CLLIssues About Therapy

- Why do we watch and wait

- What is the best front line regimen- Is it different for different subsets

- Does FISH affect choice of frontline therapy?

- What are promising new agents?

Why Not Treat CLL at Diagnosis

- indolent disease- patients often asymptomatic- median age early 70’s- no cure

Survival: Daily Chlorambucil Versus Observation

Dighiero et al N Eng J Med 338(21):1506-14,1998

Newer Prognostic Factors AssociatedWith Inferior Survival in CLL

FISH cytogenetic abnormalities 17p deletion 11q deletion Complex abnormalities

Unmutated (<2% homology with germline) immunoglobulin heavy chain variable gene (IgVH)

Expression of ZAP-70 (≥ 20% positive) Expression of CD38 (≥ 30% positive)

Early Treatment With FCR vs DeferredTreatment in High-Risk Binet Stage A

GCLLSG CLL7Diagnosed within 1 year

No pretreatmentAge ≥ 18 years

Enrollment ~ 825

0-1 risk factorsN = 600

COHORT IFCR 6

COHORT IIWatch & wait

COHORT IIIWatch & wait

R

All tested for 4 risk factors:Cytogenetics by FISH

Serum thymidine kinase > 10 U/LPredicted LDT < 12 months

Unmutated IgVH≥ 2 risk factors

N = 200

Primary objectives: Event-free survival and definition of new prognostic system

Available at: http://dcllsg.web.med.uni-muenchen.de/en/cll7/index.php.

CLL8 Study Design

Patients with untreated, active

CLL and good physical

fitness(CIRS ≤ 6,

creatinine clearance ≥ 70 ml/min)

R

FCR

FC

6 courses

Follow up

Updated results of the 2nd analysis Median observation time 37.7 months.

Hallek et al Lancet 2010;376:1164-74

FC vs FCR: Response

FC (%) FCR (%) p

CR 23 45 <0. 01CRu 5 3 0.22CRi 2 3 0.52nPR 5 3 0.15PR 50 40 <0.01OR 85 93 <0.01

Hallek et al Lancet 2010;376:1164-74

Median observation time 25.5 months

P<0.001

CLL8: Progression-free Survival

Median PFS:FCR: 51.8 monthsFC: 32.8 months(N=790Hazard ratio 0.563, ranges 0.460-0.689, p<0.001)

PFS rate 3 yrs post randomization:FCR: 64.9%FC: 44.7%

Hallek et al Lancet 2010;376:1164-74

CLL8: Overall Survival

Overall survival 3 years post randomization:FCR: 87.2%FC: 82.5%

n=817, HR 0.664, p=0.012

10

CLL8 Genetic Analyses: PFS

FC FCR

11

CLL8 Genetic Analyses: OS

FC FCR

CAM307: Response to First-line Therapy With Alemtuzumab vs Chlorambucil (N = 297)

59% PR

24% CR

52.7

01020

3040506070

8090

100

Alemtuzumab Chlorambucil

CRPR

IRRP Response Rate to First-line B-CLL Therapy

53% PR% R

espo

nse

2%

83% ORR

55% ORR

P<0.0001

Hillmen P et al. J Clin Oncol. 2007;25(35):5553-5.

Alemtuzumab Chlorambucil

Deletion N Median PFS

(mo) N Median PFS

(mo)P-value for

PFS

17p del 11 10.7 10 2.2 0.2034

11q del (no 17p del) 23 8.5 31 8.5 0.3895

Trisomy 12 (no 17p del, no 11q del)

24 18.3 10 12.9 0. 0815

Normal 25 19.9 26 14.3 0.3477

Sole 13q del 33 24.4 34 13.0 0.0107

P value is calculated using log-rank test[Data presented according to hierarchical model of Döhner (NEJM 2000; 343: 1910-6)]

CAM307: PFS by Cytogenetic Abnormality and Treatment Arm

Alemtuzumab for Fludarabine-RefractoryB-CLL: Study Results

• OR 33% (CR 2%, PR 31%)

• 59% of patients had stable disease

• Median TTP of responders 9+ months

• Fever, chills: 76% Gr 1-2, 20% Gr 3-4

• Grade 3-5 infections in 33% of patients

Keating et al. Blood 99 (10), 3554-61, 2002.

Local Injection-Site Reaction Following SC Alemtuzumab Administration

Skin reactions appear to be much less pronounced in pretreated CLL patients

Disappeared within 2 weeks of continued therapy

0

10

20

30

40

50

60

70

80

90

100

% o

f Pat

ient

sCAM307: Safety

Summary of Infection-Related Adverse Events

Bacteremia/Sepsis

Positive CMV PCR with symptoms

FebrileNeutropenia

Positive CMV PCR without symptoms

Total Infections*

CMV incidence

IV Alemtuzumab (n=147)Oral Chlorambucil (n=147)

5 3 3 2

46 50

16

53

8

(*Total infections is excluding patients with any CMV events)

Hillmen et al. JCO 2008;25:5616-23

CMV Viremia with AlemtuzumabTrial % Pts Time of Organ No. Pts. with CMV CMV Involv. DeathsKeating

93 8 on therapy no 0Nguyen

34 10 28 days no 0Ferrajoli

78 20 1st month no 0Lundin*

41 10 on therapy no 0 *initial therapy

Keating et al Blood 99(10) 3554-3561 2002, Nguyen et al Clinical Lymphoma 3(2) 105-110, 2002,Ferrajoli et al Cancer 98:773-8 2003, Lundin et al Blood 100:768-773 2002

Prophylaxis TrialInclusion

Patients receiving alemtuzumabExclusion

Cr Cl calculated < 10 cc/minSchema

1: 1 randomizationValtrex 500 QD vs Valcyte 450 BID12 weeks therapy endpoint

Results

TotalCMV

ReactivationValtrex 20 7

Valcyte 20 0p = .004

O’Brien et al. Blood 2008;111(4):1816-19

Lymphadenopathy Predicts Poor Response to Alemtuzumab in

Relapsed/Refractory CLL

Largest node No. CR OR

MRD-negative response

None 33 72 87 39<5cm 47 17 40 11>5cm 11 0 9 0

Response according to size of largest lymph node

Moreton P et al. J Clin Oncol. 2005;23:2971-2979.

% of patients

NCI Response

BendamustineBifunctional Antineoplastic Agent?

Rummel M, et al. J Clin Oncol. 2005;23:3383-3389.

ClH2CN

N

N

CH3

CO2H

Purine-like Benzimidazole RingAlkylating Group

ClH2C

Available in Germany, 1971 - 1992Unique in vitro anti-tumor profile

21

Bendamustine combined with rituximab in first-line therapy of advanced CLL:

mutlicenter phase II trial of the German CLL SG

Kirsten Fischer, MD, Paula Cramer, MD, Stephan Stilgenbauer,MD, Raymonde Busch, Leopold Balleisen, MD, Julia Kilp, MD,Anna-Maria Fink, MD, Sebastian Böttcher, MD, MatthiasRitgen, MD, Michael Kneba, MD, PhD, Peter Staib, MD,Hartmut Döhner, MD, Silke Schulte, Barbara F. Eichhorst, MD,Michael Hallek, MD and Clemens-Martin Wendtner, MD

ASH 2008 Abstract 205

* N=110 (7 pts not yet evaluable)

Response N %ORR 100 90.9CR 36 32.7nPR 3 2.7PR 61 55.5

BR Front-line Response Rate

Fischer et al; ASH 2008 Abstract 205: Bendamustine and rituximab

BR Frontline Treatment Response by FISH

Response No. ORR (%) CR (%)

+12 19 17 89.5 3 15.8

11q- 21 19 90.5 9 42.9

17p- 7 3 42.9 0 0

IGHV unmutated 63 56 88.9 25 39.7

Fischer et al; ASH 2008 Abstract 205: Bendamustine and rituximab

R

Fludarabine CyclophosphamideRituximab(FCR)

BendamustineRituximab (BR)

Fludarabine 25 mg/m² i.v., days 1–3Cyclophosphamide 250 mg/m², days 1–3,Rituximab: 375 mg/ m2 i.v. day 0, cycle 1Rituximab: 500 mg/m² i.v. day 1, cycle 2–6

Bendamustine 90mg/m² day 1–2Rituximab 375 mg/m² day 0, cycle 1Rituximab 500 mg/m² day 1, cycle 2–6

Similar efficacy of BR in comparison with FCR?Lower toxicity rate of BR?

CLL10 protocol of the GCLLSG

CLL8 Study Design

R

FCR

FC

6 courses

Follow up

Patients with untreated, active

CLL and good physical

fitness(CIRS ≤ 6,Creatinineclearance

≥ 70 ml/min)

Updated results of the 2nd analysis Median observation time 37.7 months.

Hallek et al Lancet 2010;376:1164-74

CLL8: Side effects: the effect of ageFC FCR

< 70 yrsn = 359

≥ 70 yrsn = 37 p < 70 yrs

n = 361≥ 70 yrsn = 43

p

Total AEs gr 3/4 61.0% 78.4% 0.04 75.6% 83.7% 0.24

Anemia 6.7% 8.1% 0.74 5.5% 4.7% 0.81

AIHA 1.1% 0.0% 0.52 0.6% 2.3% 0.20

Leukocytopenia 12.0% 13.5% 0.79 24.9% 16.3% 0.21

Neutropenia 19.5% 35.1% 0.03 32.4% 44.2% 0.12

Thrombopenia 11.4% 5.4% 0.26 7.8% 4.7% 0.46

Infections, unspecified 9.5% 8.1% 0.79 13.0% 18.6% 0.31

Infections, bacterial 0.7% 5.4% 0.02 1.9% 4.7% 0.26

SOB’s Quick SurveyAll patients with CLL > 70 years seen

by me in clinic last month: N = 14Eligible for CLL8 trial? 3 too old, > 80 years, so N = 11Meet creatinine clearance requirement?N = 4So 4/14 = 29% eligibleNot counting CIR score

So if FCR not SOC for Patients with 17p Deletion or Elderly, Then What Is?

17p-: clinical trialelderly:

really old, poor PS→ palliative, probably doesn’t

matterolder but good shape

→ reduced dose FCR→ clinical trial

30

Bruton’s Tyrosine Kinase (Btk)A Critical B-Cell Signaling Kinase

• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation

• Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway

• Mutations in Btk prevent B cell maturation

• Inhibitors of Btk block BCR signaling and induce apoptosis

PCI-32765: Novel Small Molecule Inhibitor of BTK

• Forms a specific and irreversible bond with cysteine-481 in Btk

• Potent Btk inhibition at IC50 = 0.5 nM

• Orally bioavailable with daily dosing resulting in 24-hr target inhibition

• Inhibits BCR signaling and active in spontaneous canine B-cell lymphoma

• In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation

• Inhibits CLL cell migration and adhesion

31

Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010Herman SEM et al: : Blood. 2011 Mar 21. [Epub]Ponader, et al., Proc ASH, 2010

N

N

N

N

NH 2

O

N

O

PCI-32765

Pattern of Response: Blood Lymphocytes vs Lymph Nodes

32

Relapsed/Refractory Patients

ALC

109

/L

Time (Day) Time (Days)Time (Days)

% o

f Bas

e S

PD

0 50 100 150 200 250 3000 50 100 150 200 250 300 0 50 100 150 200 250 300

0.0

0.5

1.0

1.5

020

040

060

0Treatment-Naïve Patients

ALC

109

/L

Time (Days) Time (Days)

% o

f Bas

e S

PD

0 50 100 150 200 250 300 0 50 100 150 200 250 300

0.0

0.5

1.0

1.5

020

040

060

0

Initial (Cycle 2) Response Assessment and Best Response (420 mg/d Cohorts)

33

Res

pons

e R

ate

%

Treatment-Naïve (420 mg/d) Relapsed/Refractory (420 mg/d)

67%

24%19%

48%

59%

41%

Cycle 2(n=21)

Best Response(n=21)

Cycle 2(n=27)

Best Response(n=27)

CR PR Nodal Response

19%

33%

Side Effects (All Grades)

34

0% 20% 40% 60% 80%

Grade 1 Grade 2 Grade 3 Grade 4

Treatment-Naïve420 mg/d (n=23)

Relapsed/Refractory420 mg/d (n=27)

0% 20% 40% 60% 80%

Fatigue

Nausea

URI

Rash

Dyspepsia

Diarrhea

Vomiting

ContusionMuscle spasms

48%39%

17%22%

26%13%

17%

4%17%

70%33%

22%19%

11%

33%37%

33%26%

Best Response by Risk Features

Best Response (%)

Molecular Risk Feature N IWG Response Nodal Response

Overall 27 48 41

Del17p 9 4/9 (44) 3/9 (33)

Del11q 8 5/8 (63) 3/8 (38)

IgVH unmutated 17 9/17 (53) 5/17 (29)

35

Relapsed/Refractory Patients: 420 mg/d Cohort

Improvement in Hematologic Parameters

36

Hemoglobin over timein subjects with Hgb <9g/dL

at study entry(n=8)

Platelets over timein subjects with plt <50x109/L

at study entry(n=12)

HG

B (g

/dL)

8

10

1

2

14

1 15 28 43 56 84 112 140 168 196 224 252

Days on Study

Plat

elet

s (1

09 /L)

0

50

1

00

1

50

1 15 28 43 56 84 112 140 168 196 224 252

Days on Study

Subjects from all treatment groups with low baseline measurements are included

Slide 37

In B-Cell Malignancies, PI3K Delta Is at theCrossroads of Critical Signaling Pathways

PI3K Delta Pathway DrivesProliferationCell survivalTrafficking

BCR

PI3KDelta

CD40

STAT

T308 S473AKT

JAKTRAF6

NF-kβpathway

JAK

mTOR

BTK

PLCγ2

PKC GSK-3

LYN

SYKα β γLYN/SYK

T-cell Signalingstimulus

gp130 gp130

STAT BTK

PLCγ2

p70s6k elf4E

Malignant B-cell membraneCXCR5BAFFR

Stromal cell

IL-6R

CXCL13BAFFIL-6

Reference: Lannutti, Blood, 2011

Slide 38

CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Potently and Selectively

Class IPI3K IsoformCell-Based Activity

PDGF-induced pAKT

LPA-induced pAKT

fMLP-induced CD63+

FcεR1-induced CD63+

EC50 (nM) >20,000 1,900 3,000 8

Alpha Beta Gamma Delta

• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)

Reference: Lannutti, Blood, 2011

CAL-101

Slide 39

Best On-Treatment Change in Tumor Size(ITT Analysis, N=55)

-100

-75

-25

0

-50*

+25

+50

+75

+100

Inevaluable (patients without a follow-up tumor assessment)

Patients with del (17p)* Criterion for response [Hallek 2008]

% C

han

ge in

Lym

ph

No

de

Are

a

Single-Agent CAL-101 Resulted in Tumor Shrinkage in All Evaluable Patients with CLL, Including Those with del (17p)

Slide 40

Marked Reductions in Peripheral Lymphadenopathy Were Observed

Pretreatment With CAL-101 Treatment

38-year-old patient with refractory CLL and 5 prior therapies

Slide 41

Hemoglobin and Platelet Counts

0 (52

)1 (

52)

2 (51

)4 (

38)

6 (32

)8 (

31)

10 (2

5)

12 (2

2)10

11

12

13

14

80

100

120

140

160

HemoglobinPlatelets

Cycle (28 days) (N)

Mea

n H

emog

lobi

n±

SEM

(g/d

L) Mean Platelets

± SEM (K

/µL)

CAL-101 Treatment Improved CLL-Related Thrombocytopenia and Anemia

Improved thrombocytopenia: Patients with baseline thrombocytopenia (platelets<100,000/uL) had sustained improvement in mean platelet countsImproved anemia: Patients with baseline anemia (hemoglobin <11 g/dL) had sustained improvements in mean hemoglobin values

Slide 42

↑

ALT/AST

Pneumonia

Anemia ↓

Platele

t F&N

Neutro

penia

0

20

40

60

80

100

5%7%

18%

Grade 3-4 Adverse Events Occuring in ≥5%of Patients Regardless of Causality (N=55)

5% 7%

24%

Non-Hematological Hematological

Adverse Event Type

Inci

denc

e, %

• Grade 3-4 adverse events largely due to prior therapy or underlying CLL• No maximum tolerated dose or dose-limiting toxicities• No pattern of drug-related symptomatic adverse events

CAL-101 Has Been Well Tolerated in Patients with CLL Over Exposure Periods Exceeding One Year

Conclusions - CLL- FCR is standard of care- 17p- is the mother of all bad prognostic

factors• clinical trials• allo SCT

- No real standard of care for elderly patients• all regimens that are effective are also

toxic- Several promising new agents in clinical trials