The NCCN-IPI Helps to Identify Very High-Risk Patients with DLBCL and Can be Improved By Other Independent Clinical Factors Including Bulky Disease and beta2-Microglobulin
Authors: Coutinho Rita , Lobato Joana , Esteves Susana , Carvalho Susana , Pierdomenico Francesca , Bernardo Paulo , Gonçalves Filipe , Desterro Joana , Martins Soraia , Silva Carla , Silva Maria Gomes 
Published: October 2019

Abstract
The International Prognostic Index (IPI) has been the basis for predicting the outcome of diffuse large B cell lymphoma (DLBCL). With the improvement in prognosis with immunochemotherapy the predictive power of the IPI has been questioned.
Recently, the enhanced NCCN-IPI has been proposed to provide a better discrimination of risk groups. Additionally, other patient- and disease-specific factors not incorporated in the prognostic algorithms and easily assessed at diagnosis have been shown to impact on the clinical course. The prognostic value of the NCCN-IPI together with other clinical characteristics remains to be widely validated.
We aimed to assess the power of NCCN-IPI in risk group discrimination and compare it with IPI, as well as to investigate if the Body Mass Index (BMI), gender, diameter of the largest mass and levels of β2-microglobulin have independent prognostic impact when controlling for NCCN-IPI risk.
We conducted a retrospective analysis of consecutive R-CHOP treated de novo DLBCL cases diagnosed between January 2002 and December 2013 in a single center.
Kaplan-Meier method was used to estimate the overall (OS) and progression-free survival (PFS) distributions for risk groups. Logrank test with p-value adjustment by Hochberg method was used for pairwise comparisons between risk groups within each index. Independent prognostic impact of BMI, gender, bulky disease and β2-microglobulin was assessed by multivariate analysis using Cox model.
410 patients were included in the analysis, with a median age of 64 (16-89) years; 51% were male. The distribution according to age, stage, extranodal (EN) sites, performance status, β2-microglobulin, BMI and bulky disease (Table 1) were similar to published data.
With a median follow-up of 59 months, 5-yr OS and PFS were 69% and 65%, respectively. The distribution of patients according to IPI and NCCN-IPI risk groups is detailed in Table 1. Both scores adequately stratified patients according to risk of progression and death. In our cohort OS and PFS of low and low-intermediate risk groups using the NCCN-IPI were not significantly different. We documented a migration of patients from low (62%) and high (48%) to intermediate risk groups using the NCCN-IPI compared to the IPI. This score allowed a better discrimination between high-intermediate and high-risk disease (pairwise comparison of OS and PFS within NCCN and IPI risk scores of p=0.0087 vs p=0.044 and p=0.032 vs p=0.096, respectively). Only 12 patients classified as intermediate-risk IPI migrated to high NCCN risk group. Of these, 5 relapsed and 6 died (4 of lymphoma).
Multivariate analysis showed that bulky disease and β2-microglobulin are independent prognostic factors for OS and PFS when controlling for NCCN-IPI.
Using a large series of unselected R-CHOP treated patients, we pursued the validation of the NCCN-IPI as a better prognostic tool for DLBCL. In contrast to the original series, the NCCN-IPI showed limited discrimination capacity for OS and PFS between low- and low-intermediate risk groups. However, the new prognostic index helps to identify particularly poor prognosis patients that might benefit from alternative therapies. We also identified bulky disease and β2-microglobulin as independent prognostic factors in addition to NCCN-IPI and that could be incorporated in future prognostic scores. Additional studies are needed to evaluate the ability of biomarkers to improve the clinical risk stratification systems. Table 1.CharacteristicsValue, n (%)AgeMedian (range), yr64 (16-89)≥60 years241 (59%)Male208 (51%)Performance status (ECOG) ≥2a66 (16%)Stage ≥ III221 (54%)BMIbUnderweight (<18.5)15 (4%)Normal (18.5-24.9)170 (43%)Overweight (25.0-29.9)139 (35%)Obese (>29.9)73 (18%)Bulky disease (>7 cm)c157 (40%)β2 microglobulin >ULNd154 (45%)≥2 EN sites92(23%)BM, CNS, liver/GI or lung involvement136 (33%)IPIe vs NCCN-IPIe (%)Low12 vs 34Low-Int38 vs 26High-Int35 vs 20High18 vs 125-yr OS (%)IPI (low, low-int, high-int, high)87, 70, 59, 50p= 8x10-12NCCN-IPI (low, low-int, high-int, high)88, 82, 59, 47p= 2x10-125-yr PFS (%)IPI (low, low-int, high-int, high)86, 66, 51, 48p= 2x10-11NCCN-IPI (low, low-int, high-int, high)84, 78, 54, 45p= 7x10-10BM: bone marrow, CNS: central nervous system, GI: gastrointestinal, int: intermediate.a: 405 pts, b: 397 pts, c: 391 pts, d: 341 pts, e: 403 pts.

Disclosures
No relevant conflicts of interest to declare.