High rate of durable responses with undetectable minimal residual disease with front-line venetoclax and rituximab in young, fit patients with chronic lymphocytic leukemia and an adverse biological profile: results of the GIMEMA phase II LLC1518 - VERITAS study

Abstract

The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.

Figure 1.

Responses at the end of combination therapy and end of treatment according to International Working Group Chronic Lymphocytic Leukemia criteria. EOCT: end of combination therapy; EOT: end of treatment; ORR: overall response rate; CR: complete response; CRI: complete response with incomplete blood count recovery; PR: partial response.

Figure 2.

Rates of responses with undetectable minimal residual disease (10^-4) in the peripheral blood and bone marrow by allele-specific oligonucleotide polymerase chain reaction at the end of combination therapy and end of treatment. EOCT: end of combination therapy; EOT: end of treatment; PB: peripheral blood; BM: bone marrow.

Figure 3.

Impact of baseline factors and complete response measured at the end of combination therapy on responses with undetectable minimal residual disease in the bone marrow at the end of treatment. CR: complete response; TP53 gene: tumor protein p53 gene; Del: deletion; Tris: trisomy; IGHV: immunoglobulin heavy chain variable region gene; TLS: tumor lysis syndrome; LR: low risk; IR: intermediate risk; HR: high risk; LDH: lactate dehydrogenase; Hb: hemoglobin; CIRS: Cumulative Illness Rating Scale; ECOG: Eastern Cooperative Oncology Group; OR: odds ratio; 95% CI: 95% confidence interval.

Figure 4.

Undetectable minimal residual disease-free survival. uMRD: unde-tectable minimal residual disease; EOT: end of treatment.

Figure 5.

Overall survival of the whole cohort of 75 patients enrolled in the study. OS: overall survival.