Secondary-type acute myeloid leukemia is associated with a higher risk of invasive fungal infection during intensive induction therapy. a correlative study on the ALFA 0702 trial. Free

Background. Invasive fungal infections (IFIs) represent a major cause of morbidity and mortality during intensive induction therapy for acute myeloid leukemia (AML). Although their incidence is increased in this setting, the associated risk factors remain poorly defined. In particular, the impact of somatic gene mutations on IFI risk during induction is not well understood. Secondary-type AML (sAML) gene mutations (ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2) define a distinct diagnostic and prognostic entity (PMID 35797463), and mutations in ≥2 genes amongst those (sAML2) may allow more robust identification of these patients (PMID 35941135)

Objectives. We aimed to investigate whether recurrent AML gene mutations are associated with higher risk of invasive fungal infections during the first time-sequential induction therapy in the ALFA 0702 trial (NCT00932412).

Methods. Main results of ALFA0702 were previously reported (PMID 28221862). IFIs were graded according to EORTC guidelines (PMID 34895843). Gene mutations were evaluated at diagnosis (PMID 32871585) and patients were classified as having secondary-type AML (sAML2) if ≥2 genes were mutated among the following: ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2. Cumulative incidence of IFI was evaluated considering death prior to start of the second course as a competing risk.

Results. Of 713 patients (pts) with AML registered in the 0702 trial, 633 (M/F 340/293, median age 47y) had complete genetic and IFI data and did not have a preexisting IFI at inclusion. 447 (71%) pts received anti-fungal prophylaxis during the first intensive course (posaconazole n=360, other n=87). IFIs occurred in 96 (15%) patients during the first induction therapy. IFIs were more frequent in males (M 19%%, F 11%, p=0.007) and in the 21% of pts with baseline Absolute Neutrophil Count (ANC) < 500 x10⁹/L (IFIs in 21% vs 12.5% in pts with ANC ≥ 500 x10⁹/L, p=0.006) whereas time to neutrophil recovery (median 29 days) had no impact on occurrence of IFI (p=0.7).

Of 38 genes recurrently mutated in at least 1% of pts, mutations in 4 genes were individually associated with increased risk of IFI when stratifying on receipt of antifungal prophylaxis (false-discovery rate [FDR] threshold 0.1), including SRSF2 (HR=2.36, FDR=0.03), BCOR (HR=1.97, FDR=0.089), CBL (HR=2.99, FDR=0.089) and SETBP1 (HR=3.30, FDR=0.089). Adjusting for sex, baseline ANC and time to neutrophil recovery led to similar results.

Mutations in SRSF2 and BCOR contribute to the definition of secondary-type AML. Genetically-defined sAML2 was found in 77 pts (12%) and was associated with increased IFI risk in a similar analysis stratified on antifungal prophylaxis (sAML2: HR=2.2, p=0.001). Specifically, the cumulative incidence of emergent IFI at 60 days from first induction course onset was 21% in sAML2 vs 11% in non-sAML2 pts receiving antifungal prophylaxis, and 45% compared to 19% respectively when not receiving antifungal prophylaxis.

The median time to neutrophil recovery was 32 days in sAML2 pts vs 28 days in other pts (p=0.0079). In a multivariable model also accounting for sex (M, HR=1.90, p=0.005), baseline neutropenia (ANC<500 x10⁹/L, HR=1.67, p=0.02) and time to neutrophil recovery (days, as a continuous variable, HR=1.0, p=0.94), sAML2 was independently associated with an increased hazard of IFI (HR=1.96, p=0.01). Of note, the IFI profiles (Candida sp. vs Aspergillus sp. vs other) were similar between sAML2 and non-sAML2 pts (p=0.78). To explore the potential causal link between sAML2 genetic profile and incidence of IFI, we leveraged data from 177 patients treated in the ALFA0701 trial with detailed morphological and genetic annotations (PMID 34615986), including 21 (11.9%) with sAML2 profile. sAML2 was associated with a specific dysgranulopoiesis notable for persistent basophilia (28.3% of sAML2s versus 8.3% of non-sAML2 cases, p=0.018). Across 2 genetically annotated transcriptomic datasets (BEAT-AML2, n=428; ALFA0701, n=180), sAML2 status was robustly associated with increased expression of both type I and II IFN pathways (all FDR < 10^-5), also possibly contributing to aberrant antifungal immunity.

Conclusion. Genetically-defined secondary-type AML patients might be more susceptible to IFI during intensive AML induction therapy regardless of baseline ANC and duration of neutropenia. These findings may guide personalized IFI prevention policies in this population.