Elderly Prognostic Index
S1918 trial design
Despite a number of significant advances in the management and treatment of aggressive lymphomas, there is a clear unmet clinical need in the elderly population. Evidenced by inferior survival and remission rates, there remains inadequate treatment approaches for elderly patients with lymphoma, particularly those who are ineligible for intensive therapy.1
Considering that non-Hodgkin lymphomas (NHL) are typically diagnosed in people aged 65–74 years, this clinical void is of significant concern. In the coming months, the Lymphoma Hub will be covering the latest information on lymphoma in the elderly, including updated results from clinical trials, novel prognostic techniques, and management of lymphoma in this population.
In a review, Sonali M. Smith2 highlights “two key knowledge gaps” in the management and treatment of aggressive lymphomas, such as diffuse large B-cell lymphoma (DLBCL), in elderly patients: (1) a global curative therapy that is inclusive of all patients; (2) novel approaches to better determine therapeutic toxicities among elderly patients to prevent undertreatment or, conversely, fatal toxicity. This article discusses the major caveats and advances in the care of elderly patients with aggressive lymphomas, focusing mainly on the most prominent subtype—DLBCL.
Arguably, at the core of the issue lies the underrepresentation of elderly patients in clinical studies. Although NHL is a condition associated with increasing age, patients aged >80 years are often excluded from prospective trials. Efforts have been made to broaden inclusivity in clinical trials but, until this change is widespread, the treatment landscape for elderly patients will remain static.
The standard therapy for patients with DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is used with curative intent in patients ≤80 years old. Additional agents have been suggested to improve the efficacy of R-CHOP in the DLBCL setting but can be accompanied with increased toxicity. A higher incidence of toxicities is particularly concerning in the elderly population and must be stringently considered in future trial designs.
The SENIOR trial was the first to exclusively enroll patients aged ≥80 years and evaluated R-mini-CHOP (rituximab plus reduced-dose CHOP) alone vs R-mini-CHOP plus lenalidomide for DLBCL. Although the addition of lenalidomide resulted in increased incidences of adverse events and limited efficacy benefits, the trial was an important landmark in the setting of elderly DLBCL.
The phase II/III S1918 trial, evaluating R-mini-CHOP alone or in combination with oral azacitidine (CC-486), is the first prospective randomized trial in older patients with DLBCL to incorporate geriatric assessment (GA). The study will utilize the Fondazione Italiana Linfomi (FIL) calculator to establish Elderly Prognostic Index (EPI) scores, allowing investigators to establish whether there is a correlation between frailty status and overall survival (OS) in patients with DLBCL, as well as determining the impact of chemoimmunotherapy on posttreatment quality of life (QoL). See more on GA methods below.
In older patients with DLBCL, prognostic predications are far more complex than for younger patients in the same setting. The defined association between increased disease risk and intensity of treatment observed in younger patients is not always applicable in the elderly population, for whom treatment decisions follow a risk-adapted approach.
Treatment avenues for elderly patients with DLBCL are largely centered around the following:
Advanced prognostic tools routinely used in DLBCL fail to account for many of these factors, meaning that they are unsuitable for use in the elderly population.
The National Comprehensive Cancer Network (NCCN) proposed an adjusted International Prognostic Index (IPI), the most widely used prognostic score for DLBCL, in 2014 to encompass sequential age groups rather than a single age cut-off. Nevertheless, in a study by the Groupe d’Etude des Lymphomes de l’Adulte (GELA), IPI was found not to be prognostic in patients aged >80 years following multivariate analysis. Instead, the study highlighted albumin level and the Instrumental Activities in Daily Living (IADL) questionnaire as prognostic factors in this setting. Another study by the Spanish Lymphoma Group, GELTAMO, which analyzed patients aged 80–100 years who underwent treatment with an R-CHOP-like regimen, established the following independent factors coupled with superior PFS and OS:
The GELTAMO analysis suggested that patients with fewer adverse prognostic factors (0–1) demonstrated superior survival following treatment with R-CHOP-like treatment versus those with 2–3 adverse factors. These findings have been used to design a prognostic model that can be investigated further in the elderly population.
Determining what patients with cancer require a complete GA prior to therapeutic intervention is challenging, and it remains unfeasible to assess every elderly patient. In recent years, advances in patient evaluation have been made, and below lies a list of tools that promise to streamline the process.
The G-8 screening tool considers age plus seven items from the Mini-Nutritional Assessment. G-8 has demonstrated impressive sensitivity, specificity, and prognostic value.
The Vulnerable Elders Survey-13 (VES-13) was implemented in 1,194 patients with NHL from the Lymphoma Epidemiology of Outcomes study, where 28% of patients were considered vulnerable. Increased age (≥65 years) was associated with a higher prevalence of vulnerable status, which was predictive of 1-year mortality across all age brackets.
A simplified comprehensive GA (sCGA) was established by the Fondazione Italiana Linfomi (FIL) and classifies patients as fit, unfit, and frail. The system considers age, IADL, and the CIRS for Geriatrics (CIRS-G). In a study of 173 patients with DLBCL aged ≥70 years, the sCGA was associated with patient survival and was efficiently applied to a multicenter setting.
Considering these findings, the Elderly Project was initiated to evaluate the value of the sCGA further, enrolling 1,207 older patients with DLBCL. Again, the data showed a correlation between the sGCA classifications and patient survival, with fit, unfit, and frail patients demonstrating 3-year OS rates of 74%, 68%, and 47%, respectively.
Additionally, a strategy combining an adapted sCGA classification, the IPI, and hemoglobin levels classified patients as low-, intermediate-, or high-risk and was associated with 3-year OS rates of 87%, 69%, and 42%, respectively. This approach has since been validated and is known as the Elderly Prognostic Index (EPI), representing the first prognostic tool to encompass both GA and clinical features—and prove feasible in practice. Routine application of the EPI promises to improve the outcomes of elderly patients with DLBCL as well as advance clinical research in the setting of elderly lymphoma. Nevertheless, the EPI requires further validation to determine its effectiveness across treatment regimens.
Due to the nature of therapeutic approaches for lymphoma, certain patients aged ≥65 years should undergo GA before beginning a treatment course. Baseline measurements consider comorbidities, function, falls, nutrition, depression, and cognition.
While the G-8 and VES-13 can be used to estimate mortality, the CARG (Cancer and Aging Research Group) or CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) approaches can predict the risk of chemotherapy-related toxicities. Although not lymphoma-specific, the CARG and CRASH methods have been adequate in the lymphoma setting.
Studies have highlighted that GA is more accurate than clinical judgement when considering patient frailty and predicting OS. Furthermore, data from recent trials have suggested that GA-based treatment decisions can accomplish enhanced QoL and reduced toxicity, while maintaining survival rates.
It is clear that, to refine care approaches for elderly patients with aggressive lymphomas, there needs to be adequate representation of these patients across clinical studies. Although there are now a number of therapy selection processes applicable to the elderly population, global uniformity is required in order to predict patient outcomes and maintain patient QoL.
Three events have been highlighted as particularly crucial in defining aspects of care for older patients with aggressive lymphomas: (1) investigation of immunochemotherapy exclusively in patients aged ≥80 years, (2) the Italian GA analysis, and (3) the incorporation of GA in clinical and real-world settings. These steps represent the start of a long journey to optimized QoL and survival outcomes in elderly patients with limited treatment and care options.
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