ABSTRACT
Background
Chronic lymphocytic leukemia (CLL) treatment choice remains a challenge in the era of molecular biology and targeted therapy.
Methods
We conducted a bicentric retrospective analysis of the impact of NOTCH1 mutation according to the treatment of CLL patients in real life.
Results
A total of 45 patients with NOTCH1 mutation have been reported, including 15 patients treated with FCR BR or DRC regimen and 18 patients with a BTK inhibitor. NOTCH1 mutation is the most frequently occurring molecular abnormality in CLL and is closely associated with poor prognosis but is not used in treatment guidelines unlike TP53 and IGHV. In our study, progression‐free survival was significantly longer in CLL patients with NOTCH1 mutation treated by BTK inhibitors compared to immunochemotherapy.
Conclusion
Routine screening for NOTCH1 mutations could identify patients who may benefit from BTKi treatment. However, the impact of NOTCH1 mutations on combination therapies, such as obinutuzumab‐venetoclax or venetoclax‐BTKi, is yet to be determined.
The authors have confirmed clinical trial registration is not needed for this submission
Keywords: CLL, NGS, NOTCH1 mutation
1.
Chronic lymphocytic leukemia (CLL) is one of the most frequently occurring hematological malignancies [1]. The TP53 and IGHV mutational status are currently used to guide the choice of treatment [2, 3]. However, the increasing availability of next‐generation sequencing (NGS) has allowed the identification of several genes of interest that could have an impact on the response to treatment.
NOTCH1 was found to be mutated at diagnosis in 20% of cases and shown to be associated with a poor prognosis according to subgroup analyses in several clinical trials (HR, 4.22; 95% CI, 2.15–8.28; p < 0.001) [4, 5]. However, none of the previous studies evaluated the impact of Bruton tyrosine kinase inhibitors (BTKis) on CLL harboring NOTCH1 mutations. Thus, we conducted a real‐life retrospective study to investigate the prognostic impact of NOTCH1 mutations in the era of targeted therapies in CLL.
Patients diagnosed with CLL according to the iwCLL guidelines [6] from January 1, 2013, to December 31, 2022 were identified in two tertiary care centers (Rennes and Tours). This study followed the MR‐004 methodology (Commission Nationale de l'Informatique et des Libertés, n° 2022_126). The NOTCH1 mutation status was determined by NGS before first‐line treatment. Patients provided written consent for the research.
Among the 229 screened eligible patients, 174 were included (Figure 1A,B). The characteristics of the included patients are shown in Table 1. Briefly, the median age at diagnosis was 63 years. The median follow‐up was 84.1 months and 66.1% of cases were Binet stage A, 25.3% Binet stage B, and 8.6% Binet stage C. We observed an unmutated IGHV status for 84 patients (48.3%), a mutated status for 62 (35.6%), and the mutational status was not available for 28 (16.1%). A total of 34 patients had a complex karyotype (20%). FISH analysis revealed a del(17p) in 6.0% of the patients and a del(11q) in 12.4%.
FIGURE 1.
Overview of CLL patients depending on NOTCH1 mutational status and treatment received. (A) Flow chart of inclusion status. (B) Pie chart of NOTCH1 mutational status and treatments received. (C) Schematic view of NOTCH1 mutations. (D) Progression‐free survival of patients without a NOTCH1 mutation. (E) Progression‐free survival of patients with a NOTCH1 mutation. (F) PFS of patients who received BTKi treatment. (G) PFS of patients who received ICT. BTKi: BTK inhibitor treatment, ICT: immunochemotherapy, NOTCH1M: NOTCH1‐mutated, NOTCH1UM: NOTCH1‐unmutated, time in months.
TABLE 1.
Characteristics of the population at the time of first treatment.
| % | n = 174 | |
|---|---|---|
| Gender | ||
| Female | 40.2 | 70 |
| Male | 59.8 | 104 |
| Age at diagnosis, years* | 63 | |
| ≤ 65 | 62.1 | 108 |
| > 65 | 37.9 | 66 |
| ECOG performance status | ||
| ≤ 2 | 89.1 | 155 |
| >2 | 10.9 | 19 |
| Time of follow‐up, months* | 84.1 | |
| ≤ 2 years | 5.2 | 9 |
| 2‐5 years | 63.8 | 111 |
| ≥ 5 years | 31.0 | 54 |
| Binet stage | ||
| A | 66.1 | 115 |
| B | 25.3 | 44 |
| C | 8.6 | 15 |
| ß2‐microbglobuline more than upper limit of normal | ||
| ≤ N | 44.9 | 48/107 |
| > N | 55.1 | 59/107 |
| Lactate dehydrogenase | ||
| ≤ N | 44.1 | 64/145 |
| > N | 55.9 | 81/145 |
| IGHV status | ||
| Mutated | 35.6 | 62 |
| Unmutated | 48.3 | 84 |
| Unknown | 16.1 | 28 |
| Cytogenetic abnormalities | ||
| del(17p) | 6.0 | 10/168 |
| del(11q) | 12.4 | 21/169 |
| 12q+ | 32.9 | 26/79 |
| del(13q14) | 26.9 | 21/78 |
| Complex karyotype | 20 | 34/170 |
| NGS mutation | ||
| TP53 | 12.1 | 21 |
| ATM | 13.8 | 24 |
| NOTCH1 | 25.9 | 45 |
| SF3B1 | 16.1 | 28 |
| First‐line treatment criteria | ||
| Lymphocytosis and/or lymph nodes/spleen | 63.8 | 111 |
| Cytopenias | 35.6 | 62 |
| None | 0.6 | 1 |
| Median time from diagnosis to the first‐line treatment, months | 41.7 | |
Before front‐line treatment, 25.9% of patients had a NOTCH1 mutation (Figure 1B). As previously reported, the most frequent mutation was a c.7541_7542 deletion in exon 34 in 29 (64.4%) patients (Figure 1C) [4]. Among the patients with a NOTCH1 mutation, 25 were older than 65 years, 11 were Binet stage B, four were Binet stage C, nine had a complex karyotype, and 31 (68.9%) had an unmutated IGHV status. NOTCH1 mutation was associated with an age > 65 years (p = 0.007) and an unmutated IGHV status (p = 0.002). There were no significant associations by Fisher test between NOTCH1 mutation and gender, Binet stage, complex karyotype, or TP53 mutation.
The median time from diagnosis to first treatment was 21.75 months for patients with a NOTCH1 mutation and 45.9 months for patients without (p = 0.06). First‐line treatment for NOTCH1‐mutated patients consisted of immunochemotherapy (ICT) (n = 15); fludarabine cyclophosphamide rituximab (FCR) (n = 8), bendamustine rituximab (BR) (n = 5), dexamethasone rituximab cyclophosphamide (DRC) (n = 2), BTKi (n = 18; ibrutinib n = 10, acalabrutinib n = 8), or a combination of obinutuzumab with venetoclax (n = 2), chloraminophene (n = 3), or acalabrutinib (n = 3), venetoclax monotherapy (n = 2), or otherwise (n = 2) (Figure 1B).
BTKi treatment was associated with better PFS in the population with a NOTCH1 mutation, with a median PFS not reached versus 50.6 months with ICT p = 0.005, HR 10.86 95% CI [1.37–85.88] (Figure 1E). There was no significant difference in OS (p = 0.22). Similar results were reported in the randomized RESONATE trial for 391 patients with previously treated CLL, for whom NOTCH1 mutations were associated with shorter PFS with ofatumumab treatment but not ibrutinib [7].
In the present study, BTKi treatment appeared to obliterate the adverse prognostic impact of CLL harboring NOTCH1 mutations. This is consistent with the results of the in vitro study of Del Papa et al. [8], in which they observed a decrease in NOTCH1 activation with ibrutinib treatment, regardless of mutational status, related to the BCR/NOTCH1 interaction. Such a relationship between BCR and NOTCH1 was also reported in a study of Arruga et al. [9], which provided a rationale for co‐targeting BCR and NOTCH1, which may also be of interest in Richter syndrome. The combination of targeted therapies could be a good option for these high‐risk CLL patients. Jain et al. [10] reported a rate of 60% negative minimal residual disease in patients harboring a NOTCH1 mutation treated with ibrutinib and venetoclax in the front‐line setting. None of the patients included in our study received this combination.
As a control, we also studied the subgroup without a NOTCH1 mutation, for which there was no significant difference in PFS between treatment with BTKi or ICT (p = 0.51) (Figure 1D,E). In the population treated with a BTKi as first‐line treatment, the estimated 2‐year PFS for patients with NOTCH1 mutations was 94% versus 84% for patients without a NOTCH1 mutation (p = 0.12) (Figure 1F). We did not find any significant difference between patients receiving ICT according to NOTCH1 mutational status (p = 0.14) (Figure 1G). Clinical trials, such as CLL4 [11], reported that NOTCH1 mutation was an independent predictor of shorter PFS and OS for previously untreated patients. Rossi et al. [4] showed a correlation between NOTCH1 mutation and survival. In these studies, ICT regimens were mostly used. In our study, we did not find any difference between PFS or OS for patients with NOTCH1 mutations who received ICT and those without the mutation. As our study was not designed to compare NOTCH1 mutated and unmutated patients, this result may be related to a lack of power.
In conclusion, in addition to routine TP53 and IGVH mutation status, our study highlights the potential value of screening for NOTCH1 mutations to identify patients who may benefit from BTKi treatment. The impact of NOTCH1 mutations on combination therapies, such as obinutuzumab‐venetoclax or venetoclax‐BTKi, is yet to be determined.
Author Contributions
Clémence Haméon, Roch Houot, Michel Ganard, Nicolas Vallet, Emmanuel Gyan, Sophie De Guibert, Cédric Pastore, and Caroline Dartigeas analyzed and interpreted the patient data concerning the hematological disease and neurological condition. Cédric Pastore, Olivier Herault, and Sébastien Lachot analyzed and interpreted the patient data concerning hematological biological aspects. All authors read and approved the final manuscript.
Ethics Statement
The authors have nothing to report.
Consent
Written informed consent was obtained from the patient's next of kin for publication of this letter.
Conflicts of Interest
The authors declare no conflicts of interest.
Haméon C., Houot R., Gyan E., et al. “ NOTCH1 Mutation Is Associated With Response to Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: A Retrospective Study.” eJHaem 6, no. 5 (2025): e70146. 10.1002/jha2.70146
Funding: The authors received no specific funding for this work.
Data Availability Statement
The authors have nothing to report.
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Associated Data
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Data Availability Statement
The authors have nothing to report.