1. Ibrutinib: First-in Class Inhibitor of BTK  Forms a specific and irreversible bond with cysteine-481 in BTK  Highly potent BTK inhibition at IC 50 = 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 N N N N NH 2 O N O 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. 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:  BRAF V600E in expression  pERK regulation, as well as other potential protein kinase targets  Serum soluble IL-2 receptor levels  MRD NCI 9268 Ibrutinib for Relapsed HCL: Objectives

5.  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 NCI 9268 Ibrutinib for Relapsed HCL: Eligibility

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