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.