Paolo Ghia earned his medical degree from the University of Torino and then completed an internal medicine residency. He earned his PhD studying the formation of normal human B cells at the Basel Institute for Immunology in Basel, Switzerland. He then went to Harvard Medical School’s Dana-Farber Cancer Institute in Boston, where he examined the molecular processes of chronic lymphoproliferative diseases, including follicular lymphoma. He is now a Full Professor of Medical Oncology at Università Vita-Salute San Raffaele and Deputy Chairman of the Division of Experimental Oncology at IRCCS Ospedale San Raffaele in Milano, where he is also Head of the Laboratory of B-Cell Neoplasia and Director of the CLL Strategic Research Program. In this video Dr. Ghia discusses First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study.
https://ash.confex.com/ash/2021/webprogram/Paper144544.html
Background: Ibr is a once-daily Bruton tyrosine kinase inhibitor that has showed a significant advantage in progression-free survival (PFS) and overall survival in various randomized phase 3 studies in first-line CLL. Ven, an oral BCL-2 inhibitor licensed for CLL treatment as a single drug or in combination with rituximab or obinutuzumab, has a high rate of undetectable MRD (uMRD). Ibr and Ven, which have different but complimentary modes of action, work together to mobilize CLL cells from lymph nodes and lymphoid niches, improve cell killing, and destroy specific CLL cell populations. CAPTIVATE (PCYC-1142; NCT02910583) is a multicenter, multinational phase 2 trial that compares first-line Ibr + Ven in two cohorts: MRD and Fixed-Duration (FD). Three cycles of Ibr were given to patients (pts), followed by 12 cycles of combination Ibr + Ven. In the MRD cohort’s primary analysis, patients with confirmed uMRD who were randomized to placebo or continued Ibr following a fixed-duration therapy had equal 1-year DFS rates (95 percent and 100 percent, respectively) after randomization (Wierda, ASH 2020). The results of a two-year post-randomization study are reported.
Methods: Pts with previously untreated CLL aged 70 years or older received three cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven (oral Ibr 420 mg/day; oral Ven ramp-up to 400 mg/day). During cycle 16, patients with Confirmed uMRD (defined as uMRD in both peripheral blood [PB] and bone marrow [BM] serially during two evaluations three months apart) were randomized 1:1 to receive double-blind treatment with placebo or single-agent Ibr. Patients who did not fulfill the criteria for Confirmed uMRD were randomly assigned to open-label therapy with single-agent Ibr or continuous Ibr + Ven. The 2-year DFS rate (defined as survival without progression [PD] or MRD relapse post-randomization) in patients with confirmed uMRD randomized to placebo vs Ibr, rates of uMRD (10–4 by 8-color flow cytometry), investigator-assessed best response per iwCLL, investigator-assessed PFS, and adverse events are among the endpoints presented (AEs).
The total number of participants was 164. The average age was 58 years old (range, 28-69). Unmutated IGHV (60 percent of pts), del(17p)/TP53 mutation (20 percent), complex karyotype (19 percent), and del(11q) without del(17p) were all high-risk characteristics (17 percent ). After 12 cycles of Ibr + Ven, 149 participants were randomly assigned to one of two groups: confirmed uMRD (n=43) or Ibr (n=43); without confirmed uMRD (n=31) or Ibr + Ven (n=32). Overall, the median follow-up time was 38.2 months (range: 15.0-47.9), and the median post-randomization follow-up time was 24.0 months (range, 5.8-33.1). There have been no new DFS events in patients with confirmed uMRD who were randomized to placebo versus Ibr since the primary analysis; 2-year DFS rates post-randomization remained unchanged at 95 percent (placebo) vs 100 percent (Ibr), for a 4.7 percent difference (95 percent CI -1.6–10.9) and overall log-rank P=0.1573 (Figure 1). Following randomization, complete response (CR) rates in the placebo and Ibr groups, including CR with incomplete bone marrow recovery (CRi), showed modest improvements (Figure 2). PFS rates at 36 months were estimated to be 95% with placebo and 100% with Ibr. Post-randomization, in pts with Confirmed uMRD assigned to Ibr vs Ibr + Ven, Ibr + Ven showed higher improvements in best uMRD rates and CR/CRi rates than Ibr (Figure 2). With both Ibr and Ibr + Ven, estimated 36-mo PFS rates were 97 percent. All pts (N=164) had a median treatment duration of 36.8 months (range, 0.5-47.9). After randomization, there were minor variations in AEs across treatment arms. Neutropenia (36 percent), hypertension (10 percent), thrombocytopenia (5 percent), and diarrhea were the most common grade 3/4 AEs across all treated patients during the research period (5 percent ). AEs led to the termination of Ibr or Ven in 13% of patients after up to 48 months of treatment; no new safety flags arose.
Conclusions: In patients with CLL, first-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free treatment that produces profound responses. With an extra year of follow-up and no new MRD relapses, PDs, or deaths in patients with confirmed uMRD, the 2-year DFS rate in the MRD-guided placebo arm remained high at 95%, while 3-year PFS rates in all randomized treatment arms were likewise high at 95%. The findings in patients with Confirmed uMRD support the possibility of treatment-free remission with fixed-duration therapy, even in those with high-risk characteristics. The safety profile of Ibr + Ven was consistent with the established safety profile for each agent, resulting in high rates of uMRD.