Long-term Outcome of Hodgkin Disease Patients Following High ...

Biology of Blood and Marrow Transplantation 12:1343-1349 (2006) 䊚 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1212-0001$32.00/0 doi:10.1016/j.bbmt.2006.08.039

Long-term Outcome of Hodgkin Disease Patients Following High-Dose Busulfan, Etoposide, Cyclophosphamide, and Autologous Stem Cell Transplantation Navin Wadehra,1 Sherif Farag,2 Brian Bolwell,3 Patrick Elder,1 Sam Penza,1 Matt Kalaycio,3 Belinda Avalos,1 Brad Pohlman,3 Guido Marcucci,1 Ronald Sobecks,3 Thomas Lin,1 Steven Andrèsen,3 Edward Copelan1 1

Division of Hematology and Oncology, The Ohio State University Hospitals, Columbus, Ohio; 2Department of Medicine, Division of Hematology and Oncology, Indiana University, Indianapolis, Indiana; 3Hematologic Oncology and Blood Disorders, The Cleveland Clinic, Cleveland, Ohio Correspondence and reprint requests: Sherif Farag, MD, PhD, Department of Medicine, Division of Hematology and Oncology, Indiana University, 635 Barnhill Drive, Indianapolis, IN 46202 (e-mail: [email protected]). Received April 17, 2006; accepted August 25, 2006

ABSTRACT Busulfan (Bu)-based preparative regimens have not been extensively investigated in Hodgkin disease (HD). The purposes of this study were to investigate the toxicity and efficacy of a novel preparative regimen of Bu 14 mg/kg, etoposide 50-60 mg/kg, and cyclophosphamide 120 mg/kg in patients with primary refractory and relapsed HD. One hundred twenty-seven patients with a median age of 33 years (range, 14-67 years) underwent transplantation. The regimen was well tolerated, with 5.5% treatment-related mortality at 100 days after transplantation. With a median follow up of 6.7 years, the 5-year progression-free survival was 48 ⴞ 5%, and the 5-year overall survival was 51 ⴞ 5%. A Cox proportional hazards model identified refractory disease at time of transplantation as the only significant factor affecting relapse and overall survival, whereas disease bulk >10 cm affected overall survival. Five patients died between 5.3 and 9.3 years of late complications, including secondary myelodysplasia or acute myeloid leukemia, secondary solid malignancies, and pulmonary toxicity. This novel Bu regimen is comparable to other radiation-free preparative regimens in its effectiveness in the control of HD and with a low-risk of early treatment-related mortality. © 2006 American Society for Blood and Marrow Transplantation

KEY WORDS Hodgkin’s disease

●

Busulfan

●

Autotransplant

INTRODUCTION Hodgkin disease (HD) is a chemosensitive disease, with 50%-60% of patients cured with conventional chemotherapy and radiation [1,2]. However, only a small proportion of patients who do not achieve complete remission or relapse after induction chemotherapy is cured with standard salvage chemotherapy [3]. For these patients, high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can improve outcome [4-9]. Although several preparative regimens with or without total body irradiation (TBI) have been investigated in HD, no superiority of a single regimen has been established [10,11]. In partic-

ular, only 1 study investigated the efficacy of highdose busulfan (Bu)-based regimens specifically in patients with HD [12]. Bu-based preparative regimens have been extensively examined and shown to be effective in ASCT and allogeneic transplantation for a wide variety of other hematologic disorders including acute and chronic leukemias and non-Hodgkin lymphoma (NHL) [13-22]. We previously reported our experience with Bubased preparative regimens in myeloid disorders and NHL [14,16,20]. The initial study with Bu 16 mg/kg and cyclophosphamide (Cy) 120 mg/kg (BuCy2) was originally evaluated but was associated with a high incidence of severe hepatic veno-occlusive disease and 1343

1344

treatment-related mortality (TRM) [14]. The BuCy2 regimen was subsequently revised in NHL to lower the dose of Bu from 16 to 14 mg/kg to decrease severe veno-occlusive disease and TRM. In addition, etoposide was added to improve effectiveness without increasing toxicity substantially. Using this regimen in NHL, 382 patients were treated with Bu, Cy, and etoposide at doses comparable to those used in our HD patient population. It was found to be effective, with a 46.9% progression-free survival (PFS) and a 2.6% TRM [20]. The Fred Hutchinson Group examined a regimen of Bu 12 mg/kg, melphalan 100 mg/ m2, and thiotepa 500 mg/m2 in 92 patients with HD. The TRM was 15% and 6-year overall survival (OS) was 55% [12]. The purpose of the present study was to investigate the long-term clinical results of the largest series of patients with primary refractory and relapsed HD treated with a radiation-free Bu regimen.

METHODS Between February 1990 and December 1998, 127 consecutive eligible patients with HD underwent high-dose therapy with Bu, Cy, and etoposide (BuCyVP) followed by ASCT at The Ohio State Medical Center and the Cleveland Clinic Foundation. The protocol was approved by the institutional review boards at both institutions and patients provided written informed consent. The techniques for marrow aspiration and peripheral blood stem cell harvest after the administration of human granulocyte colony-stimulating factor with chemotherapy, cryopreservation, thawing, and infusion have been described previously [23-25]. HD was classified according to the Rye histopathologic classification [26]. All patients were required to have adequate cardiac, renal, and hepatic functions. Preparative Regimen

The regimen was administered as previously described [20]. Briefly, Bu was administered at a dose of 1 mg/kg orally every 6 hours for 14 doses beginning 8 days before stem cell infusion. Etoposide 50-60 mg/kg was initiated 2 hours after the last dose of Bu as a 36-hour continuous intravenous infusion. Then Cy 60 mg/kg was administered intravenously on 2 consecutive days. Bone marrow and peripheral blood stem cells were infused 2 days after the completion of Cy. Phenytoin was given prophylactically for the prevention of seizures before and during Bu administration. Bu levels were not measured. Granulocyte colonystimulating factor 5 ␮g/kg was administered daily after transplantation until the neutrophil count reached 0.5 ⫻ 109/L. Prophylactic systemic antibiotics were administered when the absolute neutrophil count was

N. Wadehra et al.

⬍0.5 ⫻ 109/L and were discontinued after neutrophil engraftment when counts recovered to an absolute neutrophil count ⬎0.5 ⫻ 109/L. Statistical Analysis

A partial remission required at least a 50% decrease in the tumor size measured by the sum of the products of the perpendicular diameter of all areas of known disease. No response was defined as less than a 50% decrease in tumor size. A complete remission was defined as no evidence of residual lymph node enlargement by computed tomographic scan. Progressive disease was defined as an increase in size of any area of known disease or the appearance of new disease. Relapse was defined as a recurrence ⬎6 months after the completion of initial chemotherapy. A sensitive relapse was defined as at least a partial response to salvage therapy immediately before transplantation. Patients were considered to have refractory disease if they progressed through their initial chemotherapy regimen or if their disease showed less than a partial response to salvage chemotherapy before transplantation. Overall survival (OS) was measured from the time of transplantation until death regardless of cause, with censoring for patients alive. The cumulative incidence of relapse or progression was calculated from the time of transplantation until relapse or death, except that death in remission was regarded as a competing risk. Univariate analyses of survival and event-free survival used the Kaplan-Meier product limit method with log-rank tests of survival curves [27]. To study the independent effect of the preparative regimen and control for other baseline clinical factors such as number of previous treatments, age, presence of bulky disease (⬎10 cm) at the time of diagnosis, B symptoms at the time of diagnosis, and lactate dehydrogenase at the time of transplantation, and bone marrow involvement at the time of transplant, a Cox proportional hazards model was constructed for OS [28]. For all analysis, a 2-sided P value ⬍.05 was considered statistically significant.

RESULTS Patient Characteristics

The baseline patient characteristics are presented in Table 1. There were 91 men and 36 women in this study. The median age was 33 years (range, 14-67 years). Seventy one percent of patients had responsive disease, and 13% had bulky disease (⬎10 cm). Ninety patients were in complete or partial remission and 37 were refractory to their last therapy at the time of transplantation. Most patients (76%) had ⬍3 prior chemotherapy regimens.

1345

Long-term Outcome of Busulfan-based Treatment for HD

1.0

Table 1. Patient Characteristics Characteristics

Patients 33 14-67 91/36 90 (71%) 37 (29%)

Overall survival

.8

Age (years) Median Range Male/Female Remission status at diagnosis Responsive (CR/PR) Refractory Number of prior regimens 1-2 Regimens >3 Regimens Stem cell source Bone marrow PBSC Largest disease bulk 10 cm LDH at time of transplant Normal Elevated Prior radiation therapy None Prior RT

.6

.4

.2

96 (76%) 31 (24%)

0.0

41 (32%) 86 (68%) 111 (87%) 16 (13%) 48 (38%) 79 (62%) 60 (47%) 67 (53%)

LDH, Lactate dehydrogenase; PBSC, peripheral blood stem cells.

Overall Survival/Progression-free Survival

0

2

4

6

8

10

12

Years post-transplantation

Figure 2. OS of all patients (n ⫽ 127) with HD who received Bu/Cy/VP16 preparative regimens.

whereas disease bulk ⬎10 cm (hazard ratio, 2.9; 95% confidence interval, 2.2%-3.5%; P ⫽ .002) and refractory disease (hazard ratio, 1.9; 95% confidence interval, 1.4%-2.4%; P ⫽ .014) at time of transplantation were significant factors affecting OS (Figure 3). There A 1.0

With a median follow-up of 6.7 years (range, 3.510.2 years), the 5-year PFS was 48% (95% confidence interval, 38%-58%; Figure 1) and the 5-year OS was 51% (95% confidence interval, 42%-60%; Figure 2). The median OS was 5.7 years and the median PFS was 3.9 years. Of 20 patients alive and in remission beyond 5 years, only 2 patients died of late relapse at 5.1 and 6.8 years.

P=0.01

Overall survival

.8

.6 Remission (CR/PR)

.4

Refractory .2

Prognostic Factors

A Cox proportional hazards model identified refractory disease at time of transplantation (hazard ratio, 2.0; 95% confidence interval, 1.5%-2.6%; P ⫽ .007) as the only significant factor affecting relapse,

0.0 0

2

4

6

8

10

12


B 1.0 P=0.014

1.0

Overall survival

.8

Progression-free survival

.8

.6

.6 Bulk10 cm

0.0 0

2

4

6

8

10

12


0.0 0

2

4

6

8

10

12


Figure 1. PFS of all patients (n ⫽ 127) with HD who received Bu/Cy/VP16 preparative regimen.

Figure 3. Cox multivariate regression analyses showing (A) a significant difference in remission status on OS and (B) a statistically significant difference in the presence of bulky disease on OS. CR indicates complete remission; PR, partial remission.

1346

N. Wadehra et al.

Factor

P Value Relapse Rate

P Value OS

Bulky disease Refractory disease Age LDH > normal Sex Number of prior regimens Stem cell source

NS P ⴝ 0.007 NS NS NS NS NS

P ⴝ 0.002 P ⴝ 0.014 NS NS NS NS NS

NS, nonsignificant.

was no statistically significant influence of age, bone marrow involvement, lactate dehydrogenase, or number of chemotherapy regimens used before transplantation (Table 2). Regimen-related Toxicity

The regimen was well tolerated, with 5.5% TRM at 100 days after transplantation. Three patients died within the first 30 days. There were a total of 7 patients who had a TRM by day 100. Hepatic toxicity was the most common life-threatening toxicity and was the cause of death in 4 patients. All 3 patients who died from interstitial pneumonitis had received radiation during their treatment. The long-term toxicity of this regimen was analyzed. Three patients developed myelodysplasia (MDS) or acute myeloid leukemia (AML) at 1.9, 4.1, and 5.7 years after transplantation. All 3 patients eventually died of AML. One patient developed transitional cell bladder carcinoma 4 months after transplantation. Overall the 8-year actuarial risk of secondary malignancy was 9% (Figure 4). One patient died of long-term pulmonary complications from the transplantation. DISCUSSION Several preparative regimens in HD with or without TBI have been investigated, with no clear superiority in part because many of the studies have been small [10,11,29]. A higher incidence of secondary malignancies has been observed after TBI-containing regimens (up to 20%) compared with high-dose chemotherapy regimens [30,31]. As a consequence, several radiation-free conditioning regimens have been investigated, including, high-dose Cy, carmustine, etoposide (CBV); carmustine, etoposide, cytarabine and melphalan (BEAM); and BCNU, etoposide, cytarabine and Cy (BEAC) [31-35]. Although Bu preparative regimens are commonly used, there are few published data evaluating the efficacy and tolerability of Bu-based regimens. We analyzed our experience with the novel regimen of Bu 14 mg/kg, Cy 120 mg/kg, and etoposide 50-60 mg/kg in patients with HD. This regimen

yielded favorable results in patients with NHL [20]. The present patient population was heavily pretreated, with most having received radiation and 24% receiving ⬎3 prior chemotherapy regimens. Despite this, there was a low rate of relapse and 5-year PFS and OS were a 48 ⫾ 5% and 51 ⫾ 5%, respectively. Similar results have been reported after therapy with other non-Bu, radiation-free regimens, although only a small number of patients with HD was treated [31,34,35]. In addition, our results compare favorably to other Bu preparative regimen studies that had a subset of patients with HD [12,21,36]. A German group treated 10 patients with HD with Bu (16 mg/kg), Cy (120 mg/kg), and VP16 (30-45 mg/kg) followed by ASCT and reported an 80% 3-year OS and a 67% event-free survival [21]. In addition, the Hutchinson Cancer Research Center treated 50 patients with HD with Bu 12 mg/kg, melphalan 100 mg/m2, and thiotepa 500 mg/m2 followed by ASCT and found 55% and 51% 5-year OS and event-free survival, respectively [12,37]. However, this regimen was associated with a relatively high TRM of 15% [12]. The present study also validates that the addition of etoposide to Bu and Cy is well tolerated [17,18,38]. Previous groups have used higher doses of Bu by reducing the dose of VP16 [17-19, 21]. Specifically, the TRM of 5.5% is comparable to other reported observations in this patient population [4,7,8,39-41]. Hepatic toxicity remained the most common lifethreatening toxicity, causing the death of 4 patients. Parenteral Bu or blood level monitoring could further reduce the regimen’s hepatic toxicity, possibly by limiting hepatic exposure to Bu by providing superior dosing accuracy [42]. In addition, 3 patients who received prior radiation therapy died from interstitial pneumonitis [43]. Further, improved supportive care since the time of the study could potentially reduce toxicities, including the use of palifermin (recombinant human keratinocyte growth factor), which has been shown to reduce grade 3 or 4 oral mucositis [44]. Secondary Malignancies 1.00

Cumumative incidence

Table 2. Multivariate Analysis of Relapse Rate and Overall Survival (OS)

.80

.60

.40

.20

0.00 0

2

4

6

8

10

12


Figure 4. Overall 8-year actuarial risk for a secondary malignancy was 9%.


In this study active disease at the time of transplantation and bulky disease had a significant adverse influence on OS and PFS after transplantation. Several groups have similarly found that disease status at the time of transplantation is an important prognostic factor [11,31,34,39,45,46]. Bulky disease at the time of transplantation was also an adverse factor predicting higher risk of relapse, which has been seen in previous studies [39,47]. Due to the long follow-up, the rate of late complications and secondary malignancies could be characterized. Three patients (2.3%) developed MDS/ AML and 1 patient acquired a solid cancer with an 8-year follow-up [20,48]. The outcome for treatmentrelated MDS/AML is poor, with an median survival of 6 months and a 5-year survival of 0%-8% even after allogeneic bone marrow transplantation [49,50]. Our previous experience has shown that the incidence of MDS/AML is relatively low with Bu preparative regimens. In our study of 342 patients with NHL, only 4 patients (1.2%) developed AML or MDS 1-5 years after transplantation [20]. The relative contribution of preparative regimens containing TBI versus previous alkylating/topoisomerase II chemotherapy is still not fully known [31]. The European Bone Marrow Transplantation Group and Autologous Bone Marrow Transplant Registry have shown a low rate of MDS after transplantation with TBI regimens [7,8]. Several studies have concluded that the intensity of prior chemotherapy may be the genesis of MDS/AML after transplantation [51]. However, single-institution studies have shown an increased rate of MDS/AML with radiation-containing regimens [52-55]. In particular, treatment-associated MDS and AML is seen as a relatively frequent complication (up to 20%) and lethal late complication, especially in TBI-containing regimens [55-57]. In summary, the novel regimen of Bu 14 mg/kg, etoposide 50-60 mg/kg, and Cy 120 mg/kg is a welltolerated and active preparative regimen for autologous transplantation in patients with HD. It is associated with a low incidence of early and late TRM and a low incidence of secondary malignancy and MDS. Based on this large set of patients with long-term follow-up, it appears that the novel Bu-based preparative regimen, which also includes high-dose Cy and etoposide, is an effective and well-tolerated regimen in HD. Although promising, the definition of the optimal regimen in patients with HD will require prospective evaluation with other commonly used regimens.

REFERENCES 1. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327:1478.

1347

2. Klimo P, Connors JM. An update on the Vancouver experience in the management of advanced Hodgkin’s disease treated with MOPP/ABV hybrid program. Semin Hematol. 1994;25:34. 3. De Vita VT Jr, Hubbard SM. Hodgkin’s disease. N Engl J Med. 1993;328:560-565. 4. Linch DC, Winfield D, Goldstone AH, et al. Dose identification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet. 1993;341:1051-1054. 5. Schmitz N, Glass B, Dreger P, et al. High-dose chemotherapy and hematopoietic stem cell rescue in patients with relapsed Hodgkin’s disease. Ann Hematol. 1993;66:251-256. 6. Lancet JE, Rapoport AP, Brasacchio R, et al. Auto-transplantation for relapsed or refractory Hodgkin’s disease: long term follow-up and analysis of prognostic factors. Bone Marrow Transplant. 1998;22:265-271. 7. Lazarus HM, Rowlings PA, Zhang MJ, et al. Autotransplants for Hodgkin’s disease in patients never achieving remission: a report from Autologous Blood and Marrow Registry. J Clin Oncol. 1999;17:534-545. 8. Sweetenham JW, Carella AM, Taghipour G, et al. High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. J Clin Oncol. 1999;17:3101-3109. 9. Yuen AR, Rosenberg SA, Hoppe RT, Halpern JD, Horning SJ. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin’s disease. Blood. 1997;89:814-822. 10. 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 Hodgkin’s disease: results in 85 patients with analysis of prognostic factors. Blood. 1995;85:1381-1390. 11. 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. 12. Gutierrez-Delgado F, Holmberg L, Hooper H. Autologous stem cell transplantation for Hodgkin’s disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen. Bone Marrow Transplant. 2003;32:279-285. 13. Kliss TL, Panzarella T, Messner HA, et al. Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2003;31:73-78. 14. Avalos BR, Klein JL, Kapoor PJ, Tutschka PJ, Klein JP, Copeland EA. Preparation for marrow transplantation in Hodgkin’s and non-Hodgkin’s lymphoma using Bu/CY. Bone Marrow Transplant. 1993;12:133-138. 15. Weaver CH, Schwartzberg L, Rhinehart S, et al. High-dose chemotherapy with BUCY or BEAC and unpurged peripheral blood stem cell infusion in patients with low-grade non-Hodgkin’s lymphoma. Bone Marrow Transplant. 1998;21:383-389. 16. Copelan EA, Kapoor N, Gibbins B, Tutschka PJ. Allogeneic marrow transplantation for non-Hodgkin’s lymphoma. Bone Marrow Transplant. 1990;5:47-50. 17. Kroger N, Zabelina T, Sonnenberg S, et al. Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in

1348

18.

19.

20.

21.

22.

23. 24.

25.

26. 27. 28. 29.

30.

31.

32.

33.

34.

patients with acute myeloid leukemia. Bone Marrow Transplant. 2000;26:711-716. Zander AR, Berger C, Kroger N, et al. High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission. Clin Cancer Res. 1997;3:2671-2675. Kroger N, Hoffknecht M, Hanel M, et al. Busulfan, cyclophosphamide and etoposide as high-dose conditioning therapy in patients with malignant lymphoma and prior dose-limiting radiation therapy. Bone Marrow Transplant. 1998;21:1171-1175. Copelan EA, Penza SL, Pohlman B, et al. Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2000;25:1243-1248. Hanel M, Kroger N, Sonnenberg S, et al. Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma. Ann Hematol. 2002;81:96-102. Litzow M, Perez W, Klein JP, et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol. 2002;119:1115-1124. 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, Goolet TA, Buckner CD. The effect of cell concentration on bone marrow and peripheral blood stem cell cryopreservation. Blood. 1994;83:2731-2736. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin’s disease. Cancer Res. 1966;26:1063-1081. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. Cox DR. Regression models and life tables. J R Stat Soc. 1972; 34:187-220. 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;11:23422350. Deej HJ. Delayed complications after bone marrow transplantation. In: Forman SJ, Blum KG, Thomas ED, ed. Bone Marrow Transplantation. Boston, MA: Scientific Publications; 1994:538-544. Sureda A, Arranz R, Iriondo A, et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from Grupo Espanol de Linformas/ Transplante Autologo de Medula Osease Spanish Cooperative Group. J Clin Oncol. 2001;19:1395-1404. Jagannath S, Dicke KA, Armitage JO, et al. High-dose cyclophosphamide, carmustine and etoposide and autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann Intern Med. 1986;104:163-168. Lavoie JC, Connors JM, Phillips GL, et al. High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma: long-term outcome in the first 100 patients in Vancouver. Blood. 2005;106:1473-1478. Chopra R, McMillan 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 8 year study of 155 patients. Blood. 1993;81:1137-1145.

N. Wadehra et al.

35. Martin A, Fernandez-Jimenez MC, Calallero M, et al. Longterm follow-up [in patients treated with mini-BEAM as a salvage therapy for relapsed or refractory Hodgkin’s disease. Br J Haematol. 2001. 2001;113:171. 36. Jones RJ, Piantadosi S, Mann R, et al. High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol. 1990;8:527-537. 37. Schiffman K, Buckner C, 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. 38. Farag SS, Bolwell BJ, Elder PJ, et al. High-dose busulfan, cyclophosphamide, and etoposide do not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia. Bone Marrow Transplant. 2005;35:653-661. 39. Czyz J, Dziadziuszko R, Knopinska-Postuszuy W, et al. Outcome and prognostic factors in advanced Hodgkin’s disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Ann Oncol. 2004;15:1222-1230. 40. Reece DE, Barnett MJ, Shepherd JD, et al. High-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16) with or without cisplatin and autologous transplantation for patients with Hodgkin’s disease who fail to enter a complete remission after combination chemotherapy. Blood. 1995;86:451-456. 41. 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;11:711. 42. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant. 2002;8:493-500. 43. Crilley P, Topolsky D, Styler M, et al. Extramedullary toxicity of a conditioning regimen containing busulfan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995;15:361-365. 44. Siddiqui MA, Wellington K. Palifermin: in myelotoxic therapyinduced oral mucositis. Drugs. 2005;65:2139-2146. 45. Moskowitz C, Nimer S, Zelenetz A, 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. 2006;97:616-623. 46. 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 French registry. Bone Marrow Transplant. 1997;20:21-26. 47. Sureda A, Constans M, Iriondo A, et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16:625-633. 48. Copelan EA, Deeg HJ. Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation. Blood. 1992; 80:1658. 49. Friedberg JW, Neuberg D, Stone RM, et al. Outcome in patients with myelodysplastic syndrome after autologous bone


50.

51.

52.

53.

marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17:3128-3135. Anderson JE, Gooley TA, Schoch G, et al. Stem cell transplantation for secondary acute myeloid leukemia: an evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 1997;89:2578-2585. Metayer C, Curtis RE, Vose J, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood. 2003; 5:2015-2023. Bolwell B, Kalaycio M, Sobecks R, et al. Secondary malignancy after autologous stem cell transplantation (ABMT) for nonHodgkin’s lymphoma and Hodgkin’s disease using a busulfan containing preparative regimen. Blood. 2002;100(11):418a. Curtis R, Rowlings P, Deeg H, et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336:897-904.

1349

54. Miller JS, Arthur DC, Litz CE, Neglia JP, Miller WJ, Weisdorf DJ. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood. 1994;83:3780-3786. 55. Stone RM, Neuberg D, Soiffer R, et al. Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol. 1994;12:2535-2542. 56. Darrington DL, Vose JM, Anderson JR, et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol. 1994;12:2527-2534. 57. Andre M, Henry-Amar M, Blaise D, et al. Treatment-related deaths and secondary cancer risk after autologous stem cell transplantation for Hodgkin’s disease. Blood. 1998;92:1933-1940.