1. O N H 2 N N N N N O Ibrutinib: First-in Class Inhibitor of BTK • Forms a specific and irreversible bond with cysteine-481 in BTK • Highly potent BTK inhibition at IC50 = 0.5 nM • Orally administered with once daily dosing resulting in 24-hr target inhibition • In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation • Inhibits CLL cell migration and adhesion • No cytotoxic effect on T-cells or NK-cells Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010 Herman SEM et al: Blood 117: 6287-6296, 2011 Ponader, et al., ASH Meeting Abstracts 116:45, 2010 Ibrutinib PCI-32765

2. Burger J A et al. ASH Education Book 2011:96-103

3. Potential Role for BCR Signalling in HCL Sivina M et al. ASH Annual Meeting 2012 Abstract #1802

4. NCI 9268Ibrutinibfor Relapsed HCL: Objectives Primary Objective To determine the overall response rate after 32 wks of ibrutinib therapy Secondary Objectives • To characterize the toxicity and tolerability of single-agent ibrutinib • To characterize the progression-free (PFS) and overall survival (OS) • To determine the rate of MRD-negative CR at 32 weeks • To characterize immunologic outcomes during ibrutinib treatment • To explore the effect of ibrutinib on traditional and new biomarkers in HCL including:  • BRAFV600E in expression • pERK regulation, as well as other potential protein kinase targets • Serum soluble IL-2 receptor levels • MRD

5. NCI 9268Ibrutinib for Relapsed HCL: Eligibility • Histologically confirmed hairy cell leukemia (HCL) or variant hairy cell leukemia (vHCL) • For HCL: • ≥1 prior purine nucleoside analog-containing regimen, or • Relapsed or de novo disease if medically unfit for purine nucleoside analog treatment • For vHCL: • Both previously untreated and relapsed patients are eligible • Preserved end-organ function, ECOG ≤ 2 • Requires therapy • Hgb <11g/dL, plts <100K/mL, ANC <1,000/mL, enlarging nodes ≥2cm • Progressive organomegaly • Progressive disease-related constitutional symptoms

6. NCI 9268Ibrutinib for Relapsed HCL: Schema N = 44 patients 6 participating centers