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

DisclosuresXavier 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# NCT00535873)

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

marrowSerum immunoglobulin levels

Lenalidomide in Elderly CLL: Study Endpoints

Lenalidomide in Elderly CLL: Patient Pre-treatment Characteristics

Characteristic N (%); median [range]

Age, years 71 [66-85]

Rai stage, III or IV 18 (30)

Lymphocytes, x 109/L 76 [2.5 – 227]

2-microglobulin, mg/L 4.3 [2.0 – 10.2]

IGHV, unmutated 33/55* (60)

11q deletion 14 (23)

17p deletion 6 (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 = 60 NCI Response

n patients %

CR* 6 10

CRi* 3 5

Nodular PR 3 5

PR 25 42

ORR 37 62

*4 patients with flow cytometry negative CR

Analysis time 3 cycles 9 cycles 15 cycles 21 cycles

ITT/No on Rx. 60/54 60/43 59/38 53/30

NCI Response n (%) n (%) n (%) n (%)

CR/CRi* - 1 (2) 5 (8) 7 (13)

Nodular PR - 6 (10) 4 (7) 5 (9)

PR 24 (40) 27 (45) 27 (46) 18 (34)

ORR 24 (40) 34 (57) 36 (61) 30 (57)

Lenalidomide in Elderly CLL: Responses at Assessment Times

Patient characteristicNCI-WG Response (%)

n CR/CRi/nPR OR

Age, years65 - 74 43 26 72

≥ 75 17 6 35*

Rai stage0 – II 42 21 64

III or IV 18 17 56

β2-M, mg/L< 4 26 27 69

≥ 4 34 15 56

IGHV genesMutated 22 5* 50

Unmutated 33 30 73

FISH hierarchy

Deletion 13q 15 33 73

Negative 12 8 50

Trisomy 12 13 15 92

Deletion 11q 14 29 57

Deletion 17p 6 0 0*

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 Cycles of therapy

Hematological toxicity*Toxicity as % of cycles

Grade 3 Grade 4

Neutropenia 26 12

Thrombocytopenia 13 <1

Anemia 0 0

Lenalidomide in Elderly CLL: Hematological Toxicity

*NCI-working group criteria

Infections (N=60)Grade ≥ 3

n episodes n (%) patients

Sepsis 1 1 (2)

Pneumonia/Bronchitis 3 2 (3)

Upper Respiratory 0 0 (0)

Urinary 0 0 (0)

Other infections 1 1 (2)

Fever, neutropenic 3 3 (5)

Fever, non-neutropenic 3 2 (3)

Lenalidomide in Elderly CLL: Infections

Toxicity (N=60)Grade 1 - 2 Grade ≥3

n of patients %n of

patients%

Fatigue 53 88 2 3

Constipation 30 50 1 2

Diarrhea 30 50 0 0

Tumor flare 30 50 0 0

Rash 28 47 0 0

Nausea 21 35 0 0

Dyspnea 20 33 1 2

Pruritus 20 33 1 2

Neuropathy: sensory 9 15

0 0

Neuropathy: motor 4 7 0 0

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/CRi 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 dose NNCI-WG Response (%)

CR/CRi/nPR OR

Mean DoseCycles 1 - 6

< 5mg 26 4 35

≥ 5mg 34 32* 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