Medical University of Gdansk, Gdansk, Poland
* Correspondence to: Dr J. Czy, 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
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Abstract |
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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 1.685.08); P<0.001] and three or more previous chemotherapy lines (RR, 2.16; 95% CI 1.423.30; P<0.001). These two factors were also associated with unfavorable OS (RR, 3.32; 95% CI 1.905.79; P<0.001 and RR, 2.34, 95% CI 1.513.64; 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
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Introduction |
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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.
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Patients and methods |
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Statistical analysis
Categorical variables were compared using the chi-square test. Survival data were analyzed using the KaplanMeier 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.
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Results |
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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 354) 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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Discussion |
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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% [7, 8
, 10
13
, 15
18
, 21
]. 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 casecontrol studies [22
25
]. 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 [26
]. The cumulative risk of MDS and AML was estimated at 415% at 5 years [9
, 26
28
]. 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 [9
, 26
, 29
33
]. 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 [28
, 29
, 32
, 34
, 35
]. In our series, the only risk factor for SM was prior splenectomy. This factor was already reported in two earlier studies [26
, 36
].
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 08% [30, 37
]. 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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Appendix |
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Acknowledgements |
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Received for publication September 30, 2003. Revision received March 16, 2004. Accepted for publication March 18, 2004.
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References |
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