We evaluated prognostic factors and treatment outcome of patients with relapsed/refractory Hodgkin's disease (HD) receiving autologous stem cell transplantation (ASCT). In total, 92 patients received total body irradiation, cyclophosphamide and etoposide (TBI/CY/E) (n=42) or busulfan, melphalan and thiotepa (Bu/Mel/T) (n=50) supported with ASCT. A total of 33 (66%) patients receiving the Bu/Mel/T regimen had a prior history of dose-limiting irradiation. Mucositis, hepatic and pulmonary toxicities were the main causes of morbidity and mortality, irrespective of the conditioning regimen. The transplant-related mortality was 15%. With a median follow-up of 6 years (range 2.5–11), the cumulative probabilities of survival, event-free survival (EFS) and relapse at 6 years were 55, 51 and 32%. The 6-year Kaplan–Meier (KM) probabilities of EFS for patients with less advanced disease (patients in first chemotherapy-responsive relapse or second remission (n=42)) and more advanced disease (all other patients (n=50)) were 60 and 44%. No differences in toxicities and efficacy between the conditioning regimens were found. ASCT is an effective treatment for patients with refractory/relapsed HD. Female patients and patients with less advanced disease at transplant had a better outcome. Patients with prior irradiation benefited from the Bu/Mel/T regimen.
Hodgkin's disease (HD) is a highly chemosensitive malignancy with approximately 50–60% of patients being cured with conventional chemotherapy/radiation therapy. Patients with stage III or IV disease who fail to attain a complete remission or relapse after induction chemotherapy, however, are rarely cured from standard salvage therapies.1 High-dose chemotherapy with or without radiation therapy supported with autologous stem cell transplantation (HDC/ASCT) is potentially curative for this subset of patients.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 Total body irradiation (TBI) in combination with high-dose cyclophosphamide (CY) (TBI/CY)3,4 and etoposide (TBI/CY/E),5,6, and the combination of CY, carmustine and etoposide (CVB),5,6,9,10,12,13,14,15,16 carmustine, etoposide, cytosine arabinoside with either melphalan (BEAM)18,19 or cyclophosphamide (BEAC)20 constitute the most common high-dose regimens evaluated. The superiority of a specific regimen, however, has not been demonstrated.3,5,6
In 1993, the Fred Hutchinson Cancer Research Center (FHCRC) reported the outcomes of 127 patients with relapsed/refractory HD treated with chemotherapy-only (n=66) or TBI-based (n=61) regimens followed by autologous (n=68), allogeneic (n=53) and syngeneic (n=6) bone marrow (BM) transplantation.3 The high-dose regimens evaluated were TBI/CY (n=47), CVB (n=47), Cy and busulfan (Bu) (n=18) and others (n=15). The actuarial 5-year event-free survival (EFS) was 18% for the entire group and 22 and 14% for allogeneic and autologous recipients, respectively. No differences in EFS between the TBI-based and non-TBI-based regimens were demonstrated. In later reports, 27 patients with HD who received TBI/CY/E (n=10)22 or high-dose busulfan, melphalan and thiotepa (Bu/Mel/T) (n=17) followed by ASCT23 were found to have an actuarial 2-year EFS of 45 and 46%, respectively.
Since randomized trials comparing the efficacy and toxicity of TBI-based and non-TBI-based regimens for patients with refractory/relapsed HD have not been reported and are unlikely to be carried out, this study compares outcomes and toxicities of patients who received the TBI/CY/E and Bu/Mel/T regimens followed by ASCT.
Patients and methods
From 9/90 to 7/98, 92 patients with histologically confirmed HD were included in Phase II trials evaluating the TBI/CY/E and Bu/Mel/T regimens. The institutional review board of the FHCRC or Puget Sound Oncology Consortium (PSOC) approved the protocols and all patients gave written informed consent. Eligibility criteria, pretreatment evaluation and PSOC participants have been described elsewhere.22,23,24,25 Briefly, the main criteria to assign patients to the TBI/CY/E or Bu/Mel/T regimen was a prior history of dose-limiting radiation therapy (DLRT), defined as prior irradiation greater than 20 Gy to the liver or mediastinum or 30 Gy to the central nervous system (CNS). Initially, patients without DLRT were treated with the TBI/CY/E regimen, while patients who received DLRT were offered the CBV regimen, which has been previously reported.16 In 1993, patients with prior DLRT were offered the Bu/Mel/T regimen. By 1995, as experience was gained with this regimen, Bu/Mel/T was offered to both patients with and without DLRT. After 1995, physician preference determined which conditioning regimen was administered to patients without prior DLRT. Patients enrolled in PSOC centers after 1995 were usually given Bu/Mel/T because of greater difficulty delivering TBI in smaller centers.
HD was classified according to the Ann Arbor staging system26 and the Rye histopathologic classification.27 Patients aged 12–65 years (up to 70 years. for Bu/Mel/T) were eligible for both preparative regimens if they had failed primary treatment or were in first sensitive/untreated relapse or beyond second remission or relapse. Patients had to have a bilirubin <2 mg/dl, creatinine <2.0, pulmonary function as measured by a diffusion lung capacity for carbon monoxide (DLCO) >60%, adequate cardiac function as measured by ejection fraction (EF) >40% and a Karnofsky score of >70. Based on the clinical history prior to peripheral blood stem cell (PBSC) mobilization and HDC/ASCT, patients in second remission or with untreated or chemotherapy-sensitive first relapse were classified as having less advanced disease while all other patients were considered to have more advanced disease.22,23,24,25
TBI/CY/E and Bu/Mel/T regimens
A total of 42 patients received TBI/CY/E and 50 patients received the Bu/Mel/T regimen. A total of 39 patients (TBI/Cy/E, n=25; Bu/Mel/T, n=14) were treated prior to 1995 and 53 after 1995 (TBI/CY/E, n=17; Bu/Mel/T, n=36). The TBI/CY/E regimen included more patients who had stage III/IV disease and BM as a source of hematopoietic stem cells compared to those treated with the Bu/Mel/T regimen (88 vs 56%, P<0.005 and 26 vs 2%, P<0.01, respectively). However, a higher proportion of patients who were classified as having more advanced disease status received the Bu/Mel/T regimen (66 vs 40%, P<0.01). Of the patients who received the Bu/Mel/T regimen 64% had a prior history of dose-limiting irradiation (Table 1).
Patients received 12 Gy TBI, delivered in 1.5 Gy fractions twice a day for 4 days, with fractions separated by at least 6 h from a dual cobalt-60 source, at a dose rate of 6–7 cGy/min (n=32) or via linear accelerator at 8 cGy/min (n=10). Intravenous infusion of E (60 or 30 mg/kg for patients aged >55 years) over 4 h was administered on day −4, followed by a day of rest. CY (100 or 60 mg/kg for patients aged >55 years) was infused over 1–2 h on day −2, followed by a day of rest. Stem cells were infused on day 0.22,24,25
All patients received phenytoin, 24 h before the first dose of busulfan, continuing until 24 h after the final dose of busulfan. Patients received busulfan 1 mg/kg/dose p.o. every 6 h on days −8, −7 and −6 for a total dose of 12 mg/kg. Melphalan (50 mg/m2 i.v. per day) was given on days −5 and −4 for a total dose of 100 mg/m2. Thiotepa (250 mg/m2 i.v. per day) was administered on days −3 and −2 for a total dose of 500 mg/m2. Stem cells were infused 48 h after the last dose of thiotepa.23,25
Patients were given supportive care in accordance with the following guidelines, although there were minor inter-institutional differences. Prophylactic systemic antibiotics were administered when the absolute neutrophil count (ANC) was <0.5 × 109/l and were discontinued after neutrophil engraftment when counts recovered to ANC >0.5 × 109/l. Patients who were serologically positive for herpes simplex virus were treated with prophylactic acyclovir. Platelet transfusions were administered when the platelet level was <20 × 109/l.
BM and PBSC collection, cryopreservation and infusion
The techniques for marrow aspiration and PBSC harvest following the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) alone or with chemotherapy, cryopreservation, thawing and infusion have been described elsewhere.28,29,30 A total of 12 patients received marrow as a source of hematopoietic stem cells.31,32 PBSCs were mobilized mainly with chemotherapy and rhG-CSF and were not purged.29,33 The combination of CY/E was the most common regimen used for PBSC mobilization (n=40). Other chemotherapy regimens were dexamethasone, cytarabine and cisplatin (DHAP) (n=4), CY alone (n=2), CY Taxol (n=1), cyclophosphamide, etoposide and cisplatin (CEP) (n=3), ifosfamide+etoposide+vinblastine (n=2) and dexamethasone (n=1).
rhG-CSF, recombinant human granulocyte–macrophage colony-stimulating factor (rhGM-CSF), recombinant human interleukin 3 (rhIL-3) or granulocyte-macrophage colony-stimulating factor-interleukin-3 fusion protein (PIXY321) were administered from day 1 after transplant until engraftment to 42 (45%) patients, as per supportive care protocols in effect at the time of transplant. Ten patients who were engrafted, without a major organ toxicity or infection, with a CR, PR or stable disease and not receiving corticosteroids, were treated with interleukin-2 (IL-2) with or without lymphokine-activated killer cells within 24–58 days post transplant as per a protocol designed to explore the toxicity of post transplant immunotherapy.34 A total of 12 patients (13%) received local radiation therapy post transplant to sites of persistent disease. Restaging to assess all sites of prior disease was performed at 60 days post transplant, 1 year and thereafter according to clinical indications.
Regimen-related toxicity (RRT) was assessed according to the Bearman score.35 Idiopathic pneumonia syndrome (IPS) was defined as pulmonary infiltrates without infectious etiology.36 The diagnosis of veno-occlusive disease (VOD) was made on the basis of hepatomegaly and/or liver tenderness, weight gain >2% of baseline and an elevated serum bilirubin >2 mg/dl and/or histologically with damage to the endothelial cells at the termini of hepatic venules, dilatation of the sinusoids and necrosis of hepatocytes.37
Outcomes examined included survival and EFS and were calculated from day 0 of transplantation. Comparison of proportions was made with the Fisher's test. Probabilities of survival were estimated from day 0 to the day of last contact and from day 0 to the date of death or relapse censored by the date of last contact according to the method of cumulative incidence estimates.38 The log-rank test was used to compare survival curves. Univariate, multivariate and stepwise Cox regression analyses were performed to identify prognostic factors associated with EFS. Age, gender, histology, stage of disease, BM involvement, disease status before transplantation, the number of conventional regimens, prior DLRT, transplant preparative regimen and graft source were evaluated.
Of 92 patients who received HDC/ASCI, Seven (8%) patients died without neutrophil or platelet engraftment before day 30 and were excluded from the engraftment analysis. Neutrophil and platelet recovery occurred at a median of 11 days each for patients who received TBI/CY/E and 11 and 12 days after the Bu/Mel/T regimen, respectively.
The main grade 3 toxicities were mucositis, hepatic, pulmonary and renal. Oral grade 3 mucositis occurred in 4% of patients receiving Bu/Mel/T and in 2% after TBI/CY/E. Hepatic grade 3 toxicity was observed in 2% of patients irrespective of the regimen. Renal and pulmonary toxicities occurred in 2% of patients of each regimen. Of 42 patients who received TBI/CY/E, three (7%) died secondary to RRT. The causes of death were IPS (n=2) and VOD (n=1). RRT deaths occurred in six (12%) of 50 patients who received Bu/Mel/T. These deaths were attributed to IPS (n=2), bowel perforation (n=2) and VOD (n=2). Four of these six patients who died secondary to pulmonary and gastrointestinal toxicities after Bu/Mel/T therapy had a prior history of dose-limiting radiation therapy. There were no statistically significant differences in the rate of RRT deaths between the two regimens (7 vs 12%, P=0.3).
Deaths from other causes
Hemorrhage (n=2) and CMV infection (n=1) were the cause of death in three patients conditioned with the TBI-based regimen. Bacterial infections (n=2) were fatal in two patients who received Bu/Mel/T. One patient who received TBI/CY/E died 7 years after transplant from secondary myelodysplasia. Overall, transplant-related mortality (TRM) occurred in seven (17%) patients receiving TBI/CY/E and in eight (16%) patients after Bu/Mel/T therapy. Two (11%) of 18 patients without DLRT and six (19%) of 32 patients who had dose-limiting radiation therapy died from transplant complications (P=0.3). No statistically significant differences were observed in TRM rates between TBI/CY/E and Bu/Mel/T (17 vs 16%, P=0.9), irrespective of the disease status before transplantation and the history of prior radiation therapy.
Outcome according to regimen
TBI/CY/E. With a median follow-up of 5 years (range 4–10) after transplantation, 22 (52%) patients are alive while 19 (45%) remain in continued remission. A total of 16 (38%) have relapsed and 13 (31%) died from disease progression.
With a median follow-up of 3.5 years (range 2.5–7) since transplantation, 26 (52%) patients are alive, with 23 (46%) remaining in continued remission. A total of 17 (34%) have relapsed and 14 (28%) died from disease progression. One patient died of unknown cause.
Influence of prior dose-limiting radiation therapy
Among 50 patients receiving Bu/Mel/T, there were 18 patients without prior DLRT and 11 of 18 (61%) remain in continued remission compared to 12 (38%) of 32 patients who had prior DLRT (P=0.1). Overall, RRT deaths and overall TRM within the first 180 days of transplant were 11 and 11% for patients without DLRT and 13 and 19% for those who had prior DLRT, respectively. The probabilities of EFS at 5-years for patients without DLRT (n=18) were 55 and 36% for those who had prior DLRT (n=32) (P=0.07) after Bu/Mel/T therapy. There were no statistically significant differences in outcomes and toxicities between patients without DLRT and those who had prior DLRT.
The 5-year cumulative estimates of survival, EFS and relapse for TBI/CY/E were 57, 49 and 36% and 52, 42 and 34% for Bu/Mel/T (Figure 1); none of these results between the two regimens were significant. The 5-year probabilities of EFS for patients with less advanced disease or more advanced disease status before transplantation were: TBI/CY/E, 59 and 35% (P=0.06) (Figure 2); Bu/Mel/T, 59 and 33% (0.03) (Figure 3).
The multivariate analysis found that two factors, gender and disease status at the time of transplant, significantly affected EFS. Male patients had a 2.5. times greater risk of relapse or death (95% confidence interval 1.34–4.83) compared to female patients, P=0.004. Patients with more advanced disease (primary refractory disease, refractory relapse or >2nd remission) at transplant were 2.0 times more likely to die or relapse (95% confidence interval 1.13–3.71) than patients with less advanced disease, P=0.016. There was no statistically significant influence of age, stage of disease at transplant, marrow involvement, high-dose therapy regimen, histology, time from diagnosis to transplant or number of lines conventional chemotherapy regimens used prior to transplant.
This retrospective comparison revealed no differences between TBI/CY/E and Bu/Mel/T. It would require a large, prospective randomized trial, however, to prove equivalency with sufficient statistical power. Since it is unlikely that such a study will be performed, this type of retrospective study is necessary. Other studies comparing TBI/CY/E with chemotherapy-only regimens have similarly shown no differences.5,6 TRM in our study was 16%, which is similar to the City of Hope series but higher than the 5% TRM reported by Stanford University. Another Stanford University study, however, reported a 15% treatment-related mortality.39 In the three studies, VOD was the principal cause of toxic death after TBI/CY/E therapy, but pulmonary toxicity also accounted for increased RRT in the City of Hope and FHCRC series. Infection and hemorrhage were additional contributing factors for TRM in the present study. While the Stanford study included 82% of patients who were in a minimal disease state, this subset of patients accounted for only 54 and 58% of the patients included in the City of Hope and the FHCRC series, respectively.
From several studies of patients with refractory/relapsed HD, using a variety of doses and schedules of the CBV regimen, the EFS has ranged between 25 and 48% at 3 years of follow-up.6,12,13,14,17 Similar outcomes have also been reported after therapy with the high-dose BEAM18,19,40 and BEAC20,40 regimens. Recently, the Spanish GEL-TAMO Cooperative Group reported outcomes of 494 patients.41 In that series, 443 (90%) of the patients received chemotherapy-only regimens: CBV (53%), BEAM (18%), BEAC (14%) and others (5%). The actuarial rate of relapse for the entire group was 45%. The Bu/Mel/T regimen evaluated in our study demonstrated a comparable efficacy to the TBI-based and non-TBI-based regimens previously reported.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,40,41 In the current series, patients with more advanced disease or had received prior DLRT, who had an outcome expected to be poor, had an EFS of 33 and 36% at 5 years, respectively, after the Bu/Mel/T regimen. It was not possible to directly compare the outcome of these patients to the TBI-based regimen since prior DLRT is generally an exclusion for TBI. A history of prior irradiation to the chest and more advanced disease status are factors significantly associated with increased toxicity in our series3,16 and also in a report by Wheeler et al.42 In our study 32 (64%) of the 50 patients who received the Bu/Mel/T regimen had a prior DLRT. Of these 32 patients, 23 (72%) had more advanced disease. Six of eight toxic deaths secondary to the Bu/Mel/T regimen occurred in this subset of patients compared with two in the less advanced group. Although longer follow-up is required, the Bu/Mel/T regimen could be a therapeutic alternative for this subset of poor prognosis patients.
Several adverse prognostic factors have been identified for patients with refractory/relapsed HD after HDC therapy.5,6,8,10,12,13,14,17,18,20,21,38,43,44,45,46,47,48,49 In a study of 65 patients with relapsed or refractory HD, Moskowitz found that B symptoms, extranodal disease and less than 1 year remission duration were all adverse prognostic indicators.50 A French registry study of 280 patients with HD found chemosensitive disease and first relapse to be good prognostic indicators for survival.45 The Spanish GEL-TAMO study reported that active disease at the time of transplant and two or more conventional chemotherapy regimens were adverse prognostic factors for outcome. In our study, male patients and patients with more advanced disease at transplant had a poorer outcome when compared to female patients or patients with less advanced disease. We did not find the number of chemotherapy regimens to be significant but this is probably because 78% of our patients had received more than a single chemotherapy regimen. A seven-factor international prognostic score (IPS) has been shown to be useful for predicting freedom from progression in newly diagnosed patients with HD.49 Its value in predicting outcome after HDC for relapsed/refractory disease is, however, unknown.
Since the outcome after Bu/Mel/T appears similar to other HDC regimens, strategies for diminishing the main toxicities of this tri-alkylator regimen are being evaluated. These include the use of epithelial growth factors which may reduce mucositis, one of the main toxicities of this regimen.
De Vita Jr VT, Hubbard SM . Hodgkin's disease. N Engl J Med 1993; 328: 560–565.
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 randomised trial. Lancet 1993; 341: 1051–1054.
Anderson JE, Litzow MR, Appelbaum FR et al. Allogeneic, syngeneic and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience. J Clin Oncol 1993; 11: 2342–2350.
Philip GL, Wolff SN, Herzig RH et al. Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 1989; 73: 2086–2092.
Nademanee A, O'Donnel MR, Snyder DS et al. High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodkin's disease: results in 85 patients with analysis of prognostic factors. Blood 1995; 85: 1381–1390.
Horning SJ, Chao NJ, Negrin RS et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood 1997; 89: 801–813.
Gianni AM, Siena S, Bregni M et al. High-dose sequential chemo-radiotherapy with peripheral blood progenitor cell support for relapsed or refractory Hodgkin's disease. A 6-year update. Ann Oncol 1993; 4: 889–891.
Yahalom J, Gulati SC, Toia M et al. Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease. J Clin Oncol 1993; 6: 1062–1070.
Carella AM, Congiu AM, Gaozza E et al. High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian Study Group report. J Clin Oncol 1988; 6: 1411–1416.
Reece DE, Barnett MJ, Connors ME et al. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol 1991; 9: 1871–1879.
Lazarus HM, Crilley P, Ciobanu N et al. High-dose carmustine, etoposide, and cisplatin and autologous bone marrow transplantation for relapsed and refractory lymphoma. J Clin Oncol 1992; 10: 1682–1689.
Bierman PJ, Bagin RG, Jagannath S et al. High-dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease; long-term follow-up in 128 patients. Ann Oncol 1993; 4: 767–773.
Burns LJ, Daniels KA, McGlave PB et al. Autologous stem cell transplantation for refractory and relapsed Hodgkin's disease; factors predictive of prolonged survival. Bone Marrow Transplant 1995; 16: 13–18.
Wheeler C, Eickhoff C, Elias A et al. High-dose cyclophosphamide, carmustine and etoposide with autologous transplantation in Hodgkin's disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant 1997; 3: 98–106.
Spinolo JA, Jagannath S, Velazquez et al. Cisplatin-CBV with autologous bone marrow transplantation for relapsed Hodgkin's disease. Leukemia Lymphoma 1993; 9: 71–77.
Weaver CH, Appelbaum FR, Petersen FB et al. High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-limiting radiation therapy. J Clin Oncol 1993; 11: 1329–1335.
Reece DE, Connors ME, 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.
Chopra R, Mc Millan AK, Linch DC et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor risk Hodgkin's disease. A single-center eight-year study of 155 patients. Blood 1993; 81: 1137–1145.
Lumley MA, Milligan DW, Knechtli CJC et al. High lactate dehydrogenase level is associated with an adverse outlook in autografting for Hodgkin's disease. Bone Marrow Transplant 1996; 17: 383–388.
Rapaport AP, Rowe JM, Kouides PA et al. One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome. J Clin Oncol 1993; 11: 2351–2361.
Crump M, Smith AM, Brandwein J et al. High-dose etoposide and melphalan and autologous bone marrow transplantation for patients with advanced Hodgkin's disease: importance of disease status at transplant. J Clin Oncol 1993; 11: 704–711.
Weaver CH, Petersen FB, Appelbaum FR et al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma. J Clin Oncol 1994; 12: 2559–2566.
Schiffman K, Buckner CD, Maziarz R et al. High-dose busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell transplantation in patients with aggressive lymphoma or relapsed Hodgkin's disease. Biol Blood Marrow Transplant 1997; 3: 261–266.
Brunvand MW, Bensinger WI, Soll E et al. High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: comparison of autologous bone marrow and peripheral blood stem cells. Bone Marrow Transplant 1996; 18: 131–141.
Gutierrez-Delgado F, Maloney D, Press OW et al. Autologous stem cell transplantation for non-Hodgkin lymphoma: comparison of radiation-based and chemotherapy-only preparative regimens. Bone Marrow Transplant 2001; 28: 455–461.
Carbone PP, Kaplan HS, Musshoff K et al. Report of the Committee on Hodgkin's disease Staging. Cancer Res 1971; 31: 1860–1861.
Lukes RJ, Butler JJ . The pathology and nomenclature of Hodgkin's disease. Cancer Res 1966; 26: 1063–1081.
Thomas ED, Storb R . Technique for human marrow grafting. Blood 1970; 36: 507–515.
Bensinger W, Singer J, Appelbaum F et al. Autologous transplantation with peripheral blood mononuclear cells collected after administration of recombinant granulocyte colony stimulating factor. Blood 1993; 81: 3158–3163.
Rowley SD, Bensinger W, Gooley T et al. The effect of cell concentration on bone marrow and peripheral blood stem cell cryopreservation. Blood 1994; 83: 2731–2736.
Bast R, Ritz J, Lipton J et al. Elimination of leukemic cells from human bone marrow using monoclonal antibody and complement. Cancer Res 1983; 43: 1389–1394.
Hill R, Mazza P, Amos D et al. Engraftment in 86 patients with lymphoid malignancy after autologous marrow transplantation. Bone Marrow Transplant 1989; 4: 69–74.
Bensinger W, Appelbaum F, Rowley S et al. Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J Clin Oncol 1995; 13: 2547–2555.
Fefer A, Benyunes M, Higuchi C et al. Interleukin-2±lymphocytes as consolidative immunotherapy after autologous bone marrow transplantation for hematologic malignancies. Acta Haematol 1993; 89: 2–7.
Bearman S, Appelbaum F, Buckner C et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.
Crawford SW . Critical care and respiratory failure. In: Thomas ED, Forman SJ, Blume KG (eds). Stem Cell Transplantation. Blackwell Scientific: Boston, MA, 1999, pp 712–722.
Strasser SI, McDonald GB . Gastrointestinal and hepatic complications. In: Thomas ED, Forman SJ, Blume KG (eds). Stem Cell Transplantation. Blackwell Scientific: Boston, MA, 1999, pp 627–658.
Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 30: 695–706.
Poen JC, Hoppe RT, Horning SJ . High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin's disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 1996; 36: 3–12.
Martin A, Fernandez-Jimenez MC, Caballero M et al. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease. Br J Haematol 2001; 113: 161–171.
Sureda A, Arranz A, Iriondo A et al. Autologous stem cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol 2001; 19: 1395–1404.
Wheeler C, Antin JH, Churchill WH et al. Cyclophosphamide, carmustine and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose-finding study. J Clin Oncol 1990; 8: 648–656.
Andre M, Henry-Amar M, Blaise D et al. Comparison of high-dose chemotherapy and autologous stem cell transplantation with conventional therapy for Hodgkin's disease induction failure: a case control study. Societe Francaise de Greffe de Moelle. J Clin Oncol 1999; 17: 222–229.
Jagannath S, Armitage JO, Dicke KA et al. Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, and etoposide. J Clin Oncol 1989; 7: 179–185.
Brice P, Bouabdallah R, Moreau P et al. Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin's disease: analysis of 280 patients from the French registry. Societe Francaise de Gfreffe de Moelle. Bone Marrow Transplant 1997; 20: 21–26.
Yuen A, Rosenberg S, Hope R et al. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood 1997; 89: 814–822.
Arranz R, Tomas JF, Gil-Fernandez JJ et al. Autologous stem cell transplantation for poor prognostic Hodgkin's disease: comparative results with two CBV regimens and importance of disease status at transplant. Bone Marrow Transplant 1998; 21: 779–786.
Moreau P, Fleury J, Brice P et al. Early intensive therapy with autologous stem cell transplantation in advanced Hodgkin's disease: retrospective analysis of 158 cases from the French registry. Bone Marrow Transplant 1998; 21: 787–793.
Hasenclever D, Diehl V . A prognostic score for advanced Hodgkin's disease. N Engl J Med 1998; 339: 1506–1514.
Moskowitz CH, Nimer SD, Zelenetz ED et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 2001; 97: 616–623.
Supported by grants from the National Institutes of Health CA 18029, CA 47748, CA 15704 and the Jose Carreras Foundation against Leukemia. FG-D was supported by a grant from Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
About this article
Cite this article
Gutierrez-Delgado, F., Holmberg, L., Hooper, H. et al. Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen. Bone Marrow Transplant 32, 279–285 (2003). https://doi.org/10.1038/sj.bmt.1704110
- Hodgkin's disease
- stemcell transplant
- total body irradiation
- high dose chemotherapy
The effectiveness of busulfan‐based conditioning regimens for stem cell transplantation against lymphomas in children, adolescents, and young adults in Japan
Pediatric Blood & Cancer (2019)
Autologous hematopoietic cell transplantation using dose-reduced intravenous busulfan, melphalan, and thiotepa for high-risk or relapsed lymphomas
Bone Marrow Transplantation (2019)
Experimental Hematology & Oncology (2018)
Long-term outcomes after thiotepa-based high-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) in non-Hodgkin lymphoma (NHL)
Bone Marrow Transplantation (2017)
Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: a review
Bone Marrow Transplantation (2017)