Patterns of Lymphocytosis in Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Treated with Idelalisib
Authors: Brown Jennifer R. , Cheson Bruce D. , Furman Richard R. , Ghia Paolo , Hallek Michael , Hillmen Peter , O'Brien Susan M. , Sharman Jeff P. , Dubowy Ronald L. , Velasco Barbara , Waldapfel Christopher C. , Zelenetz Andrew D. 
Published: October 2019

Abstract
Background
Lymphocytosis is a known pharmacologic effect of B-cell receptor (BCR) targeted therapies used in the treatment of CLL and SLL. It has been reported that prolonged lymphocytosis after treatment with a BTK inhibitor was more common in patients (pts) with mutated immunoglobulin heavy chain variable region (IGHV) genes. Idelalisib (IDL) is a selective oral PI3Kd inhibitor. In the phase I idelalisib monotherapy (IDL-mono) trial (NCT00710528), the majority of pts with CLL/SLL experienced a transient increase in absolute lymphocyte count (ALC) accompanied by a reduction of lymphadenopathy.
In this post hoc analysis, laboratory data from 4 clinical trials was analyzed to characterize the patterns of lymphocytosis observed in pts with CLL/SLL treated with IDL-based regimens.
METHODS
Eligible pts included those with relapsed/refractory (R/R) CLL treated with IDL +rituximab (R) or placebo (P) +R from phase 3 study 312-116 (NCT01539512), treatment naïve (TN) CLL/SLL treated with IDL-mono or IDL+R from phase 2 study 101-08 (NCT01203930), R/R CLL treated with IDL-mono from phase 1 study 101-02 (NCT00710528), and R/R CLL treated with IDL+anti-CD20 mAb (anti-CD20), IDL +chemotherapy (C) or IDL+C+anti-CD20 from a phase 1b study 101-07 (NCT01088048). Only pts who received IDL dosed at 100 or 150mg BID were included in this analysis.
Pts were grouped by disease status (TN vs. R/R) and treatment regimen (IDL-mono vs. IDL+anti-CD20 vs. IDL+C vs. IDL+C+anti-CD20 vs. P+R). Chemotherapeutic agents included chlorambucil, bendamustine, or fludarabine. Anti-CD20 mAbs included R or ofatumumab.
Analyses with baseline characteristics were also conducted.
RESULTS
The study population included 494 pts with CLL/SLL: 75% Rai III-IV and 33% IGHV gene mutated. The analysis population included 460 pts on treatment with IDL 100/150 mg BID or P. The patterns of lymphocytosis, including peak ALC (Peak), time to peak ALC (TTPeak), and time to 50% reduction from baseline ALC (TT50%), across each group are described in Table 1. The median peak for each group was calculated from pooled ALC values for individual patients irrespective of time of assessment.
In the IDL-mono group, TN pts experienced a greater absolute increase in ALC relative to R/R pts, consistent with the higher baseline ALC expected in untreated disease. A 50% reduction from baseline ALC was achieved by 41% (TN) and 18% (R/R) at a median of 8.1 and 14.6 weeks, respectively.
In R/R pts, the lymphocytosis observed with IDL-mono was abrogated with the addition of anti-CD20 and/or C. IDL+C+anti-CD20 produced the fastest TT50%. In the IDL+anti-CD20 group, a 50% reduction from baseline ALC was achieved by 89% (TN) and 75% (R/R) at a median of 4.1 and 6.1 weeks, respectively. In the IDL+C group (R/R), a 50% reduction from baseline ALC was achieved by 91% at a median of 4.1 weeks. In the IDL+anti-CD20+C group (R/R), a 50% reduction from baseline ALC was achieved by 87% at a median of 2.1 weeks.
In a pooled subanalysis of pts on IDL-mono (n=56), IGHV gene mutational status was mutated for 17 and unmutated for 39. No difference in mean ALC over time was observed based on IGHV gene mutation status, with median 24 weeks of follow up.
CONCLUSIONS
IDL has substantial activity as mono- or combination therapy in pts with TN or R/R CLL or SLL. Similar to other BCR pathway inhibitors, treatment with IDL is associated with transient lymphocytosis. The addition of anti-CD20 and/or C to IDL ameliorates this lymphocytosis, irrespective of disease status.
Further analyses with baseline characteristics (including IGHV gene mutational status) and safety/efficacy correlates of lymphocytosis are ongoing, and will be presented at the meeting.
Table 1. Patterns of Lymphocytosis by Disease Status and Treatment Regimen TN CLL/SLL R/R CLL/SLL Category IDL-mono (n=41) IDL+anti-CD20 (n=64) IDL-mono (N=22) IDL+anti-CD20(n=150) IDL+C (n=45) IDL+C+anti CD20 (N=30) Pts with any increase in ALC post-baseline (in absence of PD), % 81 36 86 64 40 27 Peak ALC (x 10ˆ9/L): median 112.7 40.9 45.3 51.6 43.7 31.2 N 41 64 22 150 45 30 Peak ALC (% rise above baseline), median 97.8 50.8 323.9 137.7 117.6 97.2 N 33 23 19 96 18 8 TTPeak (weeks), median 4.0 4.0 3.9 2.2 4.1 2.1 N 33 25 19 97 18 8 TT50% (weeks), median 8.1 4.1 14.6 6.1 4.1 2.1 N 17 57 4 113 41 26
Peak includes baseline ALC
Time to peak and Peak ALC % change above baseline do not include pts whose baseline ALC=Peak ALC

Disclosures
Brown: Gilead: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy. Cheson:Teva: Research Funding; Ascenta: Research Funding; Pharmacyclics: Consultancy, Research Funding; MedImmune: Research Funding; Astellas: Consultancy; Roche/Genentech: Consultancy, Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding. Furman:Acerta Pharma BV: Research Funding; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Ghia:Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Janssen: Consultancy; Adaptive: Consultancy; AbbVie: Consultancy; GSK: Research Funding; Acerta Pharma BV: Research Funding. Hallek:Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Hillmen:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Acerta Pharma BV: Research Funding; Janssen: Honoraria, Research Funding. Sharman:TG Therapeutics, Inc.: Research Funding; Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding; Janssen: Research Funding; Calistoga: Honoraria. Dubowy:Gilead Sciences: Employment, Equity Ownership. Velasco:Gilead: Employment. Waldapfel:Gilead: Employment.