Page 160 - Haematologica - Vol. 105 n. 6 - June 2020

J.A. Cohen et al.
multivariable analysis was performed in these cases by including the same variables (WBC count, del11q, tris12, IGHV gene status, CD49d, age and gender), adding NOTCH1 and TP53 mutations and re-classifying del17p and/or TP53 mutated cases as TP53 disrupted.5,29-31 As shown in Online Supplementary Table S3, the CRO score variables WBC count, del11q, tris12, and IGHV gene sta- tus maintained the ability to independently predict short TFS along with TP53 disruption, in a model that included TP53 and NOTCH1 gene mutations.
Discussion
The clinical staging systems for CLL, described by Rai and Binet approximately 40 years ago, are still used in clin- ical practice today to inform prognosis and guide treat- ment decisions.1, 2 However, their predictive powers are limited.3 For example, Pflug et al. reported C-indices of 0.56 and 0.58 for Rai and Binet systems, respectively, when applied to a cohort of 1,948 patients.13 Novel model scoring systems developed in recent years have signifi- cantly improved the accuracy of prognostication by incor- porating new biomarkers and hold the potential for the development of more individualized treatment strate- gies,11-14, 26 especially in the age of an increasing sophistica- tion of novel agents alone or in combination. In this regard, the CLL-IPI was developed as an integrative tool to evaluate overall survival for all clinical stages of disease, and although it demonstrated consistency in subgroup analyses circumscribed to early-stage disease,15,32 it was not developed specifically to predict TFS.
To our knowledge, this study represents one of the largest attempts to integrate novel biomarkers with tradi- tional clinical factors, with the specific aim of predicting TFS in the setting of Rai 0 CLL. Given the multiplicity of new biomarkers, our goals were: i) to determine which ones individually influence TFS; and ii) to develop a scor- ing system to stratify risk in patients traditionally thought to harbor indolent disease.
Our training cohort was selected from a consecutive series of 1,201 CLL cases referred to a single center for immunocytogenetic analyses between 2006 and 2017. With respect to TFS, this cohort was stratified into inde- pendent risk groups using Rai staging; however, a satisfac- tory further sub-stratification of Rai 0 cases was not demonstrated using the canonical Dohner’s hierarchical classification alone.7 This observation provided the stimu- lus to investigate the potential prognostic significance of additional biomarkers in early-stage disease. One of our main strategies was to integrate known prognostic mark- ers that are commonly used in clinical practice today to increase the accessibility and cost-effectiveness of the risk tool.
Our results demonstrate that the CRO score is a power- ful tool for guiding treatment prediction in patients with Rai 0 CLL. Notably, a subset analysis of the so-called high-risk category according to the CRO score (i.e. scores 3-5), revealed that a very small subset of cases (14 cases) in a composite cohort of 1,879 training and validation cases, characterized by high WBC counts in the setting of del17p and UM IGHV gene status (i.e. CRO score 5), progressed within two years, significantly more rapidly than the other so-called high-risk cases with CRO scores of 3 or 4. Conversely, in low-risk patients, the CRO score predicted
TFS at 10 years of approximately 85%, arguing for its expanded utility in allowing clinicians to confidently pro- vide reassurance of disease quiescence to such patients. Furthermore, in comparison to the CLL-IPI,11 our model demonstrated superior performance in the training cohort and in 3 out of the 4 validation cohorts, lending credence to its role in the current compendium of comprehensive risk tools in the setting of Rai 0 CLL.
We observed significant heterogeneity in patient charac- teristics among the five cohorts included in our study (Online Supplementary Table S1). For example, 64% of patients in the Gemelli cohort were aged ≥65 years com- pared to 30% in the O-CLL cohort, and only one patient in the O-CLL had a B2M >3.5 mg, compared to 23% of the patients in the Cardiff cohort. We attribute these dif- ferences to the heterogeneity of clinical settings from which each cohort was derived, as has been observed in previous studies comparing ‘real world’ versus observa- tional study patients, single versus multicenter registries, and cases from community versus tertiary/referral centers. 33-35 In contrast to the results in these studies, which show inconsistent performance of several prognostic indexes across dissimilar cohorts, our scoring system retained powerful predictive capacity throughout, showcasing its generalizability and strength as a clinically useful decision- making tool.
In the training, composite and two out of the four vali- dation cohorts, the proposed prognostic score approached or exceeded C-index values of 0.7, a threshold necessary to confer utility at the individual patient level.36 In this regard, however, a more precise evaluation of the individ- ual predictive potential may require the application of complex statistical methods, as recently proposed.37,38
This study raises questions regarding the appropriate timing of immunocytogenetic analysis in early-stage dis- ease, which today is often postponed until the time of dis- ease progression and first treatment. We appreciate the cost-effectiveness of a 'watch-and-wait' approach, partic- ularly since studies investigating the early use of chloram- bucil and fludarabine monotherapy as well as FCR regi- mens (fludarabine/cyclophosphamide + rituximab) have failed to demonstrate improved outcomes in CLL patients.18,39,40 However, the role of the novel inhibitors in this setting remains to be elucidated,41 and the results of this study support the notion that early testing can aid risk-adapted treatment strategies and early intervention, particularly in the modern chemo-free era. In this regard, the CLL12 trial (a phase III clinical study currently under- way in Germany) is evaluating the efficacy and safety of ibrutinib compared to a 'watch-and-wait' approach in Binet A CLL using a similar comprehensive scoring system to identify high-risk patients.36 Another randomized phase II study currently underway at the Mayo Clinic is compar- ing the efficacy of the BTK inhibitor acalabrutinib alone and in combination with the anti-CD20 obinutuzumab in treating patients with early-stage CLL who are classified as high- or very high-risk according to the CLL-IPI (Sameer Parikh et al., 2018, NCT03516617). Further clinical studies are needed to aid identification of progressive cases of early-stage disease who may benefit from risk-adapted treatment approaches. An important caveat to the approach of up-front testing is that cytogenetic and TP53 mutational analysis must be repeated at the time of dis- ease progression and/or treatment particularly in previ- ously so-called “TP53 non-disrupted” cases to identify
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haematologica | 2020; 105(6)