IDH1/2 mutations predict a distinct high-risk subset in Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia

Abstract

Abstract Background: IDH1/2 mutations are very rare in B-cell acute lymphoblastic leukemia (B-ALL), and there are few data on their prognostic significance. Therefore, we conducted a retrospective study to clarify the clinical features and outcomes in Philadelphia chromosome-negative (Ph⁻ B-ALL) patients with IDH1/2 mutations. Methods Data on consecutive adults with newly diagnosed Ph⁻ B-ALL treated at Peking University People's Hospital from Jan 2020 to Mar 2025 were retrospectively analyzed. Diagnostic marrow underwent targeted NGS of full-length IDH1/2. All patients received ALL-type chemotherapy. Disease free survival (DFS) and overall survival (OS) were estimated by Kaplan–Meier and compared by log-rank. Cox regression model was used to identify prognostic factors. PSM analysis was used to balance baseline covariates between IDH1/2-mutated and non IDH1/2-mutated groups. Results 376 patients were included in this study. 27 patients (7%) were detected to have IDH1 (n = 10) or IDH2 (n = 17) mutations at diagnosis. 181 patients (48%) were male. The patients in the IDH-mutated group were older than those in the non IDH-mutated group with the median age of 50 years vs. 32 years (P < 0.001), and had lower WBC count (3.4*109/L vs. 6.8*109/L, P = 0.01) at diagnosis. There was no statistically significant difference in other baseline characteristics including chromosome karyotype and CR rates between the IDH1/2-mutated and non IDH1/2-mutated groups. In the IDH1/2-mutated group, with a median follow-up of 14 (IQR, 6 to 29) months, 14 performed transplant, 2 relapsed, and 8 died of relapse (n = 2) or transplant-related mortality (n = 6). In the non IDH1/2-mutated group, with a median follow-up of 21 (IQR, 11 to 39) months, 180 performed transplant, 56 relapsed, and 14 died of relapse (n = 3) or transplant-related mortality (n = 11). Patients in the IDH1/2-mutated group had lower probabilities of 2-year DFS (40% vs. 84%, P = 0.001) and survival (61% vs. 94%, P < 0.001) than those in the non IDH1/2-mutated group. In multivariate analysis IDH1/2 mutation (HR 2.4, 95% CI 1.1-5.3, P = 0.033 and HR 7.4, 2.9-18.7, P < 0.001) and non-transplant (HR 3.0, CI 1.6-5.3, P < 0.001) and non-transplant (HR 7.4, 2.9-18.7, P < 0.001 and 1.4-9.0, P = 0.006) were significantly-associated with adverse DFS and survival in the whole cohort. Considering the imbalance in baseline characteristics between the 2 groups, PSM analysis was performed. After PSM according to a 1:6 ratio, 27 patients with IDH1/2 mutations and 116 with non IDH1/2 mutation were well balanced. The 2-year probabilities of DFS (52% vs. 81%, P = 0.025) and survival (63% vs. 93%, P < .001) were significantly lower in the IDH1/2 mutation group. Even in the patients receiving transplant, IDH1/2 mutated group (n = 17) still had lower probabilities of 2-year DFS (61% vs. 86%, P = 0.044) and survival (81% vs. 94%, P = 0.046) than those in the wide type group (n = 103).Conclusions: In adults with newly diagnosed Ph- B-ALL, IDH1/2 mutations were an independent, adverse prognostic factor associated with markedly inferior disease-free and survival, regardless of whether transplantation was performed. Future prospective studies are needed to assess whether the addition of IDH1/2 inhibitors can improve the outcomes in Ph-B-ALL patients with IDH1/2 mutations.