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4848 Impact of Individual Comorbidities on Treatment Outcomes in Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Session: 904. Outcomes Research—Malignant Conditions: Poster III
Hematology Disease Topics & Pathways:
Diseases, Leukemia, CLL, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Max J. Gordon, MD1, Michael C Churnetski, BS2*, Hamood Alqahtani, MBBS3*, Xavier Issac Rivera, BS4*, Adam Kittai, MD5, Nur Bruss, BS1*, Sheila Hoff, BSN3*, Michael Y. Choi, MD6, Jonathon B. Cohen, MD, MS7, Daniel Persky, MD8, Byung Park, PhD1* and Alexey V Danilov, MD, PhD5

1Oregon Health and Science University, Portland, OR
2Winship Cancer Institute, Emory University, Atlanta, GA
3Moores Cancer Center at UC San Diego, San Diego, CA
4University of Arizona, Tucson, AZ
5Knight Cancer Institute, Oregon Health and Science University, Portland, OR
6Moores Cancer Center, University of California San Diego, La Jolla, CA
7Emory University, Atlanta, GA
8Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, AZ

Introduction: Chronic lymphocytic leukemia (CLL) is a common leukemia which tends to occur late in life. Comorbidities are common, and the iwCLL guidelines recommend their assessment in patients (pts) enrolled on clinical trials. The Cumulative Illness Rating Scale (CIRS) is a rigorous tool designed to evaluate the burden of comorbidities, which has been employed in therapeutic studies. Our group and others demonstrated that CIRS score predicts survival in pts with CLL treated with either chemo-immunotherapy (CIT) or novel kinase inhibitors (KI; ibrutinib) (Manda et al, 2016 & Gordon et al, 2018). However, CIRS has not become part of common clinical practice, in part due to complexities in scoring. It is also unknown whether all of the 14 organ systems included in the score carry equal weight to determine prognosis. Here we report the impact of specific comorbidities from a multicenter retrospective cohort of CLL pts treated with either CIT or KI.

Methods: We conducted a retrospective analysis of pts with CLL treated at five US academic medical centers between 2000 and 2017. CIRS score was calculated as in Salvi et al, 2008. Random forest (RF) was used to assess specific comorbidities’ impact on overall survival (OS) and event-free survival (EFS, defined as time to new therapy, disease progression or death). We adapted two separate approaches to investigate the RF variable selection process: variable Importance (VIMP), a property related to variable misspecification, and Minimal Depth (MD), a property derived from the construction of trees within the forest. Best variables were those selected consistently as top 3 in both VIMP and MD on the 500 RF repetitions. Because hepatic and renal comorbidities were rare they were excluded. OS and EFS were assessed by Kaplan-Meier estimates and Cox proportional hazard model adjusted for performance status and age. Significance was assessed with log-rank test.

Results: 398 pts were included in the final analysis. The median age was 63 years (range, 30-93). 50% of pts (n=198) had a high CIRS score (≥7). 184 pts (46%) had comorbidities assessed in relapsed setting. For all pts, the most common treatments included ibrutinib (n=145; 37%), fludarabine-containing regimens (n=104; 26%) and bendamustine (n=39; 10%). Complex karyotype was observed in 3.5% (n=14) and 10.6% (n=42) of pts had del(17p).

Pts with comorbidities (CIRS ≥7) demonstrated shortened survival following therapy, with 5-year OS of 64% vs 89% (p<0.0001) and median EFS of 24 vs 49 months (p<0.0001). Pts treated with CIT had lower CIRS scores compared pts on KIs (6.5 vs 8.7, p<0.001), however there was no difference in CIRS between pts treated with high vs. low intensity CIT (e.g. FCR/BR vs chlorambucil/rituximab [n=59]; CIRS 6.8 vs 6.6, p=0.78), indicating comorbidities are not consistently taken into account when selecting therapy.

Random forest variable selections identified vascular comorbidities (e.g. DVT/PE) as the most influential risk factor for OS with CIT treatment, while HEENT and cardiac comorbidities were most impactful to OS for patients treated with KI. For EFS, the most influential comorbidities were cardiac and vascular for the CIT treatment group and endocrine and HEENT for patients treated with KI.

Across EFS and OS, the most frequently selected variables in CIT were cardiac, hypertension, vascular and neurologic. We constructed a simplified scoring system assigning 1 point for each category. Comparing scores of 0, 1 and 2-4 (n=100, n=82, n=60), 5-year OS was 87%, 82% and 66%, respectively (p<0.0001). In an adjusted Cox model OS decreased between risk groups (HR=1.78; 95% CI, 1.2-2.6; p=0.004). Cardiac, vascular, HEENT and endocrine were the most frequently selected in pts receiving KI. Comparing scores of 0, 1 and 2-4 (n=50, n=51, n=55), 2-year OS was 98%, 87% and 81%, respectively (p=0.034). There was a trend towards increased risk of death in the adjusted cox model (HR=1.63; 95% CI, 0.80-3.34; p=0.19).

Conclusion: Comorbidities impact survival in CLL whether treated with CIT or KI. Which comorbidities are most prognostic may vary by treatment type. Vascular and cardiac comorbidities appear to be the most relevant in CLL pts treated with CIT. Meanwhile, cardiac, endocrine and HEENT had greater impact when pts were treated with KI. A simplified CIRS score is predictive of outcomes in both treatment subgroups.

Disclosures: Choi: Gilead: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy; Genentech: Speakers Bureau. Cohen: Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy. Persky: Genentech: Honoraria; Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Merck: Research Funding. Danilov: Aptose Biosciences: Research Funding; Verastem: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding.

*signifies non-member of ASH