Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients

J. Czyz*, R. Dziadziuszko, W. Knopinska-Postuszuy, A. Hellmann, L. Kachel, J. Holowiecki, J. Gozdzik, J. Hansz, A. Avigdor, A. Nagler, M. Osowiecki, J. Walewski, P. Mensah, W. Jurczak, A. Skotnicki, M. Sedzimirska, A. Lange, W. Sawicki, K. Sulek, M. Wach, A. Dmoszynska, A. Kus, T. Robak and K. Warzocha On behalf of the Polish Lymphoma Research Group

Medical University of Gdansk, Gdansk, Poland

* Correspondence to: Dr J. Czyz, Department of Haematology, Medical University of Gdansk, 80-211 Gdansk, Debinki St. 7, Poland. Tel: +48-58-349-22-30; Fax: +48-58-349-22-33; Email: jczyz{at}amgb.gda.pl


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
Background: The reported probability of survival of patients with Hodgkin's disease (HD) following high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) is 35–65% at 5 years. The Polish Lymphoma Research Group investigated retrospectively prognostic factors for overall survival (OS) and event-free survival (EFS), and the risk of secondary malignancies in a large series of patients who underwent HDC/ASCT.

Patients and methods: The data of 341 consecutive patients treated in 10 centers from 1990 to 2002 were collected and analyzed.

Results: The actuarial 5-year OS and EFS were 64% [95% confidence interval (CI) 57% to 71%] and 45% (95% CI 39% to 51%), respectively. In the multivariate model, unfavorable prognostic factors for EFS were less than partial response at the time of ASCT [relative risk (RR), 2.92 (95% CI 1.68–5.08); P<0.001] and three or more previous chemotherapy lines (RR, 2.16; 95% CI 1.42–3.30; P<0.001). These two factors were also associated with unfavorable OS (RR, 3.32; 95% CI 1.90–5.79; P<0.001 and RR, 2.34, 95% CI 1.51–3.64; P<0.001). Five-year cumulative risk of secondary malignancy was 8.4% (95% CI 2% to 13%) and the only identified risk factor was splenectomy (P=0.02).

Conclusions: HDC/ASCT should be considered early in the course of disease for patients with a response after standard therapy.

Key words: autologous transplantation, high-dose chemotherapy, Hodgkin's disease


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
The majority of patients with advanced Hodgkin's disease (HD) can be effectively treated with standard chemotherapy, which provides complete remission in >80% of patients [1Go, 2Go]. Unfortunately, patients with primary resistant or relapsed disease have a relatively low chance of cure. At present, the main approach for these patients is high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT). Reported 5-year overall survival (OS) probability is 35–60% in patients with primary resistant disease and 50–65% in patients who have relapsed after standard therapy [3Go–10Go]. There are only two relatively small randomized clinical trials comparing high-dose with standard chemotherapy in high-risk HD patients and the influence of dose escalation on OS is still debatable [11Go, 12Go]. The limited number of studies including large series of transplanted HD patients prompted us to perform the present retrospective analysis.

This study includes the data of 341 consecutive patients treated with HDC/ASCT in 10 centers co-operating in the Polish Lymphoma Research Group. We analyzed the response rates, OS and event-free survival (EFS) and the rate of secondary malignancies. Univariate and multivariate analyses were performed to identify prognostic factors important for the treatment outcome.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
The data of 341 adult patients with HD who underwent HDC/ASCT from August 1990 to March 2002 were collected retrospectively in 1999 and updated every 6 months until October 2002. In November 2002, the records of all patients were reviewed and reporting centers (nine from Poland and one from Israel) were contacted to provide additional information. Primary resistance was defined as disease progression during first-line chemotherapy or as partial remission after induction treatment with progression within 3 months of the completion of treatment. Early relapse was defined as a relapse within 12 months after HDC/ASCT. Partial remission was defined as ≥50% reduction in the greatest diameter of all sites of disease, without any new lesions. Complete remission group also included patients with persistent scan abnormalities without biopsy confirmation (complete remission uncertain). The characteristics of patients at initial therapy and details of high-dose therapy are presented in Tables 1, 2 and 3. Patient prognosis was assessed using International Prognostic Factors (IPF) score on advanced HD, as proposed by Hasenclever and Diehl [13Go]. Median time from diagnosis to HDC/ASCT was 24 months. The grafts were not manipulated in vitro, 38% of patients received hematopoietic growth factors. The response was usually assessed 3 months after the completion of chemotherapy. Physical examination, chest X-ray and computed tomography were routinely used for response evaluation. Gallium scintigraphy and magnetic resonance imaging were used in selected cases.


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Table 1. Initial patient characteristics and therapy

 

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Table 2. Patient characteristics at the time of transplantation

 

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Table 3. Characteristics of HDC/ASCT

 
Definition of sensitive and resistant disease
Patients were defined as resistant to standard chemotherapy if they did not achieve partial remission after one line of standard treatment or complete remission/complete remission uncertain after two lines of standard treatment or achieved complete remission lasting <3 months.

Statistical analysis
Categorical variables were compared using the chi-square test. Survival data were analyzed using the Kaplan–Meier method. OS was calculated from the date of transplant to the date of death from any cause or the last follow-up evaluation. For EFS, complete observations included disease relapse or death due to any reason. The log-rank test was used for univariate comparisons and multivariate analysis was performed with Cox proportional hazards model with stepwise backward selection of significant covariates based on Wald's statistics. For hypothesis testing, a type I error of 0.05 was used.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
Response to HDC/ASCT
Three months after HDC/ASCT, 238 patients (70%) were in complete response (CR) and 48 (14%) in partial response (PR). In this group 110 patients were already in CR at the time of transplantation. Thirty-seven patients (11%) did not respond or progressed after high-dose treatment. There were 18 (5%) early deaths. Fifty-nine patients (25%) in CR after HDC/ASCT subsequently relapsed. The actuarial 5-year EFS was 45% (95% CI 39% to 51%) and 5-year OS was 64% (95% CI 57% to 71%; Figure 1).



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Figure 1. Overall and event-free survival.

 
Of the treated patients (55%), 186 were defined as sensitive and 87 (26%) as resistant to standard chemotherapy according to the definition used in this study. In 68 cases (20%) response could not be assessed adequately and this group was analyzed separately. Of the sensitive patients, 168 (91%) were in CR and eight (4%) in PR after HDC/ASCT in comparison with 30 (34%) in CR and 20 (23%) in PR from the resistant group and 39 (57%) in CR and 20 (29%) in PR from the third group of patients. There were seven (4%) early deaths in the first, five (6%) in the second and five (7%) in the third group. Five-year EFS were 62% (95% CI 52% to 72%) versus 16% (95% CI 8% to 24%) and 33% (95% CI 18% to 47%). The differences between the first and the other groups were highly significant (P<0.001 for both comparisons). The actuarial 5-year OS were 79% (95% CI 71% to 87%) for sensitive, 46% (95% CI 30% to 61%) for resistant patients (P<0.001) and 49% (95% CI 31% to 67%) for non-assessed patients (P=0.002). OS according to response is presented in Figure 2.



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Figure 2. Overall survival according to disease response.

 
Prognostic factors
In the univariate analysis, five factors were identified as predictors of unfavorable EFS including less than PR at the time of ASCT, three or more previous chemotherapy lines, histological type other than LP resistance to standard chemotherapy and B symptoms (Table 4). Patients transplanted with active disease had only 16% (95% CI 7% to 24%) EFS probability at 5 years in comparison with 66% (95% CI 54% to 78%) for patients with CR and 46% (95% CI 37% to 55%) with PR (P<0.001) (Figure 4). EFS probability at 5 years for patients with three or more chemotherapy lines before HDC/ASCT was 26% (95% CI 16% to 36%) versus 56% (95% CI 49% to 64%) for those treated less extensively (P=0.01; Figure 6). Prolonged EFS was observed in patients with LP type as compared with other histological subtypes (P=0.01), but the former group included only 10 patients. In the multivariate analysis, less than PR at the time of HDC/ASCT (RR 2.92; 95% CI 1.68–5.08; P<0.001) and more than three chemotherapy lines before HDC/ASCT (RR 2.16; 95% CI 1.42–3.30; P<0.001) remained significant predictors for shorter EFS (Table 5).


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Table 4. Univariate analysis of event-free survival

 


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Figure 4. Event-free survival according to disease status at transplantation.

 


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Figure 6. Event-free survival according to number of previous chemotherapy lines.

 

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Table 5. Multivariate analysis of event-free survival

 
Four factors were identified as significant in the univariate OS analysis: less than PR at the time of HDC/ASCT, three or more chemotherapy lines before HDC/ASCT resistance to standard chemotherapy and the presence of ‘B symptoms’ at the time of transplantation (Table 7). Patients transplanted with CR had 77% (95% CI 68% to 88%) and patients with PR had 71% (95% CI 60% to 81%) 5-year OS probability (Figure 3). The survival in these two groups was significantly better than in patients with less than PR at HDC/ASCT; OS probability at 5 years of only 33% (95% CI 17% to 49%). Patients with two or less chemotherapy lines before HDC/ASCT had an excellent 5-year survival probability [78% (95% CI 71% to 85%)] in comparison with those with three or more chemotherapy lines [39% (95% CI 24–53%)] (Figure 5). The presence of ‘B symptoms’ at the time of transplantation was identified as significant in univariate analysis of OS; however, it lost its significance in the final multivariate model (Table 7).


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Table 7. Multivariate analysis of overall survival

 


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Figure 3. Overall survival according to disease status at transplantation.

 


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Figure 5. Overall survival according to number of previous chemotherapy lines.

 
Hematological recovery
The median time to granulocyte recovery of >0.5 g/l was 14 days (range 5–73). Hematological recovery was significantly faster in patients autografted with peripheral blood cells (median 13 days, range 5–73) as compared with bone marrow (median 17 days, range 8–39; P<0.001). Growth factor administration after HDC/ASCT resulted in a faster granulocyte recovery, with a median of 13 days (range 5–73) compared with 15 days (range 7–37; P=0.02) in patients not receiving growth factors. Median time to platelet recovery to >50 g/l was 15 days (range 0–90). Platelet regeneration was dependent on progenitor cell source, the use of peripheral blood significantly shortened the time of recovery: the regeneration time was 13 days (range 1–90) versus 20 days (range 8–47) in patients transplanted with bone marrow (P<0.001). Eighteen patients (5%) died without regeneration due to the toxicity of the conditioning regimen.

Secondary malignancies
Eleven cases (3.2%) of a secondary malignancy (SM) were observed, including seven cases of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), two non-Hodgkin's lymphomas and two solid tumors. Median time to SM diagnosis was 21 months (range 3–54) and the 5-year cumulative risk was 8.4% (95% CI 2% to 13%) (Figure 7). Among these patients, eight received radiotherapy before and one after HDC/ASCT; eight were transplanted with peripheral blood and three with bone marrow. Hematopoietic growth factors were administrated in five patients. The low total number of SM hampered meaningful analysis with adequate power to identify risk factors. The only identified factor increasing the risk of developing SM was splenectomy before HDC/ASCT (P=0.02). Other analyzed factors, including number of chemotherapy lines before transplantation, sex, age or radiotherapy before or after HDC/ASCT, were insignificant.



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Figure 7. Cumulative risk of secondary malignancy.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
High-dose chemotherapy with autologous stem cell transplantation is now extensively used in patients with refractory or relapsed HD. It can offer long-term freedom from progression in 40–60% of patients, depending on risk factors. In this study, we demonstrated that active disease at the time of transplant and the number of previous chemotherapy lines had a significant negative influence on post-transplant OS and EFS. These findings are consistent with the results reported by Sureda et al. in the largest reported series of 494 transplanted patients with HD [9Go]. Other groups also found the disease status at ASCT to be an important prognostic factor for EFS and OS [4Go, 5Go, 8Go, 14Go–16Go] Table 8. We did not find a difference in outcome between patients who achieved CR versus PR, whereas active disease was an adverse prognostic factor.


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Table 8. Results of larger ASCT series in patients with Hodgkin's disease

 
The second factor influencing OS and EFS was the number of chemotherapy lines before HDC/ASCT. Sureda et al. suggested that this association was in part due to significantly higher early treatment-related mortality in heavily pre-treated patients [9Go]. Worse OS and EFS in more pre-treated patients has also been demonstrated by other authors [4Go, 17Go]. Other groups have reported that patients with untested relapse had better outcome than patients with either chemosensitive or chemoresistant disease [4Go, 18Go]. On the other hand, Jostings et al. reported favorable outcome in patients transplanted at the time of maximal response to standard treatment [19Go]. In 1997, this group initiated a multicenter phase II trial with high-dose sequential chemotherapy followed by a myeloablative course [20Go]. Early results indicate that this approach could be safe and effective in selected lymphoproliferative disorders. The interim analysis of that study demonstrated the freedom from treatment failure in 30% of patients with progressive disease and in up to 68% of patients with late relapse. One of the suggested reasons for better survival in patients transplanted early in the course of the disease was lower risk of death from transplant-related complications [9Go, 17Go, 18Go]. Our results do not confirm this finding.

The definition of resistant and chemosensitive disease is often unclear, especially in retrospective studies. In this report, we have tried to analyze our data defining resistant patients as those who did not achieve partial remission after one line of standard chemotherapy or complete remission/complete remission uncertain after two lines of standard treatment or those who achieved a response lasting <3 months. We have failed to categorize 20% of patients according to these criteria even after thorough revision of our data. In particular, those patients who were transplanted prior to formal documented evaluation could not be defined appropriately. We have found marked EFS and OS differences between the group of patients with chemosensitive disease as compared with resistant and non-evaluated patients, and this finding is in accordance with other studies.

The total number of early deaths in the present series was relatively low, possibly because most of the transplants were performed during the last 10 years. The use of peripheral blood instead of bone marrow, more frequent use of hematopoietic growth factors and better selection of patients resulted in reduction of treatment-related mortality to <5% [7Go, 8Go, 10Go–13Go, 15Go–18Go, 21Go]. The use of peripheral blood resulted in more rapid granulocyte and platelet engraftment in our patients. This observation is supported by the results of randomized and case–control studies [22Go–25Go]. Currently, peripheral blood rather than bone marrow is used as the source of hematopoietic cells for ASCT in HD patients. Therefore, the relapse of the underlying disease and the risk of secondary malignancy remain the main problems accompanying ASCT in HD patients Figure 7. Treatment-related MDS and AML are the predominant types of SM after ASCT, but increased risk of solid tumors was also observed [26Go]. The cumulative risk of MDS and AML was estimated at 4–15% at 5 years [9Go, 26Go–28Go]. Several factors contribute to the development of these malignancies, including previous treatment with alkylating agents, older age at HDC/ASCT, the use of etoposide for priming PBSC and low count of infused cells [9Go, 26Go, 29Go–33Go]. Some investigators reported an association between conditioning with total body irradiation (TBI), PBSC graft and the risk of MDS/AML. However, this issue remains debatable and should be addressed through the analysis of large databases [28Go, 29Go, 32Go, 34Go, 35Go]. In our series, the only risk factor for SM was prior splenectomy. This factor was already reported in two earlier studies [26Go, 36Go].

The outcome of treatment-related MDS/AML is dismal, even with the use of salvage allogenic bone marrow transplantation. Median survival time is 6 months and 5-year EFS after allogenic marrow transplantation is 0–8% [30Go, 37Go]. Only two of seven patients with these diagnoses are still alive in our series, one without evidence of disease after allogenic bone marrow transplantation. It was postulated that most cases of MDS and AML may have been induced by the therapy applied prior to transplantation. Most probably, patients who received a significant amount of chemotherapy or combination chemoradiotherapy for resistant disease or for multiple relapses are at higher risk of SM after transplantation. Unfortunately, it is difficult to indicate any preventive strategies in patients who are at high risk for SM.

In conclusion, HDC/ASCT achieves satisfactory results in a large proportion of patients with HD at acceptable toxicity and with a relatively low early death rate. Prognostic factors should help to select the best candidates for this treatment and to avoid unnecessary morbidity in patients without chance of cure. High-dose treatment should be considered early in the course of disease for patients responding to standard therapy. Additional data are necessary to better define risk factors for the development of secondary malignancy and to establish preventive measures in this group of patients.


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Table 6. Univariate analysis of overall survival

 

    Appendix
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
List of participants: Lucja Kachel, Jerzy Holowiecki, Silesian Medical University, Katowice; Jolanta Gozdzik, Janusz Hansz, University of Medical Science, Poznan; Abraham Avigdor, Arnon Nagler, Chaim Scheba Medical Center, Tel-Hashomer; Michal Osowiecki, Jan Walewski, Maria Slodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa; Krzystof Warzocha, Institute of Haematology and Blood Transfusion, Warszawa; Patrycja Mensah, Wojciech Jurczak, Aleksander Skotnicki, Jagiellonian University, Collegium Medicum, Kraków: Mariola Sedzimirska, Andrzej Lange, Lower Silesian Centre for Cellular Transplantation with National Bone Marrow Donor Registry; Waldemar Rawicki, Kazimierz Sulek, Military Medical Center, Warszawa; Malgorzata Wach, Anna Dmoszynska, Medical University, Lublin; Agata Kus, Tadeusz Robak, Medical University, Lódz; Jaroslaw Czyz, Wanda Knopinska-Posluszny, Andrzej Hellmann, Medical University of Gdansk.


    Acknowledgements
 
We thank Jacek Jassem for an in-depth discussion of the study and Agnieszka Kukowska for help in the preparation of this manuscript.

Received for publication September 30, 2003. Revision received March 16, 2004. Accepted for publication March 18, 2004.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
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