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1567 Centralized MRD Assessment at Early Timepoints in Gimema AML1718 Trial, a Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk AML

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Minimal Residual Disease
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Paola Minetto, MD1, Fabio Guolo, MD, PhD1,2*, Sara Rosellini3*, Alfonso Piciocchi4*, Giovanni Marconi, MD5, Ernesta Audisio, MD6*, Giorgio Priolo7*, Cristina Papayannidis, MD8, Maurizio Martelli9*, Francesca Paola Paoloni4*, Monica Bocchia, MD10*, Francesco Lanza, MD11*, Albana Lico, MD12*, Fabio Ciceri13,14*, Matteo Giovanni Della Porta, MD15,16*, Marco Frigeni, MD17*, Luisa Giaccone, MD, PhD18*, Germana Beltrami, MD19*, Erika Borlenghi, MD20*, Maria Chiara Di Chio21*, Carmine Selleri, MD22, Enrico Crea, PharmD4*, Irene Urbino23*, Chiara Sartor, MD24*, Clara Minotti25*, Valentina Arena4*, Jacopo Nanni, MD24*, Giorgia Simonetti, PhD26*, Maria Teresa Bochicchio26*, Giuseppe Saglio, MD27, Adriano Venditti, MD28,29, Marco Vignetti, MD4*, Paola Fazi, MD30*, Elisabetta Tedone1*, Giovanni Martinelli, MD31,32 and Roberto M. Lemoli, MD1,2*

1IRCCS Ospedale Policlinico San Martino, Genoa, Italy
2Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
3Servizio di Citofluorimetria, Dipartimento di Anatomia Patologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
4GIMEMA Foundation, Rome, Italy
5Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l., Meldola, Italy
6SC Ematologia 2, AOU Città della Salute e della Scienza, Turin, Italy
7Haematology 2 - A.O.U San Giovanni Battista, Turin, ITA
8Istituto di Ematologia "Seràgnoli", IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
9Division of Hematology, Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
10UOC Ematologia, Azienda ospedaliero-universitaria Senese, Siena, Italy
11Division of Hematology, Onco-hematologic Department, AUSL della Romagna, Ravenna, Italy
12Hematology Unit, San Bortolo Hospital, Vicenza, Italy, Vicenza, Italy
13Unit of Hematology and Bone Marrow Transplantation, I.R.C.C.S. Ospedale San Raffaele, Milan, Italy
14Vita-Salute San Raffaele University, Milan, Italy
15Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
16Department of Biomedical Sciences, Humanitas University, Milan, Italy
17Hematology and Bone Marrow Transplant Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
18Univesity of Torino, AOU Città Della Salute E Della Scienza Di Torino,, Torino, ITA
19U.O. Ematologia e terapie cellulari, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy
20UO EMATOLOGIA, ASST Spedali Civili di Brescia, Brescia, ITA
21Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
22Department of Medicine and Surgery, Hematology, University Hospital San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy
2321. Department of Oncology and Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
24Department of Medical and Surgical Sciences, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy
25Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ITA
26IRCSS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l, Meldola, Italy
27Dept. of Clinical and Biological Sciences, University of Turin, Turin, Italy
28Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
29Department of Onco-Hematology, Fondazione Policlinico Tor Vergata, Rome, Italy, Italy
30GIMEMA Foundation, Data Center and Health Outcomes Research Unit, Rome, Italy
31Associate Professor Alma Mater Studiorum, University of Bologna, Institute of Hematology "L. and A. Seràgnoli,”, Bologna, Italy
32IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST S.r.l., Meldola, Italy

Background: New therapeutic strategies are strongly needed to improve the prognosis of high risk Acute Myeloid Leukemia (AML) patients, such as combination of novel agents and conventional chemotherapy. The Italian GIMEMA AML1718 trial (NCT03455504) investigate the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) in combination with intensive fludarabine-based induction (FLAI) [fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5] as first-line therapy for newly diagnosed non low-risk ELN AML patients. Results from the Planned Interim Analysis of Safety Run-in and Part 1 (early expansion cohorts) were presented at the last 2022 ASH Meeting. Median overall survival (OS) was not reached; probability of 12-month OS was 76%. Median disease-free survival was not reached. With a median follow-up of 10.5 months, 28 patients (49%) received allogeneic stem cell transplantation (HSCT) in first complete remission (CR).

Centralized multicolour flow cytometry minimal residual disease (MFC-MRD) assessment was planned during the phase 2, part 2 of the study (confirmatory cohort) where the lower effective dose of VEN (400 mg/day) was administered in association with FLAI. Here we report results from early time-points (TPs) MRD analysis with the aim of identify the most informative TPs for MRD assessment and prognostic correlations.

Methods: Erythrocyte-lysed whole bone marrow (BM) samples obtained at diagnosis from patients enrolled in the confirmatory cohort were centralized and analysed with a broad panel of monoclonal antibodies to identify the leukemia-associated phenotype (LAIP) which was used to track residual leukemic cells during follow-up. Eight color flow cytometry analysis was performed at pre-defined TPs (TP1: post-induction I, TP2: post induction II/consolidation I, following TPs: post consolidation/pre-transplantation) (FACSCantoII; BD Facs Diva Software V6.1.3). A positive flow MRD was defined by the presence of no less than 10 clustered leukemic cells/10^4 total events. Enrollment closed on January 2023. Collection and analysis of later TPs is ongoing.

Results: Sixty-seven patients from 11 centers were enrolled in the phase 2, part 2. Risk stratification according to ELN 2017 was intermediate in 46% of patients and high risk in 54%. Fifty-eight/67 patients (87%) obtained CR after induction I.

In the centralized MRD analysis, 170 samples has been collected and analysed so far (60 baseline samples, 110 MRD samples). Seven patients lacking baseline sample for LAIP identification were excluded from the analysis. TP1 was available in 57/59 patient achieving CR (97%), and TP2 was available in 29 patients, so far.

MFC-MRD negativity was obtained in 31/57 (54%) at TP1 (post V-FLAI, Fig. 1). An increase in MFC-MRD negativity rate was observed at TP2 (post Induction II or consolidation I) with 20 MFC-MRD negative patients/29 available samples (69%, Fig. 1).

Thirteen/110 follow up samples (8%), albeit resulting MRD negative, were considered inadequate for the analysis due to haemodilution, 9 from TP1 and 4 from TP2 (Fig. 1).

TP1 and TP2 MRD assessment were scheduled at day 28 of Induction I and Induction II/consolidation, respectively. However, in most cases, delayed haematological recovery was observed after V-FLAI, thus resulting in suboptimal samples for MRD evaluation.

Conclusions: Preliminary results from centralized MRD analysis confirm that the combination therapy is able to induce high-quality remissions with a very high percentage of MFC-MRD negativity in a difficult cohort of patients, with a higher percentage of MFC-MRD-negative after the completion of the second course of therapy. Delayed haematological recovery may impact on reliability of MRD assessment due to hypocellular and regenerative marrow samples, suggesting that in those cases MRD analysis should be postponed. Correlation with survival will be performed as the data collection will be complete.

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. Bocchia: BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Della Porta: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frigeni: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria. Borlenghi: AbbVie, BMS: Consultancy; Amgen, Incyte: Other: travel grants. Venditti: Amgen: Consultancy, Honoraria, Other: travel support ; Pfizer: Consultancy, Honoraria, Other: travel support , Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support ; Medac: Consultancy; Novartis: Consultancy, Honoraria, Other: travel support ; Janssen: Consultancy, Honoraria, Other: travel support ; Jazz: Consultancy, Honoraria, Other: travel support . Vignetti: Novartis: Speakers Bureau; Dephaforum: Honoraria; AbbVie: Honoraria; Uvet: Honoraria; IQVIA: Honoraria; ER Congressi: Honoraria.

OffLabel Disclosure: Venetoclax added to chemotherapy in newly diagnosed AML

*signifies non-member of ASH