Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia

Abstract

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a trainingvalidation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring ؉12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions. (Blood. 2013;121(8):1403-1412) Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™ . Physicians should claim only the credit commensurate with the extent of their participationin the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 1482. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in IntroductionThe course of chronic lymphocytic leukemia (CLL) ranges from very indolent with a nearly normal life expectancy to rapidly progressive leading to early death. 1,2 To better understand the genetic basis of CLL heterogeneity and improve pr...

The long‐term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years

“…The risk factors studied included those factors initially reported (Oscier et al , 2010), as well as other, more recently described, gene mutations (Oscier et al , 2013) (Table 4). The good risk factors associated with long survival mirror those identified by Rossi et al (2013) and, conversely, salvage treatment was ineffective in non‐responders to first‐line FC, two‐thirds of whom had a TP53 deletion (Fig 2D).…”

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

“…Thus, dedicated prospective clinical studies are warranted to assess the biological and prognostic associations of ICN1 expression rather than NOTCH1 mutations in CLL alone, especially in the context of anti-CD20-based therapies. This analysis may allow further refinement of the recent mutation/cytogenetic hierarchical model of classification of patients with CLL in distinct risk classes (65). Finally, we propose that ICN1 expression may also represent a more reliable biomarker of NOTCH1 activation in the testing of prognostic criteria and therapeutics agents targeting NOTCH1 (28, 66).…”

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

“…CHD2 15 , MED12 16 , NFKBIE 17 , POT1 18 , RPS15 19 , SETD2 20 , XPO1 21 ). Though integration of molecular information has been proposed to improve classical risk stratification models [22][23][24][25] , a substantial proportion of patients with a dismal clinical course will not be captured by these algorithms, hence indicating a need to identify additional molecular markers of disease aggressiveness.…”