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
Ferrajoli A, et al. Blood. 2008;111:5291-7.
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
Ferrajoli A, et al. Blood. 2008;111:5291-7.
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)
Ferrajoli A, et al. Blood. 2008;111:5291-7.
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
Ferrajoli A, et al. Blood. 2008;111:5291-7.
Lenalidomide in CLL: Plasma Cytokine Levels (N=12)
010
2030
4050
Baseline 7days 28 days
IL-10
020
4060
80100
Baseline 7days 28 days
IFN-
0100
300
500
Baseline 7days 28 days
Basic FGF
05
1015
2025
Baseline 7days 28 days
IL-1
0
50
100
150
Baseline 7days 28 days
VEGF
TNF-
0
10
20
30
Baseline 7days 28 days0
5,000
10,000
15,000
20,000
Baseline 7days 28 days
IL-2R
05
1015
2025
Baseline 7days 28 days
IL-2
020
4060
80100
Baseline 7days 28 days
IL-8
SD + NRPR + CR
0
2,000
4,000
6,000
8,000
Baseline 7days 28 days
TNF-RI
IL-6
0
20
40
60
80
Baseline 7days 28 days
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)
Ferrajoli A, et al. Blood. 2008;111:5291-7.
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
Chen C.. et al. ASH 2008 abstract # 44
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%)
Chen C.. et al. ASH 2008 abstract # 44
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
Chen C.. et al. ASH 2008 abstract # 44
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