Background

Spliceosomes are intranuclear proteins that splice pre-mRNA into mature mRNA. Somatic mutations in genes encoding spliceosome components are found in acute myeloid leukemia (AML) and can occur in SRSF2, U2AF1, SF3B1, ZRSR2, and, less frequently, in PRPF8 and LUC7L2. This study examines the clinical presentation and prognostic significance of these mutations in AML.

Methods We performed a retrospective cohort study to compare treatment outcomes in patients diagnosed with AML with mutated (mt) and wild type (wt) genes encoding spliceosome complex. Data collected included age, gender, ethnicity, comorbidities, cytogenetics, and mutational profiles (via next-generation sequencing). Outcome included composite complete response (CCR=CR+CRi), overall survival (OS), and event-free survival (EFS). Multivariable logistic [MV-LR] and Cox proportional hazards [MV-CPH] were used to adjust for age, gender, comorbidities, TP53 status, and cytogenetics.

Results A total of 971 patients with new diagnosis of AML were encountered at our center between 2015 and 2023, with an average age of 66 years and a median follow up of 41 months among survivors. The prevalence of mutant spliceosome alleles was as follows: SRSF2: 17%, (N=107 of 629 tested), U2AF1: 7.2%, (45/626), SF3B1: 6.9% (43/623), ZRSR2: 2.9%, (18/620), PRPF8: 3.8% (15/391), and LUC7L2: 0.9%, (4/432).

Compared to SRSF2-wt AML patients, SRSF2-mt patients (N=107) were older (71 vs 65 yr), more frequently male gender (68 vs 54%), had less frequent high-risk cytogenetics at baseline (18% vs 33%), and less frequent TP53 mutation (4 vs 21%) (all P<0.05). There was no difference in CCR (48% vs. 54%)[MV-LR odds ratio (OR): 0.83, 95CI: 0.5-1.4), median OS (11 vs 12 mo)[MV-CPH: hazard ratio (HR) 1.1, 95CI 0.8-1.4] or median EFS (7.4 vs 7.2 mo)[MV-CPH: HR 1.1, 95CI 0.8-1.4] between SRSF2-mt and wt AML, respectively.

Patients with U2AF1-mt AML (N=45) were more likely to be male (76% vs 55%), and had lower absolute neutrophil count (ANC) at presentation (0.5 vs 1 K/μL) than U2AF-1-wt AML (all P<0.05). Mutation in U2AF1 was not associated with different CCR (44% vs 53%)[MV-LR: OR 0.7, 95CI 0.3-1.6], median OS (9.1 vs 12 mo)[MV-CPH: HR 1.2, 95CI 0.9-1.8] or median EFS (5.7 vs 7.4 mo)[MV-CPH: HR 1.2, 95CI 0.8-1.8] compared to no mutation in U2AF1.

Compared to SF3B1-wt AML patients, SF3B1-mt AML patients (N=43) were older (71 vs 66 yr, p=0.008), had lower blasts (35% vs. 65%), higher ANC (1.5 vs 1 K/μL) and higher platelets (70 vs 52 K/μL) (all P<0.05). Patients with SF3B1-mt AML had similar CCR (42% vs 53%)[MV-LR: OR 0.7, 95CI 0.3-1.5], median OS (7.7 vs 12 mo)[MV-CPH: HR 1, 95CI 0.7-1.4] and median EFS (5.2 vs 7.4 mo)[MV- CPH: HR 1, 95CI 0.7-1.5] compared to SF3B1-wt AML .

Patients with ZRSR2-mt (N=18) and ZRSR2–wt AML had similar baseline characteristics. Similarly, patients with ZRSR2-mt AML had similar CCR (50% vs 53%)[MV-LR: OR 0.88, 95CI 0.3-3], median OS (11 vs. 12 mo)[MV-CPH: HR 1, 95CI 0.6-1.9] and median EFS (7.5 vs 7.2 mo)[MV-CPH: HR 1.2, 95CI 0.7-2.1] compared to patients with ZRSR2-wt AML.

Patients with PRPF8-mt (N=15) and PRPF8–wt AML had similar baseline characteristics. Similarly, patients with PRPF8-mt AML had similar CCR (50% vs 53%)[MV-LR: OR 0.88, 95CI 0.3-3], median OS (13 vs 11 mo)[MV-CPH: HR 0.8, 95CI 0.4-1.6] and median EFS (9.1 vs 6.9 mo)[MV-CPH: HR 0.7, 95CI 0.4-1.5] compared to patients with PRPF8-wt AML.

Patients with LUC7L2-mt (N=4) had higher WBC at presentation (67 vs 7 K/μL, P<0.05) compared to LUC7L2–wt AML. The presence of a mutation in LUC7L2 did not predict a difference in CCR (50% vs 52%, P=0.9), median OS (8.1 vs 12 mo, P=0.3), or median EFS (8.1 vs 7.2 mo, P=0.4).

Rates of AML response, MRD response, cytogenetic response, OS, and EFS were not significantly different between patients with all six spliceosome mutations when compared to each other.

Conclusion In this cohort study, we found that AML patients with spliceosome complex mutations are common and exhibited variable baseline characteristics but showed no significant differences in clinical outcomes after adjustment, including AML response rates, cytogenetic response, OS, or EFS. Although several of these mutations are designated as adverse-risk features in the ELN 2022 guidelines, our findings suggest their independent prognostic impact may be limited. Large, multi-institutional studies are warranted to clarify their clinical relevance, especially for rare mutations, like PRPF8 and LUC7L2.

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2025
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