Disease Bulk and/or Very High LDH As Adverse Factors in IPI 1-2 Diffuse Large B-Cell Lymphoma (DLBCL): A Hellenic Database Validation of the LEO Cohort
Authors: Vassilakopoulos Theodoros P. , Arapaki Maria Panagiota , Apostolopoulou Christina , Verrou Evgenia , Kalpadakis Christina H. , Piperidou Alexia , Liaskas Athanasios , Sachanas Sotirios , Triantafyllou Theodora , Bitsani Aikaterini , Dimou Maria , Ioakeim Maria Anastasia , Siakantaris Marina , Pangalis Gerassimos , Katodritou Eirini , Angelopoulou Maria , Panayiotidis Panayiotis , Pappa Vassiliki , Papageorgiou Sotirios G. 
Published: December 2024

Background: Randomized phase 3 studies in DLBCL typically utilize the international prognostic index (IPI) to identify a suitable, higher-risk population in need of investigational therapy. Despite its wide applicability, IPI fails to identify subgroups of patients with inferior outcomes among those classified as low-intermediate (IPI 2) or low-risk (IPI 1). Recently, it was argued that the observed heterogeneity in outcomes within IPI scores could be attributed to loss of information within IPI variables due to the use of dichotomous cutoffs (Maurer et al, ASH 2023). Based on previous data (Maurer et al, AJH 2016) indicating that bulky disease is an independent prognostic factor and LDH has strong prognostic value that extends beyond the upper limit of normal (ULN), Maurer et al analyzed survival data for 1560 patients from the LEO cohort. High-risk IPI was defined as the presence of either bulky disease and/or very high LDH with an IPI score of 1-2. The definition of very high LDH was LDH&gt;1.3xULN and bulky disease was defined as maximum tumor diameter (MTD) of ≥7cm. Maurer et al were able to identify a subset of IPI 1-2 patients with inferior outcomes similar to the ones of patients with IPI 3, consisting of roughly 50% of pts with IPI 1-2. This important finding warrants further validation.
Aims: We sought to validate the LEO cohort findings by analyzing survival data from the developing Hellenic database.
Methods: Among 1529 DLBCL pts treated with immunochemotherapy (ICT) and registered in our database, 1411 had full IPI data: 1235 aged ≤80 years old (yo) and 176 (12%) &gt;80yo. Data on maximal tumor diameter (MTD) were available in 1069/1411 pts (76%). Pts with IPI 1-2 were classified as “low-risk” (LR; LDH≤1.3x and MTD&lt;7cm) or “high-risk” (HR; LDH&gt;1.3x and/or MTD≥7cm). Freedom From Progression (FFP) was defined as the time between treatment initiation and death during treatment, primary refractoriness or relapse. Progression Free Survival (PFS) was defined as FFP plus death of any cause in first complete remission.
Results: The median age of the 1411 pts was 67 years (IQR 56-75), 56% were males, 48% hade stage III/IV, 20% had PS≥2, 20% had ≥2 extranodal sites, 54% elevated LDH and 37% MTD≥7cm. As expected, IPI was highly predictive of FFP and PFS both in all pts and those ≤80yo. In pts ≤80yo the 2-year FFP was 94.1%, 87.7%, 74.1%, 69.8%, 50.7% and 44.0% for pts with IPI 0, 1, 2, 3, 4 and 5 respectively (p&lt;0.001) with 2-year PFS rates roughly 1-3% lower. Pts with HR IPI1-2 (44% of all pts and 45% of those ≤80yo) had significantly inferior FFP and PFS compared to LR IPI 1-2. Roughly, in pts ≤80yo, the 2-year FFP of HR IPI1-2 pts was 71.8% vs 90.7% for LP IPI1-2 (p&lt;0.001), being only 2% higher than that of pts with IPI 3. PFS data were similar. In addition, pts with IPI 2 had inferior 2-year FFP to those with IPI 1 (74.5% vs 89.4%, p&lt;0.001 in pts ≤80yo). In multivariate analysis both HR IPI1-2 status and IPI 2 per se had independent prognostic impact with hazard ratios 2.32 and 2.42 respectively and p-values ≤0.001 for both.
Conclusion: Analysis of the Hellenic dataset corroborates the findings published by Maurer et al with similarly sized LR and HR subgroups and numerically very similar 2-year PFS with the group of patients with IPI 1-2. Identification of a new subset of DLBCL patients with inferior prognosis not previously captured by current IPI variables is of great importance and warrants further attention. The Hellenic database is currently further enriched.