Patterns of duvelisib‐induced lymphocytosis in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, including those with high‐risk factors, in the DUO trial

Purpose of the Study: Lymphocytosis is a defining feature of chronic lymphocytic leukemia (CLL) and recognized as a class effect of treatment with B‐cell receptor pathway inhibitors. Duvelisib is a first‐in‐class, oral, dual PI3K‐, inhibitor approved for the treatment of patients with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL) who have received 2 prior therapies. In the phase 3 multicenter DUO trial, duvelisib 25 mg twice daily (BID) showed a significant improvement in efficacy vs ofatumumab (mPFS, 13.3 vs 9.9 months; HR, 0.5 [P < .0001]; ORR, 74% vs 45% [P < .0001]) with a manageable safety profile.1 In preclinical studies using CLL cells from patients transferred into mice, dual PI3K‐, inhibition was more effective than PI3K‐ inhibition alone in reducing CLL cell burden.2 Herein we aim to characterize the clinical profile and kinetics associated with duvelisib‐related lymphocytosis.

Summarized Description of the Project: 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 duvelisib 25 mg BID in the DUO trial. Lymphocytosis was defined as an absolute lymphocyte count (ALC) of 5×109/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 (TTO) and median time to resolution (TTR) of lymphocytosis. Median time to resolution was defined as ALC at or below BL value or ALC of < 5×109/L, whichever occurred first.

Results: Of 158 patients treated with duvelisib, 78% experienced lymphocytosis. Median ALC at BL was 41.1×109/L (range, 0.2‐381.7). Median TTO of lymphocytosis was 1 week across all patients, including high‐risk patients. Median TTR of lymphocytosis was 14 weeks (Figure; solid arrow), with a 50% reduction from BL ALC at 21 weeks (Figure, dashed arrow). Similar results were observed for TTR regardless of high‐risk status: del(17p)/TP53, 14 weeks; del(11q), 18 weeks; bulky disease, 11 weeks; unmutated IGHV, 13 weeks. Rapid shrinkage of lymph nodes was noted, with 86% of patients achieving lymph node response. Among patients who achieved a response with duvelisib at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median TTR of lymphocytosis in these patients was 12 weeks and 18 weeks, respectively. Prolonged lymphocytosis (for >12 months) 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 months [95% CI, 12.9‐27.6]) vs [24 months [95% CI, 20.5‐NE], respectively).

Conclusion: Duvelisib monotherapy induces rapid and transient lymphocytosis concurrent with an accompanying reduction in lymphadenopathy in patients with R/R CLL/SLL. Notably, duvelisib resulted in a deep and prolonged resolution of lymphocytosis to >50% below BL. The pattern of lymphocytosis in high‐risk patients was similar to that in the general patient population and was not correlated with worse outcomes.

References

1. Flinn IW et al. Blood. 2018;132(23):2446‐2455.

2. Chen S et al. Blood. 2018;132(suppl 1) [abstract 4420].