Discussion
Targeting signaling pathways that regulate cell survival and death has
emerged as an effective therapeutic strategy in patients with AML.
Recently, numerous clinical trials have shown that the specific Bcl-2
inhibitor venetoclax combined with HMAs is effective in the treatment of
relapsed and primary refractory AML. DiNardo et al. demonstrated that
overall survival (OS) was longer and the incidence of remission was
higher among patients who received azacitidine plus venetoclax than
among those who received azacitidine alone in a randomized clinical
trial (NCT02993523) [9]. In a phase 3 clinical trial, Wei et al.
identified that venetoclax plus low-dose cytarabine (LDAC) improved
remission rate and OS compared to LDAC alone (NCT03069352) [10].
Then Karol et al. demonstrated the safety and activity of venetoclax
plus chemotherapy in pediatric patients and indicated that this
combination could be employed in newly diagnosed pediatric patients with
high-risk AML [11]. Overall, venetoclax in combination with HMAs
improves the prognosis of older patients with AML, but there are a few
clinical trials about pediatric AML.
Our patient was diagnosed with NUP98-NSD1 fusion gene, IDH1 mutation,
and GATA2 mutation by RNA sequencing, which make him to be classified to
high-risk group. Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
mutations were reported in 19% of newly diagnosed AML patients
[12]. Though the drugs targeting IDH1 mutation ivosidenib have been
approved, it is too expensive and unacquirable for the patient. Besides,
the IDH1 mutation frequency became very low after two courses of
conventional chemotherapy. However, the MRD was still very high (50%),
which was mainly caused by the high expression level of NUP98-NSD1
fusion gene (75.94%). Kivioja et al. screened patient cells and
engineered cell models with over 300 compounds, and found that the cells
expressing NUP98-NSD1 had significantly increased sensitivity to Bcl-2
inhibitors [13]. However, there are no reports on venetoclax plus
decitabine use in pediatric patients with AML expressing NUP98-NSD1
fusion.
Here we firstly employed DCAG plus venetoclax to treat the patient with
NUP98-NSD1 fusion who could not achieve CR after two courses of
chemotherapy. The combination therapy of Bcl-2 inhibitor venetoclax and
HMAs (decitabine) had a promising outcome, and the patient achieved CR
which made him to be able to accept HSCT. Overall, venetoclax could be
effective and safe for treating pediatric AML expressing NUP98-NSD1
fusion. Therefore, establishing the appropriate dosage, efficacy, and
safety of venetoclax in pediatric patients through clinical trial is
required. Further genetic and pharmacological studies of AML with
NUP98-NSD1 fusion are urgently needed to improve patient outcomes.