Identification of Prognostic Factors in Early Unfavorable Stage Hodgkin’s Lymphoma (HL): An Individual Patient Data Meta-Analysis.

Background: In patients with early unfavorable stage HL, generally defined as stage I and II patients with mediastinal bulk, elevated ESR, ³ 3 involved nodal regions, older age or extranodal involvement, progression-free-survival (PFS) is low compared to patients with early favorable or advanced stages disease. This indicates suboptimal treatment strategies and clinical heterogeneity within the group of patients with early unfavorable stage HL. An international collaborative study was initiated to identify factors that may predict for poor prognosis in this patient group.

Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials (n>100 patients per study arm) in early stage HL patients with one or more risk factors receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. Individual patient data were collected and risk factors for PFS (including disease progression, relapse or death) identified using multivariate analysis (linear stepwise proportional hazards) stratified by study.

Results: Six studies were identified; data from 4,490 adult patients enrolled between 08/1982 and 01/2003 were available for analysis. The median follow up was 64 months; 663 patients experienced an event leading to an overall 5-year PFS rate of 85% (95% CI 83%–88%). Six factors were significantly (P<0.01) associated with poor PFS: male gender (Hazard ratio (HR) 1.69), age (HR per additional life year 1.03), B symptoms (HR 1.25), anemia (HR per 1 g/dL Hb decrease 1.09), WBC (HR per 1000 WBC increase 1.02) and large mediastinal tumor (HR 1.54). Split into quintiles by predicted risk, observed 5-year PFS rates differed significantly (p<0.001): 80% of patients with early unfavorable stage HL achieved 5-year PFS rates ranging from 84% (95% CI 81%–87%) to 92% (95% CI 90%–94%) while 20% of patients had poor 5-year PFS, i.e. 76% (95% CI 73%–79%). Compared to low risk patients, those with high risk were more often male (81% vs 40%), older (median age 50 vs 29 years) and presented more often with B symptoms (62% vs 28%) and large mediastinal tumor (42% vs 27%). These data show that among stage I and II patients with at least one risk factor heterogeneity exists.

Conclusion: Using basic characteristics and routine tests, it is possible to identify a subgroup of early unfavorable stage patients with poor PFS while receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. For these patients, treatment optimization is open to discussion in particular when compared to that of patients with advanced stage disease.