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‘

ABSTRACT

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. Gra e ≥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. [Formula presented] 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 advisor 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, SpeakersBureau;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.