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• W3129394857 abstract "Chronic lymphocytic leukemia (CLL) patients demonstrate a great deal of heterogeneity in their clinical course. Some patients can be monitored off therapy for many years, while others may require treatment shortly after their CLL diagnosis. Several molecular prognostic factors associate with a short time to first treatment (TTFT), as well as predict for poor overall response and short progression-free and overall survival when using chemoimmunotherapy. These include but are not limited to IGHV mutation status, TP53 disruption, and deletion 11q, among others. Elucidation of the underlying genomic mutational landscape in CLL has identified NOTCH1 as one of the most frequently mutated genes in CLL and is associated with poor prognosis.1 Also, NOTCH1 is a transmembrane receptor that plays a vital role in cell differentiation and proliferation and has been identified as an oncogene in a variety of malignancies. In CLL, mutations in NOTCH1 have been shown to be associated with advanced stage at diagnosis, short TTFT, worse overall survival, and increased risk of Richter's transformation.2 Several proteins interact with and negatively regulate NOTCH1 activity, including MED12, FBXW7, and SPEN.3-5 Mutations impacting the function of these proteins and limiting their ability to regulate the activity of NOTCH1 may impact CLL biology and influence patient outcomes via NOTCH1 activation. In order to better understand the clinical relevance of MED12, FBXW7, and SPEN mutations in CLL patients at diagnosis, we conducted a retrospective study to establish clinical characteristics and initial clinical behavior of patients with mutations compared to those who are wild-type for MED12, FBXW7, and SPEN. The primary endpoint of this study was to examine the clinical outcome of TTFT, hypothesizing that patients with these mutations would behave similarly to NOTCH1 mutated patients compared to CLL patients without those mutations. We evaluated 362 treatment-naive CLL patients diagnosed with CLL from October 18, 1991 until January 31, 2020 who underwent a targeted lymphoid specific next-generation sequencing (NGS) panel, which included at least 75 genes (Genoptix Inc., Carlsbad, CA) between 2015 and 2019. Mutations that were called but not suspected to be pathogenic were excluded from the analysis. The study was approved by the Institutional Review Board of Weill Cornell Medicine. A Pearson's chi-square test was used to compare categorical variables between groups and a Mann–Whitney U test was used to compare continuous variables (median) between groups. All P values were based on two-tailed statistical analysis and p < .05 was considered to indicate statistical significance. Measurement of TTFT was from the date of initial diagnosis of CLL to the date of treatment initiation. Patients who had not yet been treated were censored at the date of last follow up. The TTFT was estimated using Kaplan–Meier methods, and the difference in TTFT between groups was compared using the log-rank test. Due to the low frequency of mutations, MED12, FBXW7, and SPEN mutations were grouped together and defined as NOTCH1 regulatory pathway mutations (NOTCH1rpm). For analysis purposes, NOTCH1rpm patients and NOTCH1 mutated patients were then assessed in aggregate compared to wild-type patients. Multivariable regression using a Cox proportional hazards model was used to compare TTFT between NOTCH1rpm patients, NOTCH1 mutated patients, and CLL patients without those mutations independent of well-accepted clinical risk factors for treatment initiation. Statistical analysis was performed using the R statistical package (Version 1.1.447). Of the 362 patients, 20 (5.5%) had mutations in NOTCH1 regulatory pathway genes: 6 (1.7%) had MED12 mutations, 11 (3.0%) had FBXW7 mutations, and five (1.4%) had SPEN mutations, with two patients having mutations in more than one NOTCH1 regulatory pathway gene. The NOTCH1 mutations were present in 34 patients (9.4%). Two patients had co-occurring NOTCH1rpm and NOTCH1 mutations, so in total 52 patients (14.4%) had at least one mutation in NOTCH1 or the NOTCH1 regulatory pathway. A complete listing of the 52 patients with their specific mutations can be found in Tables S3–S6. The remaining 310 patients (85.6%) did not possess a NOTCH1rpm or NOTCH1 mutation. The baseline prognostic factors of patients are listed in Table S1. NOTCH1rpm patients and NOTCH1 mutated patients had a statistically higher frequency of IGHV unmutated status, CD38 positivity and ZAP-70 expression, deletion 11q and trisomy 12 by iFISH and a lower frequency of deletion 13q14.3 compared to wild-type patients. Compared to each other, NOTCH1rpm patients had a statistically higher frequency of trisomy 12 than NOTCH1 mutated patients (63.2% vs 30.3%, p = .02). The NOTCH1rpm patients and NOTCH1 mutated patients had a higher frequency of unique pathogenically mutated genes tested on NGS with an average of 2.0 (SD 1.38) and 1.82 (SD 1.06) with clinical significance respectively compared to 0.53 (SD 0.79) in the wild-type patients (p = <.001). After a median follow-up of 4.25 years, NOTCH1rpm patients and NOTCH1 mutated patients had a significantly shorter TTFT with a median of 3.54 years (95% CI, 3.09-NA) for the NOTCH1rpm patients and 3.93 years (95% CI, 3.24–6.79) for the NOTCH1 mutated patients compared to 9.29 years (95% CI, 6.84–10.91) in wild-type patients (p = <.001) (Figure 1). There was no difference for TTFT between NOTCH1rpm patients and NOTCH1 mutated patients (p = .53). The finding of shorter TTFT in NOTCH1rpm patients or NOTCH1 mutated patients was not maintained in a multivariable analysis. Only IGHV unmutated status, deletion 11q, and TP53 disruption remained independently predictive of a shorter TTFT in a multivariable analysis (Table S2). Current iwCLL guidelines recommend mutational sequencing for TP53. However, many current clinically available mutational panels sequence additional genes and provide information of undefined clinical impact. This study established the association of mutations in NOTCH1 regulatory pathway genes with earlier TTFT compared to wild-type patients and demonstrated a similar outcome seen in NOTCH1 mutated CLL, suggesting that NOTCH1 activation may directly play an underlying role in the early proliferative behavior of CLL harboring these mutations. While we found NOTCH1rpm and NOTCH1 mutations to associate with an early TTFT in univariate analysis, these mutations were not independently prognostic in a multivariable analysis when including other high-risk variables such as IGHV unmutated status, deletion 11q, and TP53 disruption, which were all found to independently predict an early TTFT. Our data is consistent with recent reports and suggests that the impact of NOTCH1rpm or NOTCH1 mutations on early biological behavior of CLL is more likely driven by its strong association with other genetic features such as unmutated IGHV mutational status.6 Since we did observe an over two-fold difference in the mean number of unique pathogenically mutated genes in NOTCH1rpm and NOTCH1 mutated patients, it is possible that increased genomic complexity or other specific mutational combinations may still be important and independently predict early aggressive behavior in NOTCH1 disrupted populations, though due to small numbers we could not identify specific combinations that could be of interest. Our study has several limitations that should be acknowledged. Our patients did not always have the NGS panel sent at time of diagnosis, so it is also possible that some of these mutations were not present at initial diagnosis of CLL. We believe that later acquisition of these regulatory pathway mutations would be unlikely as the median time from diagnosis to NGS testing was only 1.65 years for NOTCH1 mutated patients and was even less in the NOTCH1rpm patients at 0.75 years. There is also evidence that NOTCH1 mutations found in transformed patients are commonly present at CLL diagnosis either in clonal or subclonal levels well before transformation occurs and thus a baseline driving mutation, and it is possible these regulatory pathway mutations could follow the same paradigm.7 Additionally, this is a retrospective study from a single institution with no sample size justification and needs validation from other cohorts. Despite these limitations, we believe that our study provides important and useful novel information about three mutations in CLL to both the practicing clinician and academic researcher. In summary, we identified three mutations in genes associated with the regulation of NOTCH1 signaling or target gene transcription that associate with aggressive CLL behavior similar to that seen with NOTCH1 mutated CLL. Our study shows that these mutations predict for a shorter TTFT in a univariate analysis and associate with similar baseline factors to NOTCH1 mutated CLL, such as trisomy 12, CD38 positivity, and IGHV unmutated status. The strong association with trisomy 12 among the NOTCH1rpm patients is particularly interesting as NOTCH1 mutations are also associated with trisomy 12 in CLL.8 Our study suggests the prevalence of NOTCH1 activation in trisomy 12 CLL may be underappreciated and deserves further investigation. We believe that the presence of any these three mutations in CLL should prompt consideration of clinicians to manage patients in a similar way as they might a NOTCH1 mutated patient with CLL. Future research is needed to determine whether mutations in MED12, FBXW7, or SPEN may also associate with increased transformation risk or poor response to frontline chemoimmunotherapy or targeted agents currently used in CLL. P.C. was partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01). The authors declare no conflict of interest. Daniel R. Helbig, Ghaith Abu-Zeinah, Richard R. Furman, and John N. Allan designed the study. Daniel R. Helbig and Erica Bhavsar collected the data for statistical analysis. Daniel R. Helbig, Ghaith Abu-Zeinah, and Paul J. Christos conducted statistical analysis. Daniel R. Helbig, John N. Allan, and Richard R. Furman wrote the manuscript. Ghaith Abu-Zeinah and Paul J. Christos critically reviewed the manuscript. All data is available on request from the corresponding author. Table S1 Baseline patient demographics at the time of CLL diagnosis among 362 patients who underwent NGS testing. Table S2 Univariate and multivariable analysis of TTFT of well-accepted risk factors for treatment initiation including NOTCH1 mutated patients and NOTCH1rpm patients. Table S3 Listing of the specific mutations for the 34 NOTCH1 mutated patients. Table S4 Listing of the specific mutations for the 6 MED12 mutated patients. Table S5 Listing of the specific mutations for the 11 FBXW7 mutated patients. Table S6 Listing of the specific mutations for the 5 SPEN mutated patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W3129394857 date "2021-03-10" @default.
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• W3129394857 title "Outcomes in <scp>CLL</scp> patients with <scp> <i>NOTCH1</i> </scp> regulatory pathway mutations" @default.
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