC. 19 Eighty-five percent of patients completed therapy, with a CR rate of 65% and OS and FFS of 73% and 56% at 2 years for ISC 92; and a CR rate of 69% and OS of 58% at 3 years for ISC 95. Of 33 age-adjusted-ipi 3 (AA- IPI) patients treated in these two pilot studies, there was one toxic death, 61% of patients achieved a CR, and the OS and EFS at 5 years was 51% and 42% respectively. 23 Santini et al 20 treated 40 patients with aggressive NHL and bone marrow involvement with induction VACOP-B, highdose cyclophosphamide (7 g/m 2 ) followed by PBPC supported BEAM or melphalan (140 mg/m 2 ) TBI (8 Gy). Eleven patients (27.5%) did not complete the regimen. The CR rate was 72.5% and actuarial 3-year EFS and overall survival was 40% and 48%, respectively. Vitolo et al 21 treated 50 high-risk DLCL patients with 8 weeks of induction MACOPB, followed by intensification with mitoxantrone (24 mg/m 2 ), cytarabine (12 g/m 2 ) and dexamethosone (24 mg/m 2 )(MAD). Thirty-nine patients (78%), achieving at least a PR, were consolidated with BEAM and PBPC support. There were three treatment-related deaths (6%), two after MAD and one after BEAM. The CR was 72%, and the FFS and OS were 50% and 56% at 3 years. There are two randomized trials of intensified induction and HDC with PBPC support compared to conventional therapy for poor risk NHL. The studies were of different design and reached opposite conclusions. In the first of these trials LHN93 3 from the GELA, 370 patients under 60 years with AA-IPI 2 3 factors were randomized to ACVB and sequential consolidation or a cycle of CEOP (cyclophosphamide 750 mg/m 2, epirubicin 70 mg/m 2 vincristine 1 mg/m 2, prednisone 60 mg/m 2 5) and two cycles of ECVBlP (cyclophosphamide 2 g/m 2, epirubicin 120 mg/m 2, vindesine 4 mg/m 2, bleomycin 20 mg and prednisone) followed by BEAM with PBPC support. 24 For each arm the CR rate was respectively 64% and 63%, with similar mortality (9% vs 7%) and treatment failure rates. Induction HDC did not improve 3-year survival as compared to the ACVB regimen (47% and 63 % respectively, P 0.003). Of relevance in interpreting these results is that 29% of assigned patients did not actually receive BEAM, mainly due to disease progression. In a comparative trial, Gianni et al 22 randomized 98 eligible patients with DLCL to MACOP-B or sequential high-dose therapy including cyclophosphamide (7 g/m 2 ), methotrexate (8 g/m 2 ) and etoposide (2 g/m 2 ), followed by PBPC supported TBI (12.5 Gy) and melphalan ( mg/m 2 ). The TBI containing regimen had a 40% grade 3 4 toxicity rate with three toxic deaths and was replaced by mitoxantrone (60 mg/m 2 ) and melphalan (180 mg/m 2 ). Patients progressing on either treatment arm could cross over to the alternate therapy. The overall treatment-related mortality was 8% for Table 1 Intensified sequential and high-dose chemotherapy with autologous transplantation in patients with lymphoma Disease Stage of No. patients Intensification HDC regimen % Patients CR OS Toxic Ref. therapy enrolled completing regimen (3 years) deaths NHL Induction 20 HiCHOP 3 HiCHOPECi PBPC 3 85% (17/20) 65% 73% 5% 18 NHL Induction 42 HiCHOP 2 HiCHOPECi PBPC 2 86% (36/42) 69% 58% 2% 19 NHL Induction 40 HiC BEAM or M TBI 72.5% (29/40) 72.5% 48% 2.5% 20 PBPC NHL Induction 50 MtAD BEAM PBPC 78% (39/50) 72% 56% 6% 21 NHL Induction 187 CEpOP/EpCVBIP BEAM PBPC 71% (133/187) 63% 47% 7% 24 2 NHL Induction 48 HiC/MxO/E MMt or M TBI 100% (48/48) 96% 81% a * 8% 22 PBPC/BM NHL Induction 32 HiC/MxO/E MMt PBPC 91% (29/32) 95% 67% 6.25% 25 NHL Relapse 20 HiC/MxO/E MMt PBPC 55% (11/20) 55% 0% 26 HD Relapse 21 HiCECi M PBPC 100% (21/21) 87% b 0% 27 A cytarabine; B BCNU; Bl bleomycin; Bu busulphan; C cyclophosphamide; Cb carboplatin, Ci cisplatin; D dexamethasone; E etoposide; Ep epirubicin; H doxorubicin; Mt mitoxantrone; M melphalan; Mx methotrexate; O vincristine; V vindesine; P prednisone; TBI total body irradiation; PBPC peripheral blood progenitor cells; BM bone marrow; HDC high-dose chemotherapy. a OS at 7 years. b OS at 2 years. Hi high-dose. Acronyms in table may differ from those in text.

3 the high-dose regimen vs 6% in the MACOP-B arm. Patients treated with the sequential high-dose therapy had a significantly higher CR rate (96% vs 70%, P 0.001), progression-free (84% vs 49%, P 0.001) and event-free survivals (76% vs 49%, P 0.004). A multicenter phase II study of 32 patients with high-risk NHL confirmed the efficacy and tolerability of the mitoxantrone- and melphalan-containing high-dose sequential regimen as initial therapy. The OS and RFS at 18 months for all patients in this study were 78% and 67%, respectively. 25 In contrast, Johnston et al 26 using a similar high-dose regimen in patients with high-risk or relapsed/refractory NHL found significant toxicity, and disease progression prevented half of the enrolled patients from completing the therapy. Some benefit to tandem dose-intensive chemotherapy followed by PBPC supported HDC in patients with relapsed or refractory HD is suggested by the study of Stewart et al. 27 Twenty-one patients received nonablative dose-intensive cyclophosphamide (5.25 g/m 2 ), etoposide (1.05 g/m 2 ) and cisplatin (105 mg/m 2 ) (DICEP) followed at recovery by melphalan ( mg/m 2 ) with PBPC support. There was no treatment-related mortality. Two-year EFS and OS were 71% and 87%, respectively. Although DICEP therapy was associated with better outcome than in a similar group of patients undergoing melphalan HDC, but not receiving prior DICEP, interpretation of the results is limited by the use of non-randomized historical controls. Tandem autologous transplantation A small number of studies address the issue of tandem HDC with autologous PBPC support in lymphoma (Table 2). Fitoussi et al 28 evaluated the feasibility of two myeloablative regimens supported with PBPC given at a 2- month interval in 15 patients with diffuse large cell lymphoma. Six of the patients had relapsed disease and nine had two poor prognostic factors at diagnosis. Fourteen patients received BCNU (300 mg/m 2 ), cyclophosphamide (6 g/m 2 ), etoposide (1000 mg/m 2 ), together with mitoxantrone (30 45 mg/m 2 ) in 12 patients, and one patient received BEAC as the first cycle. The second cycle of HDC consisted of carboplatin (1200 mg/m 2 ), melphalan (140 mg/m 2 ) with TBI (12 Gy) in six patients or busulphan (8 12 mg/kg) in nine patients. At day 100 following cycle 2, there was one treatment-related death due to hepatic VOD, 10 patients were in CR (67%), one PR and three had relapsed. Two additional patients developed VOD, one of whom died, leading the authors to caution against the inclusion of busulphan in the preparative regimen. With median follow-up of 12 months, median survival was 19 months. In light of the results of the PARMA study which revealed a poor outcome for patients relapsing within the first year of diagnosis, a multicenter phase II trial (PARMA2) tested the efficacy of tandem autologous HDC in this group of patients. 29 Patients with intermediate- or high-grade NHL relapsing within 1 year of initial therapy were treated with cyclophosphamide (6 g/m 2 ) and etoposide (450 mg/m 2 ). Non-progressing patients underwent the first cycle of BEAC with PBPC support, and if in CR or PR, received carboplatin (1200 mg/m 2 ), melphalan (140 mg/m 2 ) and TBI (12 Gy) or busulphan as the second HDC regimen. Of 16 patients enrolled, 14 proceeded to the first HDC cycle with BEAC. Nine patients had both HDC regimens. There were three toxic deaths following the second HDC. Of the remaining six patients, three were in CR and three were in PR. At a median follow-up of 9 months the median survival was 5 months. Due to the perceived poor results and high toxic death rate this study has been halted. Following a standard or abbreviated course of conventional-dose chemotherapy, Ballestrero et al 30 treated 25 patients with aggressive NHL with tandem HDC. After receiving cyclophosphamide (6 7 g/m 2 ) for PBPC mobilization, patients were given mitoxantrone (60, 75 or 90 mg/m 2 ) and melphalan ( mg/m 2 ) and PBPC support, followed at recovery by etoposide (1.5 g/m 2 ) and carboplatin (1.5 g/m 2 ). Of 25 patients, 22 completed the tandem regimen and the CR rate was 92%. Two patients with progressive disease at entry failed to respond to the tandem regimen. Patients with AA-IPI 1 had 2-year OS and FFS of 91%, and for AA-IPI 2 3 patients the estimated OS and FFS were 79%. Hesdorffer et al 31 reported on a phase I II trial of tandem autologous transplantation in which mitoxantrone (30 50 mg/m 2 ) and melphalan (180 mg/m 2 ) were administered as the first cycle of HDC with PBPC support, and etoposide phosphate ( mg/m 2 ), thiotepa (500 mg/m 2 ), and carboplatin (800 mg/m 2 ) (ETCb) as the second HDC with PBPC support. Radiotherapy was given for bulky disease. Thirty-two patients of median age 36 years are enrolled to date, including 16 patients with NHL (10 with DLC), Table 2 Tandem high-dose chemotherapy and autologous transplantation in patients with lymphoma Disease Stage of No. pts HDC regimen 1 HDC regimen 2 % Patients CR OS Toxic Ref. therapy enrolled completing 1 and 2 (2 years) deaths NHL Relapse 15 BCEMt PBPC CbM & TBI or Bu PBPC 100% (15/15) 67% 41% 7% 28 NHL Relapse 16 BEAC PBPC a CbM & TBI or Bu PBPC 64% (9/14) 21% 21% 29 NHL Induction 25 MtM PBPC a CbE PBPC 88% (22/25) 92% 84% 0% 30 NHL/HD Relapse 32 MtM PBPC ETCb PBPC 69% (22/32) 44% 58% 19% Unpubl HD Relapse 43 BCEMt PBPC AM & TBI or Bu PBPC 82% (32/39) 61% 65% 3% 32 A cytarabine; B BCNU; Bu busulphan; C cyclophosphamide; Cb carboplatin; E etoposide; Mt mitoxantrone; M melphalan; TBI total body irradiation; PBPC peripheral blood progenitor cells; HDC high-dose chemotherapy. a PBPC mobilized with cyclophosphamide 6 7 g/m 2. Acronyms in table may differ from text.

4 532 patients with Hodgkin s disease and six patients with T cell lymphomas. Eighty-four percent were stage III or IV and 75% of patients had previously received 2 chemotherapeutic regimens. Following mitoxantrone and melphalan there were three toxic deaths, one due to delayed engraftment and presumed mitoxantrone-related myocarditis (at a dose of 40 mg/m 2 ). The major extramedullary toxicity was limited to grade III/IV mucositis. Two patients had disease progression and five patients chose not to undergo the second HDC. Twenty-two patients (69%) completed both HDC cycles. There were three toxic deaths following the second HDC, all occurring in patients receiving 700 mg/m 2 of etoposide. Complete remission (CR) was noted in 11 of the 22 patients (50%) completing both transplants. For the 32 enrolled patients and the 22 patients completing the tandem transplant, the 2-year overall survival is 58% and 71%, respectively. A multicenter study of tandem autologous HDC enrolled 43 patients with HD who had failed induction, had refractory relapse or had progression within 12 months and were stage III or IV at relapse. 32 Thirty-nine patients received the first HDC regimen of BCNU (300 mg/m 2 ) cyclophosphamide (6 g/m 2 ), etoposide (1000 mg/m 2 ) and mitoxantrone (30 mg/m 2 ) with PBPC support. Patients without severe toxicity or disease progression received cytarabine (6 g/m 2 ), melphalan (140 mg/m 2 ) and TBI (12 Gy) or busulphan (12 16 mg/kg). Despite a median age of 29 years, only 74% of enrolled patients completed both cycles, with disease progression and insufficient PBPC collection accounting for the majority of patients being unable to proceed. There was one toxic death and two patients developed VOD. On an intention-to-treat analysis the CR rate is 51%. For the 43 enrolled patients and the 32 patients completing the tandem transplant, the 2-year survival were 65% and 74%, respectively. The HD patients with induction failure undergoing tandem transplant had a 2-year survival rate of 53%. Tandem autologous and non-myeloablative allogeneic transplantation The curative potential of allogeneic PBPC transplantation is mediated in part by an immune graft-versus-malignancy effect. There is evidence for a graft-versus-lymphoma effect. In nine patients with relapsed NHL after allogeneic transplantation, van Besien et al 33 demonstrated a 50% response rate following withdrawal of immunosuppressive therapy. Evidence of concomitant tumor regression with late onset of GVHD has also been demonstrated. 34 To capitalize on this phenomenon, but potentially minimize the morbidity and mortality associated with GVHD, non-myeloablative immunosuppression regimens with allogeneic PBPC transplantation have been explored in patients with relapsed lymphoma. 35 As single modality therapy, these non-myeloablative conditioning regimens appear to be tolerable and show encouraging short-term results in heavily pretreated older patients with relapsed lymphoma who are ineligible for standard allo-transplantation. Fludarabine based regimens were used to treat seven such patients with low-grade and intermediate-grade lymphomas and resulted in engraftment and response in all but one patient, with five achieving CR. 36 Non-ablative transplantation has also been used without prohibitive regimen-related toxicity in patients who have relapsed following autologous transplantation. 37 Twenty patients with HD, 15 of whom had failed autografting received conditioning with fludarabine 30 mg/m 2 5, CAMPATH-1H 20 mg/day 5 and melphalan 140 mg/m 2. All patients showed sustained donor engraftment. Toxicity was remarkably low with this particular regimen; there were no transplant-related deaths and only two patients (10%) developed grade I agvhd. Two-year actuarial OS and PFS were 92% and 55%, respectively. 38 Nagler et al 39 treated 23 lymphoma patients with a fludarabine-based regimen comprising fludarabine 180 mg/m 2, busulphan 8 mg/kg, and ATG 40 mg/kg. Five of these patients had received prior autologous transplants. Treatment-related mortality was 30% and four patients died of grade III IV agvhd. Median survival was 13 months, and OS and DFS at 37 months were both 40%. Similarly Anderlini et al 40 treated six patients with advanced HD, who had progressed following autologous PBPC transplant, with fludarabinebased non-myeloablative regimens. Transplant-related mortality was 33% (2/6) and grade II agvhd occurred in three patients. Three patients attained CR and two remain alive at 15 and 31 months, respectively. While these initial reports suggest some patients may benefit from this approach, data from the EBMT registry calls for caution. 41 In reviewing 76 patients with NHL and 39 with HD who underwent non-myeloablative allogeneic transplantation, acute GVHD II IV developed in 20% of patients and transplant-related mortality was 28% at 1 year. Causes of TRM were GVHD (55%), infection (30%) and multi-organ failure (15%). Overall progression-free survival was 44%. Granted that many patients were likely high-risk with relapsed disease, the 1-year progression-free and overall survivals for high-grade lymphoma patients were 29% and 41%, respectively. Extending this work, Carella et al 42 have pioneered planned tandem autologous HDC and non-myeloablative immunosuppression with allogeneic PBPC transplant in the treatment of patients with resistant HD and NHL. Fifteen patients, 10 with resistant HD and five with NHL received cyclophosphamide mobilized PBPC following high-dose therapy with carmustine, etoposide, cytarabine and melphalan. When clinically stable, at a median of 61 days, they were treated with fludarabine (30 mg/m 2 ) and cyclophosphamide (300 mg/m 2 ) for 3 days prior to infusion of non-tdepleted donor PBPC. Methotrexate and cyclosporine were used for GVHD prophylaxis and to prevent graft rejection. Seven patients experienced grade 2 agvhd and two had extensive cgvhd. Thirteen patients achieved 100% donor engraftment (seven subsequent to donor lymphocyte infusion). After autotransplantation, three patients were in CR and 12 in PR. Following allotransplantation, nine patients attained CR, one had continued CR and three had progressive disease. Eleven of 15 patients had CR following both procedures. Five patients have died, two with extensive cgvhd and one with grade 3 agvhd. Median survival is approximately 14 months and five patients are alive without disease.

5 Conclusions ation in its various guises discussed above is feasible and for the most part tolerable, although unexpectedly high morbidity and mortality have been noted in some studies. The central issue of tandem transplantation in lymphoma, whether this involves autologous progenitor cells or the use of allogeneic cells, revolves around whether this more aggressive strategy improves the overall survival of patients. The combination of regimens likely to prove most effective is undetermined. This question is pertinent even in single autologous transplants, where the literature is replete with phase II trials of active combination highdose therapy regimens, but with little data to recommend a best choice. Interpretation of the results of phase II tandem transplant trials, and the wider implementation of this strategy in poor-risk patients, is confounded by the inherent selection bias of patients able to undergo this therapy. Not only must patients be approved by third-party insurers and have adequate PBPC collected to support two cycles of HDC, 32 but they should ideally have non-progressive disease and minimal or absent visceral organ damage after the first treatment to allow for the safe completion of the tandem transplant. Recent improvement in supportive care, with for example keratinocyte growth factor that reduces mucositis, 43,44 may assist in alleviating acute toxicities that can delay treatment. The application of microarray technology and clinical prognostic indices to accurately identify poor-risk lymphoma patients with little likelihood of cure using a single cycle of high-dose chemotherapy remains an important goal. Such patients would be suitable candidates for inclusion in randomized trials testing the efficacy of conventional or single transplant therapy vs the tandem transplant strategy. In the absence of data from randomized trials of tandem transplant for poor-risk patients with relapsed disease, choosing which of the treatment options is most appropriate for a particular patient is challenging. Factors to be taken into account include the patient s age and prior therapy, adequacy of PBPC, tumor chemosensitivity and availability of an allogeneic donor. In the setting of a clinical trial, patients with an allogeneic donor and with PBPC sufficient for only one cycle of HDC or who respond with less than a PR to the first cycle of HDC, should be offered a subsequent planned non-myeloablative transplantation. Until mature data on non-myeloablative therapy are available it is reasonable to offer patients with chemosensitive disease and sufficient PBPC, even those with allogeneic donors, tandem autotransplantation as first choice. The CR rate for poor-risk patients undergoing tandem therapy is improved. However, many of these patients relapse, and when one considers the increased toxicity, it is not clear that the possible benefit of this strategy can balance the effect on quality of life and potential for medium- to long-term toxicity. One challenge is to prevent recurrence in patients achieving CR following tandem transplantation, and the inclusion in sequential HDC regimens of newer therapeutic modalities with non-overlapping mechanisms of action and toxicities, such as unlabelled or radio-labeled antibodies, is an exciting area of active investigation. 45 Better understanding and differentiation of the graft-versus-lymphoma from the graft-versus-host effect, may further help optimize the use of the tandem autologous and non-myeloablative transplant approach. In this context, peptide or dendritic-cell-based vaccines may be useful in educating the reconstituted immune system and enhance the anti-lymphoma effect while reducing the GVH response. A clear demonstration of clinical benefit with acceptable longterm toxicity is necessary before tandem transplantation becomes a viable therapeutic choice over the current approaches to poor-risk patients. Acknowledgements This work was supported in part by the Julie Gould Fund (KPP). References 1 Linch D, Winfield D, Goldstone A et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin s disease: results of a BNLI randomised trial. Lancet 1993; 341: Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high-dose therapy in poor-risk aggressive non-hodgkin s lymphoma: final analysis of the prospective LNH87 2 protocol a groupe d Etude des Lymphomes de l Adulte study. J Clin Oncol 2000; 18: Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin s lymphoma. New Engl J Med 1995; 333: Philip T, Gomez F, Guglielmi C et al. 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