Definition and Validation of the New Elderly Prognostic Index (EPI) for Elderly Patients with Diffuse Large B-Cell Lymphoma Integrating Geriatric and Clinical Assessment: Results of the Prospective "Elderly Project" on 1353 Patients By the Fondazione Italiana Linfomi

Abstract

Introduction: Management of elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL) is challenging. A simplified Comprehensive Geriatric Assessment (sCGA) based on ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales has demonstrated to be better than clinical judgement to stratify patients' outcome but has never been included in initial assessment. To further assess the impact of sCGA on patients' outcome, we conducted a prospective observational study on a large series of elderly patients with DLBCL. Methods: Patients were enrolled if 65 year old or older, with an untreated de novo DLBCL. sCGA was available at a web based platform that classified patients as FIT, UNFIT, and FRAIL, as shown in Table 1. Treatment choice was left at physician discretion. According to anthracycline dose, therapy was classified as curative (≥70% of full anthracycline dose), intermediate (<70%) or palliative (no anthracycline). Primary study endpoint was Overall Survival (OS). Results: From December 2013 to December 2017, 1353 patients have been registered by 37 centres and 1207 were eligible. Median age was 76 years (65-94), 68% had stage III-IV, and 55% had an International Prognostic Index(IPI) ≥3; 500 (42%), 304 (25%), and 403 (33%) were classified as FIT, UNFIT and FRAIL, respectively. Data on treatment were available in 1164 patients: rituximab was used in 96% of patients; treatment was curative in 89%, 53%, and 36% of FIT, UNFIT, and FRAIL patients, respectively; intermediate in 10%, 39%, and 31%, palliative in 0%, 8%, and 33% of patients. The OS was available in 1158 out 1164 cases. With a median follow up of 30 months (1-59) 3y-OS was 64% (95% CI 61% to 67%). According to sCGA the OS was significantly different among the 3 geriatric groups. Correlation with OS was improved when sCGA was integrated with age < or ≥ 80 years to define 3 groups of patients (Table 2): FIT and UNFIT younger than 80 years (sCGA Group 1; 55%, 3 yr OS 75%), UNFIT ≥ 80 years and FRAIL younger than 80 years (sCGA Group 2: 28%, 3yr OS 58%), FRAIL ≥ 80 years (sCGA Group 3: 17%; 3yr OS 43%). Univariable and multivariable analysis for OS was conducted using the 3 sCGA groups and other clinical and laboratory features. The 3 sCGA groups were shown as independent prognostic factors with IPI and with anemia (Hb < 12 g/dl). We used results of multivariable analysis to build a categorical prognostic index assigning different weights to prognostic features based on their Hazard Ratio (HR) (Table 3). The Elderly Prognostic Index (EPI) was defined as the score obtained from the sum of the weights and allowed to define 3 risk groups: Low Risk (LR: score 0-1; 23% of patients); Intermediate Risk (IR; score 2-4; 48%); High Risk (HiR; score 5-7; 29%). The 3 EPI risk groups had a different 3 year OS of 87%(95%CI 81-91), 69%(95%CI 63-73), and 42% (95%CI 36-49); HR for IR vs LR 2.57 (1.72, 3.84); HiR vs LR 6.21(4.17 -9.25), HiR vs IR 2.42 (1.91-3.05) (Figure1). Regarding treatment modality, curative, intermediate and palliative therapies were adopted in 89%, 10%, and 1% of the LR group; 70%, 24%, 7% of the IR group, and 37%, 35%, 28% of the HiR group. The model was internally validated by means of 1000 procedures confirming good performance (slope shrinkage 0.935 and c-Harrell 0.675 in validation sample compared with 0.682 in training sample). The EPI was also tested in an external validation data set that was identified from the pivotal study of sCGA in DLBCL (N=172 patients, Tucci A. et al, Leuk Lymph, 2015) (Figure 1). Conclusion: Using data from this large prospective observational study on elderly DLBCL patients we were able to build a new prognostic index that allows to identify 3 risk groups with significant differences in terms of 3 years OS. The EPI is the first index that integrates geriatric assessment with clinical features and contributes to improving management and clinical research in elderly patients with DLBCL. Disclosures Spina: Servier: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Sandoz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other; Roche: Other: lecture fee; Teva: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; GILEAD: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Celgene: Other: lecture fee; BMS: Other: lecture fee; Sanofi Genzyme: Other: lecture fee; CTI: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Menarini: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee, Research Funding; Takeda: Other: lecture fee; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Pfizer: Membership on an entity's Board of Directors or advisory committees. Merli:Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Cavallo:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Chiappella:Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Ferrero:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Luminari:ROCHE: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; GILEAD: Other: Lecturer; TAKEDA: Other: Travel Grant.

The use of frailty assessments in treating older adults with aggressive lymphomas

“…A categorical prognostic index using a revised version of sCGA groups, the IPI and Hb levels was developed identifying three risk groups each associated with a different three‐year OS: the Low‐Risk group (23% of patients) had a three‐year OS of 87%, the Intermediate‐Risk group (48% of patients) had a three‐year OS of 69%, and the High‐Risk group (29% of patients), who had a three‐year OS of 42%. The index was validated in patients treated with ACRs and on an independent external series of patients 24 . This ‘Elderly Prognostic Index’ (EPI) is the first validated, prospective index to integrate GA with clinical features and may contribute to improving management and clinical research in elderly patients with DLBCL.…”

“…The index was validated in patients treated with ACRs and on an independent external series of patients. 24 This 'Elderly Prognostic Index' (EPI) is the first validated, prospective index to integrate GA with clinical features and may contribute to improving management and clinical research in elderly patients with DLBCL. Whether the EPI or other scoring systems can be used to precisely direct the use of specific immunochemotherapy dose intensity and predict for fitness for anthracycline-based treatment remains an open question.…”

A Multicenter Study of 239 Patients Aged Over 70 Years With Diffuse Large B-Cell Lymphoma in China

“…According to the IPI score, there are significant differences in PFS and OS between the IPI ≤ 3 and IPI > 3 groups, suggesting that the IPI score could predict the prognosis in elderly patients. Recently, a study from Italy reported that combining the comprehensive geriatric assessment (CGA) with the IPI score could identify three risk groups with notable differences in terms of OS ( Spina et al, 2019 ; Merli et al, 2021 ), which would help clinicians to evaluate the prognosis of patients with greater precisely.…”

Clinical characteristics and outcomes among 2347 patients aged ≥85 years with major lymphoma subtypes: a Nordic Lymphoma Group study

“…The improved survival seen for patients with aggressive lymphomas who received active treatment calls for better tools to evaluate treatment eligibility in the oldest old, to avoid diagnostic delay and to identify regimens with high tolerability. Currently, there are no perfect methods to do this as both the well‐validated Complete Geriatric Assessment (CGA) and Q8‐questionnarie have the inherent risk of interpreting lymphoma‐associated symptoms as frailty, 3,7,28 although a prognostic score integrating the CGA, IPI and haemoglobin value has demonstrated prognostic significance 29 . Further, more liberal use of RT and supportive drugs, such as granulocyte‐colony stimulating factors, optimisation of general health and involvement of family caregivers could potentially increase the number of patients eligible for active treatment 3 .…”

“…Currently, there are no perfect methods to do this as both the well-validated Complete Geriatric Assessment (CGA) and Q8-questionnarie have the inherent risk of interpreting lymphoma-associated symptoms as frailty, 3,7,28 although a prognostic score integrating the CGA, IPI and haemoglobin value has demonstrated prognostic significance. 29 Further, more liberal use of RT and supportive drugs, such as granulocyte-colony stimulating factors, optimisation of general health and involvement of family caregivers could potentially increase the number of patients eligible for active treatment. 3 Prior studies have reported improved survival rates with pre-planned dose reductions among patients aged ≥85 years.…”