|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Autologous Stem-Cell Transplantation for Hodgkin’s Disease: Results and Prognostic Factors in 494 Patients From the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative GroupFrom the Hospital de la Santa Creu i Sant Pau, St Antoni Maria Claret, Barcelona, Spain. Address reprint requests to Anna Sureda, MD, Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, St Antoni Maria Claret, 167, 08025 Barcelona, Spain; email: asureda{at}hsp.santpau.es
PURPOSE: To analyze clinical outcome and significant prognostic factors for overall (OS) and time to treatment failure (TTF) in a group of 494 patients with Hodgkin’s disease (HD) undergoing autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Detailed records from the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative Group Database on 494 HD patients who received an ASCT between January 1984 and May 1998 were reviewed. Two hundred ninety-eight males and 196 females with a median age of 27 years (range, 1 to 63 years) received autografts while in complete remission (n = 203) or when they had sensitive disease (n = 206) or resistant disease (n = 75) at a median time of 26 months (range, 4 to 259 months) after diagnosis. Most patients received high-dose chemotherapy without radiation for conditioning (n = 443). The graft consisted of bone marrow (n = 244) or peripheral blood (n = 250).
RESULTS: The 100-day mortality rate was 9%. The 5-year actuarial TTF and OS rates were 45.0% (95% confidence interval [CI], 39.5% to 50.5%) and 54.5% (95% CI, 48.4% to 60.6%), respectively. In multivariate analysis, the presence of active disease at transplantation, transplantation before 1992, and two or more lines of therapy before transplantation were adverse prognostic factors for outcome. Sixteen patients developed a secondary malignancy (5-year cumulative incidence of 4.3%) after transplantation. Adjuvant radiotherapy before transplantation, the use of total-body irradiation (TBI) in the conditioning regimen, and age CONCLUSION: ASCT achieves long-term disease-free survival in HD patients. Disease status before ASCT is the most important prognostic factor for final outcome; thus, transplantation should be considered in early stages of the disease. TBI must be avoided in the conditioning regimen because of a significantly higher rate of late complications, including secondary malignancies.
MOST PATIENTS suffering from Hodgkin’s disease (HD) can be successfully treated with radiotherapy (RT) or conventional-dose chemotherapy (CT), with 70% of them being alive 10 years after diagnosis.1,2 Results of salvage CT in patients who relapsed after first-line RT are comparable to those obtained with up-front CT.3,4 Among patients relapsing after initial CT, RT alone may be curative in some instances.5,6 In contrast, patients whose disease is primarily refractory to CT or who relapse after more than one CT regimen have a poor prognosis, with only 20% of them becoming long-term disease-free survivors.7,8 High-dose therapy with autologous stem-cell transplantation (ASCT) has been extensively used in patients with refractory or relapsed HD.9-17 Analyses of prognostic factors in several studies indicate that earlier extensive RT, short remission duration, resistance of disease to conventional-dose CT, and bulky disease at the time of transplantation seem to be adverse features for the outcome of the procedure. Of particular interest is the analysis of the results of high-dose therapy at the time of first relapse after CT in patients with HD.12,15,16,18 Single-institution studies show better outcome after ASCT in this group of patients when compared with historical controls receiving conventional treatment.19,20 Two prospective randomized studies in patients with HD in first relapse also indicate a significant advantage of intensification versus conventional salvage regimens for long-term disease-free survival (DFS).21,22 Because patients with adverse features at diagnosis receiving CT alone have a 5-year DFS of only 40% to 50%, early consolidation of high-dose therapy and ASCT in patients with HD in first remission has recently been investigated.23-25 For a better knowledge of the results of ASCT in HD and with the objective of identifying the prognostic factors in this setting, the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea (GEL/TAMO) group established a prospective observational registry. We report here the outcome of a cohort of 494 patients autografted for HD and reported to this registry during a period of 15 years.
From January 1984 to May 1998, a total of 494 patients with HD who received an ASCT were communicated to the GEL/TAMO Spanish Cooperative Group, which includes 46 centers. Reported data were centrally reviewed to detect inconsistencies. All reporting physicians were contacted to provide additional information on patients’ characteristics at presentation when required. Follow-up was updated in May 1999, when all living patients had been observed for at least 1 year after ASCT.
Eligibility Criteria
Study Definitions
Patients were clinically staged at the time of ASCT, 90 days after ASCT, every 6 months for the first 2 years, then yearly or as clinically indicated. Patients who survived more than 90 days after ASCT without evidence of tumor, by clinical and radiologic evaluation, were classified as CR. Patients with small residual radiographic abnormalities, which did not progress for 6 months after transplant, were also classified as CR. Partial remission was defined as a
Patients
Initial treatment varied according to the initial HD stage, the date of diagnosis, and the protocol used in each hospital; most patients received either mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or derivatives (n = 147, 30% of the series), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (n = 82, 17%), or MOPP alternating with ABVD (n = 168, 34%). A smaller proportion of patients received hybrid regimens such as MOPP/ABV (n = 58, 12%) and a minority of patients received other protocols (n = 12, 2%). Twenty-seven patients were initially treated with RT alone (5%). Complementary RT was used in 174 of the 467 patients initially treated with CT, according to active protocols in participating institutions. In patients who achieved a first CR with CT, the median remission duration was 15 months (range, 1 month to 208 months); of them, 117 patients relapsed within 12 months of achieving CR, and 167 thereafter. Data were not available for 37 additional patients. The time interval between diagnosis and the date of ASCT ranged from 4 to 259 months, with a median of 26 months. Disease status at ASCT is listed in Table 2. Two hundred three patients were autografted in CR, 57 in first CR because of two or more poor prognostic features at diagnosis following Straus classification27 (n = 40) or treatment failure with only one line of CT (n = 19), 107 in second CR and 39 in third CR. One hundred ninety-seven patients were autografted with active chemosensitive disease: 66 in first PR and 131 in SR. Seventy-five patients showed NR or less than 50% response to the latest CT, classified as resistant disease: 49 patients had primary refractory disease (PRD) and 26 were in ReR. Nineteen patients proceeded to ASCT without receiving conventional salvage treatment at the time of their latest relapse (untreated relapse).
Source of Autologous Stem Cells Two hundred forty-four patients (49%) were autografted using bone marrow (BM) as the source of hematopoietic stem cells. Bone marrow was harvested under general anesthesia and cryopreserved following standard guidelines. ASCT from peripheral-blood progenitor cells (PBPCs) was introduced in 1991 and used in 250 patients (51%). PBPCs were initially collected during the phase of hematologic recovery after mobilizing CT (n = 84) and more recently after 5 to 7 days of hematopoietic growth factor administration (n = 166).
High-Dose Therapy and Transplantation Procedures A total of 247 patients (60%) received granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) until the absolute neutrophil count exceeded 0.5 x 109/L for 3 consecutive days.
Statistical Analysis Comparison of the survival curves in univariate analysis was performed using the log-rank test.30 Analysis of prognostic factors influencing both CR and TRM rates was performed by Fisher’s exact test and logistic regression analysis. Comparison of continuous variables was performed by Mann-Whitney’s U test and linear regression analysis.
Multivariate analysis was performed using a forward stepwise Cox proportional hazards model. The prognostic factors analyzed for both TTF and OS were sex, histology (nodular sclerosis v mixed cellularity v lymphocyte predominance), year of transplant (December 1991 v January 1992), previous splenectomy, complementary RT, first line therapy (seven to eight drugs treatment v other protocols), number of treatment lines (one v two or more), duration of first CR (< 12 months v All P values reported are two-sided and statistical significance is defined as a P value less than .05. The statistical analyses were computed with SPSS statistical software (SPSS, Inc, Chicago, IL).
Response to ASCT and Survival Outcome. At 3 months, 378 patients (76.5%) were classified as complete responders, although 189 of them (38%) were already in CR at ASCT (continuous CR). Twenty-nine patients (6%) were in PR, and 41 (8%) did not respond or progressed after ASCT. In patients with measurable HD at ASCT, the only factor which became predictive for achieving a CR was disease status, with a higher probability in patients with sensitive disease than in those with chemoresistant disease (RR [relative risk], 4.98%; 95% CI [confidence interval], 2.67% to 9.3%; P = .00001). The actuarial TTF at 5 years was 45% (95% CI, 39.5% to 50.5%) for the entire group with an OS of 54.5% (95% CI, 48.4% to 60.6%) at the same time point ( Fig 1). Median follow-up of the surviving patients was 30.5 months (range, 12 to 139 months).
Prognostic factors. TIME TO TREATMENT FAILURE. Significant variables on univariate analysis are listed in Table 3. On multivariate analysis ( Table 4), disease status at ASCT ( Fig 2) and the number of lines of therapy before ASCT ( Fig 3) were the factors that significantly influenced TTF.
In this series, patients autografted in CR had a significantly better TTF outcome than patients autografted with visible disease (63.2% [95% CI, 53.8% to 72.6%] v 32.2% [95% CI, 25.9% to 38.5%], P = .00001). There were no significant differences between patients autografted in first, second, and third CR (70.4% [95% CI, 54.4% to 86.4%], 62.3% [95% CI, 50.8% to 73.8%], and 58.5% [95% CI, 32.7% to 84.3%], respectively, P = .59). Nevertheless, there was a trend for a better TTF for patients autografted in first CR than those transplanted in second or third CR. Outcome was especially good in patients autografted in first PR (n = 66) and in untested relapse (n = 19) with actuarial PFS at 5 years of 45.0% (95% CI, 29.4% to 60.6%) and 57.0% (95% CI, 34.5% to 79.5%), respectively. In contrast, patients in ReR or with PRD had the poorest outcome (26.0% [95% CI, 9.0% to 43.0%] and 13.0% [95% CI, 2.1% to 23.9%] TTF at 5 years, respectively). OVERALL SURVIVAL. The results of univariate analysis are listed in Table 5. On multivariate analysis (Table 4), transplant in remission, ASCT after 1991 and a single line of therapy before the procedure were significantly associated with improved survival.
Relapse After ASCT Of the 378 patients who were in CR 3 months after transplantation, 99 (26%) relapsed at a median time of 12 months (range, 2 to 92 months) after ASCT. Sixty-four patients (65%) relapsed within the first year after ASCT; nevertheless, five patients in this series relapsed more than 4 years after transplantation, almost 8 years after transplantation in one case. Forty-one of the relapsed patients are still alive and 58 have died, 53 from progressive disease and five from a secondary malignancy that developed after transplantation.
Hematologic Recovery and Complications
TRM. Overall TRM was 8.5% (95% CI, 4.5% to 12.5%) at 4 years by Kaplan-Meier analysis. Both the use of TBI in the conditioning regimen (RR 2.3%; 95% CI, 1.12% to 4.75%; P = .02) and the use of two or more lines of therapy before transplant (RR 6.93%; 95% CI, 1.65% to 29.03%; P = .008) were significant prognostic factors in the multivariate analysis. Early TRM. There were a total of 46 early deaths (eTRM of 9%). The causes were interstitial pneumonitis/adult respiratory distress syndrome (IP/ARDS) in 19 patients, infectious episodes in 14 patients (bacterial in six, fungal in five, viral in one, and CMV pneumonitis in two patients), cardiac toxicity in four patients, multiorgan failure in another four patients, hemorrhage in three cases, and veno-occlusive disease in two patients. Multivariate analysis identified the number of lines of treatment before ASCT (1 v 2 or more; RR 4.46%; 95% CI, 1.05% to 18.90%; P = .042) and the year of transplantation (December 1991 v January 1992; RR 1.95%; 95% CI, 1.01% to 3.76%; P = .042) as significant prognostic factors for eTRM. Late TRM. Eighteen patients (3.5% of the series) died beyond the first 100 days after ASCT from transplant-related causes: second malignancies in nine patients, infectious episodes in seven patients (four bacterial and three fungal) and IP/ARDS in two patients. The use of TBI significantly increased late lethal complications in the multivariate analysis (RR 5.21%; 95% CI, 1.72% to 16%; P = .004).
Secondary malignancies.
Sixteen patients (3.2%, 5-year cumulative incidence of 4.3%) developed a secondary malignancy (SM) at a median time of 24.5 months (range, 10 to 76 months) after transplantation: 12 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) (75%), one acute lymphoblastic leukemia (ALL) (6%), one NHL (6%), and two solid tumors (13%) (one rhabdomyosarcoma and one adenocarcinoma of the lung). All these patients had been treated with two or more lines of chemotherapy before ASCT. Eight patients had received BM and eight patients had received PB for autografting. Four of the patients developing SM had been conditioned with TBI-containing regimens and the remaining 12 had received chemotherapy alone. Five of these patients were in CR at ASCT: two in first CR, two in second CR, and one in third CR. Two patients received adjuvant RT after transplantation. Four patients are alive (three in CR and one in relapse) and 12 have died, nine from the SM (eight in CR, two of them in CR after relapse after ASCT, and one with progressive HD) and three from progressive HD. In a multivariate analysis, the use of complementary RT before transplantation (RR 3.15%; 95% CI, 1.00% to 10.01%; P = .05), the administration of TBI in the conditioning regimen (RR 4.64%; 95% CI, 1.31% to 16.66%; P = .01), and patient age
Since first introduced in patients with HD more than 15 years ago, high-dose therapy and ASCT has become the treatment of choice for many patients with this disease whose treatment fails or disease relapses after induction therapy. The increasing number of ASCT worldwide is partially because of significant reduction in eTRM during recent years. We analyzed a large prospective observational series of 494 HD patients autografted over a 14-year period. In our experience, disease status at ASCT was the most important prognostic factor for both OS and TTF, with best results for patients in CR. This finding is consistent with previous reports.12,18,31-34 In this sense, Crump et al13 found a significantly better DFS for patients autografted in CR than for those transplanted with residual or bulky disease (P = .0002). Arranz et al,35 in a group of 51 patients with poor prognosis HD, also found that disease status before transplant was the main prognostic factor for PFS (78% for CR patients v 9% for AD, P = .0006). Accordingly, Rapoport et al14 found significant differences in the actuarial event-free survival between patients autografted with minimal disease versus bulky disease in both HD (n = 47) and NHL (n = 53). Although the absence of visible disease at ASCT seems to be determinant for a good outcome, a group of patients in relapse may have relatively good prognosis. This group would include patients transplanted in untreated relapse12,16 (5-year TTF 45%; 95% CI, 29.4% to 60.6%; in our series) or those in first partial response25 (5-year TTF of 57.0%; 95% CI, 34.5% to 79.5%; in our series). The number of lines of therapy before transplant (one v two or more different protocols) was also a significant prognostic factor, for both OS and TTF in our series. This finding was partially because patients receiving more than one line of treatment before ASCT had significantly higher eTRM than the remainder (10.8% v 2.3%, P = .042). For this reason, early transplantation is recommended, before the development of resistance and cumulative organ toxicity from cytotoxic agents, to reduce the TRM. The same finding was reported by other authors, Chopra et al12 showed that the amount of CT before ASCT discriminated two prognostic groups for survival (one v two or more lines of CT) and Nademanee et al15 demonstrated that patients who had received more than two lines of CT had poor DFS and were at increased risk of relapse and death from transplant-related complications. Accordingly, Bierman et al,16 in a retrospective analysis of 128 HD patients, and Sweetenham et al,36 in a group of 175 primary refractory HD patients reported to the European Bone Marrow Transplantation Group, found that the number of lines of CT before ASCT significantly influenced the final outcome. Year of ASCT was another prognostic factor. Improvements in supportive care, a more rapid marrow recovery, or better patient selection may explain why TRM was higher in patients autografted before January 1992 than in patients transplanted after January 1992 (14.4% v 7.3%, P = .042). A similar observation was made by Lancet et al,34 who reported a TRM of 13% in a group of 46 relapsed or refractory HD patients transplanted before 1993 and only 4% in 24 patients autografted after January 1993. Several factors, taken together, may account for this improvement, a more frequent use in the second period of chemotherapy-based regimens (82% v 17%), the introduction of PB (65% v 8%), and the increase in ASCT expertise. Of note, hematologic recovery was significantly faster both for neutrophils and platelets for patients autografted from PB than for those autografted from BM, with a median difference of 7 and 5 days, respectively. Administration of growth factors after progenitor-cell infusion significantly enhanced neutrophil recovery in both BM and PB recipients without influencing platelet recovery. The eTRM observed in this series was 9%, a rate within the range of those reported by other centers using a number of different conditioning regimens. In general, the risk of early TRM in HD patients has a trend downwards from 10% to 20% in some of the earlier studies10,12,14,37 to 5% to 10%, or even lower, in more recent studies.15,18,38 Late TRM occurred in 18 additional patients from this series (raw incidence of 3.5%), the most frequent causes being SM and infectious complications. Other studies of ASCT in HD patients have reported similar causes of late fatal complications, with raw incidences ranging from 0.5% to 3%.11-13,15,31,32 The contribution of the T-cell defects in this disease39 leading to posttransplant immunodeficiency40 is unclear. As in other studies,41 this lTRM was significantly associated with the use of TBI as a conditioning regimen.
Therefore, SM emerged as a serious problem after ASCT for HD. The 5-year cumulative incidence was 4.3% and MDS or AML developed in 12 patients (75%). This actuarial incidence was similar to others reported in the literature.42-45 Since 1969, when Crosby46 first suggested that acute leukemia developing after the cure of HD could be related to the therapy, MDS/AML and solid tumors secondary to conventional CT and irradiation have been recognized as a complication of HD treatment. Alkylating agents,47 radiation therapy,48 combined-modality therapy,49 and splenectomy50 have all been implicated in the development of these poor-prognosis tumors. Some recent series reported the occurrence of MDS/AML after ASCT for lymphoid malignancies,42-45 and the role of high-dose therapy versus previous conventional treatment in the development of SM is controversial. It is remarkable that in a French study,42 the risk of MDS/AML was not increased after ASCT versus a matched group of 1,179 conventionally treated HD patients; in contrast, the risk of solid tumors was increased in the ASCT group. They found that age Late relapses can occur and the long-term outcome for patients after ASCT for HD is somewhat less clear because of this possibility. In our series of 494 patients, they are the main cause accounting for the absence of a plateau in both TTF and OS curves. The European Bone Marrow Transplantation Group reported one relapse in a patient more than 6 years after autologous bone marrow transplantation for HD.53 Reece et al10 described two relapses at 40 and 42 months after ABMT, Phillips et al9 described four relapses between 3.3 and 4.5 years after ABMT, and investigators from the Royal Marsden noted one relapse occurring 29 months after ABMT.54 In our series, one patient autografted in first CR relapsed 92 months after ASCT. Prolonged follow-up and updated results of previously reported series will help to determine the long-term outcome of patients after ASCT for HD. In summary, this study highlights the possibility of achieving long-term TTF and good disease control with ASCT in HD patients, even in those autografted in advanced stages of the disease. However, it also indicates the need to select HD patients who are "good candidates" for an ASCT in terms of disease status, sensitivity, and the number of lines of CT received before transplantation. ASCT results have improved over time but late relapses may occur and this should be taken into account when giving information about the long-term outcome of this procedure to patients. TBI must be avoided in the conditioning regimen to decrease the incidence of SM after ASCT. Major issues remain to be addressed in the future by means of comparative clinical trials. These issues include the optimal timing for high-dose therapy, the best preparatory regimen, the role of additional conventional therapy, and strategies to reduce adverse late effects.
APPENDIX
APPENDIX (Cont’d) 
Supported in part by grants no. FIS 94/0063-01 and FIS 97/0626 awarded by the Fondo de Investigaciones Sanitarias del Ministerio de Sanidad y Consumo, Spain.
1. Longo DL, Young RC, Wesley M, et al: Twenty years of MOPP therapy for Hodgkin’s disease. J Clin Oncol 4: 1295-1306, 1986 2. Prosnitz LR, Farber LR, Kapp DS, et al: Combined modality therapy for advanced Hodgkin’s disease: 15 year follow-up data. J Clin Oncol 6: 603-612, 1988[Abstract] 3. Canellos GP, Young RC, DeVita VT: Combination chemotherapy for advanced Hodgkin’s disease in relapse following extensive radiotherapy. Clin Pharmacol Ther 13: 750-757, 1979 4. Timothy AR, Sutcliffe SBJ, Wrigley PFM, et al: Hodgkin’s disease: Combination chemotherapy for relapse following radical radiotherapy. Int J Radiat Oncol Biol Phys 5: 165-171, 1979[Medline]
5.
Mauch P, Tarbell N, Skarin A, et al: Wide-field radiation therapy alone or with chemotherapy for Hodgkin’s disease in relapse from combination chemotherapy. J Clin Oncol 5: 544-550, 1987
6.
Roach M III, Kapp DS, Rosenberg SA, et al: Radiotherapy with curative intent: An option in selected patients relapsing after chemotherapy for advanced Hodgkin’s disease. J Clin Oncol 5: 550-556, 1987
7.
Hoppe RT: Development of effective salvage treatment programs for Hodgkin’s disease: An ongoing challenge. Blood 77: 2093-2095, 1991 8. Longo DL, Duffey PL, Young RC, et al: Conventional dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: The low probability for cure. J Clin Oncol 10: 210-218, 1992[Abstract]
9.
Phillips GL, Wolff SN, Herzig RH, et al: Treatment of progressive Hodgkin’s disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 73: 2086-2092, 1989 10. Reece DE, Barnet MJ, Connors JM, et al: Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol 9: 1871-1879, 1991[Abstract]
11.
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 4: 767-773, 1993
12.
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 81: 1137-1145, 1993 13. 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 11: 704-711, 1993[Abstract]
14.
Rapoport AP, Rowe JM, Kouides PA, et al: One hundred autotransplants for relapsed or refractory Hodgkin’s disease and lymphoma: Value of pretransplant disease for predicting outcome. J Clin Oncol 11: 2351-2361, 1993
15.
Nademanee A, O’Donell 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 85: 1381-1390, 1995
16.
Bierman PJ, Anderson JR, Freeman MB, et al: High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin’s disease patients following first relapse after chemotherapy. Ann Oncol 7: 151-156, 1996 17. Caballero MD, Rubio V, Rifón J, et al: BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: Analysis of efficacy, toxicity and prognostic factors. Bone Marrow Transplant 20: 451-458, 1997[Medline]
18.
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 83: 1193-1199, 1995
19.
Lohri A, Barnett M, Fairey RN, et al: Outcome of treatment of first relapse of Hodgkin’s after primary chemotherapy: Identification of risks factors from the British Columbia experience 1970 to 1988. Blood 77: 2292-2298, 1991
20.
Yuen AR, Rosenberg SA, Hoppe RT, et al: Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin’s disease. Blood 89: 814-822, 1997 21. 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 341: 1051-1054, 1993[Medline] 22. Schmitz N, Sextro M, Pfistner B, et al: High-dose therapy followed by hematopoietic stem transplantation for relapsed chemosensitive Hodgkin’s disease: Final results of a randomized GHSG and EBMT trial (HD-R1). Proc Am Soc Clin Oncol 18: 2a, 1999 (abstr) 23. Carella AM, Carlier P, Congiu A, et al: Autologous bone marrow transplantation as adjuvant treatment for high-risk Hodgkin’s disease in first complete remission after MOPP/ABVD protocol. Bone Marrow Transplant 8: 99-103, 1991[Medline] 24. Sureda A, Mataix, R, Hernández-Navarro F, et al: Autologous stem cell transplantation for poor prognosis Hodgkin’s disease in first complete remission: A retrospective study from the Spanish GEL-TAMO Cooperative Group. Bone Marrow Transplant 20:283-288, 1997 25. Moreau P, Fleury J, Brice P, et al: Early intensive therapy with autologous stem cell transplantation in advanced Hodgkin’s disease: A retrospective analysis of 158 cases from the French registry. Bone Marrow Transplant 21: 787-793, 1998[Medline]
26.
Carbone PP, Kaplan HD, Musshogg K, et al: Report of the committee of Hodgkin’s disease staging. Cancer Res 31: 1860-1861, 1971 27. Straus DJ, Gaynor JJ, Myers J, et al: Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin’s disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol 8: 1173-1186, 1990[Abstract] 28. Kaplan EL, Meier P: Nonparametric estimation from incomplete estimations. J Am Stat Assoc 53: 457-481, 1958
29.
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17: 1244-1253, 1999 30. Mantel N, Haenzel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719-723, 1958
31.
Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: Analysis of the Stanford University results and prognostic indices. Blood 89: 801-813, 1997 32. Sweetenham JW, Taghipour G, Milligan D, et al: High-dose therapy and autologous stem cell rescue for patients with Hodgkin’s disease in first relapse after chemotherapy: Results from the EBMT. Bone Marrow Transplant 20: 745-752, 1997[Medline] 33. 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. Bone Marrow Transplant 20: 21-26, 1997[Medline] 34. Lancet JE, Rapoport AP, Brasacchio R, et al: Autotransplantation for relapsed or refractory Hodgkin’s disease: Long-term follow-up and analysis of prognostic factors. Bone Marrow Transplant 22: 265-271, 1998[Medline] 35. Arranz R, Tomás JF, Gil-Fernández JJ, et al: Autologous stem cell transplantation (ASCT) for poor prognostic Hodgkin’s disease (HD): Comparative results with two CBV regimens and importance of disease status at transplant. Bone Marrow Transplant 21: 779-786, 1998[Medline]
36.
Sweetenham JW, Carella AM, Taghipour G, et al: High dose therapy and autologous stem cell transplantation for adult patients with Hodgkin’s disease who fail to enter remission after induction chemotherapy: Results in 175 patients reported to the EBMT. J Clin Oncol 17: 3101-3109, 1999
37.
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 11: 1062-1070, 1993 38. 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 8: 648-656, 1990[Abstract] 39. Schulof RS, Bockman RS, Garofalo JA, et al: Multivariate analysis of T-cell functional defects and circulating serum factors in Hodgkin’s disease. Cancer 48: 964-973, 1981[Medline]
40.
Guillaume T, Rubinstein DB, Symann M: Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood 92: 1471-1490, 1998 41. Subirà M, Sureda A, Martino R, et al: Autologous stem cell transplantation for high-risk Hodgkin’s disease at a single institution: Improvement over time and impact of conditioning regimen. Haematologica 85: 167-172, 2000[Medline]
42.
André M, Henry-Amar M, Blaise D, et al: Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 92: 1933-1940, 1998
43.
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 12: 2527-2534, 1994
44.
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 12: 2535-2542, 1994
45.
Miller JS, Arthur DC, Litz CE, et al: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy. Blood 83: 3780-3786, 1994 46. Crosby WH: Acute granulocytic leukemia, a complication of therapy in Hodgkin’s disease? Clin Res 12: 1103-1107, 1969 47. Tucker MA, Meadows AT, Boice JD, et al: Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst 78: 459-464, 1987 48. Tucker MA, Coleman CN, Cox RS, et al: Risk of second cancer after treatment for Hodgkin’s disease. N Engl J Med 318: 76-81, 1988[Abstract] 49. Andrieu JM, Ifrah N, Payen C, et al: Increased risk of acute leukemia following extended-field radiation therapy combined with MOPP chemotherapy for Hodgkin’s disease. J Clin Oncol 8: 1148-1154, 1990[Abstract] 50. Van Leeuwen FE, Somers R, Hart AM. Splenectomy in Hodgkin’s disease and second leukaemias. Lancet 2:210, 1987 (letter) 51. Maille H, Baker J, Simon W, et al: Age related rejoining of broken chromosomes in human leukocytes following X-irradiation. Mech Ageing Dev 65: 229-238, 1992[Medline]
52.
Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. N Engl J Med 339: 1506-1514, 1998 53. Green ES, Taghipour G, Goldstone AH: Report of the EBMT registry of ABMT in Hodgkin’s disease: Outcome in patients followed for at least three years. Bone Marrow Transplant 5: 23, 1990 (suppl 2, abstr)[Medline] 54. Russell JA, Selby PJ, Ruether BA, et al: Treatment of advanced Hodgkin’s disease with high-dose melphalan and autologous bone marrow transplantation. Bone Marrow Transplant 4: 425-429, 1989[Medline] Submitted March 23, 2000; accepted November 16, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
40 years were found to be predictive factors for the development of second cancers after ASCT. 
65 years, left ventricular ejection fraction more than 50%, forced expiratory volume in 1 second (FEV1) more than 50%, diffusion capacity of the lung for carbon monoxide (DLCO) greater than 50% of predicted, and absence of major organ dysfunction of cause different to HD. All patients gave written informed consent before undergoing ASCT. 
