The International Prognostic Factors Project score for advanced Hodgkin’s disease is useful for predicting outcome of autologous hematopoietic stem cell transplantation

P. J. Bierman1,+, J. C. Lynch2, R. G. Bociek1, V. L. Whalen1, A. Kessinger1, J. M. Vose1 and J. O. Armitage1

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The International Prognostic Factors Project on Advanced Hodgkin’s Disease developed a seven-factor prognostic score consisting of serum albumin, hemoglobin, gender, stage, age, leukocytosis and lymphocytopenia for newly diagnosed Hodgkin’s disease patients who receive chemotherapy. The purpose of this study was to determine whether this prognostic score would also be useful for Hodgkin’s disease patients undergoing autologous hematopoietic stem cell transplantation.

Patients and methods:

We performed a retrospective review of 379 patients who had autologous transplants for Hodgkin’s 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 0–1, 2–3 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 Hodgkin’s disease patients undergoing high-dose therapy followed by autologous hematopoietic stem cell transplantation.

Key words: autologous transplantation, Hodgkin’s disease, prognostic factors


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
High-dose therapy followed by autologous hematopoietic stem cell transplantation is an accepted therapy for patients with relapsed and refractory Hodgkin’s disease. A large number of prognostic factors are predictive of outcome for Hodgkin’s disease patients who undergo autologous transplantation. Recently, the International Prognostic Factors Project on Advanced Hodgkin’s Disease developed a scoring system comprising seven factors (serum albumin <4 g/dl, hemoglobin <10.5 g/dl, male gender, age >=45 years, Ann Arbor stage IV disease, white blood cell count >=15 000/mm3, and lymphocyte count <600/mm3 and/or <8% of the total white blood cell count) [1]. Each of these factors was independently associated with a similar risk of disease progression following primary chemotherapy treatment for patients with advanced Hodgkin’s disease. A prognostic score was developed based upon the total number of the seven prognostic factors that were present at diagnosis. This prognostic score was inversely correlated with freedom from progression and overall survival (OS). The purpose of this study was to test whether the same prognostic score could be applied to patients undergoing autologous hematopoietic stem cell transplantation for Hodgkin’s disease.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We performed a retrospective review of 379 Hodgkin’s disease patients at the University of Nebraska Medical Center who received high-dose therapy followed by autologous hematopoietic stem cell transplantation between 1 October 1984 and 30 December 1999. The majority of patients transplanted prior to 30 June 1992 have been reported previously [24]. Patients who had a second autologous transplant were excluded from the analysis. All patients signed informed consent documents before bone marrow harvest or peripheral blood stem cell collection, and before starting high-dose chemotherapy.

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 Hodgkin’s 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 {chi}2 statistic.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics are displayed in Table 1. The median follow-up was 5.1 years (range 12 days to 15.3 years). The estimated 10-year EFS was 24% [95% confidence interval (CI) 19% to 29%], and the estimated 10-year OS rate was 32% (95% CI 26% to 38%).


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 
The distribution of the adverse characteristics that were identified by the International Prognostic Factors Project on Advanced Hodgkin’s Disease as applied to our patient population are displayed in Table 2. The number of adverse prognostic factors (0–7) in each patient was calculated to determine an overall prognostic score. The distribution of prognostic scores is displayed in Table 3. Multivariate analyses were performed to determine whether any of the factors identified by the International Prognostic Factors Project on Advanced Hodgkin’s Disease were independently associated with EFS or OS (Table 4). We found that low serum albumin, anemia, age and lymphocytopenia were independently associated with shorter EFS. Anemia, age and lymphocytopenia were also associated with shorter OS, and low serum albumin was associated with a trend towards poorer OS (P = 0.07). All four of these factors were associated with a similar risk of treatment failure or death. Gender, stage and leukocytosis were not associated with significantly shorter EFS or OS.


View this table:
[in this window]
[in a new window]
 
Table 2. Distribution of adverse prognostic factors
 

View this table:
[in this window]
[in a new window]
 
Table 3. Distribution of prognostic scores
 

View this table:
[in this window]
[in a new window]
 
Table 4. Multivariate analysis of prognostic factors
 
We then applied the prognostic score developed by the International Prognostic Factors Project on Advanced Hodgkin’s Disease to our patients who had received autologous hematopoietic stem cell transplants. Event-free survival and OS were significantly associated with prognostic score (Figure 1). The individual prognostic scores were then compressed into three groups that also showed significant differences in EFS and OS (Figure 2). The estimated 10-year EFS rates for patients with 0–1 risk factors, 2–3 risk factors and >=4 risk factors were 38% (95% CI 28% to 59%), 23% (95% CI 16% to 30%) and 7% (95% CI 0% to 14%), respectively. The estimated 10-year OS rates were 48% (95% CI 36% to 60%), 30% (95% CI 23% to 38%) and 15% (95% CI 6% to 24%), respectively.



View larger version (31K):
[in this window]
[in a new window]
 
Figure 1. Outcome following autologous hematopoietic stem cell transplantation for Hodgkin’s disease according to the Prognostic Score for Advanced Hodgkin’s Disease developed by the International Prognostic Factors Project on Advanced Hodgkin’s Disease. (A) Event-free survival (P <0.001). (B) Overall survival (P <0.001).

 


View larger version (22K):
[in this window]
[in a new window]
 
Figure 2. Outcome following autologous hematopoietic stem cell transplantation for Hodgkin’s disease according to the Prognostic Score for Advanced Hodgkin’s Disease developed by the International Prognostic Factors Project on Advanced Hodgkin’s Disease, where the scores are compressed into three groups. (A) Event-free survival (P <0.001). (B) Overall survival (P <0.001).

 
Since gender, stage and leukocytosis were not significantly associated with poorer outcomes in the multivariate analysis, we calculated a prognostic score based upon the four characteristics that were significantly associated with poorer outcomes (low serum albumin, anemia, age and lymphocytopenia). A simplified prognostic score based upon these four characteristics was also predictive of EFS and OS (Figure 3). The estimated 10-year EFS for patients with 0, 1, 2 and >=3 of these risk factors was 40% (95% CI 29% to 52%), 23% (95% CI 12% to 35%), 22% (95% CI 14% to 30%) and 9% (95% CI 2% to 16%), respectively. The estimated 10-year OS rates were 48% (95% CI 34% to 61%), 35% (95% CI 22% to 48%), 27% (95% CI 18% to 36%) and 20% (95% CI 11% to 29%), respectively.



View larger version (26K):
[in this window]
[in a new window]
 
Figure 3. Outcome following autologous hematopoietic stem cell transplantation for Hodgkin’s disease according to the number of adverse prognostic characteristics, using a simplified index including only serum albumin, anemia, age and lymphocytopenia. (A) Event-free survival (P <0.001). (B) Overall survival (P <0.001).

 
The outcome of autologous hematopoietic stem cell transplantation for Hodgkin’s disease is influenced by the status of disease at the time of transplant. Therefore, we also applied the simplified prognostic score to patients who failed to enter remission with their initial chemotherapy regimen (primary refractory disease), first relapse patients and patients who were transplanted after first relapse. The EFS and OS correlated with the simplified prognostic score regardless of disease status at the time of transplantation (Table 5).


View this table:
[in this window]
[in a new window]
 
Table 5. Outcome of autologous haematopoietic stem cell transplantation according to disease status using the simplified prognostic scorea
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A variety of patient-, disease- and transplant-related factors have been shown to influence outcome following high-dose therapy and autologous hematopoietic stem cell transplantation for Hodgkin’s disease. A wide variety of prognostic factors also influence outcome for primary therapy, and the seven-factor scoring system developed by the International Prognostic Factors Project on Advanced Hodgkin’s Disease has proven to be useful in risk stratification for newly diagnosed patients.

The International Prognostic Index is a similar risk stratification system that was developed for newly diagnosed patients with aggressive non-Hodgkin’s 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-Hodgkin’s 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 I–II, as compared with 20% for patients with a score of III–IV (P = 0.04). In the same manner, we wished to test whether the Prognostic Score for Advanced Hodgkin’s Disease, which was developed for primary therapy, would also be useful for Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s disease. Investigators from Birmingham found no survival differences following autologous transplantation for Hodgkin’s 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 Hodgkin’s disease [3, 1014]. However, in most series of autologous transplantation for Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s disease from University College Hospital [10]. However, the largest trials of autologous hematopoietic stem cell transplantation for Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s disease [17]. The univariate analysis from a previous report from our institution showed that OS was significantly worse for patients with stage III–IV disease at time of transplant, as compared with stage I–II 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 Hodgkin’s 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 Hodgkin’s disease.

Several other indices have also been published for patients undergoing autologous transplantation for Hodgkin’s disease. A prognostic index from Vancouver was developed for Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s disease patients undergoing autologous hematopoietic stem cell transplantation for Hodgkin’s 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 Hodgkin’s 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 Hodgkin’s Disease is also applicable to patients with relapsed and refractory Hodgkin’s 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.


    Footnotes
 
+ Correspondence to: Dr P. J. Bierman, Department of Internal Medicine, Section of Oncology-Hematology, University of Nebraska Medical Center, Omaha, NE 68198-3330, USA. Tel: +1-402-559-5520; Fax: +1-402-559-6520; E-mail: pjbierma{at}unmc.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. N Engl J Med 1998; 339: 1506–1514.[Abstract/Free Full Text]

2. Armitage JO, Bierman PJ, Vose JM et al. Autologous bone marrow transplantation for patients with relapsed Hodgkin’s disease. Am J Med 1991; 91: 605–611.[ISI][Medline]

3. 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: 767–773.[Abstract]

4. 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: 151–156.[Abstract]

5. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

6. Cox DR. Regression models and life-tables. J R Stat Soc 1972; 34: 187–202.[ISI]

7. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994.[Abstract/Free Full Text]

8. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant 1999; 23: 561–567.[ISI][Medline]

9. Lumley MA, Milligan DW, Knechtli CJC et al. High lactate dehydrogenase level is associated with adverse outlook in autografting for Hodgkin’s disease. Bone Marrow Transplant 1996; 17: 383–388.[ISI][Medline]

10. 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 eight-year study of 155 patients. Blood 1993; 81: 1137–1145.[Abstract]

11. Horning SJ, Chao NJ, Negrin RS et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood 1997; 89: 801–813.[Abstract/Free Full Text]

12. Wheeler C, Eickhoff C, Elias A et al. High-dose cyclophosphamide, carmustine, and etoposide with autologous transplantation in Hodgkin’s disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant 1997; 3: 98–106.[Medline]

13. 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 1997; 20: 21–26.[ISI][Medline]

14. Lazarus HM, Rowlings PA, Zhang M-J et al. Autotransplants for Hodgkin’s disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 1999; 17: 534–545.[Abstract/Free Full Text]

15. 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 1997; 20: 745–752.[ISI][Medline]

16. Sweetenham JW, Carella AM, Taghipour G et al. High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. J Clin Oncol 1999; 17: 3101–3109.[Abstract/Free Full Text]

17. 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 Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative Group. J Clin Oncol 2001; 19: 1395–1404.[Abstract/Free Full Text]

18. Anderson JE, Litzow MR, Appelbaum FR et al. Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin’s disease: the 21-year Seattle experience. J Clin Oncol 1993; 11: 2342–2350.[Abstract]

19. Nademanee A, O’Donnell 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: 1381–1390.[Abstract/Free Full Text]

20. 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 1994; 83: 1193–1199.[Abstract/Free Full Text]