AUTHORS
Fabio Guolo, MD, PhD, Michele Gottardi, MD2, Giovanni Marconi, MD3, Paola Minetto, MD, PhD4, Ernesta Audisio, MD5, Carola Riva, MD6, Lorenzo Brunetti7, Caterina Alati8, Crescenza Pasciolla, MD9, Sara Rosellini10, Enrico Carminati11, Monica Messina12, Claudia La Torrella13, Antonio Curti Sr, MD14, Marco Frigeni, MD15, Massimo Bernardi16, Giuseppe Lanzarone, MD17, Elisabetta Tedone18, Elisabetta Lugli19, Clara Minotti20, Paola Fazi21, Adriano Venditti, MD22, Roberto M. Lemoli23, Alfonso Piciocchi, MS24
AFFILIATIONS
1 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy, University of Genoa, Genoa, Italy
2 IOV “Venetian Oncology Institute” IRCCS, Castelfranco Veneto, Italy
3 University of Bologna, Ospedale S. Maria delle Croci in Ravenna, Ravenna, Italy
4 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy
5 Città della Salute e della Scienza di Torino, Turin, Italy
6 University of Genoa, Genoa, Italy
7 AOU OSPEDALI RIUNITI UMBERTO I - G.M. LANCISI - G. SALESI- ANCONA - SOD CLINICA EMATOLOGICA, Ancona, Italy
8 'Bianchi-Melacrino-Morelli' Hospital, Reggio Calabria, Italy
9 UO Ematologia, IRCCS Oncologico Istituto Tumori Giovanni Paolo II, Bari, Italy
10 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy
11 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy
12 GIMEMA Foundation, Rome, Italy
13 GIMEMA Foundation, Rome, Italy
14 IRCCS AOU Bologna, “Seràgnoli” Institute of Hematology, Bologna, Italy
15 Department of Hematology-Oncology ASTT Papa Giovanni XXIII, Bergamo, Italy
16 “San Raffaele” Scientific Institute, Milano, Italy
17 Città della Salute e della Scienza di Torino, Turin, Italy
18 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy
19 AUSL, Reggio Emilia, Italy
20 Sapienza University of Rome, Rome, Italy
21 GIMEMA Foundation, Rome, Italy
22 University Tor Vergata, Rome, Italy
23 IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy, University of Genoa, Genoa, Italy
24 GIMEMA Foundation, Rome, Italy
ABSTRACT
Background:
The incorporation of targeted therapies into frontline treatment has increased the complexity of acute myeloid leukemia (AML) management. FLT3 mutations occur in approximately 30% of AML cases and are associated with poor prognosis. Although the addition of midostaurin to standard "3+7" chemotherapy has improved outcomes, remission rates remain suboptimal. Gilteritinib, a potent and highly selective FLT3 inhibitor, has demonstrated significant activity in relapsed/refractory FLT3-mutated AML. Furthermore, intensive fludarabine-based regimens, such as FLAI, may provide a more effective chemotherapy backbone for integrating targeted agents. Based on this rationale, the GIMEMA AML2924 phase II trial (EUDRACT No. 2024-518617-25-00) was designed to evaluate the efficacy of FLAI plus gilteritinib (FLAI-G) as frontline therapy for younger patients with FLT3-mutated AML. We report the first interim results.
Methods:
This multicenter phase II study plans to enrol 80 newly diagnosed patients aged 18–65 years with FLT3-mutated (ITD or TKD) AML across major Italian centers. Induction consists of up to two cycles of FLAI combined with gilteritinib 120 mg daily on days 6–26, with optional omission of fludarabine during the second induction. Consolidation includes up to three cycles of high-dose cytarabine plus 21 days of gilteritinib. Allogeneic hematopoietic stem cell transplantation (HSCT) is allowed at the investigator's discretion after a response is achieved. Bone marrow response is assessed at day 28 after induction and before each subsequent treatment cycle. Measurable residual disease (MRD) is centrally evaluated by standardized multiparameter flow cytometry (positivity threshold 0.1%; minimum 500,000 acquired events), PCR and NGS after cycle 1 and cycle 2 and at the end of treatment, or pre-HSCT in transplanted patients. PCR and NGS MRD data will be analysed after the completion of the enrolment.
The primary endpoint is complete remission (CR) after the first induction cycle, while the key secondary endpoint is MFC MRD-negative CR. Additional secondary endpoints include survival, safety, and quality of life.
The study has three pre-planned interim analysis, at 25% at 50% and at 75% of enrolment. Herein we report the results of the first preliminary analysis. The study conducted by the Italian non-profit organization GIMEMA with unrestricted funding support from Astellas.
Results:
At the time of analysis, 28 patients had been enrolled across 13 Italian centers. Response assessment was available for 23 patients. Median age was 50 years (range, 18–63), 43% were male, 21 patients (91%) harboured FLT3-ITD mutations, and 2 (9%) FLT3-TKD mutations. A co-mutation in NPM1 was reported in 17 patients (61%).
Following the first induction cycle, 22 of 23 patients (96%) achieved CR, while one patient achieved partial remission. No cases of primary refractory disease were observed. Eight patients received a second induction cycle (without fludarabine), and five subsequently received high-dose cytarabine consolidation.
No induction related mortality was observed.
MRD assessment after the first induction was technically adequate in 16 patients, all of whom achieved MRD negativity (100%). In the remaining seven patients, MRD evaluation was not adequate because the minimum acquisition threshold of 500,000 events was not reached (however it resulted negative in all cases).
Overall, seven patients (30%) proceeded to allogeneic HSCT: one after the first induction cycle, two after the second induction, and four following consolidation cycles. Seven more patients are awaiting transplantation (30%). All transplanted patients were MRD-negative before HSCT.
After a median follow-up of 8 months, only one patient has relapsed.
Conclusions:
FLAI combined with gilteritinib demonstrated remarkable early activity as frontline treatment for younger patients with FLT3-mutated AML. The regimen achieved a 96% CR rate after a single induction cycle, with MRD negativity among all evaluable responders and no cases of primary induction failure. These encouraging preliminary findings support the ongoing evaluation of FLAI-G as a highly active frontline strategy for FLT3-mutated AML.
DISCLOSURES
Fabio Guolo, MD, PhD: No relevant conflicts of interest to declare.