Background

Secondary acute myeloid leukemia (sAML) designates AML arising from prior hematologic disorder or chemo/radiation. sAML cases evolving from myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are often grouped under AML with myelodysplasia-related changes (AML-MR). Within this subset, CMML-derived sAML remains clinically and biologically poorly characterized and underreported in clinical trials and registry studies.

Objectives In this multicenter study, we analyze the characteristics and outcomes of sAML arising from CMML treated with intensive chemotherapy (IC), hypomehtylating agents (HMAs), and modern strategies including CPX-351 and HMAs plus Venetoclax (HMA-VEN).

Methods Overall, 355 patients diagnosed between 2005-2025 with AML (blast counts > 20%) evolving from previous CMML were included . This retrospective study combined patients from PETHEMA, UK, GROM-L, and 9 additional Italian centers. Genetic analyses were performed locally. The study was approved by institutional review board. Patients who did not receive therapy were excluded from the present analysis.

Results Median age at diagnosis was 68.9 years (39-87), with prevalence of male gender (72%). All patients had previous documented diagnosis of CMML, and 67 (18.9%) received HMAs at their chronic phase. Median bone marrow blast infiltration was 35% (18-100) and median WBC 24.1 x106 (0.2-453). Normal karyotype was present in 39.2%, karyotype with trisomies in 16.5% (trisomy 8 in 7%), and complex in 15.0%. MRC cytogenetic adverse risk represented 14.0% ,intermediate 64.8%, and favorable 3%.Molecular biology by PCR , available in 300 patients, showed NPM1 (17%), FLT3-ITD in (13%), IDH1 (4%) and IDH2 (9.5%). NGS studies, available in 185 patients, disclosed median 3 mutations/pt (1-8); most frequently mutated genes were ASXL1 (n=64;42%), SRSF2 (n=61;40%), TET2 (n=56,;37%), RUNX1 (n=48;32%), KRAS/NRAS/CBL (n=51;44%), DNMT3A (n=17;11%), EZH2 (n=13,

;8.6%), and TP53 (n=5;3%). As per ELN2010 patients were classified in adverse (n=49,14%), favorable (n=37,10%), and intermediate risk (n=205,58%). For patients with available molecular data, ELN2022 stratified most patients in adverse risk (n=164,74%), intermediate (n=25,11%) and favorable (n=31,14%). Overall, 172(48%) patients received IC induction including 3+7 (n= 88), FLA-G-IDA (n=28), CPX-351 (n=36), other IC (n=20), while 183 (51%) received non intensive approaches including HMA-VEN (n=60), HMAs (n=54), less intensive chemo (FLUGA, n=36), LDAC-VEN (n=7), LDAC (n=6), or other non intensive (n=11). CR/CRi rate for the entire cohort was 35%, partial remission (PR) 14%, primary resistance 38%, early death (ED) 10%. Induction responses after IC were CR/CRi 42%, PR 14%, primary resistance 35%, and ED 7.2%. 3+7 showed higher rate of CR/CRi (53%) compared to CPX-351 (30.6%) and FLAG-IDA/FLA-IDA(32%) (p=0.01). 40/172 (23%) of IC patients underwent allo-SCT. Responses in the non-intensive group were CR/CRi 29%, PR 14%, primary resistance 43%, and ED 12%. HMA-VEN had highest CR/CRi (55%) vs HMAs (24%) and FLUGA (5.6%) (p=0.001). 4/58 patients treated with HMA-VEN proceeded to allo-SCT. OS for the entire cohort was 8.3 mos (0.95 CI, 6.9-9.5); 8.6 mos after IC (0.95CI, 7.5-11.9), and 8.3 mos after non intensive (0.95 CI, 6.3-12.8). For IC, 3+7 showed OS of 11.2 mos(0.95CI, 8.5-17.3), higher when compared to CPX-351 7.1 mos (0.95CI, 3.8-10.6) and FLA-IDA/FLAG-IDA 9.5 (0.95CI 5.12-na)( p=0.02). For the non intensive approaches, HMA-VEN OS was 14.1 mos(0.95CI, 7.4-21.8) and for HMAs 6.7(0.95CI, 5.3-16). OS for patients undergoing allo-SCT(n=44) was significantly superior to those not transplated (28.6 mos [0.95 CI, 17.7-nr] vs 6.55 [0.95 CI, 5.2-8; p<0.001].

Conclusions

sAML following CMML presents distinct cytogenetic/molecular profile and dismal outcome. Cytogenetics is enriched in normal karyotype and trisomies with lower rates of complex. NGS showed frequent ASXL1, TET2, RUNX1 and SRSF2 mutations and NRAS/KRAS/CBL pathways, with low rate of TP53. Allo-SCT offers survival benefit, but only 23% of pts were successully bridged. 3+7 showed better outcomes in IC, compared to CPX-351 and fluda-based regimens while HMA-VEN yielded best CR/CRi and OS rates in the non-intensive setting. Multivariate and propensity score analyses will be performed in order to address impact of treatment and patient´s characteristics on outcomes.

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2025
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