A Phase II Study of Lenalidomide as Initial Treatment of Elderly Patients with Chronic Lymphocytic Leukemia Xavier Badoux, William Wierda, Susan O'Brien, Stefan Faderl, Steven Kornblau, Kimberly Yerrow, Zeev Estrov, Hagop Kantarjian, Michael Keating and Alessandra Ferrajoli

Disclosures Xavier Badoux, MB BS Research Support/P.I. No disclosures Employee No disclosures Consultant No disclosures Major Stockholder No disclosures Speakers’ Bureau No disclosures Scientific Advisory Board No disclosures Presentation includes discussion of off-label use of lenalidomide in CLL.

Lenalidomide in Elderly CLL: Introduction Median age at diagnosis of CLL: 72 years Elderly patients with CLL –Under-represented in clinical trials –Increased toxicity with chemoimmunotherapy Lenalidomide –Immunomodulatory drug –Oral administration –Active in relapsed CLL SEER Cancer Statistics Review, NCI (2009); Eichhorst B, Leuk & Lymph (2009); Chanan-Khan A et al. JCO (2006); Ferrajoli A et al. Blood (2008).

Lenalidomide in Elderly CLL: Study Design Phase II, 60 patients Untreated and symptomatic (NCI-WG) Age ≥ 65 yrs Creatinine <2 mg/dL, bilirubin<2 mg/dL Performance status 0-2 Response assessed at end of Cycle 3, then every 6 cycles (2008 NCI-WG) ClinicalTrials.gov (ID# NCT )

Lenalidomide in Elderly CLL: Treatment Schedule Lenalidomide –5 mg orally daily x 2 cycles (56 days) –Increase by 5 mg/cycle (28 days) to maximum 25 mg daily –Treatment continued until progression Allopurinol 300 mg d1-14 No mandated antibiotic, anti-viral, DVT or tumor flare prophylaxis

Efficacy: 1. Progression-free survival 2. Clinical Responses (2008 NCI-WG) Toxicity: Grade 3-4 non-hematological Correlative Studies: Lymphocyte subsets analysis: blood and marrow Serum immunoglobulin levels Lenalidomide in Elderly CLL: Study Endpoints

Lenalidomide in Elderly CLL: Patient Pre-treatment Characteristics CharacteristicN (%); median [range] Age, years71 [66-85] Rai stage, III or IV18 (30) Lymphocytes, x 10 9 /L76 [2.5 – 227]  2 -microglobulin, mg/L 4.3 [2.0 – 10.2] IGHV, unmutated33/55* (60) 11q deletion14 (23) 17p deletion6 (10) Marrow CD38, ≥30%30/59** (51) Not evaluable: *IgVH: n=5, **CD38: n=1

Lenalidomide in Elderly CLL: Response (2008 NCI-WG Criteria) N = 60NCI Response n patients% CR*610 CRi*35 Nodular PR35 PR2542 ORR3762 *4 patients with flow cytometry negative CR

Analysis time3 cycles9 cycles15 cycles21 cycles ITT/No on Rx.60/5460/4359/3853/30 NCI Responsen (%) CR/CR i *-1 (2)5 (8)7 (13) Nodular PR-6 (10)4 (7)5 (9) PR24 (40)27 (45)27 (46)18 (34) ORR24 (40)34 (57)36 (61)30 (57) Lenalidomide in Elderly CLL: Responses at Assessment Times

Patient characteristic NCI-WG Response (%) nCR/CRi/nPROR Age, years ≥ * Rai stage 0 – II III or IV β 2 -M, mg/L < ≥ IGHV genes Mutated225*50 Unmutated FISH hierarchy Deletion 13q Negative12850 Trisomy Deletion 11q Deletion 17p600* Lenalidomide in Elderly CLL: Responses by Pre-treatment Characteristics *p<0.05

Lenalidomide in Elderly CLL: Overall and Progression-free Survival Median follow-up 23 months: OS = 90% PFS = 60%

Lenalidomide in Elderly CLL: Normalization of PB Lymphocytes (n=38) *p<0.001

Lenalidomide in Elderly CLL: Reconstitution of BM Lymphocytes (n=38) *p<0.001,**p<0.01 (%)

Lenalidomide in Elderly CLL: Improvement in Serum Igs (n=37) 8 / 16 (50%) patients with IgG<600mg/dl → normalized serum IgG * p<0.001 Cycles of therapy

Hematological toxicity* Toxicity as % of cycles Grade 3Grade 4 Neutropenia2612 Thrombocytopenia13<1 Anemia00 Lenalidomide in Elderly CLL: Hematological Toxicity *NCI-working group criteria

Infections (N=60) Grade ≥ 3 n episodesn (%) patients Sepsis11 (2) Pneumonia/Bronchitis32 (3) Upper Respiratory00 (0) Urinary00 (0) Other infections11 (2) Fever, neutropenic33 (5) Fever, non-neutropenic32 (3) Lenalidomide in Elderly CLL: Infections

Toxicity (N=60) Grade Grade ≥3 n of patients% % Fatigue Constipation Diarrhea Tumor flare Rash Nausea Dyspnea Pruritus Neuropathy: sensory Neuropathy: motor47 00 Lenalidomide in Elderly CLL: Other Toxicities

Lenalidomide as frontline therapy in elderly CLL –Estimated 2-year OS 90%; 2-year PFS 60% –ORR 62 %; CR/CR i 15% –Quality of response improves with time Myelosuppression most common toxicity No severe tumor flare or tumor lysis syndrome ↑ serum Ig levels Normalization of lymphocyte populations Lenalidomide in Elderly CLL: Conclusions

Thank you

Lenalidomide doseN NCI-WG Response (%) CR/CRi/nPROR Mean Dose Cycles < 5mg26435 ≥ 5mg3432*82** Lenalidomide in Elderly CLL: Clinical Responses by Dose Intensity *p<0.01, **p<0.001

Lenalidomide in Elderly CLL: Best Clinical Response: 2008 NCI-WG