Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study

William G. Wierda, Constantine S. Tam, John N. Allan, Tanya Siddiqi, Thomas J. Kipps, Stephen Opat, Alessandra Tedeschi, Xavier C. Badoux, Bryone Kuss, Sharon R. Jackson, carol moreno, Ryan Jacobs, John M. Pagel, Ian W. Flinn, Cathy Zhou, Edith Szafer-Glusman, Joi Ninomoto, James P. Dean, Danelle F. James, Paolo Ghia

Research output: Contribution to journalMeeting Abstractpeer-review


Background : Ibr is an established standard of care in CLL and is the only once-daily Bruton tyrosinekinase inhibitor with significant overall survival benefit in randomized phase 3 studies in first-line CLL(RESONATE-2; ECOG1912). The synergistic combination of Ibr + Ven (oral inhibitor of BCL2) hasbeen shown to mobilize and clear CLL cells from multiple disease compartments leading to deepresponses, providing a rationale to evaluate time-limited treatment (Jain et al. NEJM 2019). CAPTIVATE(PCYC-1142) is a multicenter phase 2 study (NCT02910583) of first-line Ibr + Ven with 2 cohorts: MinimalResidual Disease (MRD) and Fixed-Duration (FD). For both cohorts, patients (pts) received 3 cyclesof Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Pts in the MRD cohort were randomized byMRD status to placebo or further treatment. In the pre-randomization phase of the MRD cohort, Ibr +Ven resulted in high rates of undetectable MRD (uMRD) in both peripheral blood (PB; 75%) and bonemarrow (BM; 72%), with concordant uMRD results in 93% of pts with matched samples (Tam, ASH 2019).We present primary results from the MRD-guided randomization phase of the MRD cohort, evaluatingwhether this regimen allows for treatment-free remission in the setting of uMRD.Methods : Pts <70 years with previously untreated CLL/SLL requiring therapy received 3 cycles of Ibrlead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/day PO; Ven ramp-up to 400 mg/day PO). Pts withConfirmed uMRD (defined as uMRD serially over ≥3 cycles, and in both PB and BM) after 12 cycles ofIbr + Ven were randomized 1:1 to receive double-blind treatment with placebo or Ibr; pts who did notmeet the definition of Confirmed uMRD were randomized 1:1 to receive open-label treatment with Ibror continued Ibr + Ven. Primary endpoint was 1-year DFS rate in the Confirmed uMRD pts randomizedto placebo vs Ibr; DFS was defined as survival without progression or MRD relapse. Key secondaryendpoints were rates of uMRD (<10-4 by 8-color flow cytometry), response per iwCLL, progression-freesurvival (PFS), and adverse events (AEs).Results : 164 pts were enrolled in the MRD cohort. Median age was 58 years (range, 28-69); baselinehigh-risk features included del(17p) in 16% and del(11q) in 17%; del(17p) or TP53 mutation in 20%;complex karyotype in 19%; and unmutated IGHV in 60%. Median time on study was 31.3 mo (range,15.0-41.0). 90% of pts completed planned treatment with 3 cycles of Ibr lead-in followed by 12 cyclesof combined Ibr + Ven. Of 149 randomized patients, 86 (58%) with Confirmed uMRD (100% uMRDin PB and BM) were randomized to placebo (n=43) or Ibr (n=43). 63 of 149 pts (42%) did not achieveConfirmed uMRD as defined above and were randomized to Ibr (n=31) or Ibr + Ven (n=32); uMRDrates at randomization in this group were 48% in PB and 32% in BM. In the Confirmed uMRD group, 1-year DFS rate was not significantly different for pts randomized to placebo (95.3%; 95% CI 82.7-98.8)versus Ibr (100%; 95% CI 100-100) (P=0.1475; Figure). In the group without Confirmed uMRD who were
randomized to continue Ibr or Ibr + Ven, uMRD rates improved to 57% in PB and 54% in BM during theoverall study period. 30-mo PFS rates were >95% across all randomized arms (Table). Full results ofendpoints by randomized arms will be presented. The median duration of treatment was 28.6 mo (range,0.5-39.8) with Ibr and 12.0 mo (range, 0.8-34.1) with Ven. AEs were primarily grade 1/2 and mostlyoccurred in early cycles of Ibr + Ven, with modest differences by randomized treatment arm. During theoverall study period across all-treated pts (with median treatment duration 29 mo), most common grade3/4 AEs (≥5% of pts) were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea(5%).Conclusions : First-line Ibr + Ven treatment is an all-oral, once-daily, chemotherapy-free regimen thatconfers high rates of PB and BM uMRD in pts with CLL, and a 90% reduction in high-risk TLS monitoring(Siddiqi, EHA 2020). The 1-year DFS in pts randomized to placebo after Ibr + Ven combination wassimilar to that of pts continuing Ibr, supporting a fixed-duration treatment that offers treatment-freeremissions in pts with CLL/SLL. The depth of response achieved with this regimen is reflected in the 30-
mo PFS rate of ~95% across all treated pts. The safety profile of Ibr + Ven was consistent with knownAEs for Ibr and Ven, and no new safety signals emerged.
Original languageEnglish
Pages (from-to)16-17
Number of pages2
Issue numberS1
Publication statusPublished - 5 Nov 2020
Event62nd ASH Annual Meeting and Exposition -
Duration: 5 Dec 20208 Dec 2020
Conference number: 62


  • Ibrutinib
  • venetoclax
  • first-line treatment
  • chronic lymphocytic leukemia (CLL)
  • small lymphocytic lymphoma (SLL)
  • Disease-Free Survival (DFS)
  • Tyrosine kinase inhibitor


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