Efficacy and Safety of Front-Line Venetoclax and Rituximab (VenR) for the Treatment of Young Patients with Chronic Lymphocytic Leukemia and an Unfavorable Biologic Profile. Preliminary Results of the Gimema Study ‘Veritas’

Mauro, Francesca Romana

Oral and Poster Abstracts
642. CLL: Therapy, excluding Transplantation: Poster III

Leukemia, Biological, Diseases, CLL, Therapies, Combinations, Young Adult, Lymphoid Malignancies, Study Population, Clinically relevant

Francesca Romana Mauro, MD, PhD¹^*, Gianluigi Reda, MD²^*, Valentina Arena, MS³^*, Livio Trentin, MD⁴, Marta Coscia, MD, PhD⁵^*, Paolo Sportoletti, MD⁶^*, Luca Laurenti, MD⁷^*, Gianluca Gaidano⁸, Roberto Marasca, MD⁹, Lorella Orsucci, MD¹⁰^*, Roberta Murru, MD¹¹^*, Caterina Stelitano¹²^*, Fiorella Ilariucci, MD¹³^*, Donato Mannina, MD¹⁴^*, Massimo Massaia, MD¹⁵, Gian Matteo Rigolin¹⁶^*, Lydia Scarfo¹⁷^*, Monia Marchetti, MD¹⁸^*, Luciano Levato, MD¹⁹^*, Monica Tani, MD²⁰^*, Annalisa Arcari, MD²¹^*, Gerardo Musuraca, MD²²^*, Marina Deodato²³^*, Piero Galieni²⁴^*, Catello Califano, MD²⁵^*, Daniela Gottardi, MD²⁶^*, Anna Marina Liberati, MD²⁷, Daniela Pietrasanta, MD²⁸^*, Stefano Molica, MD²⁹, Ramona Cassin, MD³⁰^*, Andrea Visentin, MD PhD³¹^*, Candida Vitale, MD, PhD³²^*, Gianfranco Lapietra, MD³³^*, Irene Della Starza, PhD¹^*, Maria Stefania De Propris, PhD¹^*, Sara Raponi, PhD¹^*, Mauro Nanni, PhD¹^*, Ilaria Del Giudice, MD, PhD¹^*, Giorgia Giuliani, PhD³⁴^*, Marco Vignetti, MD³⁵^*, Anna Guarini, PhD³⁶^*, Francesco Albano³⁷^*, Antonino Neri, MD³⁸, Antonio Cuneo, MD³⁹^* and Robin Foà, MD¹

¹Hematology, Department of Translational and Precision Medicine, 'Sapienza' University, Rome, Italy
²Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
³GIMEMA Foundation, Rome, Italy
⁴Hematology and Clinical Immunology Unit, Department of Medicine-DIMED, University of Padua, Padua, Italy
⁵Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy
⁶Department of Medicine, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
⁷Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
⁸Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
⁹Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Modena, Italy
¹⁰Hematology, Città della Salute Hospital and University, Torino, Italy
¹¹Haematology and Stem Cell Transplantation Unit, Ospedale A. Businco, Cagliari, CAGLIARI, Italy
¹²Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, RC, ITA
¹³Azienda Ausl IRCCS Santa Maria Nuova Reggio Emilia, Reggio Emilia, Italy
¹⁴UOC di Ematologia, Azienda Ospedaliera Papardo, Messina, ITA
¹⁵Division of Hematology, AO S.Croce e Carle, Cuneo, Italy, Torino, Italy
¹⁶Hematology, St. Anna University Hospital, Cona, Ferrara, Italy
¹⁷Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy
¹⁸Hematology Day Service, Oncology Unit, Hematology Unit, Az Osp SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
¹⁹Hematology Unit, A. Pugliese Hospital, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy
²⁰Unit of Hematology, Santa Maria delle Croci Hospital, Ravenna, Italy
²¹21Hematology Un it, Ospedale Guglielmo da Saliceto, Piacenza, Italy
²²Hematology Unit, IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola (FC), Italy
²³Department of Hematology, Niguarda Cancer Center, Niguarda Hospital, Milano, Italy
²⁴UOC Ematologia e Terapia Cellulare, Ospedale "C. e G. Mazzoni", Ascoli Piceno, Italy
²⁵U.O. Oncoematologia, P.O. "Andrea Tortora", Pagani, Italy
²⁶Divisione Universitaria di Ematologia e Terapie Cellulari, Divisione Universitaria di Ematologia e Terapie Cellulari, Ospedale Mauriziano Umberto I, Torino, Italy
²⁷Department of Onco-Hematology, University of Perugia, Santa Maria Hospital, Terni, Italy
²⁸Hematology Division, Dipartimento Internistico Struttura complessa di Ematologia Ospedale civile SS Antonio e Biagio, Alessandria, Italy
²⁹Dipartimento Onco-Ematologico, Azienda Ospedaliera Pugliese - Ciaccio, Catanzaro, Italy
³⁰Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
³¹Hematology and Clinical Immunology Unit, Department of Medicine, Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padova, Italy
³²Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, TX, Italy
³³Hematology, Department of Translational and Precision Medicine, Sapienza University, Policlinico Umberto I, Roma, Italy
³⁴GIMEMA Foundation, Rome, ITA
³⁵GIMEMA Foundation, Roma, ITA
³⁶Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
³⁷Hematology and Stem cell Transplantation Unit - Department of Emergency and Organ Transplantation (D.E.T.O.) - University of Bari, Bari, Italy
³⁸BMT Center - Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, MI, Italy
³⁹Hematology, Azienda Ospedaliero Universitaria di Ferrara – University of Ferrara, Ferrara, ITA

Fixed-duration treatment with venetoclax (Ven), a highly selective Bcl-2 inhibitor combined with an anti-CD20 monoclonal antibody, showed high efficacy inducing high rates of deep responses with undetectable minimal residual disease (uMRD) in patients with previously treated and untreated chronic lymphocytic leukemia (CLL). The efficacy and safety of the Ven and rituximab (VenR) combination have been investigated in a multicenter, prospective study of the GIMEMA group that included young patients with previously untreated CLL (LLC 1518, VERITAS, NCT03455517). The primary endpoint of this study was the CR rate assessed according to the iwCLL criteria.

Inclusion criteria were: treatment requirement per iwCLL criteria, age ≤65 years, cumulative Illness rating scale score ≤6, creatinine clearance ≥30 mL/min, and an unfavorable biologic profile with IGHV unmutated and or TP53 disruption. Treatment consisted of the Ven dose ramp-up (from 20 to 400 mg daily, during 5-weeks) followed by Ven 400 mg daily, combined with R for six 28-day courses (375 mg/m², course 1; 500 mg/m², courses 2-6). Patients continued with Ven single agent, 400 mg daily, until month 13. Tumor lysis syndrome (TLS) prophylaxis measures included hydration, allopurinol, or rasburicase. All patients received Pneumocystis Jirovecii prophylaxis. G-CSF was given in patients with recurrent and severe granulocytopenia. Adverse events (AEs) were graded according to the CTCAE criteria v.5, TLS events were classified according to Howard's criteria. Response was assessed at months 7 and 15 and included clinical examination, PB evaluation, BM aspirate, BM biopsy, and CT scan. MRD was checked centrally in the PB and BM by a 6/4-color flow-cytometry assay with a sensitivity of at least 10^–4 according to the internationally standardized European Research Initiative on CLL. Quantitative MRD results assessed by flow-cytometry were categorized as uMRD (uMRD4; <10^-4), intermediate MRD, or high MRD (≥10^-2). MRD was further evaluated by allele-specific oligonucleotide PCR with a sensitivity up to 10^–5 in the PB and BM of patients who showed uMRD4 by flow-cytometry. During the follow-up, MRD was monitored every 6 months.

Between October 2018 and May 2020, 77 patients with CLL were included in this study. Two patients were off study before the start of treatment (withdrawal of consent, 1; Covid-19 infection, 1) and were not included in the analysis. The median age was 53.5 years (range 38-65). Binet stage B/C was present in 84% of patients, increased beta-2 microglobulin in 41%. Seventy-one (96%) of patients were IGHV unmutated, while 3 (4%) were IGHV mutated and showed TP53 mutation (Table 1). At the data cutoff of June 30, 2020, 65 (87%) patients completed the ramp-up phase. The planned 400 mg dose of Ven was reached within 5 weeks in 78.5% of patients. Response was assessed in 34 patients at the end of the VenR combination therapy. A response was achieved by 32 (94%) patients. Responses included 20 (59%) CRs, 1 CRi (3%) and 11 (32%) PRs due to residual enlarged nodes (median maximum size, 1.9 cm). Treatment failure due to toxicity was recorded in 2 (6%) patients. Overall, a response with uMRD4 by flow-cytometry in the PB was observed in 26 (76.5%) cases, and in the PB and BM, in 17 (50.0%). The rates of patients with CR and uMRD4 by flow-cytometry in the PB, and both in the PB and BM, were 44%, and 35%, respectively (Table 2). No detectable disease by PCR, both in the PB and BM, was observed in 4 (12%) patients. With a median follow-up of 4.5 months from the start of therapy, no patient has progressed or died. Fifty-three percent of patients were hospitalized during the first seven days of the Ven ramp-up phase. A transient laboratory TLS was observed in 3 patients. Treatment was discontinued after the first dose of Ven in 1 patient with evidence of laboratory TLS associated with severe neurologic toxicity due to the concomitant administration of fentanyl. Selected grade ≥3 AEs included neutropenia in 10 patients (ramp-up phase, 5) and neutropenic fever in 4. Grade ≥3 infection was recorded in 3 patients and was the reason for treatment discontinuation in 1 who developed COVID-19 pneumonia.

In conclusion, the preliminary results of this study demonstrate the high efficacy of the front-line VenR combination, which resulted in a high proportion of CRs and responses with uMRD4 in young patients with CLL and an unfavorable biologic profile.

Disclosures: Mauro: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Consultancy. Reda: Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Trentin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Coscia: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sportoletti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laurenti: Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Membership on an entity's Board of Directors or advisory committees. Marasca: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Murru: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin: Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scarfo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Marchetti: Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Levato: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galieni: Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Liberati: Verastem: Research Funding; Onconova: Research Funding; Janssen: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Takeda: Research Funding. Molica: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Visentin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale: Janssen: Honoraria. Del Giudice: Janssen: Other: grant for meeting participation; Tolero: Membership on an entity's Board of Directors or advisory committees; Roche: Other: grant for meeting partecipation; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Cuneo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.

See more of: 642. CLL: Therapy, excluding Transplantation: Poster III
See more of: Oral and Poster Abstracts

<< Previous Abstract | Next Abstract >>

^*signifies non-member of ASH

3142 Efficacy and Safety of Front-Line Venetoclax and Rituximab (VenR) for the Treatment of Young Patients with Chronic Lymphocytic Leukemia and an Unfavorable Biologic Profile. Preliminary Results of the Gimema Study ‘Veritas’