Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis.

No 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...

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n ‫؍‬ 309) and validation (n ‫؍‬ 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. (Blood. 2012;119(2): 521-529) IntroductionChronic lymphocytic leukemia (CLL) is the most common leukemia in adults. [1][2][3][4] The clinical course of CLL ranges from very indolent, with a nearly normal life expectancy, [5][6][7][8][9] to rapidly progressive leading to death and occasionally undergoing transformation to aggressive lymphoma, known as Richter syndrome (RS). [10][11][12][13][14][15][16][17][18] At presentation, several clinical and biologic features may help to predict, at least in part, the clinical course of CLL. [19][20][21] Of the biologic prognosticators that have been developed, current guidelines for clinical practice recommend screening only for TP53 disruption by mutation, deletion, or both of the locus, that identifies a fraction of high-risk CLL destined to experience a very short survival. 2,[21][22][23][24][25][26][27][28] High-risk CLL, however, cannot be fully recapitulated by TP53 disruption, and other lesions of cancer genes may be implicated in this aggressive phenotype. 29 Recently, two independent investigations of the CLL coding genome have revealed that activating mutations of the NOTCH1 proto-oncogene are recurrently associated with CLL. 30,31 Based on current knowledge, NOTCH1 mutations occur in ϳ 10% CLL at diagnosis and their frequency increases in advanced disease phases, as exemplified by the case of RS. 30,31 The relevance of NOTCH1 mutations in CLL is reinforced by knowledge of activation of the NOTCH1 pathway in this leukemia, 32 and by the possibility of targeting NOTCH1 with drugs currently under development in other clinical contexts. 33 Although not designed to fully assess clinical correlates, the pivotal studies that have ident...

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.