Consistently High 5.5-Year Progression-Free Survival (PFS) Rates in Patients with and without Bulky Baseline Lymphadenopathy ≥5 Cm Are Associated with High Undetectable Minimal Residual Disease (uMRD4) Rates after First-Line Treatment with Fixed-Duration Ibrutinib + Venetoclax for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) in the Phase 2 CAPTIVATE Study
Authors: Wierda William G. , Jacobs Ryan , Barr Paul M , Allan John N. , Siddiqi Tanya , Tedeschi Alessandra , Kipps Thomas J. , O'Brien Susan M. , Badoux Xavier C. , Visentin Andrea , Lasica Masa , Carney Dennis A. , Elinder Cambrun Anna , De la Serna Javier , Szafer Glusman Edith , Zhou Cathy , Neuenburg Jutta K. , Neumayr Lynne , Szoke Anita , Dean James P. , Ghia Paolo , Tam Constantine S. 
Published: December 2024

Introduction: First-line all-oral, once daily ibrutinib (Ibr) + venetoclax (Ven) for CLL/SLL was investigated in 2 cohorts of the phase 2 CAPTIVATE study: Minimal Residual Disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). With up to 5.5 years of follow-up, FD Ibr+Ven demonstrated sustained PFS, including in patients (pts) with high-risk genomic features (Wierda et al, ASCO 2024). Explorations of baseline (BL) lymph node (LN) size, depth of LN and MRD response, and outcomes after FD Ibr+Ven are reported.

Methods: Pts aged ≤70 years with previously untreated CLL/SLL received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/day orally; Ven, 5-week ramp up to 400 mg/day orally) (FD cohort); the included MRD cohort pts received 1 additional cycle of Ibr+Ven while being randomized to placebo. Post hoc exploratory analyses were performed to evaluate response per iwCLL criteria, undetectable MRD (uMRD4; &lt;10-4 by flow cytometry), PFS, and overall survival efficacy outcomes in pt subgroups defined by maximal LN long diameter (LDi) at BL and at end of treatment (EOT). Treatment-emergent safety outcomes were evaluated in pt subsets defined by BL LN LDi.

Results: Of 202 pts who completed FD Ibr+Ven in the FD cohort (n=159) or MRD cohort placebo arm (n=43), 66 (33%) had BL LDi ≥5 cm. In pts with BL LDi &lt;5 vs ≥5 cm, both groups had median age of 60 years and 29% had Rai stage III/IV, while 60% vs 74% were male, 35% vs 39% had BL cytopenia, and 78% vs 70% had absolute lymphocyte count ≥25 × 109/L, respectively; high-risk genomic features included unmutated IGHV (54% vs 70%), del(17p)/mutated TP53 (18% vs 8%), del(11q) (14% vs 26%), and complex karyotype (≥3 aberrations, 15% vs 21%). BL LN LDi correlated well with BL LN sum of the product of diameters (Pearson correlation, 0.84). At EOT, high uMRD4 rates were achieved in peripheral blood (PB) at 65% and 77% in pts with BL LDi &lt;5 cm and ≥5 cm (66% and 75% bone marrow uMRD4, respectively), while complete response (CR, including CR with incomplete bone marrow recovery) rates were 66% and 21%, respectively. Exploring EOT LN depth of response, LDi ≤1.5 cm and ≤2 cm, respectively, were achieved in 71% and 89% of pts with BL LDi &lt;5 cm and in 27% and 54% of pts with BL LDi ≥5 cm, respectively. EOT uMRD4 rates in pts with EOT LDi of ≤1.5 cm and ≤2 cm, respectively, were consistently high at 71% and 69% in PB, and 72% and 70% in bone marrow (in pts with EOT LDi &gt;2 cm: 71% in PB, 68% in bone marrow). With a median time on study of 69 months (range, 1-84), 5.5-year PFS (67% and 63%) and overall survival (97% in both) rates were very similar in pts with BL LDi &lt;5 or ≥5 cm. Interestingly, 5.5-year PFS rates were high irrespective of EOT LDi ≤1.5 or &gt;1.5 cm (69% vs 64%) or EOT LDi ≤2 or &gt;2 cm (67% vs 63%). On the other hand, as expected, 5.5-year PFS rates were consistently higher in pts with EOT PB uMRD4 vs those with detectable MRD irrespective of depth of EOT LDi: with LDi of ≤1.5 cm, &gt;1.5 to ≤2 cm, or &gt;2 cm, rates were 77% vs 50%, 75% vs 43%, and 72% vs 42%, respectively (corresponding rates with EOT bone marrow uMRD4 vs detectable MRD were very consistent with PB in these subgroups). As previously seen with chemoimmunotherapy, 5.5-year PFS rates were higher in pts with PB uMRD4 irrespective of iwCLL response category (75% whether with CR or partial response [PR]) vs those with detectable MRD (54% with CR and 46% with PR). Again, bone marrow uMRD4 vs detectable MRD outcomes were very consistent with PB. Treatment-emergent grade ≥3 adverse events (AEs) occurred in 64% and 58% of pts with BL LDi &lt;5 cm and ≥5 cm, respectively. AEs leading to discontinuation occurred in 3% and 6% of pts with BL LDi &lt;5 cm and ≥5 cm, respectively.

Conclusions: Ibr+Ven is an all-oral, once-daily, chemotherapy-free FD regimen for first-line treatment of CLL/SLL that provides durable PFS and OS with long-term follow-up. In pts with or without bulky baseline LN disease ≥5 cm, similarly durable long-term PFS and OS outcomes were observed and associated with similarly high rates of EOT uMRD4. Assessed at EOT, depth of lymph node responses at LDi ≤1.5 vs ≤2 cm cutoffs were associated with similar 5.5-year PFS outcomes while uMRD4 status was again more strongly correlated with PFS. Long-term PFS was associated most strongly with uMRD4 status while depth of response per iwCLL criteria (CR vs PR) had a minor impact, which was seen only in pts with detectable MRD. The safety profile of FD Ibr+Ven was tolerable and similar irrespective of lymph node bulk at baseline.