Background. The aim of intensive induction treatment in acute myeloid leukemia (AML) is the achievement of complete remission (CR). After the establishment of “3+7” regimen as the standard induction, several efforts were pursued for improvement through different modalities, among which the increase of anthracycline and cytarabine doses. All these approaches provided a survival advantage in specific subgroups, generally offset by increased toxicity. Since 2017, novel agents have received approval for frontline treatment of selected patient categories, changing the uniform management to a targeted diversification of therapeutic approaches: the incorporation of the FLT3 inhibitor Midostaurin for FLT3-mutated patients, the use of CPX-351 for therapy-related AML and AML with myelodysplasia-related changes, the implementation of Gemtuzumab ozogamicin prominently in patients with favorable-risk cytogenetics. Nonetheless, induction treatment is still conceived as a single treatment block, the response to which is appreciated only 3-4 weeks after its completion. We previously provided evidence that the kinetics of blast reduction in the peripheral blood (PB) during the first days of “3+7” course might reflect AML chemosensitivity. The analytical approach was based on the quantification of leukemia-associated aberrant immuno-phenotype(s) (LAIP) by multi-parameter flow cytometry (MFC) in PB before starting the induction on day 1 (baseline), and daily thereafter up to day 8. We defined the “clearance of peripheral blast cells” (PBC) as the logarithmic ratio between the absolute blast count on the day of chemo start and the values measured daily. In an exploratory cohort of 61 patients, followed by prospective analysis in the of NILG 02-06 randomized clinical trial, we showed the potential of PBC to predict the achievement of CR and measurable residual disease (MRD) negative status.

Rationale. We reasoned that an early appraisal of chemosensitivity based on PBC might support the modulation of induction regimen. Accordingly, we envisioned to continue standard induction in patients where PBC data predict a good response, while in patients with a low clearance of PB blasts, immediate switching to an intensified induction could be offered. Such a PBC-driven approach is meant to increase the rate of CR, but with lower overall toxicity, by early identification of patients with lower probability to achieve CR. The second component of this personalized approach regards the early assessment of disease-associated risk: based on the correlation of PBC with survival and MRD, PBC-low patients will be considered as high-risk and early allocated to allogeneic HSCT. The rationale is to avoid delaying HSCT and prevent delivering of additional chemotherapy courses that are predicted to have very low chance to improve the response depth.

Study design. AMELIORATE is a phase 3, randomized, trial aiming to personalization of treatment in FLT3-mutated AML (EudraCT number 2019-003936-21). The study is sponsored by GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) and co-funded by MYNERVA (MYeloid NEoplasms Research Venture AIRC). Key eligibility criteria are a diagnosis of untreated AML according to WHO 2016 and the presence of FLT3 mutation, either ITD and/or TKD. PBC is calculated on day 4 of induction as a logarithmic ratio between the absolute PB LAIP+ cell count on day 1 (baseline) and on day 4. A threshold of 2.0 log is decisional to assign patients to different arms. Patients with PBC >2 (PBC-high) complete the standard induction course and are managed according to standard practice. Patients with PBC≤2 (PBC-low) are randomized at day 4 between a standard (analogue to PBC-high) and an experimental approach providing two main modifications: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m2 bid on days 5, 6 and 7); and the early allocation to high-risk category, to be refined later, based on ELN stratification and post-induction MRD status. All patients receive Midostaurin as per standard practice. Event free survival (EFS) is selected as the primary endpoint.

Recruitment. Between April 2020 and June 2025, 28 study sites adhered to the trial and 147 FLT3-mut pts were enrolled so far. Based on the expected distribution of patients into PBC-high and PBC-low category, a total of 172 subject is to be recruited to include 86 PBC-low patients suitable for randomization to the conventional and experimental arm

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2025
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