Page 161 - Haematologica - Vol. 105 n. 6 - June 2020

Early treatment prediction in Rai 0 CLL
those that have undergone clonal evolution which could affect treatment decisions.
We recognize that our study has several limitations. For example, we did not include TP53 gene mutation, an important adverse prognostic factor that, together with del17p, recapitulates the so-called “TP53 disrupted” cases.31 While the established cut off of 10% for del17p has little biological substantiation, its selection helps mit- igate false positive rates. In the era of next generation sequencing, however, TP53 mutational analysis is admit- tedly preferred. Despite the exclusion of TP53 mutational analysis in this study, we were able to achieve superior prognostic power with respect to the CLL-IPI, in keeping with the notion that the majority of del17p cases also bear TP53 mutations in the undeleted allele,29,30 and that the clinical impact of subclonal TP53 mutations,31 espe- cially if detected alone in early-stage disease, is still not completely understood. Furthermore, subgroup analysis of 304 cases from the training cohort demonstrated the preservation of CRO score variables even in the presence of TP53 and NOTCH1 gene mutations (Online Supplementary Table S3). We also excluded from our analysis other gene mutations usually associated with disease progression, namely BIRC3 and SF3B142-45 although, notably, these mutations have mainly failed to operate as independent predictors when tested in large cohorts.5,46 Similarly, we did not include in our panel of biomarkers the evaluation of serum thymidine kinase lev- els, that, according to some studies, is a test with inde- pendent clinical relevance as a predictor of overall sur- vival.13 This assay, however, is of limited application in CLL and is currently not routinely employed in many US or European clinical laboratories.
We have not overlooked the uniqueness of including WBC count as a prognostic biomarker in this study. More commonly, B-cell lymphocyte count is employed in the diagnosis and response to therapy in CLL.18 However, we demonstrate here that, commensurate with previously
published studies,47 WBC count may deserve considera- tion as a clinically useful surrogate marker of disease bur- den particularly in the setting of untreated disease where, alongside del17p and unmutated IGHV gene status, it appears to demonstrate prognostic significance. This observation is consistent with previous data demonstrat- ing WBC count, along with IGHV, as independent predic- tors of TFS in Binet A CLL.48
Finally, CD49d, a well-proven independent prognostica- tor in CLL,19,49 including in cases of early-stage disease,50 failed, perhaps surprisingly, to emerge in multivariable analysis as an independent factor in our Rai 0 training cohort. We hypothesize that the dropout of CD49d in multivariate analysis was due to the close relationship between CD49d and tris12,51 the latter maintained in the final multivariable model; this idea is supported by bivari- ate analysis of these two variables wherein CD49d lost significance (data not shown).
In conclusion, we present here a novel laboratory-based scoring system for Rai 0 CLL to aid clinical decision mak- ing in cases of early-stage disease. These findings advo- cate a role for immunocytogenetic analysis in Rai 0 CLL at the time of diagnosis to aid prognosis, particularly in today’s chemo-free era where early intervention is acquir- ing momentum in the investigative setting. Further inves- tigation is needed to definitively validate its utility in risk- adapted treatment.
Acknowledgements
The study was supported by the Associazione Italiana Ricerca Cancro (AIRC), Investigator Grants IG-21687; Progetto Ricerca Finalizzata PE 2016-02362756, Ministero della Salute, Rome, Italy; Associazione Italiana contro le Leucemie, Linfomi e Mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Linfo-check - Bando ricerca - contributo art. 15, comma 2, lett b) LR 17/2014; “5x1000 Intramural Program”, Centro di Riferimento Oncologico, Aviano, Italy. SAP is a Scholar in the Mayo Clinic Paul Calabresi Program in Translational Research (K12 CA090628).
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