Outcomes in CLL patients with NOTCH1 regulatory pathway mutations

Chronic lymphocytic leukemia (CLL) patients demonstrate a great deal of heterogeneity in their clinical course. Some can be monitored off therapy for many years, while others may require treatment shortly after CLL diagnosis. Several molecular prognostic factors associate with short time to first (TTFT), as well predict poor overall response and progression-free survival when using chemoimmunotherapy. These include but are not limited IGHV mutation status, TP53 disruption, deletion 11q, among others. Elucidation the underlying genomic mutational landscape has identified NOTCH1 one most frequently mutated genes is associated prognosis.1 Also, transmembrane receptor that plays vital role cell differentiation proliferation been an oncogene variety malignancies. In CLL, mutations have shown advanced stage at diagnosis, TTFT, worse survival, increased risk Richter's transformation.2 proteins interact negatively regulate activity, including MED12, FBXW7, SPEN.3-5 Mutations impacting function these limiting ability activity impact biology influence patient outcomes via activation. order better understand relevance SPEN we conducted retrospective study establish characteristics initial behavior compared those who wild-type SPEN. The primary endpoint this was examine outcome hypothesizing would behave similarly without mutations. We evaluated 362 treatment-naive diagnosed from October 18, 1991 until January 31, 2020 underwent targeted lymphoid specific next-generation sequencing (NGS) panel, which included least 75 (Genoptix Inc., Carlsbad, CA) between 2015 2019. were called suspected pathogenic excluded analysis. approved by Institutional Review Board Weill Cornell Medicine. A Pearson's chi-square test used compare categorical variables groups Mann–Whitney U continuous (median) groups. All P values based on two-tailed statistical analysis p < .05 considered indicate significance. Measurement TTFT date diagnosis initiation. Patients had yet treated censored last follow up. estimated Kaplan–Meier methods, difference log-rank test. Due low frequency mutations, grouped together defined regulatory pathway (NOTCH1rpm). For purposes, NOTCH1rpm then assessed aggregate patients. Multivariable regression Cox proportional hazards model patients, independent well-accepted Statistical performed R package (Version 1.1.447). Of 20 (5.5%) genes: 6 (1.7%) MED12 11 (3.0%) FBXW7 five (1.4%) two having more than gene. present 34 (9.4%). Two co-occurring so total 52 (14.4%) or pathway. complete listing found Tables S3–S6. remaining 310 (85.6%) did possess mutation. baseline listed Table S1. statistically higher unmutated CD38 positivity ZAP-70 expression, 11q trisomy 12 iFISH lower 13q14.3 Compared each other, (63.2% vs 30.3%, = .02). unique pathogenically tested NGS average 2.0 (SD 1.38) 1.82 1.06) significance respectively 0.53 0.79) (p <.001). After median follow-up 4.25 significantly shorter 3.54 years (95% CI, 3.09-NA) 3.93 3.24–6.79) 9.29 6.84–10.91) <.001) (Figure 1). There no .53). finding maintained multivariable Only disruption remained independently predictive (Table S2). Current iwCLL guidelines recommend TP53. However, current clinically available panels sequence additional provide information undefined impact. This established association earlier demonstrated similar seen suggesting activation directly play early proliferative harboring While univariate analysis, other high-risk such all TTFT. Our data consistent recent reports suggests biological likely driven its strong genetic features status.6 Since observe over two-fold mean number it possible complexity combinations still important aggressive disrupted populations, though due small numbers could identify interest. several limitations should acknowledged. always panel sent also some CLL. believe later acquisition unlikely testing only 1.65 even less 0.75 years. evidence transformed commonly either clonal subclonal levels before transformation occurs thus driving mutation, same paradigm.7 Additionally, single institution sample size justification needs validation cohorts. Despite limitations, our provides useful novel about three both practicing clinician academic researcher. summary, regulation signaling target gene transcription shows 12, positivity, status. particularly interesting CLL.8 prevalence underappreciated deserves further investigation. presence any prompt consideration clinicians manage way they might Future research needed determine whether frontline chemoimmunotherapy agents currently P.C. partially supported following grant: Clinical Translational Science Center Medical College (1-UL1-TR002384-01). authors declare conflict Daniel R. Helbig, Ghaith Abu-Zeinah, Richard Furman, John N. Allan designed study. Helbig Erica Bhavsar collected Paul J. Christos Allan, Furman wrote manuscript. Abu-Zeinah critically reviewed request corresponding author. S1 Baseline demographics testing. S2 Univariate initiation S3 Listing S4 S5 S6 5 Please note: publisher responsible content functionality supporting supplied authors. Any queries (other missing content) directed author article.