Medical Comorbidities Assessed By CIRS Negatively Impact Survival in the Era of Targeted Therapies in CLL: A Multicenter Retrospective Analysis
Authors: Gordon Max J , Amrock Stephen M , Rivera Xavier Issac , James Spencer , Manda Sudhir , Spurgeon Stephen E , Persky Daniel , Danilov Alexey 
Published: April 2021

Abstract
Introduction: The majority of patients with chronic lymphocytic leukemia (CLL) present with comorbidities, commensurate with the median age at diagnosis of 71 years. The Cumulative Illness Rating Scale (CIRS) is a widely used index which has been incorporated into clinical research in CLL. CIRS consists of 14 categories related to different body systems and scores the severity of each condition from 0-4. We have previously reported in a single-center study that CIRS predicted outcomes in patients with CLL treated with chemo-immunotherapy (CIT). However, to date it is not yet known how comorbidities impact outcomes in the era of novel agents. We tested a hypothesis that CIRS and severe organ dysfunction would retain prognostic significance.
Methods: We conducted a retrospective analysis of patients with CLL who underwent treatment at three academic medical centers between 2000 and 2016. CIRS score was calculated as in Salvi et al, 2008. Overall survival (OS) and progression-free survival (PFS) were assessed by Cox proportional hazards models adjusting for performance status (PS), age group, and chemotherapy regimen. Survival analysis in patients treated with ibrutinib was adjusted for age, PS, Rai stage, del17p and prior treatment. In addition, the impact of severe organ dysfunction (CIRS-3+, i.e. CIRS score ≥3 in single organ system) was assessed.
Results: Median age in patients receiving CIT was 65 years (N=233). The most common comorbidities were hypertension, endocrine (e.g. diabetes mellitus) and vascular (e.g. deep vein thrombosis). Fludarabine-Rituximab (N=61), Fludarabine-Cyclophosphamide-Rituximab (N=67), Rituximab-Cyclophosphamide-Vincristine-Prednisone (N=35), Bendamustine-Rituximab (N=38) and chlorambucil (N=47) were the most commonly used regimens. 79.5% of treatments were administered in a frontline setting. Average total CIRS was 6.6 and 47% had CIRS-3+. Median OS among all patients receiving CIT was 112 months (95% CI: 105 - 128 months). CIRS≥7 and CIRS3+ were associated with inferior OS compared to patients without significant comorbidities (87, 92 and 129 months, respectively, p&lt;0.05). In multivariate analysis, OS and PFS both decreased with each increase in total CIRS by one point (HR=1.09; p=0.006 and HR=1.05; p = 0.02), while CIRS-3+ was associated with inferior OS among patients treated with CIT (HR=1.50, p=0.01).
In patients treated with ibrutinib the median age was 71 years (N=83), which was significantly older than in the CIT cohort (p&lt;0.001). The most common comorbidities were musculoskeletal (e.g., osteoarthritis), and gastrointestinal (e.g., acid reflux). Median follow up was 12 months (range, 1-39 months). Contrary to patients receiving CIT, 86% of patients had relapsed/refractory disease, with a median of 2 prior treatments (range 0-6). 35% had received prior fludarabine and 54% had received an alkylating agent. Average CIRS was 8.6 and 67% had CIRS-3+. Patients treated with ibrutinib who required dose reductions had higher CIRS (mean score 11.6 vs 7.6; p&lt;0.0003). CIRS-3+ was also associated with dose reduction (RR=4.6, p=0.01). In multivariable analysis, time to treatment failure, defined as ibrutinib discontinuation due to either disease progression or intolerable side effects, shortened with each increase in total CIRS score by one point (HR=1.23; p&lt;0.001). CIRS-3+ was similarly associated with increased risk of treatment failure in multivariable analysis (HR=3.80; p=0.02). In univariate analysis comparing low vs high CIRS (CIRS &lt;7 vs CIRS≥7), median time to treatment failure was 37 vs 23 months (p=0.01; Fig. 1A). OS at 24 months was 100% vs 79% (p=0.02; Fig 1B).
Conclusion: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with CLL treated with either CIT or ibrutinib, where increased comorbidities correlate with shortened progression-free and overall survival. CIRS appears to carry prognostic value in both upfront and relapsed settings, including patients whose disease can be salvaged with ibrutinib. Larger prospective studies of patients with lymphoid malignancies who have comorbidities are necessary to better define the prognostic value of CIRS in the era of targeted agents and determine the optimal approach to therapy of such patients.
Figure 1 Figure 1.

Disclosures
Persky: Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.