Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI), a Novel Comorbidity Measure, Predicts Outcomes in the Context of Targeted Agents and in a Large National Registry
Authors: Gordon Max J. , Kaempf Andy , Rotbain Emelie , Sitlinger Andrea , Shouse Geoffrey , Mei Matthew , Brander Danielle M. , Salous Tareq , Hill Brian T. , Choi Michael , Cohen Jonathon B. , Stephens Deborah M. , Persky Dan O. , Patel Krish , Shadman Mazyar , Park Byung , Niemann Carsten Utoft , Danilov Alexey V. 
Published: November 2021

Abstract
Introduction: Comorbidities are common in CLL and associated with shorter overall survival (OS) and disease specific survival (Rotbain, Leukemia, 2021). Using an ensemble machine learning approach, we identified the comorbidities most strongly associated with event free survival (EFS) in CLL in order to construct the CLL-CI (Gordon et al, 2021). Our initial report included heterogeneously-treated derivation (N=570) and validation (N=167) cohorts of patients with CLL. Median EFS in the derivation cohort was 58, 33 and 20 months for low, intermediate and high-risk CLL-CI groups, respectively (p&lt;0.001). We now report on the performance of CLL-CI in patients treated with targeted therapies and conduct additional validation of the score using a National Registry.
Methods: In our multicenter CLL cohort, we retrospectively analyzed patients from 10 academic centers who received targeted therapies, e.g. ibrutinib, acalabrutinib, idelalisib and venetoclax. Secondly, we now compiled a validation cohort which included patients from the Danish National CLL registry. CLL-CI score was assigned as previously reported (Gordon et al, 2021). Briefly, one point was assigned, if present, for any cumulative illness rating scale (CIRS) vascular comorbidity, moderate/severe upper gastrointestinal CIRS comorbidity and moderate/severe endocrine CIRS comorbidity, for a total maximum score of 3 (Fig. 1A). A score of 0 signifies low risk disease, 1-intermediated risk and 2-3-high risk. The Kaplan-Meier method and Cox models were used to estimate the association between CLL-CI, EFS (defined as death or next therapy) and OS.
Results: CLL patients treated with targeted therapies (N=448) had a median age of 68 years (range, 26-91), 124 pts (28%) had TP53 aberrancy, 268 (60%) were treated in the relapsed/refractory (R/R) setting and 398 (89%) received ibrutinib. By CLL-CI group, 194 (43%) were low risk, 173 (39%) intermediate risk and 81 (18%) high risk. Median EFS was 57, 35 and 17 months for low, intermediate and high-risk groups, respectively (p&lt;0.001; Fig. 1B). Estimated 2-year OS was 93%, 86% and 55%, respectively (p&lt;0.001: Fig. 1C). In multivariable models, CLL-CI was independently associated with EFS and OS when adjusted for TP53 aberrancy, age, prior lines of therapy and Rai stage (high risk vs. low risk HR, 3.31; p≤0.001 and HR 2.42; p=0.02, respectively). There was no observed difference in survival comparing ibrutinib to non-ibrutinib treated patients.
The validation cohort (N=4975) included patients from the Danish CLL registry. Median age was 71 years, 1630 (33%) had low risk CLL-IPI and 425 (8.5%) had high or very-high risk CLL-IPI; 87% received chemoimmunotherapy. From time of diagnosis, in low, intermediate and high risk CLL-CI groups the median OS was not reached, 8.5 and 6 years, respectively (p&lt;0.0001). The median EFS from time of diagnosis was 8.4, 4.4 and 2.2 years, respectively (p&lt;0.0001). CLL-CI was associated with time to first treatment: 56% of high risk patients vs. 20-30% of low and intermediate risk patients received treatment within 4 years of diagnosis (p&lt;0.0001), and independently associated with OS when adjusted for CLL-IPI category. Furthermore, CLL-CI risk group was associated with OS from time of first treatment: medians of 8.2, 6.0, and 4.4 years (p&lt;0.0001) and EFS medians of 3.6, 2.9, and 1.9 years (p=0.0064), respectively. Interestingly, high CLL-CI score, compared to low/intermediate, was associated with unmutated IGHV (46% vs. 30%), TP53 aberrancy (10% vs. 5%), elevated B2 microglobulin (31% vs. 13%) and Binet stage B or C (29% vs. 18%; P&lt;0.001 for all).
Conclusions: Here we report that a novel comorbidity index, CLL-CI, predicts outcomes in patients with CLL treated with targeted therapies. Furthermore, we validate this index in a large National Registry. Thus, CLL-CI is a validated measure of comorbidity in CLL which provides important prognostic information for patients with early stage disease treated with a watch and wait approach and in patients with advanced stage disease receiving targeted therapies or chemoimmunotherapy.
Figure 1 Figure 1.

Disclosures
Rotbain: Abbvie: Other: travel grants; AstraZeneca: Consultancy, Other: travel grants; Janssen: Other: travel grants . Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria. Mei: Morphosys: Research Funding; BMS: Research Funding; Epizyme: Research Funding; TG Therapeutics: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Beigene: Research Funding. Brander: Ascentage: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; ArQule: Research Funding; DTRM: Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; MEI Pharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Verastem: Consultancy; NCCN: Other: panel member; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; ArQule/Merck: Consultancy. Hill: Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Cohen: Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy. Stephens: Abbvie: Consultancy; Novartis: Research Funding; JUNO: Research Funding; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel: Kite Pharma: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Abbvie: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Danilov: Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Rigel Pharm: Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding.