Copyright © 2011 Research To Practice. All rights reserved.

Interest in Topics Related to the Treatment of Patients with CLL (Percent Responding 9 or 10)

37%

37%

35%

39%

44%

0% 10% 20% 30% 40% 50%

Initial therapy forpatients >70 yo

Cytogeneticsand FISH

Treatment ofrelapsed CLL

Initial therapy forpatients <70 yo

New agents/regimens

State of the Art Management of Chronic Lymphocytic Leukemia

Michael HallekUniversity of Cologne

Professional Experience Required to “Tailor” CLL Therapy: Characteristics at

Presentation• Median age at diagnosis: 72 years1

• Elderly patients may be fit or have comorbidities

1 Ries LAG et al. SEER Cancer Statistics Review 1975–2005.2 Yancik R. Cancer 1997; 80:1273–83.

Age at CLL diagnosis (years)

Patients1 (%)

Mean comorbidities2

(all cancer types, n)

≤54 11 n/a55–64 19 2.965–74 27 3.675+ 43 4.2

Mean no. of co-morbidities

2.9

3.6

4.2

n/a

Gribben JG. Blood 2009;114:3359-60; Balducci L, Extermann M. Oncologist 2000;5:224-37.

Classification of Patients by a Comprehensive Geriatric Assessment (CGA)

GO

SLOW

NO

Suitable for standard treatment

Suitable for reducedtreatment

Suitable for supportive care

Cumulative Illness

Rating Scale

Comparison of Fludarabine (F), Bendamustine (Ben), Alemtuzumab (Al) and Chlorambucil (Chl) as

Single AgentsRai 20001 Hillmen 20072 Knauf 20093

RegimenN

F Chl179 193

Al 149

Chl148

Ben157

Chl157

Median age, years 64 62 59 60 63 66

Rai Stage III-IV or Binet C, % 39 41 34 33 29 29

Grade 3/4 ↓ ANC, % 27 19 41 25 23 10.6

CR, % 20 4 24 2 31 2OR, % 63 37 83 55 68 31Med. PFS (mo) 20 14 14.6 11.7 21.6 8.3

1 Rai KR et al. N Engl J Med 2000;343:1750–57. 2 Hillmen P et al. J Clin Oncol 2007;25:5616–23.3 Knauf W et al. J Clin Oncol 2009;27:4378-84.

CLL5 Protocol, Patients >65 Years (Median 70)

Eichhorst et al, Blood 114, 3382 (Oct 15, 2009)

193 patients were randomly assigned to receive fludarabine 25 mg/m2 (5d IV q28d x 6 cycles) vs chlorambucil 0.4 mg/kg body weight (q15d x 12 mo)

Overall survival, 46 mo vs 64 mo (p-value = 0.15)

Eichhorst BF et al. Blood 2009;114(16):3382-91.

FC Improves Overall Survival in Non-High Risk CLL

GCLLSG CLL4 protocol- 375 patients (<66 years) with advanced CLL were

randomly assigned to fludarabine 25 mg/m2 x 5d IV q28d vs FC (fludarabine 30 mg/m2 and cyclophosphamide 250 mg/m2 x 3d IV q28d)

- Complete remission rate, 24% vs 7% (p < 0.001)

- Overall response rate, 94% vs 83% (p = 0.001)

- Progression-free survival, 48 mo vs 20 mo (p = 0.001)

- Treatment-free survival, 37 mo vs 25 mo (p < 0.001)

Eichhorst BF et al. Blood 2006;107(3):885-91.

Outcome n 6-year OS p-value

F 190 54%

F + (M or C) 140 59%

R-FC 300 77%

p = 0.37

p < 0.001

Improved Efficacy by Combining FC Chemotherapy with Rituximab

(MD Anderson, historical comparison)

Tam CS et al. Blood 2008;112:975–80.

F = fludarabine; M = mitoxantrone; C = cyclophosphamide; R-FC = fludarabine, cyclophosphamide and rituximab

Median Progression-Free Survival

N = 817

FCR, 57.9 mo vs FC, 32.9 mo

Hazard ratio = 0.563

p < 0.0001

Hallek M et al. Lancet 2010;376:1164-74.

Median Overall Survival408 patients were assigned to fludarabine, cyclophosphamide and rituximab (FCR) and 409 patients to fludarabine and cyclophosphamide (FC)

FCR resulted in significant overall survival benefit:

FC, 48.4 mo vs FCR, 60.7 mo Hazard ratio = 0.75 p = 0.039

At 4 years postrandomization:

75.5% alive on the FC arm 81.8% alive on the FCR arm

Hallek M et al. Lancet 2010;376:1164-74.

FCRFC

3-yr OS*None: 83.8%12q+: 95.8% 11q-: 93.7%13q-: 94.9%17p-: 38.1%

3-yr OS*None: 86.9%12q+: 85.8% 11q-: 82.6%13q-: 89.1%17p-: 36.5%

Overall Survival and Cytogenetic Abnormalities According to the

Hierarchical Model

* p < 0.05

Hallek M et al. Lancet 2010;376:1164-74.

N = 110 (7 pts not yet evaluable)

Bendamustine plus Rituximab

Fischer et al, ASH 2009;Abstract 205.Response N %ORR 100 90.9CR 36 32.7nPR 3 2.7PR 61 55.5SD 10 9.1PD - -

Chlorambucil (Chl) plus Rituximab (R)in Older CLL Patients

Hillmen et al, ASH 2010 Foa et al, ASH 2010

Trial Therapy nResponse

CR OR SD/PDChl-R (Foa) A 54 (of 98) 16.7% 81.4% 7.4%

Chl-R (Hillmen) B 100 9 (9%) 82 (82%) 15 (15%)

UK CLL4(Chl only) C 200 12 (6%) 132 (66%) 60 (30%)

A) CLB 8 mg/m2 d1-7 q28d up to 8x + R 375 mg/m2 c1-2, 500 mg/m2 c3-8, followed by R-maintenance 375 mg/m2 q 2 m for 2 yrs

B) CLB 10 mg/m2 d1-7 q28d up to 6x + R 375 mg/m2 c1, 500 mg/m2 c2-6C) CLB like B without R

CD20 Targeting

RITUXIMAB OFATUMUMAB GA101

STATUS Licensed Licensed Phase III

TYPE Chimeric Humanized Humanized

EPITOPE Type I Type I Type II

ADCC + + +++

CDC + ++ –

CELL DEATH + ± +++

Adapted from Lim et al, Haematologica 2010

CLL11 Protocolfor Unfit, Slow Go Patients

Chlorambucil combined with GA101

GChl

Randomization

ChlorambucilChl

Chlorambucil combined with rituximab

RChl

Summary:Translation into Clinical

Practice

Therapy of CLL 2011Stage Fitness

del(17p)p53mut

Therapy

Binet A-B, Rai 0-II, inactive

Irrelevant Irrelevant None

Active disease or Binet C or Rai III-IV

Go goNo FCR

Yes AlloSCT

Slow goNo CLB

Yes Al, HD R or O

CLL 2011: Second-Line TherapyResponse to First-Line Therapy

Fitness Therapy

Standard Alternatives (trials)

Refractory or progress within 2 years

Go go Al, FA, FCRAllo SCT

Flavopiridol, lenalidomide, BR

Slow go

Change therapy(if possible, include

in trial)

Al for del(17p),FCRlite, BR,bendamustine,lenalidomide, ofatumumab, HD rituximab

Progress after 2 years

All Repeat first-line therapy

W&W

Inactive Binet A Active disease + all Binet C, not del(17p)

CLL12 CLL10 CLL11

Go go Slow goWhich is the best score to

define high risk?

yesno

CLB CLB + RBR FCRtreatW&W

Disease (MRD) eradication Longer survival

Symptom control Longer disease-free

survival

CLB + GA101

Third Generation of Trials of the GCLLSG:

Risk, Stage and Fitness Adapted

CD20 Targeting

RITUXIMAB OFATUMUMAB GA101

STATUS Licensed Licensed Phase III

TYPE Chimeric Humanized Humanized

EPITOPE Type I Type I Type II

ADCC + + +++

CDC + ++ –

CELL DEATH + ± +++

Adapted from Lim et al, Haematologica 2010

Copyright © 2011 Research To Practice. All rights reserved.

What is your usual preferred induction systemic regimen in a younger patient (60 years old) requiring treatment for CLL?

0%

0%

2%

3%

3%

17%

3%

71%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Other

Chlorambucil

Lenalidomide

Alemtuzumab

Rituximab monotherapy

BR

FR

FCR

Copyright © 2011 Research To Practice. All rights reserved.

What is your usual preferred induction systemic regimen in an older patient (age 75) requiring treatment for CLL?

0%

11%

1%

1%

15%

49%

16%

7%

0% 10% 20% 30% 40% 50% 60%

Other

Chlorambucil

Lenalidomide

Alemtuzumab

Rituximab monotherapy

BR

FR

FCR

Copyright © 2011 Research To Practice. All rights reserved.

What Clinicians Want to Know

A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical

Management of Select Hematologic CancersSunday, June 5, 2011

7:00 PM – 9:30 PMChicago, Illinois

Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD

ModeratorNeil Love, MD

Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek