A Phase 2 Study of Idelalisib Monotherapy in Previously Untreated Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Authors: Zelenetz Andrew D. , Lamanna Nicole , Kipps Thomas J. , Coutre Steven E. , O'Brien Susan , Aiello Maria , Cho Yoonjin , Dubowy Ronald L. , Flinn Ian W. 
Published: October 2019

Abstract
BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (Zydelig, IDELA,), a potent and selective orally administered inhibitor of PI3Kδ, in combination with rituximab weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report describes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy.
METHODS: Enrollment began in November, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measurable lymphadenopathy, were treated with IDELA 150 mg bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012).
RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microglobulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisib exposure was 4.8 months (range 0.9-8.5). There has been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median absolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluable for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluable pts and hepatomegaly in 75% of 4 evaluable pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was observed in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent lab abnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thrombocytopenia. One pt had a TEAE leading to dose reduction.
CONCLUSIONS: IDELA has substantial single agent activity in treatment-naïve pts with CLL or SLL. Early lymphocytosis is observed with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximab. IDELA was well tolerated and had a manageable safety profile in this preliminary analysis.

Disclosures
Zelenetz: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.