-Author name in bold denotes the presenting author
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4362 Minimal Residual Disease Evaluation in the Context of V-Rbac, a Risk-Tailored Phase II Trial of the Fondazione Italiana Linfomi (FIL)

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Clinical Research, Diseases, Real-world evidence, Aggressive lymphoma, Lymphoid Malignancies, Measurable Residual Disease
Monday, December 9, 2024, 6:00 PM-8:00 PM

Riccardo Bomben, PhD1*, Daniela Drandi2*, Irene Della Starza, PhD3*, Clara Bono4*, Andrea Evangelista5*, Omar Perbellini6*, Tamara Bittolo, PhD1*, Elisa Genuardi7*, Massimo Degan, PhD1*, Simone Ragaini8*, Maria Chiara Tisi9*, Anna Merli10*, Francesca Quaglia11*, Alessandro Re, MD12*, Claudia Castellino13*, Vittorio Ruggero Zilioli14*, Francesco Piazza, MD15*, Paolo Corradini, MD16, Stefan Hohaus17,18,19*, Gerardo Musuraca, M.D., Ph.D.20*, Francesca Gaia Rossi21*, Benedetta Puccini, MD22*, Federica Cavallo23*, Filippo Ballerini24*, Luca Arcaini, MD25*, Valter Gattei, MD1, Ilaria Del Giudice26*, Sara Galimberti, MD4*, Carlo Visco, MD27* and Simone Ferrero, MD28

1Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
2Hematology Division I, Department of Molecular Biotechnologies and Health Sciences, University of Turin/University Hospital A.O.U. “Città della Salute e della Scienza”, Torino, Italy, Italy
3AIL Roma ODV, Rome, Italy
4Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
5Unit of Cancer Epidemiology, A.O.U Città della Salute e della Scienza di Torino, Torino, Italy
6Ospedale S. Bortolo – Ematologia, Vicenza - ULSS 8 Berica, Vicenza, Italy
7Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, Torino, Italy
8Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy
9Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
10Ospedale degli Infermi di Rimini - U.O. di Ematologia, Rimini, ITA
11Hematology Unit, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy, Verona, ITA
12Lymphoma Unit, Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
13A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo, Cuneo, Italy
14Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, Milano, IT-MI, Italy
15UOC Di Ematologia Azienda Ospedale Università Padova, University of Padua, Padua, Italy
16Hematology Division, University of Milan. Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
17Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma, Italy
18Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
19Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
20IRCCS Istituto Romagnolo per lo studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
21Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, ITA
22A.O.U. Careggi, Firenze, Italy
23Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, A.O.U., Città della Salute e della Scienza di Torino, Torino, Italy
24IRCCS Ospedale Policlinico San Martino, Genoa, Italy
25Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
26Hematology, Department of Translational and Precision Medicine, Sapienza University, Roma, Italy
27Hematology and Bone Marrow Transplant Unit, Department of Engineering for Innovative Medicine, University of Verona, Verona, Italy
28Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, Torino, TO, Italy

Introduction. R-BAC (rituximan-bendamustine-cytarabine) is an highly effective first-line immunochemotherapy regimen for elderly fit patients with mantle cell lymphoma (MCL), allowing a considerable progression-free survival (PFS), particularly in low-risk (LR) patients, even without maintenance. On the other hand, outcomes in high-risk (HR) patients are still unsatisfactory, even with this therapy. To address this issue, the Fondazione Italiana Linfomi (FIL) designed the risk-tailored “V-RBAC” trial (NCT03567876), that showed how the addition of venetoclax to R-BAC in HR cases improved the performance of the induction strategy.

Methods. This study is a multicenter, phase 2 trial for elderly (>64 years) fit MCL patients, offering consolidation (800 mg/day) and maintenance (400 mg/day up to 18 months) with venetoclax monotherapy after abbreviated R-BACx4 for HR patients; HR was defined as the presence of any risk factor among blastoid morphology, Ki67 ≥30%, or TP53 mutation/deletion. To investigate the efficacy of this novel regimen, HR patients were studied for minimal residual disease (MRD) both by standardized allele-specific oligonucleotide-droplet digital PCR (ddPCR), targeting either IGHV or IGH::BCL1 rearrangements, and by multiparametric flow cytometry (MFC). Bone marrow (BM) and peripheral blood (PB) samples were centralized in the four EuroMRD labs of the FIL MRD Network at baseline and at predetermined time points (before consolidation, after consolidation and at the end of treatment). Clinical data and primary endpoint of the trial were already reported[Visco, ASH 2023], we here describe in detail the MRD results.

Results. Between September 2018 and July 2021, 54 HR MCL patients were prospectively enrolled in the trial. A reliable molecular marker for MRD by ddPCR was retrieved in 49 cases (91%), namely 29 IGHV only, 4 IGH::BCL1 only and 16 both markers. Overall, only 35 patients were evaluable for MRD in at least one timepoint, as 6 patients progressed during the induction and 8 interrupted the treatment due to toxicity or investigators decision. Nonetheless, the RBAC regimen resulted highly effective in clearing the MRD even in this HR population, with 25/33 (75%) patients achieving MRD negativity in BM and 28/35 (80%) in PB after four cycles of induction therapy. Moreover, after four cycles of venetoclax consolidation the rate of MRD negativity further raised to 86% (26/30) in BM and 90% (28/31) in PB, highlighting the activity of this drug in clearing the MRD at least in a subset of cases. Finally, after 18 months of venetoclax maintenance, the MRD negativity rate was 93% (13/14) in BM and 88% (15/17) in PB. Based on these data, we investigated the capacity of MRD to be a prognostic marker for PFS. Overall, MRD positivity at any timepoint was associated with an higher risk of relapse (HR 5.75, 95%CI 1.93-17.18, p=0.002 in BM and HR 7.89, 95%CI 2.65-23.53, p<0.001 in PB, respectively). In particular, the three patients still MRD positive after venetoclax consolidation experienced a dismal outcome with a relapse event after 7, 9 and 25 months, respectively. Finally, a direct comparison between ddPCR and MFC approach to detect MRD in PB was performed: detailed data are still under evaluation and will be presented during the meeting.

Conclusion. We here described the MRD monitoring results in the risk-tailored phase II trial FIL V-RBAC. Four cycles of R-BAC regimen provided high rates of molecular MRD negativity in HR elderly fit MCL patients, further improved by a venetoclax consolidation. Patients MRD positive after induction or consolidation still experience dismal outcome and should be considered for alternative, experimental approaches.

Disclosures: Tisi: Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gylead Science: Membership on an entity's Board of Directors or advisory committees; Novatis: Membership on an entity's Board of Directors or advisory committees; Jansenn: Speakers Bureau; Lilly: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Quaglia: ASTRAZENECA: Speakers Bureau; Kite Gilead: Speakers Bureau; Beigene: Speakers Bureau; Sandoz: Consultancy; Roche: Other: Congress participation; Novartis: Other: Congress participation; GSK: Other: Congress participation. Re: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Sobi: Speakers Bureau. Zilioli: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Consultancy; Janssen: Speakers Bureau; Lilly: Speakers Bureau. Corradini: GlaxoSmithKline: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Incyte: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Janssen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Kyowa Kirin: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Novartis: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Daiichi Sankyo: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Gilead/Kite: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Pfizer: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Celgene: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Amgen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; AbbVie: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Roche: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Sanofi: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); SOBI: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Takeda: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Bristol Myers Squibb: Other: Support for travel and accommodations. Hohaus: Gilead: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Musuraca: SOBI: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Jansenn: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Puccini: MSD: Research Funding. Arcaini: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Del Giudice: AstraZeneca: Other: educational and editorial projects; Jansenn: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Other: educational and editorial projects. Galimberti: Jazz: Honoraria, Other: support for attending meetings; Roche: Honoraria, Other: support for attending meetings; Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Other: support for attending meetings; AstraZeneca: Honoraria, Other: support for attending meetings; AbbVie: Honoraria, Other: support for attending meetings; Pfizer: Honoraria; Janssen: Honoraria. Ferrero: Gentili: Speakers Bureau; Eli Lilly: Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

*signifies non-member of ASH