Introduction: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the EU for the treatment of CLL. Ibr results in rapid reduction in lymphadenopathy, often accompanied by early, transient lymphocytosis. Venetoclax (ven) received FDA accelerated approval for relapsed del17p CLL and EMEA conditional approval for relapsed CLL and has noteable risk of TLS that is associated with increased disease bulk defined by absolute lymphocyte count (ALC) and lymph node (LN) diameter. Translational studies suggest synergistic anti-tumor activity of ibr plus ven. We assessed how ibr lead-in may reduce TLS risk for ven in considering this combination. Methods: Data from 3 single-agent ibr (420 mg once daily until PD/ intolerance) studies in CLL/SLL were analyzed (N = 424): PCYC-1102 in relapsed/refractory (R/R) pts (n = 67) and treatment-naïve (TN) pts ≥65 y (n = 27); RESONATE (PCYC-1112) in R/R pts (n = 195); and RESONATE -2 (PCYC-1115) in TN pts ≥65 y excluding del17p (n = 135). TLS risk categories were defined per ven USPI (Table). First CT response assessment occurred on day 56 (PCYC-1102), 78 (RESO-NATE), and 113 (RESONATE-2). Results: Approximately, 80% of pts were moderate or high risk for TLS at baseline (Table). Baseline largest diameter of LN (LDi) ≥5 cm was more common in R/R vs TN pts. In both groups, the proportion of pts with LDi ≥5 cm decreased at first CT assessment (Table). Bulky disease resolved to LDi <5 cm in 90% of TN and 85% of R/R pts with baseline LDi ≥5 cm. Median baseline ALC was higher in TN pts vs R/R pts (49 vs 21 × 10 9 /L). ALC initially increased in many pts, but decreased with continued ibr. During ibr therapy, 87% of TN and 45% of R/R pts with high-risk TLS at baseline were reduced to low risk, and the majority of moderate-risk TLS pts were reduced to low risk (Table). At first assessment, 54% of TN and 45% of R/R pts were moderate risk, and 7% and 14% were high risk, respectively; a minority of pts had increased risk due to transient ALC increase. In RESONATE-2, 82% of TN pts were moderate to high risk for TLS at baseline (32% high-risk); 88% of high-risk TLS was reduced to low risk. At first assessment in RESONATE -2, 50% were moderate risk, and high-risk TLS was reduced to 8%. Conclusions: Our analyses demonstrate that most pts with baseline high-risk TLS were reduced to moderate or low risk at first assessment. This suggests that tumor debulking with ibr lead-in may effectively reduceTLS risk for ven and the intensity of TLS monitoring for ibr + ven in pts with CLL.
