C028 | THE EVOLVING PICTURE OF CLINICO-GENOMIC FEATURES IN THERAPY-RELATED MYELOID NEOPLASMS (T-MN) IN THE LAST 10 YEARS IN ITALY

t-MN include AML, MDS or MDS/MPN, developing after cytotoxic treatment for solid or lymphoid malignancies, or autoimmune diseases. Recent evidence showed that genetic features supersede previous patient history in the 2022 classifications of MN, and therapy-related is nowadays considered a “diagnostic qualifier”. Given the changes observed in cancer treatments in the last 10 years, we leveraged the Italian network to update the cartography of clinical-molecular features, treatment, and outcome of t-MNs. To-date, our study includes 488 patients diagnosed with t-MN (46% MDS and 54% AML), at 27 Italian hematological centers between 2015 and 2024. M/F ratio was 1, and median age at t-MN diagnosis 69 years (range, 20-91). The latency between cytotoxic therapy and t-MN was 60 months (IQR, 24-120). Overall, 74% of patients had received prior chemotherapy +radiotherapy (40%), including PARPinhibitors in 13% of cases. Fig.1 shows the distribution or primary cancer types. Cytogenetics was normal in 38% of cases, 4% had a “favorable-risk” t-AML (t-APL or CBF- rearranged), 13% NPM1 mut AML, 33% complex karyotypes, with chromosome 7 (6%) as the most frequent isolated alteration. TP53 was mutated in 43% of t-MN, while DNMT3A was mutated in 23%, and TET2/ASXL1 in 20% each. Overall, 34% of patients received hypomethylating agents (HMA), 21% HMA/Venetoclax, 16% CPX-351, 14% other conventional chemotherapy, and 19% were consolidated with allo-HCT. With a median follow-up of 2 years (IQR, 0.9-4.6), 44% of pts are alive. Previous disease type (hematological vs solid) influenced the genomic architecture of t-MN, with less frequent del5q (1 vs 6%, p=0.01) and NPM1 mutations (5% vs 17%, p=0.01), and increased frequency of complex karyotypes (39 vs 29%, p=0.01) and ASXL1 mutations (29 vs 14%, p=0.02). Conversely, PARPi treatment (HR=2.00, p=.02) and specific mutations (TP53, HR=3.72, p<0.01; IDH2, HR=2.19, p=0.04; JAK2, HR=2.74, p=0.03; PTPN11, HR=2.41, p=0.04) negatively influenced outcomes. Patients treated with intensive chemotherapy had better survival than those receiving HMA/Venetoclax (p=0.04). Our study provides an updated cartography of t-MN, as compared to the prior Italian Network report (PMID: 25653205). In the last 10 years, lymphoproliferative diseases are less represented among primary tumors (30% vs 38%, p=0.038), while GU tumors result overrepresented (21% vs 12%, p=0.001). Survival remains poor, despite availability of new treatments.