Clinical Relevance of NOTCH1 Mutations in Ibrutinib-Treated Chronic Lymphocytic Leukemia (CLL)

Background Ibrutinib, inhibitor of Bruton9s tyrosyne kinase (BTK), demonstrated exceptional activity both in untreated and relapsed/refractory CLL patients, obtaining overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) far superior to chemoimmunotherapy (Byrd, 2014). Interestingly, NOTCH1 mutations (M) were significantly correlated with CD49d overexpression which identified cases with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by remarkable expression of the NF-kB pathway genes (Benedetti, 2017) and thus may confer poor response to ibrutinib. Aims On this background, the primary aims of our research were: i) to correlate NOTCH1 M with biological and clinical prognosticators in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M both on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on ORR, PFS and OS; iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Patients and Methods Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 166 patients recruited from three independent cohorts from Italy, median age 61 years (27-85), median number of previous regimens 2 (0-4; 15% previously untreated). Noteworthy, 23/60 (38%) TP53M patients were treated in first line with ibrutinib (p Results Sixty-one patients were NOTCH1 M (36.75%). NOTCH1 M were significantly correlated with trisomy 12 (p=0.00045) and with CD49d >30% (p=0.001). Absolute lymphocyte counts (ALCs) were collected before treatment and at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were significantly correlated with lower median ALCs measured both before (28.9 x 106/ml vs 57.0 x 106/ml; p=0.0006) and during (28.0 x 106/ml vs 54.6 x 106/ml; p=0.0005) ibrutinib therapy. Also the median SPD, calculated at 3-6 months on ibrutinib, was significantly lower in NOTCH1 M patients (51.8% vs 75.7%; p or Conclusions NOTCH1M patients were characterized by a reduced redistribution lymphocytosis and by a lower and/or slower nodal response under ibrutinib treatment. The clinical consequences were a significant higher number both of PR without lymphocytosis and relapses. Therefore, evaluation of NOTCH1 M in patients initiating ibrutinib may identify those cases that would benefit from combination therapy approaches, which are already underway in experimental protocols, using new molecules working through different pathways, such as venetoclax or obinutuzumab. Disclosures Del Principe:Gilead: Membership on an entity9s Board of Directors or advisory committees.