NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

Abstract

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia

“…We also performed a longitudinal analysis in 48 Figure 14). Twenty of them lacked mutations in any of the 5 genes analyzed at sampling.…”

Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference

“…7,14,15 Trisomy 12 is the second most frequent recurrent chromosomal aberration in CLL and is associated with clinical and biological heterogeneity, potentially linked to the presence of additional genomic aberrations. This concept is reinforced by our present findings regarding the biological background and clinical presentation/outcome of subgroups of +12 CLL patients defined by the presence of extra trisomies.…”

The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy

“…1 In the last decades, the aim of therapy for patients with CLL has shifted from palliation 2 to disease eradication, particularly for younger patients who account for almost a third of the entire population with this disease. 3 Moreover, we are now able to predict the outcome of these patients more accurately using a plethora of prognostic markers such as molecular cytogenetics; 4 point mutations in a variety of genes, including TP53, NOTCH1, SF3B1 and POT1; [5][6][7][8][9] DNA methylation, 10 immunoglobulin heavy chain gene (IGHV) mutational status; 11,12 CD38 and ZAP-70 expression; 12,13 serum β 2 -microglobulin levels; 14 and clinical stage; 15,16 all of which have a significant impact on time to first treatment, overall survival, treatmentfree survival or progression-free survival after therapy.…”