P205 | THE PROGNOSTIC VALUE AND CLINICAL IMPACT OF ASXL1 MUTATIONS IN MYELOFIBROSIS: A RETROSPECTIVE COLLECTION

• Published in: Haematologica
• Main Authors: A. Laganà, E. Rossi *, G. Iaquinta *, F. Ramundo, F. Frioni, M. Rossi, L. Maurillo, R. Latagliata, S.L. Crescenzi, A. Tamburini, K. Paciaroni, M. Santopietro, C. Tatarelli, P. Grammatico, V. De Stefano, P. Chiusolo, and M. Breccia, N/A *
• Format: Article
• Language: English
• Published: Ferrata Storti Foundation 2025-09-01
• Online Access: https://haematologica.org/article/view/12402
• ISSN: 0390-6078; 1592-8721

BACKGROUD: Next-generation sequencing (NGS) has unveiled novel non-driver mutations in myelofibrosis (MF), beyond the common driver mutations. Among these, ASXL1 gene is the most frequently involved and is considered within the high-molecular risk (HMR) group alongside EZH2, SRSF2, IDH1/2, and U2AF1, due to their possible progression to acute myeloid leukemia (AML). ASXL1 alterations include frameshift, nonsense, and missense mutations. These non-benign variants are classified according to ACMG guidelines as pathogenic (class 1), likely pathogenic (class 2), or variants of unknown significance (VUS, class 3). METHODS: We retrospectively collected 125 adult MF patients, 69 (55.2%) with primary MF and 56 (44.8%) with secondary MF, harboring an ASXL1 non-benign variant from 8 hospitals in the Lazio region. We evaluated the association between ASXL1 variant classes and disease features, molecular landscape, clinical characteristics, and prognosis. RESULTS: Median age at diagnosis was 59 years (IQR, 54-66), with 76 patients (61%) being male. ASXL1 mutations were distributed as follows: 57 cases (46%) as class 1; 48 cases (38%) as class 2; 20 cases (16%) as VUS. The most common mutation was the Gly646Trpfs*12 (class 1) present in 38 patients (30%). As shown in the table, given the comparable disease characteristics between class 1 and 2 ASXL1 mutations, these were grouped together for comparison with VUS. Patients with class 1/2 ASXL1 mutations harbored a higher number of additional pathogenic variants of other genes (p=0.005). The most common associated non-driver mutation was TET2 (10 cases – 8%). Cases with class 1/2 ASXL1 alterations showed a more aggressive phenotype at presentation, such as lower hemoglobin level (p=0.004), greater spleen enlargement (p=0.049), and more symptoms (p=0.015). They were also associated with a worse risk category per IPSS, DIPSS, and MIPSS70 (p<0.001) and a higher AML evolution rate (21.9% vs. 0%; p=0.024). Excluding 44 patients who underwent allo-HSCT and other 39 patients who received ruxolitinib that might have influenced prognosis, class 1/2 ASXL1 mutations had a shorter median OS compared to ASXL1 VUS (43.4 months vs median not reached - p=0.033). CONCLUSIONS: Class 1 and 2 ASXL1 seem to determine a similar more aggressive MF phenotype and increased AML progression rate, often necessitating an intensive approach to mitigate their adverse prognostic impact. These findings underscore the utmost importance to consider all class 1/2 ASXL1 mutations for the optimal MF management.