Abstract

Background: Detailed knowledge on prognostic factors in patients with rrHL treated with ASCT is essential to determine which patients could benefit from innovative treatment approaches with novel drugs to either improve prognosis or decrease toxicity. In this study we therefore aimed at developing a comprehensive prognostic score for progression free survival (PFS) after ASCT in a large international cohort.

Methods: A comprehensive set of risk factors was evaluated in patients of the German Hodgkin Study Group (GHSG) and the French H96 trial in phase I of the study. Potential risk factors at relapse including clinical stage, B-symptoms, extranodal disease, time to relapse (TTR), performance status (ECOG), mediastinal or lung involvement, bulky disease, anemia, lymphopenia, leukocytosis, albumin, LDH, ESR, chemosensitivity and number of salvage regimens were analyzed with multivariable Cox proportional hazards regression analyses. Sensitivity analyses accounted for missing values with covariance based estimation techniques in the full data set. Validation in phase II was performed in patients treated at the Memorial Sloan Kettering Cancer Center and in Danish hospitals.

Results: In phase I we identified 656 patients treated with single ASCT after salvage and high-dose chemotherapy (HDCT) from 1993 to 2012.The median age was 35 years and the median follow-up after ASCT was 60 months. All above listed risk factors with exception of LDH, albumin, leuko- and lymphocytes and mediastinal involvement had significant impact on PFS with hazard ratios (HR) from 1.39 to 2.22. The multivariate analysis identified stage IV disease, TTR ²3 months, ECOG ³1, bulk ³5 cm and inadequate response to salvage chemotherapy (<PR) as significant and not redundant risk factors for PFS. A prognostic score with equal weighting of these factors allowed identification of at least three risk groups for PFS and OS (table 1). In phase II the prognostic score was successfully validated in an independent sample of 390 patients treated in different clinical settings with evaluation of response to salvage therapy by investigator-read functional imaging instead of CT.

Conclusions: Based on this to date largest analysis (N=1046), precise and reliable risk stratification in patients with rrHL who successfully undergo ASCT can be achieved with five easily available clinical risk factors potentially representing five distinct dimensions: disease extent, tumor growth, performance status, tumor volume and chemosensitivity of disease.

Table 1.
Variable 2-Year PFS 5-Year PFS 5-Year OS Cox Univar.
Hazard Ratio
(95% CI) 
Cox Multivar.
Hazard Ratio
(95% CI) 
Multivar.
p-value
(n=371) 
stage IV 
RF- 434 75.9% 66.9% 76.6% -- --  
RF+ 201 54.2% 48.1% 58.1% 1.86 (1.44,2.41) 1.85 (1.29,2.67) 0.0009 
TTR <= 3 months 
RF- 555 72.7% 63.7% 75.4% -- --  
RF+ 101 51.8% 45.6% 47.9% 1.97 (1.46,2.67) 1.96 (1.08,3.54) 0.0261 
ECOG >= 1 
RF- 363 73.7% 65.8% 76.0% -- --  
RF+ 148 64.1% 55.4% 68.2% 1.53 (1.13,2.06) 1.51 (1.02,2.23) 0.0392 
bulk >= 5 cm 
RF- 347 76.4% 66.9% 76.0% -- --  
RF+ 174 61.5% 50.2% 64.2% 1.73 (1.30,2.31) 1.60 (1.11,2.30) 0.0114 
Non-response to salvage (<PR) 
RF- 429 73.7% 65.9% 77.3% -- --  
RF+ 84 51.2% 46.8% 58.0% 1.90 (1.34,2.68) 1.59 (1.02,2.50) 0.0416 
Prognostic score 
112 83.7% 76.8% 87.7% -- --  
129 76.0% 67.9% 79.1% 1.58 (0.96,2.61) 1.58 (0.95,2.61) 0.0764 
94 63.8% 56.7% 70.0% 2.28 (1.38,3.79) 2.33 (1.40,3.89) 0.0012 
3 - 5 36 39.1% 34.8% 46.5% 5.06 (2.85,8.99) 5.04 (2.76,9.21) <0.0001 
Variable 2-Year PFS 5-Year PFS 5-Year OS Cox Univar.
Hazard Ratio
(95% CI) 
Cox Multivar.
Hazard Ratio
(95% CI) 
Multivar.
p-value
(n=371) 
stage IV 
RF- 434 75.9% 66.9% 76.6% -- --  
RF+ 201 54.2% 48.1% 58.1% 1.86 (1.44,2.41) 1.85 (1.29,2.67) 0.0009 
TTR <= 3 months 
RF- 555 72.7% 63.7% 75.4% -- --  
RF+ 101 51.8% 45.6% 47.9% 1.97 (1.46,2.67) 1.96 (1.08,3.54) 0.0261 
ECOG >= 1 
RF- 363 73.7% 65.8% 76.0% -- --  
RF+ 148 64.1% 55.4% 68.2% 1.53 (1.13,2.06) 1.51 (1.02,2.23) 0.0392 
bulk >= 5 cm 
RF- 347 76.4% 66.9% 76.0% -- --  
RF+ 174 61.5% 50.2% 64.2% 1.73 (1.30,2.31) 1.60 (1.11,2.30) 0.0114 
Non-response to salvage (<PR) 
RF- 429 73.7% 65.9% 77.3% -- --  
RF+ 84 51.2% 46.8% 58.0% 1.90 (1.34,2.68) 1.59 (1.02,2.50) 0.0416 
Prognostic score 
112 83.7% 76.8% 87.7% -- --  
129 76.0% 67.9% 79.1% 1.58 (0.96,2.61) 1.58 (0.95,2.61) 0.0764 
94 63.8% 56.7% 70.0% 2.28 (1.38,3.79) 2.33 (1.40,3.89) 0.0012 
3 - 5 36 39.1% 34.8% 46.5% 5.06 (2.85,8.99) 5.04 (2.76,9.21) <0.0001 

Disclosures

Bröckelmann:Takeda: Research Funding. Casasnovas:Roche: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Consultancy. Hutchings:Takeda: Research Funding. von Tresckow:Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events ; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Borchmann:Millennium: Research Funding. Moskowitz:Takeda: Research Funding. Engert:Takeda: Consultancy, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.