Background: The therapeutic landscape of acute myeloid leukemia (AML) has evolved substantially over the past three decades. While intensive chemotherapy (IC) was the mainstay until the mid-2000s, the advent of hypomethylating agents (HMA), venetoclax-based regimens, and targeted therapies (e.g., FLT3 or IDH1 inhibitors) has changed clinical practice, especially in older or unfit patients. However, population data describing the evolution of patient characteristics, treatment allocation, and outcomes remain limited.

Methods: Out of 21,371 patients, we retrospectively analyzed 17,908 evaluable adult patients with newly diagnosed AML (non-APL) reported to the PETHEMA epidemiologic registry (NCT02607059) between 1990 and 2024 (Spain, Portugal, Colombia, Chile, Mexico, and Uruguay). Patients were grouped into three eras based on major therapeutic changes: 1990–2006 (one size fits all), 2007–2016 (tailored therapies), and 2017–2024 (targeted therapies). Variables included baseline characteristics, treatment and outcomes. Survival analyses used Kaplan-Meier and Cox regression.

Results: Median age at diagnosis increased over time, from 62 years in 1990–2006 to 65 years in 2017–2024 (p<0.001), with patients aged ≥80 increasing from 6.9% to 14%. Despite this, baseline ECOG ≥2 decreased from 31% to 21% (p<0.001). Secondary AML increased from 20% to 31%, while extramedullary disease declined from 25% to 16% (p<0.001). No significant differences were observed in sex distribution. Hemoglobin levels declined slightly (median 9.0 to 8.8 g/dL; p=0.019), while median white blood cell and platelet counts remained stable through eras. Serum creatinine and bilirubin slightly decreased (p<0.001), and albumin increased modestly (p<0.001), suggesting improved baseline condition at diagnosis.

Frontline treatment strategies evolved markedly. IC remained predominant but declined from 80% (in 1990-2006) to 67% (in 2017-2024), p<0.001. Non-intensive therapies rose from 1.1% to 23% (p<0.001), while best supportive care (BSC) declined from 20% to 10%, indicating broader access to active treatment. Within the IC group, conventional 7+3-like regimens remained dominant until 2016 (around 90%) but decreased to 71% in 2017–2024, with increasing use of CPX-351 (5.2%), IC+FLT3 inhibitors (10%), and IC+gemtuzumab ozogamicin (2.7%). In the non-intensive setting, venetoclax + HMA combinations emerged as a key component (31% in 2017-2024), although HMA monotherapy remained the most frequently administered option (48%). In contrast, low-dose cytarabine-based regimens declined from 65% to 16%.

CR/CRi rates remained stable in the three periods for IC (65% vs. 61% vs. 63%%). The proportion of patients transplanted in first CR/CRi remained stable (23% vs. 18% vs. 20%). A shift from autologous to allogeneic transplant was evident: autologous transplant use declined from 15% to 3%, while allogeneic transplant increased from 8% to 17% (p<0.001).

Among 17,908 patients, median overall survival (OS) improved significantly from 9.3 months in 1990–2006, 9.3 months in 2007-2016, and 12.8 months in 2017–2024 (p<0.001). In univariate analysis, OS improved in most subgroups during the last diagnostic period, including all age categories, both sexes, patients with ECOG <2, de novo AML, those treated with front-line IC (from 12.9 to 20.4 months), those who underwent allogeneic or autologous transplantation, and even among non-transplanted patients. However, no significant gains were observed in patients with ECOG ≥2, secondary AML, or those treated with non-intensive therapies or BSC. Median OS among patients aged <50 increased from 27.2 to 65.8 months, from 5.8 to 10.3 months among those aged 65–74, and from 3.0 to 6.1 months among those aged 75–79. Median OS for ECOG ≥2 patients remained poor across all periods (approximately 3 months). Survival in the BSC group declined from 1.6 to 0.6 months.

In multivariate analyses, the diagnostic period remained independently associated with OS after adjusting for age, sex, AML type, ECOG status, transplant, and treatment strategy (p<0.001).

Conclusions:This large real-world study spanning more than three decades highlights substantial improvements in survival and evolving treatment patterns in AML. Despite an older population, better functional status and supportive care, and increased use of both intensive and non-intensive active therapies likely contributed to improved outcomes.

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2025
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