A Laboratory Based Scoring System Predicts Early Treatment in Rai 0/Binet a CLL
Authors: Cohen Jared A , Rossi Francesca Maria , Bomben Riccardo , Terzi-di-Bergamo Lodovico , Bulian Pietro , Degan Massimo , Zucchetto Antonella , D'Arena Giovanni Francesco , Santinelli Enrico , Zaja Francesco , Pozzato Gabriele , Rossi Davide , Chiarenza Annalisa , Di Raimondo Francesco , Laurenti Luca , Innocenti Idanna , Del Poeta Giovanni , Fegan Christopher , Pepper Chris , Chaffee Kari G. , Parikh Sameer A. , Kay Neil E. , Gattei Valter 
Published: October 2019

Abstract
Introduction:
Observation is the standard of care for asymptomatic early stage chronic lymphocytic leukemia (CLL) however these cases follow a heterogenous course. Recent studies show novel biomarkers can delineate indolent from aggressive early stage disease and current clinical trials are exploring the role of early intervention in high risk cases. Although several scoring systems have been established in CLL, most are designed for overall survival, do not circumscribe early stage disease, and require cumbersome calculations relying on extensive laboratory and clinical information.
Aim:
We propose a novel laboratory-based prognostic calculator to risk stratify time to first treatment (TTFT) in early stage CLL and guide candidate selection for early intervention.
Methods:
We included 1574 cases of early stage CLL in an international cohort from Italy, the United Kingdom and the United States using a training-validation model. Patient information was obtained from participating centers in accordance with the Declaration of Helsinki. The training cohort included 478 Rai 0 cases from a multicenter Italian cohort, all referred to a single center (Clinical and Experimental Onco-Hematology Unit of the Centro Riferimento Oncologico in Aviano, IT) for immunocytogenetic lab analyses.
Considering TTFT as an endpoint, we evaluated 8 variables (age>65, WBC>32K, 17p-, 11q-, +12, IGHV status, CD49d+, gender) with univariate and multivariate Cox regression internally validated using bootstrapping procedures. FISH thresholds were 5% for 11q-, and +12 and 10% for 17p-. Cases were categorized according to the hierarchical model proposed by Dohner. IGHV status was considered unmutated at ≥98%. CD49d+ was set at >30%. WBC cutoff of >32K was established by maximally selected log rank analysis. Variables were weighted based on the proportion of their normalized hazard ratios rounded to the nearest whole integer. We used recursive partitioning for risk-category determination and Kaplan-Meier analysis to generate survival curves. We compared the concordance index (C-index) of our model with the CLL international prognostic index (CLL-IPI) for 381/478 cases in the training cohort with available beta-2-microglobulin data and for all validation cohorts. We used 3 independent single-center cohorts for external validation.
Results:
The training cohort had 478 cases of Rai 0 CLL with a median (95% CI) TTFT of 124 months (m) (104-183m). Five prognostic variables emerged with respect to TTFT, and each assigned a point value of 1 or 2 according to their respective normalized HR values as follows: 17p-, and UM IGHV (2 pts); 11q-, +12, and WBC>32K (1 pt). We identified three risk groups, based on point cut-offs of 0, 1-2, and 3-5 established by recursive partitioning analysis with a median (95% CI) TTFT of 216m (216-216m), 104m (93-140m) and 58m (44-68m) (p<0.0001, C-index 0.75) for the low, intermediate, and high-risk groups, respectively (figure 1). A comparison with the CLL-IPI was possible in 381 cases with available beta-2-microglobulin data. In this subset, the C-index was 0.75 compared to 0.68 when patient risk groups were split according to the CLL-IPI.
The scoring system was then validated in 3 independent cohorts of early stage CLL:
i) Gemelli Hospital in Rome, IT provided 144 Rai 0 cases. Median (95% CI) TTFT was 86m (80-94m, 95% CI). Median (95% CI) TTFT for the low, intermediate and high-risk groups was 239m (239-239m), 98m (92-132m) and 85m (60-109m) respectively (p=0.002 between low and intermediate groups, p=0.09 between intermediate and high groups; C-index 0.64 v 0.60 for CLL-IPI).
ii) Cardiff University Hospital in Wales, UK provided 395 Binet A cases. Median (95% CI) TTFT was 74 m (67-81m) overall and NR, 111m (97-146m) and 70m (29-114m) for the low, intermediate and high-risk groups respectively (p<0.001 between low and intermediate groups, p=0.009 between intermediate and high groups; C-index 0.63 v 0.63 for CLL-IPI).
iii) Mayo Clinic in Rochester, MN provided 557 Rai 0 cases. Median (95% CI) TTFT was 127m (96m-NR) overall and NR, 76m (64m-NR) and 36m (31-59m) for the low, intermediate and high-risk groups respectively (p<0.0001; C-index 0.72 v 0.68 for CLL-IPI).
Conclusion:
We present a novel laboratory-based scoring system for Rai 0/Binet A CLL to aid case selection in risk-adapted treatment for early disease. Further comparison to existing indices is needed to verify its utility in the clinical setting.

Disclosures
Zaja: Novartis: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Fegan:Roche: Honoraria; Napp: Honoraria; Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria. Pepper:Cardiff University: Patents & Royalties: Telomere measurement patents. Parikh:AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees.