【Cancer】NOTCH mutation is a poor prognostic factor for treatment-naïve AML

NOTCH mutation

The NOTCH signaling pathway regulates different gene expression in different cells, resulting in widely variable outcomes in NOTCH signaling, and the role of abnormal NOTCH activation in certain types of hematologic malignancies remains unclear
to date.
For example, in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphoblastic leukemia, the proportion of NOTCH^mutations (NOTCH mut) is more than half and 8.
3%, respectively, and may be a predictor
of adverse outcomes.

However, there are few studies of NOTCH mut in acute myeloid leukemia (AML), and it is speculated that because the detection of NOTCH mut is rare, it is still unclear whether NOTCH^mut affects the prognosis of AML, in view of this, Professor Wu Depei and Professor Han Yue of the First Affiliated Hospital of Soochow University conducted a retrospective study in a large cohort of 878 AML patients.
to better understand mutation profiles, clinical relevance, and outcomes
in patients with NOTCH^mut.
The results of the study were recently published in Cancer
.

Research methods

The authors screened 878 patients with continuous treatment-naïve AML who were treated at the First Affiliated Hospital of Soochow University between February 7, 2015 and July 20, 2019, with data cut-off on June 30, 2021, and a median follow-up of 45.
2 months
for all patients 。 Induction therapy is primarily based on age, performance status, organ function, and comorbidities: young (age < 60 years) and FIT patients receive standard therapy, older (age ≥ 60 years) or unfit patients receive low-intensity chemotherapy with demethylating drugs (HMAs), and a small number of patients receive other treatment options
.
Post-remission therapy for patients with AML includes chemotherapy consolidation therapy and allogeneic hematopoietic stem cell transplantation (allo‐HSCT), based on ELN 2017 and NCCN guideline selection
.
The regimen of induction therapy and post-remission therapy is as follows
.

Study results

Baseline characteristics

A total of 878 patients with newly diagnosed AML, including 32 (3.
6%) patients with NOTCH^mut, were characterized in Table 1
.
773 (88.
0%) Patients aged < 60 years, 105 (12.
0%) Patients aged ≥ 60 years; The median age of patients with NOTCH^mut and NOTCH wild type (NOTCH^wt) was 44 and 43 years, respectively, and was not statistically significant; There were no sex differences
in either group.
In addition, patients with NOTCH^mut had significantly lower platelet counts (29 vs 42 x 10⁹/L, p=0.
024), while haemoglobin, white blood cell count, and bone marrow blast levels were similar
to NOTCH^wt.
According to the ELN 2017 guidelines, 12 (37.
5%) patients with NOTCH^mut were classified as low-risk, 10 (31.
3%) as intermediate-risk, and 10 (31.
3%) as high-risk
.

There was no significant difference in ELN stratification between NOTCH mut and NOTCH wt (p = 0.
560), and the proportion of patients with NOTCH^mut receiving low-intensity regimens with induction therapy was higher (35.
7% vs.
53.
1%) and lower with standard care (58.
5% versus 40.
6%) compared with patients with NOTCH^wt
。 There was no statistically significant difference in induction strategies between NOTCH mut and NOTCH wt (p=0.
124), but the proportion of patients with NOTCH^mut receiving transplantation was lower than that in patients with NOTCH^wt (34.
4% vs 59.
0%; p= 0.
006）
。

NOTCH^MUT PANORAMA

Details of amino acid changes were lost in 5 patients with NOTCH mut, 29 NOTCH mutations were detected in 27 patients with newly diagnosed AML, resulting in 25 AML cases identifying NOTCH1 mut and 2 identifying NOTCH2^mut
.
Mutation types include 25 substitution missense mutations, 2 frameshift mutations, 1 substitution nonsense mutation, and 1 insertion frame (Figure 1A).

To better visualize the NOTCH mutation profile in AML patients, the authors also analyzed coexisting genes in NOTCH mut AML (Figure 1B): in general, NOTCH mut is more common (compared to NOTCH^mut ) occurred co-with BCOR/BCORL mutations (15.
6% vs 3.
2%, p = 0.
001), DNMT3A mutations (28.
1% vs 12.
5%, p = 0.
021), and MPL mutations (9.
4% vs 0.
8%, p = 0.
004), in addition to NOTCH^mut The association with double-mutant CEBPA (CEBPAdm) (p = 0.
160), NPM1 (p = 0.
536), FLT3-ITD (p = 0.
346), and TP53 mutations (p = 0.
687) was less significant
.
In addition, NOTCH^mut was associated with a higher rate of DNA methylation mutations (46.
9% versus 28.
8%; p = 0.
028; Figure 1C).

Response to treatment

Of the 32 patients with NOTCH^mut, 17 (53.
1%) received HMA-based low-intensity regimens, another 13 (40.
6%) received standard chemotherapy, and 2 (6.
3%) received other regimens (Table 1).

The authors evaluated the response of patients with AML after the first two cycles of induction chemotherapy and found that NOTCH^mut had an overall response (ORR 78.
1% versus 87.
4%; p = 0.
209 cases) and CR/CRi (75.
0% vs 80.
3%; p = 0.
465) had no significant effect, regardless of
the induction regimen.

In terms of efficacy, patients with NOTCH mut who received standard regimens had a lower ORR trend than those with NOTCH wt (69.
2% vs 89.
7%, p = 0.
058), but there were no significant differences in ORR and CR/CRi between the NOTCH ^wt and NOTCH^mut groups in the low-intensity induction regimen
。

Outcomes for patients with NOTCH^mut

Effect of NOTCH mut on survival: The median follow-up time for the NOTCH wt and NOTCH mut cohorts was 45.
3 and 40.
4 months, respectively, and the OS of patients with NOTCH^mut was significantly shorter than that of NOTCH^wt Patients (median 28.
5 months vs not achieved; 1-year OS 68.
0% vs 84.
2%; 3-year OS 48.
3% vs 59.
6%; p = 0.
059; Figure 2A, table above); Patients with NOTCH^mut also had shorter RFS than those with NOTCH^wt (1-year RFS 78.
3% versus 85.
4%; 3-year RFS 54.
5% vs 76.
9%; p = 0.
018; Figure 2B, table above), but none of the median RFS was reached
.
Patient outcomes achieving CR/CRi: 75.
0% of patients with NOTCH^mut achieved CR with OS and RFS compared with NOTCH^wt (median OS 37.
3 months vs NR, p = 0.
006; median RFS NR vs NR, p = 0.
027).

Patients with NOTCH^mut based on ELN 2017 stratified outcomes

The authors assessed whether the effect of NOTCH mut status on outcomes depended on ELN risk category: the OS and RFS of NOTCH mut were similar to those of NOTCH^wt in low-risk patients (median OS NR vs NR, p = 0 .
877; median RFS NR vs NR, p = 0.
382), while NOTCH^mut in intermediate-risk patients Patients had worse OS (median 16.
6 months vs 60.
7 months, p = 0.
012; Figure 2C) and RFS (median 14.
2 months vs NR, p = 0.
082; Figure 2D), and the presence of NOTCH^mut in high-risk patients was also associated with poorer OS (median 21.
5 months vs 33.
2 months, p = 0.
187; Figure 2E) and RFS (median: 32.
8 months vs NR, p = .
069; Figure 2F).

Outcomes of different treatments after remission in patients with NOTCH^mut

To assess whether allo-HSCT can eliminate the adverse effects of NOTCH mutations, the authors also compared patients with NOTCH mut who received allo-HSCT with patients with NOTCH^mut who did not receive allo-HSCT
.
368 (41.
9%) of the 878 patients received consolidation chemotherapy as post-remission therapy, including 347 of NOTCH wt and 21 of NOTCH^mut, whose RFS was lower than that of NOTCH ^wt (median 32.
8 months vs NR, p = 0.
006, figure B below
。 Although 510 of the 878 patients (58.
1%, 499 patients with NOTCH wt and 11 patients with NOTCH mut) received allo-HSCT, allo-HSCT was in the NOTCH^mut group and NOTCH^wt Both groups improved OS and RFS, and there was no difference in survival between the two groups (median OS NR vs NR, p = 0.
360; median RFS NR vs NR, p = 0.
967, C and D below).

For patients with NOTCH^mut, both OS and RFS were superior to chemotherapy in allo-HSCT patients (median OS versus 21.
5 months, p = 0.
075; median RFS NR vs 32.
8 months, p = 0.
148, E and F below).

Outcomes in patients with coexisting NOTCH^mut and other mutations

NOTCH^mut had a negative effect on OS in patients with DNMT3A mutation (median 16.
6 months vs 27.
0 months, p = 0.
048; Figure A) and CEBPAdm (median 25.
7 months vs NR, p = 0.
002; Figure C below), without significant effect on RFS (Figure B, D below).

At the same time, NOTCH^mut had no effect
on the prognosis of NPM1 and FLT3-ITD mutations.

Multivariate analysis of lifetime

To evaluate the contribution of NOTCH^mut to adverse outcomes, the authors constructed a multivariate analysis model, including relevant variables related to OS and RFS in univariate analysis (Table 2).

In univariate analysis, NOTCH^mut was associated with OS defect (HR=1.
579; p = 0.
059）
。 Moreover, NOTCH^mut is a significant and independent risk factor for predicting an increased risk of recurrence in patients with newly diagnosed AML (HR=2.
153; p=0.
014).

conclusion

This study is the largest study to confirm the clinical manifestations and outcomes of NOTCH mut in treatment-naïve AML, finding that 32 (3.
6%) of 878 patients with treatment-naïve AML had NOTCH^mut, consisting of
substitution-missense, frameshift mutation, substitution-nonsense, and insertion-in-frame.
Patients with NOTCH^mut had lower platelet counts (29 vs 42 x 10 9/L, p = 0.
024) and BCOR/BCORL1 (15.
6% vs 3.
2%, p = 0.
001), DNMT3A (28.
1% vs 12.
5%, p = 0.
021), and MPL (^9.
4% vs 0.
8%, p = 0.
004) than NOTCH wild type ( NOTCH^wt)
。

THERE WAS NO SIGNIFICANT DIFFERENCE IN TREATMENT RESPONSE BETWEEN NOTCH MUT AND NOTCH^WT, BUT NOTCH^MUT WAS ASSOCIATED WITH POORER OS (68.
0% vs.
84.
2% AT ONE YEAR; 3-year OS 48.
3% vs 59.
6%; p = 0.
059) and RFS (1-year RFS 78.
3% vs 85.
4%; 3-year RFS 54.
5% vs 76.
9%; p = 0.
018), especially in
the ELN 2017 intermediate-risk population.
In addition, allogeneic hematopoietic stem cell transplantation may eliminate the adverse effects
of NOTCH^mut on RFS.
Multivariate analysis found that NOTCH^mut was an independent factor that negatively affected RFS (HR=2.
153; p=0.
014).

Overall, the discovery of the novel role of NOTCH^mut in predicting the risk of AML treatment failure may provide a promising area of research for the potential mechanism of the NOTCH pathway in AML and provide a potential therapeutic target
.

References

Haohao Han, Yifang Yao, Hong Wang,et al.
Landscape and clinical impact of NOTCH mutations in newly diagnosed acute myeloid leukemia.
Cancer .
2022 Nov 12.
doi: 10.
1002/cncr.
34534.

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