Real-world outcomes of FLAG-ida salvage therapy in relapsed/refractory AML and validation of the salflage score: A pethema registry study

Abstract Background: Most adult patients with acute myeloid leukemia (AML) will relapse after achieving a first complete remission (CR) or show primary resistance. The prognosis of relapsed/refractory (R/R) AML remains poor, with no universally accepted salvage regimen. FLAG-Ida (fludarabine, high-dose cytarabine, idarubicin, and G-CSF) is used due to its potential to induce remissions suitable for allogeneic stem cell transplantation (allo-HCT), the main potentially curative option in this setting. Methods: We retrospectively analyzed 1,093 adult patients with non-M3 AML from the PETHEMA registry (NCT02006004) treated with FLAG-Ida between 1997 and 2024 for their first R/R episode. Eligible patients had either primary refractory disease (defined as >5% bone marrow blasts or persistent extramedullary disease after one or two identical induction cycles) or relapsed after first CR/CRi. Responses were assessed using ELN 2022 criteria. Median follow-up was 52.0 months. Results: Median age at first salvage was 52 years (range 16–77); 168 (16%) had secondary AML, and the median leukocyte count at initial AML diagnosis was 11.5 ×10⁹/L. Primary refractory disease was present in 404 (37%), early relapse (relapse-free interval [RFI] <1 year) in 431 (39%), and late relapse (RFI ≥1 year) in 258 (24%). Prior transplantation was reported in 336 (32%), including 220 (21%) allogeneic and 116 (11%) autologous. According to MRC 2010 classification, 105 (10%) were low-, 563 (53%) intermediate-, and 299 (27%) high-risk. Among evaluable cases, NPM1, FLT3-ITD, and IDH1/2 mutations were present in 194 (18%), 174 (16%), and 77 (7%), respectively; and 77 (7%) had inv(16). A total of 558 patients (51%) achieved CR, 43 (4%) CRi, and 19 (2%) MLFS, resulting in a composite CR (CRc) rate of 620 (57%). Partial response was seen in 57 (5%), 323 (30%) had no response, and 93 (8%) induction death. Allo-HCT in CRc was performed in 403 (37%). Median overall survival (OS) for the entire cohort was 10.4 months (95% CI, 9.5–11.7), with 2- and 5-year OS rates of 30% and 21%, respectively. Patients with late relapse (n=258) had superior median OS (14.9 months, 95% CI 14.1–19.5) compared to those with early relapse (n=431, 8.2 months) or primary refractory disease (n=404, 10.2 months; p<0.001). Prior allo-HCT (n=220) was associated with better OS (21.6 months, 95% CI 14.4–29.0) than no prior transplant (8.4 months) or autologous transplant (14.2 months; p<0.001). Regarding molecular subgroups, FLT3-ITD-mutated (n=174) had worse OS (8.0 months, 95% CI 6.8–10.4) than FLT3-ITD wild-type (12.2 months; p<0.001). In contrast, IDH1/2-mutated (n=77) showed improved OS (18.0 months, 95% CI 12.0–NR) versus IDH1/2 wild-type (10.5 months; p=0.004). Patients with inv(16) showed 2- and 5-year OS rates of 65% and 47%, respectively, and higher median OS of 58.4 months (95% CI, 25.3–NR) versus 9.7 months in the rest of the cohort (p<0.001). Regarding treatment periods, 102 (9%) received FLAG-Ida before 2006, 482 (44%) between 2006–2016, and 509 (47%) between 2017-2024. Median OS improved from 8.0 months pre-2006 to 9.9 in 2006–2016 and 11.1 in 2017-2024 (p=0.20). The 30 days survival improved in the last period as compared to the previous one: 91%, 86%, and 92% (p=0.008). The rate of allo-HCT increased from 23%, 34% and 42% across eras (p<0.001). Prognostic stratification in three groups using the previously published SALFLAGE score (based on age, relapse type, prior SCT, FLT3-ITD status, and MRC cytogenetics) was validated in 764 patients: low- (n=206, 27%), intermediate- (n=227, 30%), and high-risk (n=331, 43%). Median OS was 18.9 months in the low-, 12.3 in the intermediate-, and 7.4 in the high-risk group (p<0.001), with 2-year OS rates of 45%, 35%, and 25%, and 5-year OS rates of 36%, 25%, and 15%, respectively. Conclusion: This study represents the largest series of R/R AML patients treated with FLAG-Ida to date. Despite the inherent limitations of retrospective analyses, the inclusion of all patients captured in the PETHEMA registry provides a comprehensive real-world overview. FLAG-Ida achieved 57% CRc rate with relatively low induction death rate (8%). Outcomes improved over time, with median OS reaching 11.1 months and allo-HCT rates increasing to 42% after 2016. The SALFLAGE score was validated and reliably stratified patients into prognostic groups with significantly different survival. These findings reinforce FLAG-Ida as a key salvage option for fit R/R AML patients.