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NOTCH1 mutations in CLL
observed, as well a trend towards an association between NOTCH1 M and IGHV UM status, in keeping with previ- ous observations by us and others.27, 21,4,28 Further, co-occur- rence of NOTCH1 M and TP53 M characterized 13% of our patients (23 of 178), a rather high percentage if com- pared to previous reports where concomitant NOTCH1 M and TP53 M, preferentially affecting the same leukemic cells,29 accounted for 1.2-2.6% of CLL patients.20,23 This may be due to the high number of pre-treated patients and to the low cut-off chosen by us for NOTCH1 M detection. We confirmed that NOTCH1 M were strongly correlated with trisomy 12, in line with previous reports describing a high NOTCH1 M rate in CLL cases with isolated trisomy 12 and a lower frequency in cases characterized by additional chro- mosomal abnormalities.30-32 In particular, a mutation fre- quency of 41.9% was reported in aggressive trisomy 12 cases, suggesting a pivotal role of NOTCH1 activation in this group.33 Moreover, we observed here a lower BAX/BCL-2 ratio in NOTCH1 M patients, in keeping with our previous studies showing NOTCH1-dependent activa- tion of the NF-kB pathway that may result in the upregula- tion of target genes, including BCL-2.4
The strong correlation between lower BAX/BCL-2 ratio and NOTCH1 M suggests that the poor prognosis of NOTCH1 M patients may be related to the lack of apop- tosis, although these observations need further confirma- tion.
The variability in the degree and kinetics of ibrutinib- induced recirculation lymphocytosis has been highlighted by several studies,34,35 and was also confirmed in the present study. Here we show that at 3 months on ibrutinib, the typ- ical ibrutinib-induced peak of lymphocytosis is observed in NOTCH1 WT patients, but not in NOTCH1 M cases. Moreover, even though the analysis of nodal response con- firmed an overall significant reduction in organomegaly and lymph node size in most cases at 6 months on ibrutinib, NOTCH1 M cases experienced a significant lower nodal response compared to NOTCH1 WT cases. These results may be explained by the strong correlation between CD49d overexpression and NOTCH1 M (51 of 65 cases), in line with the reported involvement of the NOTCH1 path- way in the regulation of CD49d expression.4 Consistently, CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with CLL.36
A
B
Figure 4. Progression-free survival and overall survival curves in relation to combined BAX/BCL-2 ratio and NOTCH1. Progression-free survival (PFS) and overall survival (OS) were shorter within the NOTCH1 mutated (NOTCH1 M) plus BAX/BCL-2 <1.5 subgroup (A-B), showing additive prognostic properties.
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