* Correspondence to: Dr A. Sureda, Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Antoni Maria i Claret, 167, 08025 Barcelona, Spain. Tel: +34-93-2919396; Fax: +34-93-2919466; Email: asureda{at}hsp.santpau.es
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Abstract |
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Methods: Two hundred and twenty males and 137 females with a median age of 29 years were autografted in second remission (n=181), first sensitive relapse (n=148) and first resistant relapse (n=28).
Results: Five-year actuarial TTF and OS were of 49% ± 3% and 57% ± 3%. Advanced stage at diagnosis, complementary radiotherapy before ASCT, a short first complete response (CR) and detectable disease at ASCT adversely influenced TTF. Year of transplant 1995, bulky disease at diagnosis, a short first CR, detectable disease at ASCT and
1 extranodal areas involved at ASCT were adverse factors for OS.
Conclusions: ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.
Key words: autologous stem cell transplantation, first relapse, Hodgkin's lymphoma
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Introduction |
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High-dose therapy with autologous stem cell transplantation (ASCT) has been extensively tested in patients with relapsed and refractory HL during recent years [514
]. Of particular interest is the analysis of the results of high-dose therapy in patients with HL at the time of first relapse after chemotherapy [8
, 11
, 12
, 15
]. Single institution studies have shown better outcome after ASCT in this group of patients when compared to historical controls receiving conventional treatment [16
, 17
]. Indeed, two prospective randomised analyses, which include patients with HL in first relapse, also indicate a significant advantage of intensification versus conventional salvage regimens, in terms of long-term DFS [18
, 19
], especially in patients relapsing after a short first complete remission (CR) [19
]. Retrospective analyses performed by several groups indicate that the extent of prior chemotherapy [8
, 11
], disease status at relapse [8
, 15
, 20
23
], chemosensitivity to salvage chemotherapy [22
, 23
] and duration of initial CR [15
, 20
] emerge as significant prognostic factors for the long-term outcome of intensive therapy in this setting. The purpose of the present analysis was to determine independent prognostic factors correlated with the long-term outcome of ASCT performed after a first relapse in a cohort of 357 HL patients reported to The Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO) Cooperative Group prospective observational registry during a period of 15 years.
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Patients and methods |
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Eligibility criteria
Common eligibility criteria for ASCT in all institutions were age 65 years, left ventricular ejection fraction >50%, forced expiratory volume in 1 s (FEV1) >50%, diffusion capacity of the lung for carbon monoxide (DLCO) >50% predicted, and absence of major organ dysfunction of cause different to HL. All patients gave written informed consent before undergoing ASCT.
Study definitions
Patients were required to have progression of HL proven by biopsy or unequivocal radiological progression after a CR induced by primary chemotherapy. Relapse was distinguished from primary progressive disease by a period of at least 3 months in remission after completion of first-line treatment. A sensitive relapse was defined as at least a 50% reduction in the bidimensional measurements of the disease with the use of conventional salvage chemotherapy. A resistant relapse was defined as <50% reduction in the size of the tumour with the use of conventional salvage chemotherapy. Early relapse was defined as CR after first-line therapy lasting 312 months. Late relapse was defined as CR lasting >12 months after completion of induction treatment.
Patients were staged according to the Ann Arbor system [24]. Patients were clinically staged at the time of ASCT, on day +90 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 tumour, by clinical and radiological evaluation including computed tomography scan, were classified as CR. Patients with small residual radiographic abnormalities, which did not progress for 6 months after transplant, were also classified as being in CR. Partial remission (PR) was defined as a
50% reduction of pre-transplant measurable disease, for at least 1 month. Patients achieving <50% tumour reduction after ASCT were considered to be non-responders (NR).
Patients
Main characteristics of the 357 patients at diagnosis and at ASCT are shown in Tables 1 and 2, respectively. Two hundred and twenty (62%) patients were male and 137 were female (38%). The median age at the time of ASCT was 29 years (range 865 years). At initial presentation, 54% of the patients had stage IIIIV disease. Other adverse features were B symptoms (52%) and bulky disease only in 27% of the whole series.
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Disease status at ASCT appears in Table 2. One hundred and eighty-one patients achieved a second CR after salvage chemotherapy (51% of the series) and the remaining 176 patients were autografted with visible disease: 134 with active chemosensitive first relapse, 28 (8%) with resistant first relapse and 14 (4%) proceeded to ASCT without receiving conventional salvage treatment at the time of their relapse (untreated first relapse).
Source of autologous stem cells
Two hundred and thirty-two patients (65%) were autografted using peripheral blood progenitor cells (PBPCs) as the source of hematopoietic stem cells and the remaining 125 (35%) were autografted using bone marrow (BM). Bone marrow was harvested under general anaesthesia and cryopreserved following standard guidelines.
High-dose therapy and transplantation procedures
Details of high-dose therapy are given in Table 2. Regimens that included total body irradiation (TBI) were used in 7% of the patients (n=26). The remaining 93% received chemotherapy-only high-dose regimens, the most frequent being CBV (n=162, 45%) which consisted of cyclophosphamide (1.21.8 g/m2 i.v. for 4 days), etoposide (125400 mg/m2 twice daily i.v. for 3 days) and BCNU (300600 mg/m2 i.v. for 1 day). The BEAM protocol was administered to 110 patients (31%) [BCNU (300400 mg/m2 i.v. for 1 day), etoposide (150200 mg/m2 i.v. for 4 days), cytarabine (100200 mg/m2 twice daily i.v. for 4 days) and melphalan (140 mg/m2 i.v. for 1 day)] and the BEAC combination to 43 patients (12%), this regimen being the association of BCNU (300400 mg/m2 i.v. for 1 day), etoposide (150200 mg/m2 i.v. for 4 days), cytarabine (200 mg/m2 twice daily i.v. for 4 days) and cyclophosphamide (1.52.5 g/m2 i.v. for 3 days) and 16 patients (5% of the series) received other combination chemotherapy protocols.
A total of 186 patients (52%) 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 per 3 consecutive days.
Statistical analysis
Actuarial curves were performed according to the KaplanMeier method [25]. Overall survival (OS) was calculated in months from the date of autologous stem cell reinfusion to the date of death from any cause. Time to treatment failure (TTF) was measured in months from the date of transplantation to the time of failure or death from any cause following previously described criteria for non-Hodgkin's lymphomas (NHL) [26
]. Overall non-relapse mortality (NRM) was defined as death from any cause other than HL.
Comparison of the survival curves in univariate analysis was performed using the log rank test [27]. Analysis of prognostic factors influencing both CR and NRM rates was performed by Fisher's exact test and logistic regression analysis. Comparison of continuous variables was performed by MannWhitney's U test and linear regression analysis.
Multivariate analysis was performed using a forward stepwise Cox proportional-hazards model. The prognostic factors analysed for both TTF and OS were: age at transplantation, year of transplant according to the median (1995 and >1995), complementary RT, first-line therapy (MOPP-like regimens versus other protocols), number of treatment lines (one versus two or more), duration of first CR (
12 months versus >12 months), conditioning regimen (TBI versus chemotherapy alone), source of stem cells (BM versus PB), Ann Arbor stage (early versus advanced), B symptoms, extranodal involvement, BM involvement, bulky disease and Eastern Cooperative Oncology Group (ECOG) performance status (01 versus
2). The last six characteristics were evaluated at diagnosis and at ASCT.
All P values reported are two-sided and statistical significance is defined as a P <0.05. The statistical analyses were computed by means of the SPSS statistical software.
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Results |
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NRM. Thirty-seven patients (10%) died after ASCT due to procedure-related complications: 26 patients during the first 3 months after ASCT (early NRM) and the remaining 11 patients later (late NRM). Overall NRM was 8.0% [95% confidence interval (CI): 5.011] at 1 year. Both the use of TBI-containing protocols as conditioning regimen [relative risk (RR) 6.09, 95% CI 2.2916.18, P=0.0001] and year of ASCT 1995 (RR 3.44, 95% CI 1.438.27, P=0.006) were independent adverse prognostic factors for NRM in the multivariate analysis (Table 3). Patients autografted
1995 had some differential characteristics with respect to those autografted after this year that can account for the significant difference in NRM [more frequent use of MOPP-like protocols (34% versus 16%, P=0.001), of TBI-containing protocols as conditioning regimen (10% versus 3%, P=0.015 and of BM as the source of hematopoietic stem cells (57% versus 3%, P=0.0001)]. When considering only those patients autografted after 1995 with chemotherapy-containing protocols (n=140) whose overall NRM was 3% at 12 months (95% CI 1.54.5), the only significant adverse prognostic factor for NRM was refractoriness to salvage chemotherapy before ASCT (RR 15.15, 95% CI 1.88125.0, P=0.011). The causes of death were infectious episodes in 13 patients (bacterial in three, fungal in seven, and CMV pneumonitis in three patients), interstitial pneumonitis/adult respiratory distress syndrome (IP/ARDS) in nine patients, secondary neoplasias in six patients (one patient died 169 months after ASCT), multi-organ failure in four patients, hemorrhage in two patients, venooclusive disease in two patients and cardiac toxicity in one patient. Three other additional patients developed and died from a secondary neoplasia after having relapsed from their underlying disease.
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The actuarial TTF at 5 years was 49% (95% CI 4652%) for the entire group of patients with an OS of 57% (95% CI 5460%) at the same time point (Figures 1 and 2). Median follow-up of the surviving patients was 39 months (range 12174). Prognostic factors influencing TTF in the univariate analysis are shown in Table 4. On multivariate analysis (Table 4), advanced stage at diagnosis (RR 1.6, 95% CI 1.12.2, P=0.007), complementary RT (RR 1.9, 95% CI 1.32.2, P=0.0001), first CR 12 months (RR 1.6, 95% CI 1.12.3, P=0.005) and refractoriness to salvage chemotherapy (RR 4.5, 95% CI 2.77.6, P=0.0001) significantly shortened TTF. The combination of these four adverse prognostic factors was used to construct a prognostic factor model that distinguishes patients with different degrees of prognosis after ASCT ranging from good (01 adverse factor) to poor (
2 factors) (Figure 3A). Chemosensitivity to prior CT was one of the most important prognostic factors for TTF (Figure 4) with figures ranging from 68% ± 4% at 5 years for patients autografted in second CR to 34% ± 5% and 11% ± 6% for patients autografted with sensitive and resistant disease, respectively.
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Discussion |
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In the present analysis we have evaluated the prognostic factors influencing long-term outcome after an ASCT in a group of 357 patients autografted for HL relapsing after first line therapy with a median follow-up for surviving patients of 42 months (range 12174). Five-year OS and TTF were 57% (95% CI 5460%) and 49% (95% CI 4652%), respectively, for the entire group of patients, but these results significantly worsened in those patients presenting three or more risk factors analysed at relapse. In our study, two factors before relapse (advanced stage at diagnosis and the use of complementary RT to first line) and two factors at relapse (short first CR and the presence of visible disease after salvage chemotherapy) have become indicators of a poor outcome after transplantation. Patients with none or one risk factor had a 5-year TTF of 71%±4% after ASCT, whereas patients with three or more risk factors presented a 5-year TTF of only 18% ± 5%. The duration of the first CR, extranodal involvement at relapse and the present of visible disease at ASCT also significantly influenced long-term OS as well as the year of transplantation, an indirect indicator of the continuous improvement on transplant support in the last 10 years, and the presence of bulky disease at diagnosis. Patients with none or one of these risk factors had a 5-year OS of 82% ± 5% while patients with three or more risk factors had a 5-year OS of only 39% ± 5%.
One of the most important prognostic factors for relapsed HL patients is the duration of the first CR. In 1992, The National Cancer Institute updated their experience with the long-term follow-up of patients who had relapsed after polychemotherapy [3]. Patients were divided into those whose initial CR had lasted for at least 12 months and those in whom the first CR had been shorter. The same applies for high-dose therapy and autologous rescue as has been previously indicated by the prospective randomised HDR-1 protocol [19
]. In our analysis, the duration of the first CR also was one of the most important predictive factors both for TTF and OS: 5-year TTF was of 57 ± 4% for patients with a long first CR while it was only of 43% ± 4% for patients that relapsed earlier. In the same way, response to second-line chemotherapy (chemosensitive disease) has been used as the major selection criterion to proceed to ASCT. In our series, over 95% of the patients were tested for chemosensitivity and treated with salvage therapy before ASCT. Those patients entering a second CR had the best long-term prognosis with a 5-year TTF and 5-year OS of 68% ± 4% and 75% ± 4%, respectively. By contrast, patients with refractory relapse had a significantly poorer outcome with a 5-year TTF of only 11% ± 6% and a 5-year OS of 19% ± 7% (Figure 4). Although, it has recently been indicated that chemorefractory HL patients had survival indexes not different from those presented by sensitive patients [28
], our multicentre results suggest that these patients should be offered a different therapeutical approach. Our analysis, although retrospective in nature, suggests the benefit of achieving a CR before transplantation. Although in most studies it seems clear that chemosensitivity before transplantation is one of the major favourable prognostic factors for long-term outcome, the issue of number of cycles of salvage chemotherapy before transplantation and the need to achieve a CR before transplant has not been fully addressed. This issue should be prospectively analysed in future trials. Other prognostic factors may also predict for long-term survival in patients with relapsed and refractory HL and several reports describe prognostic factors identifiable before transplantation that can predict for a poor outcome with this approach; the extent of extranodal significantly influences both TTF and OS in our study, as previously indicated by Reece et al. [15
] in a group of 58 patients autografted in a single institution, by the group of City of Hope and Stanford University [11
, 21
] as well as by the French group in their retrospective analysis involving 270 patients [20
]. Year of transplantation has also been found to have an impact on OS in our analysis, as previously described by others [22
]. The impact of modern supportive care that includes hematopoietic growth factor support, peripheral blood instead of BM as the source of hematopoietic progenitor cells and newer antibiotic and antifungal agents have markedly decreased transplant-related toxicity in the last 10 years. The long time period over which patients included in this study have been autografted is a clear reflection of this fact. Finally, we have also found other variables, which measure tumour burden at diagnosis, to significantly modify long-term outcome after the intensive procedure. As in our analysis, prior RT has also been described to negatively influence the results of ASCT by City of Hope [11
].
There have been other attempts to construct prognostic indexes at relapse with the objective to identify subgroups of patients with a poor outcome with a conventional ASCT. In a series of 128 patients with relapsed HL homogeneously treated with the CBV protocol, Bierman et al. [7] found that a poor performance status, the failure of two or more chemotherapy protocols, and the presence of mediastinal disease predicted for a poor outcome after ASCT, with a 4-year failure-free survival of only 10% in those patients failing with two or more protocols. Reece et al. [15
] reported an analysis on 58 patients treated with ASCT in a single institution. Four prognostic groups were identified according to the presence of the following parameters at relapse: B symptoms, extranodal disease and a short first CR. Patients with no risk factor had a 3-year progression-free survival of 100% compared with 81% in patients with one risk factor, 40% in those with two risk factors and finally, 0% in patients with three risk factors. In patients autografted with the CBV protocol or the combination of TBIcyclophosphamide and etoposide, the group of City of Hope showed that more than two prior chemotherapy protocols, prior RT and extranodal disease at ASCT predicted for a poor outcome after the procedure [11
]. Similarly, and in a group that included 119 relapsed or refractory HL patients autografted with the CBV regimen or the TBIcyclophosphamide and etoposide protocol, the combination of B symptoms at relapse, BM or pulmonary involvement at ASCT and the presence of lymph nodes
2 cm were able to separate different prognostic groups with 4-year event-free survivals of 85% in patients with no adverse prognostic factors compared with 41% in patients with one bad-prognosis factor [21
].
Up to now, the largest report dealing with prognostic factors at relapse after a first CR had been reported by the French cooperative group (GELA) in 280 patients undergoing an ASCT [20]. They developed a two-factor model incorporating a short first CR and the presence of extranodal disease at relapse as adverse prognostic factors. With this model, patients with zero, one or two risk factors presented progression-free survival rates of 93%, 59% and 43%, respectively.
Finally, two other groups of investigators have analysed the usefulness of risk factors at relapse to predict long-term outcome. The GHSG [29] retrospectively analysed the prognostic risk factors at relapse in a group of 422 patients from an initial cohort of 4754 patients registered in the GHSG database between 1988 and 1999. In multivariate analysis, independent risk factors were time to relapse, clinical stage at relapse and anemia at relapse. The constructed prognostic score was independent of the type of therapy used to treat the relapse (e.g. conventional chemotherapy or high-dose therapy with ASCT). More recently, the Memorial SloanKettering Cancer Center investigators [30
] have developed a prognostic model of risk factors at relapse (B symptoms, extranodal disease and CR duration of <1 year) in a group of 65 patients (22 primary refractory and 43 relapsed) treated with two biweekly cycles of ifosfamide, carboplatin and etoposide. The presence of zero to one risk factor was associated with an event-free survival rate of 83% while it decreased to 10% in patients presenting with the three risk factors. This prognostic model has been used to develop tailored therapeutic strategies [31
].
The results and usefulness of a prognostic factor analysis are limited not only by the selection of the factors as potential candidates for the analysis but also by the population of patients included into it. One of the potential pitfalls of our analysis is the inevitable selection bias related to a study only involving patients reported to a transplant database, but the number of patients involved in the analysis is significantly higher to what has been previously reported and the follow-up is significantly longer (>3 years for the surviving patients).
In summary, the results of the present study indicate that it is possible to construct a prognostic factor score using easily collectable clinical variables that can identify cohorts of patients with a significantly different long-term outcome after high dose therapy and ASCT. The prognostic factors identified may be useful to develop tailored therapeutic approaches, with special clinical relevance in patients with poor-risk relapse who should be treated with innovative strategies.
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Acknowledgements |
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Received for publication July 28, 2004. Revision received October 8, 2004. Accepted for publication November 23, 2004.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 1988; 6: 603612.[Abstract]
3. 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 1992; 10: 210218.[Abstract]
4. Bonfante V, Santoro A, Viviani S et al. Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. J Clin Oncol 1997; 15: 528534.[Abstract]
5. Phillips GL, Wolff SN, Herzig RH et al. Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 1989; 73: 20862092.[Abstract]
6. 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 1991; 9: 18711879.[Abstract]
7. 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: 767773.[Abstract]
8. 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: 11371145.
9. 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: 704711.[Abstract]
10. 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 1993; 11: 23512361.[Abstract]
11. 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 1995; 85: 13811390.
12. 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 1996; 7: 151156.[Abstract]
13. 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 1997; 20: 451458.[CrossRef][ISI][Medline]
14. Sureda A, Arranz R, Iriondo A et al. Autologous stem cell transplantation for Hodgkin's disease: Results and prognostic factors in 494 patients from the GEL/TAMO Spanish Cooperative Group. J Clin Oncol 2001; 19: 13951404.
15. 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 1995; 83: 11931199.[ISI]
16. 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 1991; 77: 22922298.[Abstract]
17. 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 1997; 89: 814822.
18. 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: 10511054.[CrossRef][ISI][Medline]
19. Schmitz N, Pfistner B, Sextro M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy requiring autologous haemopoietic stem cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002; 359: 20652071.[CrossRef][ISI][Medline]
20. Brice P, Bouabdallah R, Moreau P et al. Prognostic factors for survival after HDT and ASCT for patients with relapsed HD: Analysis of 280 patients from the French Registry. Bone Marrow Transplant 1997; 20: 2126.[CrossRef][ISI][Medline]
21. 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 1997; 89: 801813.
22. 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 1998; 22: 265271.[CrossRef][ISI][Medline]
23. Fermé C, Mounier N, Divine M et al. Intensive therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: Results of the Groupe d'Études des Lymphomes de l'Adulte H89 Trial. J Clin Oncol 2002; 20: 467475.
24. Carbone PP, Kaplan HD, Musshogg K et al. Report of the Committee of Hodgkin's Disease staging. Cancer Res 1971; 31: 18601861.[ISI][Medline]
25. Kaplan EL, Meier P. Nonparametric estimation from incomplete estimations. J Am Stat Assoc 1958; 53: 457481.[ISI]
26. 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 1999; 17: 12441253.
27. Mantel N, Haenzel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1958; 22: 719723.[ISI]
28. Fung HC, Nademanee A, Krishnan A et al. Autologous hematopoietic cell transplantation (ASCT) for patients with chemo-refractory Hodgkin's lymphoma (HL). Blood 2003; 102: 119a (Abstr 404).[CrossRef]
29. Josting A, Franklin J, May M et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the Database of the German Hodgkin's Study group. J Clin Oncol 2002; 20: 221230.
30. Moskowitz CH, Nimer SD, Zelenetz AD et al. A 2-step comprehensive high-dose chemotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 2001; 97: 616623.
31. Moskowitz CH, Kewalramani T, Nimer SD et al. Risk-adapted high dose chemoradiotherapy and ASCT for patients with relapsed or refractory Hodgkin's disease: An intent to treat analysis. Blood 2003; 102: 118a (Abstr 403).[CrossRef]
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