lenalidomide : un nuovo farmaco nell’armamentario terapeutico della llc alessandra ferrajoli...

Lenalidomide: un nuovo farmaco nell’armamentario

terapeutico della LLC Alessandra Ferrajoli

Department of Leukemia The University of Texas M.D. Anderson Cancer Center

Houston, TX, USA

Lenalidomide

Thalidomide analogue

Immunomodulatory drug (IMiD)

3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

• del(5q) MDS

Inhibition of del(5q) erythroid progenitors (↑SPARC and actinin)1

• Multiple Myeloma

Changes in BM microenviroment, ↑apoptosis, ↓cell adhesion2

• CLL (??)

immunological synapses formation3

T-cell and NK-cells function4

Interference with the microenvironment pro-survival cytokines (TNF-, VEGF, IL-8, IL-6)

Pro-apoptotic effect1 Pellagatti et al. PNAS 2007; 101:950-68.2 Mitsiades et al. J Cell Biochem 2007; 104:11406-11.3 Ramsey G. et al. J. Clin. Invest 2008; 118: 2427-2437 4 Hayashi T et al. Br J. Haem. 2005 128:192-203

Lenalidomide: Mechanisms of Action

Lenalidomide in CLL: Background

• TNF- and VEGF contribute to CLL proliferation:

–High levels of VEGFR2 are associated with decreased survival1

–TNF- levels are elevated in the plasma of patients with CLL and TNF- is a prognostic factor in CLL2

TNF- = tumour necrosis factor ; VEGFR2 = vascular endothelial growth factor receptor 2 (KDR).

1. Ferrajoli A, et al. Clin Cancer Res. 2001;7:795-9.

2. Ferrajoli A, et al. Blood. 2002;100:1215-9.

Trial Design: Lenalidomide in Recurrent/Refractory CLL

• Phase II

• Previous treatment (purine analogue-based chemotherapy)

• Lenalidomide 10 mg/day– titrate up by 5 mg every 28 days to 25 mg

daily (minimum 5 mg, days 1–21)

• Treatment continued until progression

Ferrajoli A, et al. Blood. 2008;111:5291-7.

Characteristic N = 44

Median age (range), years 64 (49–86)

Number (range) of prior therapies 5 (1–15)

Serum 2-microglobulin (range), g/ml 4.3 (1.6–10.1)

Rai disease stage III or IV, % 45

Fludarabine refractory, n (%) 12 (27)

Alkylating-agent refractory, n (%) 11 (25)

Bulky lymphadenopathy, n (%) 17 (39)

Unfavourable cytogenetic features, n (%)

del(11q23) 18 (41)

del(17p) 8 (18)

Unmutated VH, n (%)* 29 (66)

*Not tested, n = 11.VH = immunoglobulin variable heavy chain.

Lenalidomide in Recurrent/Refractory CLL: Patient Characteristics


ResponsePatients, n (%)

(N = 44)

Complete response 3 (7)

Nodular partial response 1 (2)

Partial response 10 (23)

Stable disease* 11 (25)

Progressive disease‡ 19 (43)

*Continued lenalidomide treatment.‡ Including 2 early deaths.

ORR 32%

Responses evaluated according to 1996 NCI-WG guidelines

Lenalidomide in Recurrent/Refractory CLL: Responses


Adverse events, n (%)

Grade 1 or 2 Grade 3 or 4

Hematological

Neutropenia 35 (11) 135 (41)

Thrombocytopenia 52 (16) 51 (15)

Anemia 63 (19) 9 (3)

Non-hematological

Fatigue 71 (22) 4 (1)

Diarrhea 44 (13) 6 (2)

Rash 43 (13) –

Tumour flare** 31 (10) 2 (2)**Occurred in 9 of 17 patients with lymph nodes > 5 cm and in 4 of 27 patients with lymph nodes < 5

Lenalidomide in Recurrent/RefractoryCLL: Adverse Events per Course (N=333)


Awais A, et al. Clinical Infect Dis. 2008, 46: 69-71.

Rapid Resolution of Chronic Skin Infection During Lenalidomide Therapy

for CLL

Infection with Mycobacterium marinum

Lenalidomide in Recurrent/Refractory CLL: T-cell Counts

Lym

ph

ocy

tes

(× 1

03 /l

)

CD

3 ce

lls

(× 1

03 /l

)

0

10

20

30

40

50

60

Baseline Month 3 Month 60

0.5

1.0

1.5

2.0

2.5

3.0

Baseline Month 3 Month 6


Lenalidomide in CLL: Plasma Cytokine Levels (N=12)

010

2030

4050

Baseline 7days 28 days

IL-10

020

4060

80100


IFN-

0100

300

500


Basic FGF

05

1015

2025


IL-1

0

50

100

150


VEGF

TNF-

0

10

20

30

Baseline 7days 28 days0

5,000

10,000

15,000

20,000


IL-2R

05

1015

2025


IL-2

020

4060

80100


IL-8

SD + NRPR + CR

0

2,000

4,000

6,000

8,000


TNF-RI

IL-6

0

20

40

60

80


CR = complete response; FGF = fibroblast growth factor; IFN = interferon; IL = interleukin; NR = no response; PR = partial response; SD = stable disease; TNF-R1 = TNF receptor 1.

Cyt

ok

ine

con

cen

trat

ion

(p

g/m

l)


Patients (%)

Overall responseCR*PRSD

57.5184014

Lenalidomide in Recurrent/Refractory CLL: Roswell Park Experience

Chanan-Khan A, et al. Presented at XII IWCLL, 2007. Chanan-Khan A, et al. J Clin Oncol. 2006;24:5343-49.

*Molecular remission occurred in 3 patients with a CR.

Total number of patients accrued = 45Evaluable patients = 32Non-evaluable patients = 13

Response (intent-to-treat analysis)

Lenalidomide 25mg/day Day 1–21

Lenalidomide in Recurrent/Refractory CLL: Conclusions

• Responses seen with an immunomodulatory agent

• Patients treated with oral therapy on a daily basis

• Time to response is prolonged, best responses seen after 6-9 months

• The toxicity profile is manageable and the treatment can be safely given as outpatient

• Myelosuppression is frequent, requires dose reduction

Lenalidomide as Initial Treatment of Elderly CLL: Background

• Active in relapsed CLL 1,2

• Treatment-naïve patients may benefit

from an immunostimulatory agent

• No consensus on best treatment for

elderly patients

• Oral agent 1 Chanan-Khan AA et al. J Clin Oncol 2006 2 Ferrajoli A et al. Blood 2008

Lenalidomide in Elderly CLL: Study Design

• Phase II, 60 patients (11/07-4/09)

• Untreated and symptomatic

• Age ≥ 65 yrs

• Creatinine <2 mg/dL, bilirubin<2 mg/dL

• Zubrod/WHO performance status 0-2

• Response assessment at end of cycle 3, cycle 9 and every 6 cycles

Lenalidomide in Elderly CLL: Doses and Schedule

Lenalidomide

- 5 mg orally daily x 2 cycles (56 days)

- by 5 mg/cycle (28 days) max 25 mg daily

- Treatment continued until progression

Response assessment at 3, 9, 12 and 15 months

Allopurinol 300 mg d 1 -14

No antibiotic or anti-viral prophylaxis required

No DVT prophylaxis required

Lenalidomide in Elderly CLL: Patient Characteristics (N=60)

Characteristic Value

Median age (range), yrs 71 (66-85)

Rai stage III/IV, N (%) 18 (30)

11q-, N (%)17p-, N (%)

14 (23) 6 (10)

Median β2M (range), mg/dL 4.3 (2-10)

Unmutated VH, N (%)

ZAP-70+, N(%)

33/55 (55)

31/48 (52)

Updated IWCLL 2009

Lenalidomide in Elderly CLL: Responses

Time on therapy

N. Evaluable

Cycle 3

59

N (%)

Cycle 9

58

N (%)

Cycle 15

43

N (%)

Cycle 21

25

N (%)

CR 0 1 (2) 2 (5) 1 (4)

Nod. PR / CRi 0 6 (10) 6 (14) 4 (16)

PR 24 (41) 25 (41) 17 (40) 9 (36)

Overall Response 24 (41) 32 (53) 25 (58) 14 (56)

Stable disease 26 (44) 5 (9) - -

Discontinued 6 (10) 17 (29) 17 (40) 11 (44)

Progression 3 (5) 4 (7) 1 (2) -

Updated IWCLL 2009

Lenalidomide in Elderly CLL: Absolute and T-cell (CD3+) Lymphocytes

59

9 9 30

10

20

30

40

50

60

70

80

Pre-treatment

3 9 15

Number of Cycles

All lymphocytes

CD3+ Lymphocytes

ALC

(X 109/l)

p<0.001p<0.001

p<0.001

N=27

Updated IWCLL 2009

Lenalidomide in Elderly CLL: CD4 and CD8 Lymphocytes

% p

eri

ph

era

l blo

od

lym

ph

oc

yte

s

N=27

8

2130

37

7

17

25

27

0

10

20

30

40

50

60

70

80

90

100

Pre-

treatment

3 9 15

Number of Cycles

%CD8

%CD4

p<0.001

p<0.001

p<0.001

Updated IWCLL 2009

Lenalidomide in Elderly CLL: Serum Immunoglobulin G Levels

10881064

776

875

713651

502495

All patients (n=27)

Pre-treatment IgG < 700mg/dl (n=12)

Pre-treatment 3 9 15

Cycles of therapy

1400

1200

1000

800

600

400

200

0

Imm

un

og

lob

ulin

G (

mg

/dl)

p<0.001p<0.001

Updated IWCLL 2009

Lenalidomide in Elderly CLL: Regulatory T Cells in Blood

Courtesy of B-N Lee

Percent CD4 CD25hi FoxP3

Baseline 3 cycles 9/15 cycles0

1

2

3

4

5

p=0.005

p=0.024

p=0.001

%

Abs CD4 CD25hi FoxP3

Baseline 3 cycles 9/15 cycles0

50

100 p<0.001p=0.003

Coun

t

Lenalidomide in Elderly CLL: Overall Survival and Time to Treatment Failure

0 6 12 18 24

Months

0.0

0.2

0.4

0.6

0.8

1.0

OS 60 pts. 3 Died TTF 60 pts. 20 Failed

Lenalidomide in Elderly Patients: Hematological Toxicities (N=60)

Grade > 3 Hematologic

N pts % courses

Neutropenia 47 35

Anemia 3 <1

Thrombopenia 11 4

Updated IWCLL 2009

Infections N pts (%)

Neutropenic sepsis pneumonia 2 (3)

Pneumonia 5 (8)FUO (Gd. 3) 3 (5)Neutropenic fever 2 (3)

Minor infections 40 (5*)

* N(%) courses

Lenalidomide in Elderly Patients: Infectious Complications

Updated IWCLL 2009

Lenalidomide in Elderly Patients: Grade 1-2 Toxicities

Other Grade < 3 N courses (%)

Tumour flare 38 (5)

Rash/itch 77 (10)

GI – Constipation* 40 (5)

GI – Diarrhea 44 (5)

Neuropathy 11 pts ‡

Fatigue† 71 (9)*Gd 3 n=1, †Gd 3 n=2, ‡ Median dur’n 287d.

Updated IWCLL 2009

Lenalidomide in Elderly Patients: Tumor Flare

Lenalidomide in Elderly Patients: Conclusions

• Lenalidomide well tolerated in elderly pts with CLL

• Rapid decrease in lymphocyte count

• After 15 cycles: OR 58%; CR 5%

• Response rate improves with continued treatment (2

flow negative CR)

• Myelosuppression is common

• No deaths or increased rate of infections

• More rapid dose escalation and support with growth

factors may improve rate and quality of responses

A phase II study of lenalidomide in patients with untreated, symptomatic CLL

PatientsPatients Chronic lymphocytic leukemiaChronic lymphocytic leukemiaUntreated but symptomaticUntreated but symptomatic

TreatmentTreatment Lenalidomide 10mg daily starting dose days 1-Lenalidomide 10mg daily starting dose days 1-21 on a 28 day cycle21 on a 28 day cycleDose escalations by 5 mg weeklyDose escalations by 5 mg weeklyTarget dose 25mg dailyTarget dose 25mg dailyAllopurinol cycle 1, ASA 81 mg dailyAllopurinol cycle 1, ASA 81 mg daily

EndpointsEndpoints Objective responseObjective response

DesignDesign Phase II two-stage designPhase II two-stage design

Sample sizeSample size 25 patients25 patients

Chen C.. et al. ASH 2008 abstract # 44

Lenalidomide Frontline in CLL

Study activated in October 2006Study activated in October 2006Patient 1 - 62 yo male - 62 yo malerapid lymphocyte decrease rapid lymphocyte decrease reached target dose 25mg reached target dose 25mg week 5 tumor lysis with ARF and MIweek 5 tumor lysis with ARF and MIPatient 2 – 64 yo male – 64 yo maleGrade 4 neutropenia at 10mg Grade 4 neutropenia at 10mg septic death septic death

Modified treatment plan : Modified treatment plan :

0

20

40

60

80

100

120

140

160

180

Cycle 1 (Month 1)Cycle 1 (Month 1) 2.5 mg daily x 21/28 days2.5 mg daily x 21/28 days

Cycle 2Cycle 2 5.0 mg daily 5.0 mg daily

Cycle 3Cycle 3 10 mg daily

Cycle 4 and Cycle 4 and beyondbeyond

Continued monthly escalation to Continued monthly escalation to 25mg allowed for nonresponders25mg allowed for nonresponders


Lenalidomide Frontline in CLL: Toxicities

Tumor flare – 80% of patients (20/25)– frequently associated with

rash, nasal coryza, scalp itching

– 30% of all cycles– all grade 1-2– 40% required steroids

Hematological Grade 3-4

NeutrophilsNeutrophils 16 (64%)16 (64%)

PlateletsPlatelets 3 (12%)3 (12%)

HemoglobinHemoglobin 3 (12%)3 (12%)


Lenalidomide Frontline in CLL: Conclusions

• Lenalidomide is highly active as a first-line Lenalidomide is highly active as a first-line agent in CLL - RR 56%agent in CLL - RR 56%

• Toxicities Toxicities – Myelosuppression, TLS Myelosuppression, TLS – Tumor flare is mild and manageableTumor flare is mild and manageable

• Dosing recommendationsDosing recommendations– Start low and go slowStart low and go slow– Rebound lymphocytosis suggests continuous Rebound lymphocytosis suggests continuous

dosing may be preferabledosing may be preferable


Lenalidomide and Rituximab in CLL: Background

• Different mechanisms of action

• Non-overlapping toxicity profile

• Ameliorate the tumor flare reaction

Lenalidomide and Rituximab as Salvage Therapy in CLL: Potential Synergism

• Lenalidomide enhances NK-cell and monocyte-mediated ADCC of rituximab-treated NHL and CLL cells 1

• Immunomodulatory drugs stimulate NK-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo 2

• Lenalidomide and rituximab increase MCL cells apoptosis and rituximab-dependent NK-cell mediated cytotoxicity. 3

1 Wu, L. Blake Bartlett J. et al. Clin Cancer Res 2008;14:4650-46572 Reddy N. Br J Haematol. 2008 Jan;140(1):36-45. 3 Zhang L. and Wang M. Am. J. Hematol. E-pub, 2009

Lenalidomide and Rituximab as Salvage Therapy in CLL: Potential Antagonism

• Lenalidomide down-regulates the CD20 antigen and antagonizes direct and ADCC of rituximab on primary CLL cells 1

1 Lapalombella, R., Byrd J. et al. Blood 2008;112:5180-5189

Lenalidomide and Rituximab as Salvage Therapy in CLL: Study Design

• Phase II, 42 patients (10/08-7/09)

• Prior purine-analogue

• Creatinine <2 mg/dL, bilirubin<2 mg/dL

• Zubrod/WHO performance status 0-2

• Response assessment at end of cycles

3, 6, 12 and then every 6 cycles

Lenalidomide and Rituximab as Salvage Therapy in CLL: Doses and Schedule

• Rituximab (375 mg/m2) Days 1, 8, 15 and 22 and once every four weeks during cycles 3-12.

• Lenalidomide 10mg/day started on Day 9 of cycle 1 and continued daily for twelve cycles (each cycle consists of 28 days)

• Lenalidomide continued until progression in responders

Allopurinol 300 mg d 1 -14 No antibiotic or anti-viral prophylaxis No DVT prophylaxis required

Characteristic N = 37

Median age (range), years 59 (44–83)

Number (range) of prior therapies 2 (1–9)

Serum 2-microglobulin (range), g/ml 3.6 (1.5–9)

Rai disease stage III or IV, % 41

Fludarabine refractory, n (%) 9 (24)

Prior rituximab, n (%) 37 (100)

Unfavourable cytogenetic n (%)

del(11q23) 10 (37)

del(17p) 9 (24)

Unmutated VH, n (%)* 26 (70)

VH = immunoglobulin variable heavy chain.

Lenalidomide and Rituximab in Recurrent CLL: Patient Characteristics

Ferrajoli A, et al. ASH 2009 submitted

Lenalidomide and Rituximab in Recurrent

CLL: Toxicities (N=37 ) Grade ≥ 3 Adverse Event N. (%)

• Hematological Neutropenia Thrombopenia

16 (43) 4 (11)

• Non-hematological FUO Pneumonia Sepsis

6 (16) 2 (5) 1 (3)

Tumor lysis syndrome Pain

1 (3) 1 (3)

Tumor Flare Reaction Grade 1 Grade 2

8 (22) 1 (3)

Lenalidomide: Ongoing TrialsFront-line treatmentLenalidomide and rituximab [lenalidomide first] (CLL Research Consortium)Lenalidomide Vs Chlorambucil (age > 65 years, ORIGIN trial, Celgene)Phase I Lenalidomide + Fludarabine + Rituximab (Dana-Farber Cancer Institute)FR Vs FR + lenalidomide cons. Vs FCR (CALG-B)

Salvage treatmentBendamustine+ Rituximab+ Lenalidomide ( Univ. Wisconsin)Phase I-II Bendamustine+ Rituximab+ Lenalidomide ( Georgetown Univ.)Phase I-II Lenalidomide+Dasatinib (Scripps Cancer Center)Phase I Lenalidomide + Alvocidib (Ohio State)Phase I-II Lenalidomide + Fludarabine + Cyclophosphamide (GIMEMA)Phase II Lenalidomide + Ofatumumab (MDACC)

Consolidation treatmentLenalidomide (MDACC)Lenalidomide after FR as initial therapy (Georgetown Univ.)Lenalidomide after PCR as initial therapy (Mayo Clinic)Lenalidomide Vs placebo after 2nd line therapy (CONTINUUM trial, Celgene)

Thank you!!

Studies Exploring Lenalidomide-based Combination Therapies in

CLL Investigator Trial Name Trial Number

or countryChemotherapy combination with Chemotherapy

BrownA Phase 1 Dose Escalation Study of Lenalidomide in Combination With Fludarabine-Rituximab for Previously Untreated CLL/SLL

NCT00543114

Byrd(CALGB)

A Randomized Phase 2 Study of 3 Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated CLL

NCT00602459

Cheson Lenalidomide Following Rituximab and Fludarabine in Untreated CLL

NCT00860457

ChesonPhase 1 Clinical Trial of Bendamustine, Lenalidomide and Rituximab in B-Cell Lymphoid Malignancies

NCT00864942

FerrajoliLenalidomide in Combination With Rituximab as Treatment for Patients With Relapsed CLL

NCT00759603

Flinn A Phase 1/2 Study of Fludarabine, Rituximab, and Lenalidomide in Minimally Treated and Untreated Patients With CLL

NCT00536341

“Chemo-Free” RegimensChanan-Khan Lenalidomide + Rituximab NCT00096044

FerrajoliLenalidomide in Combination With Rituximab as Treatment for Patients With Relapsed or Refractory CLL

NCT00759603

JamesCRC and UCSD

A Two-Arm, Multi-Center Trial of Lenalidomide and Rituximab, for First-Line Treatment in Patients With B-CLL

NCT00628238

Pinilla (MCL/CLL)

A Phase 2 Study of Lenalidomide in Combination With Rituximab for Patients With CD5+/CD20+ Hematologic Malignancies Who Relapse or Progress After Rituximab

NCT00609869

SigalA Phase 1/2 Study of Combination Dasatinib and Lenalidomide in Purine Analogue-Failed CLL

NCT00829647

Updated June 19, 2009. Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

Studies Exploring Lenalidomide-based Combination Therapies in

CLL Investigator Trial Name Trial Number

or country

Lenalidomide in maintenance or consolidation setting

Ferrajoli A Study of Lenalidomide in Patients With CLL and Residual Disease After Chemotherapy

NCT00632359

Shanafelt/Kay

Phase 2 Trial of Pentostatin, Cyclophosphamide, and Rituximab Followed by Lenalidomide Consolidation for Previously Untreated B-CLL/ SLL

NCT00602836

Cheson Lenalidomide Following Rituximab and Fludarabine in Untreated Chronic Lymphocytic Leukemia

NCT00860457

Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide Followed by Rituximab/Lenalidomide in Untreated CLL -- a Dose-Finding Study With Concomitant Evaluation of Safety and Efficacy

AustriaUpdated June 19, 2009. Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

Open Celgene Sponsored Studies That are

Actively Accruing Patients • CONTINUUM (NCT 00774345): a phase 3 trial evaluating the role

of lenalidomide in the maintenance setting after second-line therapy– To date, there has been no CLL registration study focused on maintenance

therapy

– Since no CLL patient is “cured,” maintenance presents an opportunity to achieve sustained disease control by extending response rates

• ORIGIN (NCT 00910910): a phase 3 trial to assess the role of lenalidomide in treating elderly patients (65 years of age) with CLL – CLL is a disease that mainly impacts the elderly

– To date, there has been no registration study focused on patients 65 years of age

– Traditional chemotherapy is often poorly tolerated by patients who tend to be infirm and to have comorbidities

Clinicaltrials.gov Web site. clinicaltrials.gov. Accessed November 16, 2009 ; Data on file, Celgene.

A. Ferrajoli Disclosure Information

Consultant: Bayer, Genzyme

Grant/Research Support: Bayer, Celgene, Genentech

Speaker’s Bureau: none

Major Stock Shareholder: none

The use of lenalidomide for the treatment of CLL is considered off label

lenalidomide : un nuovo farmaco nell’armamentario terapeutico della llc alessandra ferrajoli...

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