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1536 Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies, Minimal Residual Disease
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Giovanni Marconi, MD1, Alfonso Piciocchi, MS2*, Ernesta Audisio, MD3*, Cristina Papayannidis, MD4, Fabio Guolo, MD, PhD5,6*, Marco Cerrano, MD7*, Valentina Arena, MS2*, Capria Saveria8*, Michela Rondoni9*, Matteo Giovanni Della Porta, MD10*, Geramana Beltrami11*, Monica Bocchia, MD12*, Albana Lico, MD13*, Luisa Giaccone, MD, PhD14*, Marianna Rossi, MD15*, Catello Califano, MD16*, Matteo Giovanni Carrabba17*, Chiara Cattaneo, MD18, Marco Frigeni, MD19*, Maria Chiara Di Chio20*, Bianca Serio21*, Roberto Freilone, MD22*, Antonio Curti, MD, PhD23, Paola Minetto, MD24, Giovanni Marsili25*, Clara Minotti26*, Beatrice Zannetti27*, Francesca Cotugno25*, Jacopo Nanni, MD28*, Giorgia Simonetti, PhD29*, Maria Teresa Bochicchio29*, Sara Rosellini30*, Elisabetta Tedone31*, Adriano Venditti, MD32, Roberto Massimo Lemoli, MD33,34*, Marco Vignetti, MD35*, Paola Fazi, MD2* and Giovanni Martinelli36*

1IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”,, Meldola, Italy
2GIMEMA Foundation, Data Center and Health Outcomes Research Unit, Rome, Italy
3SC Ematologia 2, AOU Città della Salute e della Scienza, Turin, Italy
4Istituto di Ematologia "Seràgnoli", IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
5Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
6Clinic of Hematology, Department of Internal Medicine (DiMI), Policlinico San Martino, IRCCS per l’Oncologia, University of Genoa, Genoa, Italy
7Division of Hematology, Department of Oncology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
8Policlinico Umberto I, Ematologia, Roma, Italy
9Hematology Unit & Metropolitan Transplant Network, AUSL Romagna, Ravenna, Italy
10Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
11IRCSS S. Martino, Hematology and Transplant Unit, Genova, Italy
12UOC Ematologia, Azienda ospedaliero-universitaria Senese, Siena, Italy
13Hematology Unit, San Bortolo Hospital, Vicenza, Italy, Vicenza, Italy
14Univesity of Torino, AOU Città Della Salute E Della Scienza Di Torino,, Torino, ITA
15Division of Hematology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy, Pavia, ITA
17Unit of Hematology and Bone Marrow Transplantation, I.R.C.C.S. Ospedale San Raffaele, Milan, Italy
18Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
19Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy, Bergamo, Italy
20Istituto Nazionale Tumori, Milano, Italy
21University Hospital "san Giovanni Di Dio E Ruggi D'Aragona", Salerno, ITA
22Hematology Division, A.O.U Città della Salute e della Scienza di Torino, Torino, Italy
23IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
24Clinica Ematologica, Dipartimento di Oncologia e Ematologia, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
25Fondazione Gimema, Roma, Italy
26Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ITA
27Hematology Unit & Metropolitan Transplant Network, Ravenna and Stem Cell Transplant, AUSL Romagna, Ravenna, Italy
28Department of Medical and Surgical Sciences, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy
29IRCSS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l, Meldola, Italy
30Servizio di Citofluorimetria, Dipartimento di Anatomia Patologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
31IRCCS Ospedale Policlinico San Martino, Genoa, Italy
32Department of Onco-Hematology, Fondazione Policlinico Tor Vergata, Rome, Italy, Italy
33Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy, Genoa, Italy
34Clinic of hematology, Department of Internal medicine (DiMI), University of Genoa, Genoa, Italy
35GIMEMA Foundation, Rome, Italy
36IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Medola, Italy

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint.

Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses.

Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available.

The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow).

With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%).

The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms.

Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

Disclosures: Papayannidis: Abbvie, Astellas, Servier, Menarini/Stemline, BMS, Pfizer, Amgen, Janssen, Incyte, Novartis: Honoraria; Pfizer, Astellas, Janssen, GSK, Blueprint, Jazz Pharmaceuticals, Abbvie, Novartis, Delbert Laboratoires: Membership on an entity's Board of Directors or advisory committees. Cerrano: Insight Novartis Servier Abbvie Janssen Jazz Astellas Italfarmaco: Honoraria. Della Porta: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bocchia: Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cattaneo: pfizer, jazz: Other: travel grants. Frigeni: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Venditti: Pfizer: Consultancy, Honoraria, Other: travel support , Speakers Bureau; Medac: Consultancy; Novartis: Consultancy, Honoraria, Other: travel support ; Amgen: Consultancy, Honoraria, Other: travel support ; Jazz: Consultancy, Honoraria, Other: travel support ; AbbVie: Consultancy, Honoraria, Other: travel support ; Janssen: Consultancy, Honoraria, Other: travel support . Vignetti: Novartis: Speakers Bureau; Uvet: Honoraria; AbbVie: Honoraria; Dephaforum: Honoraria; ER Congressi: Honoraria; IQVIA: Honoraria.

OffLabel Disclosure: Venetoclax is registered in the induction therapy of elderly or unfit AML patients in combiantion with HMSs or low dose cytarabine. In this study, venetocalx is used in combination with high dose chemotherapy in the young population.

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