1 Department of Internal Medicine, Section of Oncology-Hematology; 2 Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
Received 22 November 2001; revised 25 January 2002; accepted 11 February 2002
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Abstract |
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The International Prognostic Factors Project on Advanced Hodgkins Disease developed a seven-factor prognostic score consisting of serum albumin, hemoglobin, gender, stage, age, leukocytosis and lymphocytopenia for newly diagnosed Hodgkins disease patients who receive chemotherapy. The purpose of this study was to determine whether this prognostic score would also be useful for Hodgkins disease patients undergoing autologous hematopoietic stem cell transplantation.
Patients and methods:
We performed a retrospective review of 379 patients who had autologous transplants for Hodgkins disease, at the University of Nebraska Medical Center between October 1984 and December 1999. Multivariate analysis was performed to determine whether the prognostic factors identified by the International Prognostic Factors Project adversely influenced event-free survival (EFS) or overall survival (OS).
Results:
Low serum albumin, anemia, age and lymphocytopenia were associated with poorer EFS and OS. Gender, stage and leukocytosis were not associated with significantly poorer outcomes. Estimated 10-year EFS was 38%, 23% and 7% for patients with 01, 23 or 4 of the adverse prognostic characteristics identified by the International Prognostic Factors Project, respectively.
Conclusions:
The prognostic score for advanced disease is also useful for relapsed and refractory Hodgkins disease patients undergoing high-dose therapy followed by autologous hematopoietic stem cell transplantation.
Key words: autologous transplantation, Hodgkins disease, prognostic factors
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Introduction |
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Patients and methods |
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Patients were analyzed with respect to event-free survival (EFS) and OS. Event-free survival was defined as time from transplant until relapse, disease progression, or death from any cause. Patients alive and free from relapse or progression were censored at the date of last follow-up. Overall survival was defined as the time from transplant until death from any cause, or to time of last follow-up for patients who remained alive. EFS and OS were estimated using the method of Kaplan and Meier [5]. Comparisons of time-to-event distributions were performed using the log-rank test.
Univariate analyses were performed with respect to the seven prognostic factors identified in the International Prognostic Factor Project on Advanced Hodgkins Disease [1]. When the value of a risk factor was unknown (serum albumin, n = 27; hemoglobin, n = 9; white blood cell count, n = 9; lymphocyte count, n = 11; disease stage, n = 4), the risk factor was considered to be absent. For example, unknown serum albumin levels were considered to be 4 g/dl. Since laboratory parameters can be influenced by the use of hematopoietic growth factors and the collection of peripheral blood stem cells, these values were obtained immediately prior to mobilization, or for non-mobilized patients immediately prior to the start of high-dose therapy. Laboratory values for patients transplanted with autologous bone marrow and values for the other non-laboratory components of the prognostic score were obtained immediately prior to the start of high-dose therapy. The independent contribution of factors found to be significantly associated with transplant outcome in the univariate analyses were assessed using the Cox proportional hazards model [6]. Reported P values for these models were based on the likelihood ratio
2 statistic.
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Results |
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Discussion |
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The International Prognostic Index is a similar risk stratification system that was developed for newly diagnosed patients with aggressive non-Hodgkins lymphoma [7]. This index stratifies patients according to age, performance status, serum lactate dehydrogenase level, stage and number of extranodal sites of disease. Although the International Prognostic Index was developed for newly diagnosed patients, investigators from Memorial Sloan-Kettering applied the index to relapsed and refractory non-Hodgkins lymphoma patients who received conventional salvage therapy followed by high-dose therapy and autologous hematopoietic stem cell transplantation [8]. The estimated 2-year failure-free survival was 59% for patients with a score of III, as compared with 20% for patients with a score of IIIIV (P = 0.04). In the same manner, we wished to test whether the Prognostic Score for Advanced Hodgkins Disease, which was developed for primary therapy, would also be useful for Hodgkins disease patients who have autologous transplants.
We found that low serum albumin, anemia, age and lymphocytopenia were associated with shorter survival, as shown in the Prognostic Score for Advanced Hodgkins Disease. The influence of serum albumin, anemia and lymphocyte counts have not been examined for their prognostic impact in large series of autologous transplantation for Hodgkins disease. Investigators from Birmingham found no survival differences following autologous transplantation for Hodgkins disease when results in patients with hemoglobin levels <12 g/dl were compared with patients with hemoglobin levels 12 g/dl [9]. In contrast to our results, most large series have not identified age as an important predictor of outcome following autologous hematopoietic stem cell transplantation for Hodgkins disease [3, 1014]. However, in most series of autologous transplantation for Hodgkins disease, the average age of patients is
30 years and relatively few patients are 45 years of age or older. In our series, only 11% of patients were
45 years of age.
Unlike the Prognostic Score for Advanced Hodgkins Disease, we failed to show that gender, leukocytosis or stage had a significant impact on outcome. It is interesting that female gender, rather than male gender, was associated with poorer progression-free survival in the analysis of autologous bone marrow transplantation for Hodgkins disease from University College Hospital [10]. However, the largest trials of autologous hematopoietic stem cell transplantation for Hodgkins disease have not identified gender as a significant prognostic factor [3, 1117]. The influence of leukocytosis has not been examined in other large series of autotransplants for Hodgkins disease, and it should be noted that only 7% of patients in our series had this characteristic.
Other series have also failed to identify stage as an important prognostic variable for patients undergoing autologous hematopoietic stem cell transplantation for Hodgkins disease [17]. The univariate analysis from a previous report from our institution showed that OS was significantly worse for patients with stage IIIIV disease at time of transplant, as compared with stage III disease, although this difference was not observed in the multivariate analysis [3]. Similar results were also seen in a series from Seattle that included patients who received both allogeneic and syngeneic transplants [18]. However, patients with extranodal disease are often classified as stage IV, and other investigators have suggested that the presence of extranodal disease at conditioning [12, 19] or at relapse may be an adverse prognostic factor [11, 13, 20].
Since only four of the prognostic factors found to be significant in the Prognostic Score for Advanced Hodgkins Disease were significant in our analysis, we carried out a separate analysis that included only serum albumin, hemoglobin, age and lymphocyte count. We found that a simplified prognostic index using these variables was also able to identify subgroups with significantly different EFS and OS, without using the variables of gender, stage and leukocytosis. This index uses easily identifiable variables that are obtainable for virtually all patients who undergo autologous hematopoietic stem cell transplantation for Hodgkins disease.
Several other indices have also been published for patients undergoing autologous transplantation for Hodgkins disease. A prognostic index from Vancouver was developed for Hodgkins disease patients undergoing autologous bone marrow transplantation in first relapse [20]. A model was created that identified systemic symptoms at relapse, initial complete remission duration of <1 year, and extranodal disease at relapse as significant variables for progression-free survival. The actual 3-year progression-free survival was 100%, 81%, 40% and 0% for patients with 0, 1, 2 or all 3 risk factors, respectively. A similar index from Stanford University identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse, and more than minimal disease (>75% reduction in bulky masses 10 cm or no lymph nodes >2 cm, and <10% bone marrow involvement) at transplant as significant prognostic factors in patients with recurrent or refractory Hodgkins disease [11]. The actuarial 3-year freedom from progression was 85%, 57%, 41% and <20% for patients with 0, 1, 2 or 3 risk factors, respectively. Another analysis of Hodgkins disease patients undergoing autologous hematopoietic stem cell transplantation for Hodgkins disease identified progressive disease at the time of transplant, more than one site of extranodal disease, and abnormal performance status as significant prognostic factors for progression-free survival and OS [12]. The 3-year actuarial survival was 82%, 56% and 19% for patients with 0, 1 or
2 risk factors, respectively. Another analysis from the French registry evaluated prognostic factors for Hodgkins disease patients in first relapse [13]. An interval of <1 year between end of treatment and relapse, and extranodal relapse, were identified as adverse prognostic factors. The 4-year OS rates were estimated at 93%, 59% and 43% for patients with 0, 1 or 2 risk factors, respectively.
We have demonstrated that the Prognostic Score for Advanced Hodgkins Disease is also applicable to patients with relapsed and refractory Hodgkins disease who undergo high-dose therapy with autologous hematopoietic stem cell transplantation. We did not find that stage, gender or leukocytosis were significantly associated with EFS or OS. A simplified prognostic score based upon serum albumin, hemoglobin, age and lymphocytopenia was also useful. Furthermore, the simplified prognostic score was independent of the status of disease at the time of transplant. These prognostic factors are readily available, although it is not known whether this prognostic score has advantages over other indices that have been reported, or whether other prognostic variables such as chemotherapy sensitivity or extent of prior therapy would be more useful.
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Footnotes |
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References |
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