PS1160 PATTERNS OF DUVELISIB‐INDUCED LYMPHOCYTOSIS IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA INCLUDING THOSE WITH HIGH‐RISK FACTORS TREATED IN THE DUO TRIAL
Authors: J. Barrientos, I. Flinn, M. Davids, A. Cashen, N. Chiorazzi, S.‐S. Chen, S. Hidy, J. Pachter, S. Lustgarten, D. Weaver, J. Brown
Journal: HemaSphere (2019)

Background: Although lymphocytosis is a defining feature of chronic lymphocytic leukemia (CLL), it is also recognized as a class effect of treatment with B‐cell receptor pathway inhibitors. Duvelisib (DUV) is a first‐in‐class, oral, dual PI3K‐δ,γ inhibitor approved for the treatment of patients with relapsed/refractory (R/R) CLL or small lymphocytic leukemia (SLL) who have received ≥2 prior therapies. In the phase 3 multicenter DUO trial, DUV 25 mg twice daily (BID) showed a significant improvement in efficacy vs ofatumumab (mPFS, 13.3 vs 9.9 mo; HR, 0.5 [ P &lt; .0001]; ORR, 74% vs 45% [ P &lt; .0001]) with a manageable safety profile (Flinn et al. Blood. 2018). In preclinical studies using CLL cells from patients transferred into mice, dual PI3K‐δ,γ inhibition was more effective than PI3K‐δ inhibition alone in reducing CLL cell burden (Chen et al. ASH 2018). Herein we aim to characterize the clinical profile and kinetics associated with DUV‐related lymphocytosis. Aims: This post hoc analysis characterized response in patients with R/R CLL/SLL, including high‐risk subgroups—defined by unmutated IGHV (n = 110 [70%]), del(17p)/ TP53 mutation (n = 48 [30%]), del(11q) (n = 38 [24%]), and bulky disease (n = 74 [47%])—who received DUV 25 mg BID in the DUO trial. Methods: Lymphocytosis was defined as an absolute lymphocyte count (ALC) of ≥5 × 10 9 /L and a ≥50% increase of ALC from baseline (BL). ALC measured by local laboratories to determine peak ALC, median time to 50% reduction from BL ALC, and median time to onset and resolution of lymphocytosis. Median time to resolution was defined as ALC at or below BL value or ALC of &lt;5 × 10 9 /L, whichever occurred first. Data were summarized using descriptive statistics, including medians for continuous variables and proportions for discrete variables. Results: Of 158 patients treated with DUV, 78% experienced lymphocytosis. Median ALC at BL was 41.1 × 10 9 /L (range, 0.2–381.7). Median time to onset of lymphocytosis was 1 wk across all patients, including high‐risk patients. Median time to resolution of lymphocytosis (&lt;5 × 10 9 /L or BL) was 14 wk (Figure; solid arrow), with a 50% reduction from BL ALC at 21 wk (Figure, dashed arrow). Similar results were observed regardless of high‐risk status: del(17p)/ TP53 , 14 wk; del(11q), 18 wk; bulky disease, 11 wk; unmutated IGHV , 13 wk. Rapid shrinkage of lymph nodes was noted, with 86% of patients achieving lymph node response. Among patients who achieved a response with DUV at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median time to resolution of lymphocytosis in these patients was 12 and 18 wk, respectively. Prolonged lymphocytosis (for &gt;12 mo) occurred in 12 patients (8%). The ORR in patients with prolonged lymphocytosis was 83%. Of note, the median PFS was similar among patients with and those without prolonged lymphocytosis (22.1 mo [95% CI, 12.9–27.6]) vs [24 mo [95% CI, 20.5‐NE], respectively). Summary/Conclusion: DUV monotherapy induces rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in patients with R/R CLL/SLL. Notably, DUV resulted in a deep and prolonged resolution of lymphocytosis to &gt;50% below BL. The pattern of lymphocytosis in high‐risk patients was similar to that in the general patient population. image