9 stephen mulligan

STEPHEN MULLIGAN, MD

University of Sydney, Australia

Professor, Department of Hematology, University of Sydney,

Australia

Dr. Mulligan is the founding Chair of the CLL Global Consortium in

Australia. He is also the director of the Ruffle Pathology and

Hematology Program of the Institute of Molecular Biology

Science, the School of University of Sydney, and the founder and

president of the Chronic Lymphocytic Leukemia Australian

Research Consortium (CLLARC). Besides, he is a Fellow of the

Royal Australian College of Physicians (FRACP) as well as one of

the Royal College of Pathologists of Australia (FRCPA). Professor

Mulligan’s research interests include the mechanism of action of

purine nucleoside analogues, the ATM/p53 pathway and molecular

mechanisms of resistance, signaling pathway inhibitors in CLL, the

incidence and nature of small B-cell clones, and all aspects of

clinical and experimental CLL.

Breakthroughs in

Chronic Lymphocytic Leukaemia

2014 - 2015

Stephen Mulligan MB BS (Hons), Ph.D., FRACP, FRCPA

Royal North Shore Hospital, Sydney

Kolling Institute and University of Sydney

Laverty Pathology NSW, Sydney

CLL ARC

Australian

Research

Consortium

APHCON / BTG 2015, Beijing, 1st February, 2015

“Triple Revolution” in CLL:

1. “Immunochemotherapy [FCR] Revolution”

Median PFS extended from ~20 to 57 months

Median Time to 2nd Treatment almost a decade

- Still in progress …

2. “Molecular Revolution”

TP53, Notch-1, SF3B1, BRIC3

Key molecular lesions of CLL disease progression

3. “Non-genotoxic Novel Therapy Revolution”

B-cell receptor inhibitors, bcl-2 inhibitor, novel monoclonal antibodies

Breakthroughs in CLL 2014 (15)

1. FCR > BR

2. FCR in Fit Elderly

3. Obtinutuzumab + Cbl for comorbid CLL

4. Notch-1 – no benefit from rituximab over FC

5. Idelalisib + Rituximab in R/R CLL

6. Ibrutinib in R/R CLL

7. Ibrutinib resistance mechanisms

8. Double and triple BCR signal molecule inhibitors

9. Abt-199 / venetoclax – TLS resolved, MRD-negativity

10. PD-L1 / PD-1 in CLL

FRONTLINE CHEMOIMMUNOTHERAPY WITH

FLUDARABINE (F), CYCLOPHOSPHAMIDE (C), AND

RITUXIMAB (R) (FCR) SHOWS SUPERIOR EFFICACY IN

COMPARISON TO BENDAMUSTINE (B) AND RITUXIMAB

(BR) IN PREVIOUSLY UNTREATED AND PHYSICALLY FIT

PATIENTS (PTS) WITH ADVANCED CHRONIC

LYMPHOCYTIC LEUKEMIA (CLL):

FINAL ANALYSIS OF AN INTERNATIONAL, RANDOMIZED

STUDY OF THE GERMAN CLL STUDY GROUP (GCLLSG)

(CLL10 STUDY)

56th ASH Annual Meeting San Francisco, December, 2014

Eichhorst B, Fink A-M, Busch R, Kovac G, Maurer C, Lange E, Köppler H, Kiehl

M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M,

Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner C-M, Klapper

W, Kreuzer K-A, Stilgenbauer S, Boettcher S, Hallek M on behalf of an

international group of investigators and of the CLLSG

CLL10 STUDY: FCR VS BR IN FRONT-LINE

Design

Non-Inferiority of BR in comparison to FCR for PFS:

HR (λ BR/FCR) less than 1.388

Randomization

Patients with untreated, active CLL without del(17p) and good physical fitness

(CIRS ≤ 6, creatinine clearance ≥ 70 ml/min)

FCR Fludarabine 25 mg/m² i.v., days 1-3

Cyclophosphamide 250 mg/m², days 1-3,

Rituximab 375 mg/ m2 i.v. day 0, cycle 1

Rituximab 500 mg/m² i.v. day 1, cycle 2-6

BRBendamustine 90mg/m² day 1-2

Rituximab 375 mg/m² day 0, cycle 1

Rituximab 500 mg/m² day 1, cycle 2-6


Patients´ characteristics

Baseline characteristics FCR

n=282

BR

n=279

p value

Median age (y) 61.0 62.1 0.131

Age > 65 30.5% 38.7% 0.042

Male 71.3% 74.2% 0.450

Median time since

diagnosis (months)

21.6 24.6 0.846

ECOG = 0 64.1% 64.1% 0.194

CIRS, median 2 2 0.489

Mean number of cycles 5.27 5.41 0.022


Patients´ characteristics: prognostic factors

Baseline prognostic

factors

FCR

n=282

BR

n=279

p value

Binet stage A 22.3% 22.2%

0.846Binet stage B 37.3% 38.4%

Binet stage C 40.4% 39.4%

IGHV Unmutated 55.3% 67.8% 0.003

11q deletion 24.1% 22.6% 0.691

Trisomy 12 12.4% 12.2% 1.000

13q deletion 55.0% 52.7% 0.612

s- TK (U/L) > 10.0 72.8% 72.6% 1.000

s- β2m (mg/l) > 3.5 30.9% 38.1% 0.086

CLL10 STUDY: FCR VS BR IN FRONTLINE

ITT Best Response according to IWCLL

Response FCR (%)

n=282

BR (%)

n=279

p value

CR (CR + CRi) 39.7 30.8 0.034

CR 35.1 30.4

CRi 4.6 0.4

PR 55.7 64.9

ORR 95.4 95.7 1.0

SD/PD 2.2 2.2

Missing response 2.5 2.1


ITT Progression-free survival = Primary endpoint

P < 0.001HR = 1.626 =

> 1.388

Median PFS

FCR 55.2 months

BR 41.7 months


PFS in IGHV matched population (n=398: FCR= 201; BR =197)

P = 0.005

HR = 1.565 =

> 1.388

Median PFS

FCR NR

BR 43.1 months


Progression-free survival by age group

Patients ≤ 65 years: P < 0.001

FCR 53.6 months BR 38.5 months

Patients > 65 years: P = 0.170

FCR not reached BR 48.5 months


Conclusion

Final analysis shows inferiority of BR versus FCR with regard to

PFS and CRR.

FCR is remains standard therapy in fit patients.

BR may be considered in fit, but elderly patients as alternative.

BR is associated with lower rates of neutropenias and severe

infections in elderly patients.

The safety and tolerability of

oral fludarabine, ± oral cyclophosphamide and

intravenous rituximab therapy in previously

untreated patients with CLL aged ≥65 years

– FINAL analysis from the

Australasian Leukaemia and Lymphoma Group (ALLG) and

CLL Australian Research Consortium (CLLARC) CLL5 Study.

Stephen P Mulligan, Devinder Gill, Paul Turner, William Renwick,

Maya Latimer, Leanne Berkahn, David Simpson, Phillip Campbell,

Rosemary Harrup, Cecily Forsyth, Melanie Sulda, Giles Best,

Bryone Kuss and Gavin Cull for the CLLARC and ALLG.


ALLG CLL5 / OFOCIR trial

CLL ARC

Australian

Research

Consortium

Regimen

Oral

Fludarabine

Oral

Cyclophosphamide

IV

Rituximab

Cohort 1

“FR5”24 mg/m2

Days 1-5

Cycle 1: 375mg/m2 D0

Cycles 2-6: 500mg/m2 D1

Cohort 2

“FCR3”

24 mg/m2

Days 1-3

150 mg/m2

Days 1-3



Cohort 3

“FCR5”*

24 mg/m2

Days 1-5

150 mg/m2

Days 1-5



*Oral FC in FCR5 identical to oral FC dose in UK CLL4 Study, & dose equivalent to IV FCR*Catovsky et al., Lancet, 370: 230-239; 2007

ALLG CLL5 / OFOCIR trial

CLL ARC

Australian

Research

Consortium

Haematologic and non-Haematologic Toxicity:

Dose delay and stopping rules

Toxicity Grade Dose Delay or Stopping Rule

Grade 1 or 2Continue Fludarabine / cyclophosphamide at prescribed dose

Supportive care per local guidelines and investigator discretion

Grade 3 or 4 Hold next cycle until RESOLVES to ≤ Grade 2

CONTINUE therapy with SAME dose (i.e. no dose reduction)

Grade 3 or 4

If FAILS TO RESOLVE to ≤ Grade 2 by 2 WEEKS,

or RECURS in subsequent cycles → OFF STUDY Then treat as per physician discretion.

End of Recruitment

120 recruited from 29 centres in Australia and New Zealand Median age Age at randomisation (in years)Mean 71.7Median 71Range 65 – 83

Age range No. %65 – 69 years 42 35.9%70 – 74 years 45 38.5%75 – 79 years 21 17.9%80 – 84 years 9 7.7%

Binet stage at registration

A 20 17.1%

B 55 47.0%

C 42 35.9%

Recruitment of 120 pts was completed in July 2012.

117 fulfilled eligibility, 1 had no treatment or follow-up with remaining

cohort to 116 patients for analysis

Responses

Final Pathological Staging 2 months Post-Rx or at Rx end

Treatment armTotal

(n=116)FR5 FCR3 FCR5

(N=37) (N=41) (N=38)

BM confirmed CR 27% 44% 45% 39%

CR 9 (24% ) 13 (32% ) 8 (21% ) 30 (26% )

CR-i 1 (3% ) 5 (12% ) 9 (24% ) 15 (13% )

Total MRD Negative(including PB MRD-neg CRu and CRi/u)

14 (38% ) 21 (51% ) 30 (79% ) 65 (56%)

nPR 11 (30% ) 13 (32% ) 3 (8% ) 27 (23% )

PR 10 (27% ) 5 (12% ) 4 (11% ) 19 (16% )

SD 1 (3% ) 1 (2% ) 0 (0% ) 2 (2% )

Progressive Disease (PD) / early death 1 (3% ) 1 (2% ) 1 (3% ) 3 (3% )

Overall Response Rate (ORR - CR, CR-i, CR-u, CR-i/u, nPR, PR)

35

(95% )

39

(95% )

37

(97% )

111

(96% )

Responses

ORR was high in all 3 arms (95-97%)

MRD-negative rates were significantly higher with

FCR5 (79%) FCR5 (p<0.001) vs FCR3 and FR5

(FCR3 vs FR5 NSS)

PFS (p=0.672) and OS (p=0.164) between treatment

arms was not statistically significant (NSS).

At 12 months PFS 83% and OS 95%

At 18 months PFS 69% and OS 90%

At 18 months, PFS and OS by treatment arm was NSS

PFS FR5 65% FCR3 75% FCR5 65%

OS 97% 90% 83%

Toxicity

Grade 3+ Adverse Events

by Treatment Arm

Treatment armTotal

(n=116)FR5 FCR3 FCR5(N=37) (N=41) (N=38)

Haematological 15 (41% ) 26 (63% ) 29 (76% ) 70(60%)

Neutropenia 14 (38% ) 20 (49% ) 24 (63% ) 58 (50% )

Febrile Neutropenia / Infection 5 (14% ) 6 (15% ) 13 (34% ) 24 (21% )

Thrombocytopenia 2 (5% ) 5 (12% ) 12 (32% ) 19 (16% )

Anaemia 3 (8% ) 6 (15% ) 6 (16% ) 15 (13% )

Haemolytic Anaemia 0 (0% ) 2 (5% ) 3 (8% ) 5 (4% )

At least 1 grade 3+ AE 21 (57%) 34 (83%) 35 (92%) 90(78%)

Early cessation

due to toxicity2 (5.6%) 1 (2.4%) 13 (34%) 16 (14%)

Toxicity

Toxicity was lower with FR5 compared to FCR3 and FCR5

(p=0.004) (FCR3 vs FCR5 NSS).

Dose delay occurred in 43pts (37%):FR512 (32%), FCR3 14 (34%), FCR517 (44%) (p=0.653)

Early cessation due to toxicity more common with FCR5

(p<0.001).

11/13 pts stopping early due to toxicity received ≥3 cycles of therapy

(mean 3.5)

Cyclophosphamide with FR adds toxicity but improves CR rate

Conclusions

Oral F(C)R therapy appears safe and well tolerated in

fit CLL patients aged ≥65 years requiring 1st-line therapy

Toxicity - mostly haematological and manageable

Response rates very high - 96% ORR

No association between toxicity and CIRS 0–6 or age.

Full dose FCR is highly effective with higher cessation

due to toxicity but higher CR: ?dose intensity effect?

Novel therapies in CLL

Agent Development Phase Sponsor

CD20 mAb

Obinutuzumab Phase III Roche

BTK inhibitors

Ibrutinib

CC-292

ONO-4059

ACP-196

Registration Phase III

Phase Ib

Phase I

Pending Phase II

Pharmacyclics, Inc.

Celgene Corporation

Ono Pharmaceutical

Acerta

PI3KΥ/δ inhibitors

Idelalisib

GS-9820

IPI-145

AMG 319

TGR-1202

SAR245408 (XL147)

Registration Phase III

Phase I

Pending Phase III

Phase I

Phase I

Phase I

Gilead Sciences

Gilead Sciences

Infinity Pharmaceuticals

Amgen

TG Therapeutics

Sanofi

BCL-2 inhibitor

ABT-199 Phase Ib AbbVie/Roche

Obinutuzumab + Chlorambucil

1st line CLL with comorbidities

G-Clb (n=333)

%

R-Clb (n=329)a

%

Response rate

ORR 78 65

p <0.0001

CRb 21 7

PRc 58 58

SD 5 15

PD 4 11

Not evaluabled 13 9

CLL11 – G+Cbl End-of-treatment response

a Assessment not reached by data cut-off in 1 patient in R-Clb arm; as assessed by iwCLL criteria 3 months after end of treatmentb Confirmed by imaging and bone marrow, and includes incomplete CRc Includes nodular PRd Due to missing data or withdrawal from study treatment prior to response assessment

ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease Slide Dr Valentin Goede

BCR SIGNAL INHIBITION IN CLL

Nat Rev Immunol 2:945

Ibrutinib

Idelalisib

Pattern of Response:

Blood Lymphocytes vs Lymph Nodes

SPD = sum of products of lymph node dimension

SPD

0 1 2 3 4 5 6 7 8 9 10 11

550

450

350

250

150

50

-50

ALC

Month Month

-100

-75

-50

-25

0

25

Me

an

Pe

rce

nt C

ha

ng

e fro

m B

ase

line

0 1 2 3 4 5 6 7 8 9 10 11

Slide Dr Susan O’Brien

Significant lymphocytosis at same time as dramatic nodal response

American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 28

Response Over Time

21

42

58

6773

7780

83 85

4842

29

2015

12 106 5

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18 21 24 27 30 33 36

Pat

ien

ts W

ith

Re

spo

nse

* (%

)

Months From Initiation of Study Treatment

CR/PR

PR-L

Best response to ibrutinib improves over time

Median time to first response:

1.9 months (range, 1.4–23.2)

Median time to best response:

7.3 months (range, 1.7–31.8)

92% of patients who achieved a PR-L converted to better response

*Cumulative response as assessed by investigator

*Ibrutinib is not licensed for use in Australia

3 months

12 months

36 months

36 months

Prolonged lymphocytosis on ibrutinib

All patients on PCYC-1102-CA Study n=85

Lymphocytosis in 77%;

Median time to normalisation 6.2 mo

At 12 months, 17 patients (20%) still had a lymphocytosis

- Active downstream signaling, but Btk still blocked

- No adverse outcomes

PR-L

CR or PR

*Ibrutinib is not licensed for use in Australia

Idelalisib + Rituximab in R/R CLL

Study 116: Randomized, Double-Blind, Placebo-Controlled

Extension Single-Agent Therapy

Extension Study 117

RandomizedCombination Therapy

ContinuingSingle-Agent Therapy

Primary Study 116

Arm A(N=110)

Arm B(N=110)

Idelalisib (150 mg BID)

Placebo (BID)

Rituximab (6 months)

Rituximab (6 months)

Screening



Rituximab administration• 375 mg/m2, then 500 mg/m2 Q2W x 4,

then 500 mg/m2 Q4W x 3

Clinical Endpoints• Primary: PFS as assessed by IRC• Events: Disease progression or death • Secondary: ORR, LNR, OS

Dise

aseP

rogre

ssion

Planned interim analyses at 50% and 75% of events

Slide Dr Richard Furman

0 2 4 6 8 1 0 1 2 1 4 1 6

0

2 5

5 0

7 5

1 0 0

T im e (m o n th s )

Pro

gre

ss

ion

-fre

e

su

rviv

al

(%)

ID E L A + R it u x im a b

P la c e b o + R it u x im a b

M e d ia n P F S = 5 .5 m o n t h s

M e d ia n P F S : n o t r e a c h e d

H R = 0 .1 5

9 5 % C I (0 .0 8 , 0 .2 8 )

p < 0 .0 0 0 1

6 9 4 4 3 4 3 0 1 4 6 2 0ID E L A + R : 1 1 0

6 2 3 0 1 8 1 3 6 1 1 0P la c e b o + R : 1 1 0

S u b je c ts a t r is k , n

Primary Endpoint: Progression-Free Survival

Slide Dr Richard Furman

Ibrutinib vs Ofatumumab in R/R CLL

American Society of Clinical Oncology 2014, PCYC 1112 , Byrd et al.

Stratification according to:– Disease refractory to purine analog chemoimmunotherapy (no response or relapsed

within 12 months)– Presence or absence of 17p13.1 (17p del)

At time of analysis, median time on study was 9.4 months

34

RESONATE™ Phase 3 Study Design

R

A

N

D

O

M

I

Z

E

Oral ibrutinib 420 mg

once daily until PD or unacceptable toxicity

n=195

IV ofatumumab initial dose of 300 mg followed by 2000

mg x 11 dosesn=196

1:1

Patients with previously

treatedR/R

CLL/SLL

PD, progressive disease.

Cross over to ibrutinib 420 mg once daily after IRC

confirmed PD (n=57)

American Society of Clinical Oncology 2014, PCYC 1112 , Byrd et al. 35

Progression-Free Survival

0 3 6 9 12

195 183 116 38 7196 161 83 15 1 0

150

10

20

30

40

50

60

70

80

90

100P

rogr

ess

ion

-Fre

e S

urv

ival

(%

)

No. at riskIbrutinib:

Ofatumumab:

Months

IbrutinibOfatumumab

Ofa IbrutinibMedian time (mo)

8.08 NE

Hazard ratio

0.215

(95% CI) (0.146-0.317)

Log-rank P value

< 0.0001

Ibrutinib significantly prolonged PFS with the median not reached versus 8.1 months for ofatumumab

This represents a 78% reduction in the risk of progression or death in patients treated with ibrutinib compared with ofatumumab

Richter’s transformation was confirmed in 2 patients on each arm. An additional patient on the ibrutinib arm experienced disease transformation to prolymphocytic leukemia

American Society of Clinical Oncology 2014, PCYC 1112 , Byrd et al.

0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n-F

ree

Su

rviv

al (

Pro

po

rtio

n)

0 6 12 18 24 30 36 42

Months From Initiation of Study Treatment

36

Progression-Free Survival by Cytogenetics (FISH) in Relapsed/Refractory Population

Del17p Del11q No del17p/11q

30-monthPFS 45.9% 74.2% 89.0%

(95% CI) (25.0–64.6) (53.3–86.8) (69.0–96.4)

Median PFS 28.1 months Not reached Not reached

del17p

del11q

No del17p or del11q

+ Censored

Ibrutinib resistance – Btk and PLCg2 mutations

Andrew J SteeleSouthampton, UK

The dual PI3K/mTOR inhibitor PF-04691502 induces substantial apoptosis in chronic lymphocytic

leukaemia cells in vitro and prolongs survival in the Eµ-TCL1 mouse model


DUAL AND MULTIPLE MOLECULAR

BCR INHIBITORS

PF-04691502 induces apoptosis of CLL cells

Median IC50 - 0.65µMMean IC50 - 0.96µM

NA

IDE

L ()

EV

E (

mT

OR

)

IDE

L +

EV

E

PF

-04691502

0

2 0

4 0

6 0

8 0

1 0 0

% o

f C

on

tro

l (P

I/A

nn

ex

in V

-v

e c

ell

s)

p = 0 .0 3

p < 0 .0 2

p < 0 .0 2

Bcl-2 Family Regulates Apoptosis

– ABT-199 / VENETOCLAX

Conformational

changeOligomerization

Small molecules that disrupt

these interactions

induce apoptosis

BH3

Bax

Bak

Bax

Bak

Bax

Bak

Bax

Bak

Apoptosis

MOMP

Cyt C

Bax

Bak

Death signals

Bim, Puma, Bad,

Bid, Bik, Noxa,

Hrk, Bmf

Bcl-2, Bcl-xL,

Bcl-w, Mcl-1, A-1

Caspaseactivation

Bcl-2

like

Abt-199 (Venetoclax) Adverse Events

All Grades

≥20% of pts

N=105

n (%)

Diarrhea 42 (40)

Neutropenia 38 (36)

Nausea 37 (35)

Upper respiratory tract infection 35 (33)

Fatigue 27 (27)

Cough 21 (20)

Grades 3/4

≥ 5% ptsn (%)

Neutropenia 35 (33)

Anemia 10 (10)

Febrile neutropenia 7 (7)

Thrombocytopenia 7 (7)

Hyperglycemia 7 (7)

Tumor lysis syndrome (TLS) 7 (7)

Hypokalemia 5 (5)

ABT-199 Monotherapy in Rel / Ref CLL Seymour et al. EHA 2014, Abstract S702

ABT-199 (Venetoclax) Dosing SchemaDaily ABT-199 doses increased weekly to the designated cohort dose (DCD)

Initial Ramp-Up Schema: Dose Escalation

Ramp-Up Schema: Expanded Safety Cohort

* 3 patients (1 each in cohorts 2, 3, & 5) received ABT-199 20 mg as initial dose** Step-up doses range from 100 to 400 mg# DCD ranges from 150 to 1200 mg


Objective Responses of ABT-199 (Venetoclax)

ResponsesAll

n (%), n = 78del (17p)

n (%), n = 19F-Refractoryn (%), n = 41

IGHV Unmutatedn (%), n = 24

Overall response 60 (77) 15 (79) 31 (76) 18 (75)

Complete response (CR/CRi)# 18 (23) 5 (26) 9 (22) 7 (29)

Partial response* 42 (54) 10 (53) 22 (54) 11 (46)

Stable disease 10 (13) 2 (11) 7 (17) 2 (8)

Disease progression 2 (3) 1 (5) 1 (3) 2 (8)

D/C Prior to assessment+ 6 (8) 1 (5) 2 (5) 2 (8)Some patients may have more than one high risk marker. #4 patients have CRi; +D/C = discontinued, first assessment at 6 weeks*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks)

• As of April 9, evaluable patients (n=78) had 2 CT scans, performed approximately 8 weeks apart, n=55 from dose escalation and n=23 from the safety expansion cohort

• A total of 26 patients are not yet evaluable in the SE cohort (12 patients had a PR at their first scan, 14 patients have not yet reached their first assessment)

• The median duration of response has not yet been reached based on current patient enrollment numbers.


Some patients MRD-negative

Progression Free Survival (PFS) at 400 mg or Higher

• Median PFS for patients treated at or above 400 mg has not yet been reached,(median follow-up of 5.3 months, range [0.03 – 22])

• As of April 9, 2014, the median PFS for all patients is approximately 18 months


Genetics from CLL8 trial

Stilgenbauer, Blood, 22nd May, 2014, 123: 3247

Long term remissions after FCR chemoimmunotherapy

Progression free survival (PFS) in IGHV mutated / unmutated patients

Fischer K et al. iwCLL 2013

Median observationtime

5.9 years

Median PFS

FCR IGHV mutated

Not reachedFC IGHV mutated

42 monthsFCR IGHV unmutated

42 monthsFC IGHV unmutated

29 months

FC vs. FCRHR 2.12,

95% CI 1.464 - 3.063

Novel Genetic Markers in CLL8

1. TP53 and SF3B1 strongest predictive markers

2. Notch1 – FC with rituximab fails to improve

response and survival

Stilgenbauer et al., Blood, 2014, 123: 3247

PD-L1 Immune Checkpoint Blockade Prevents

Immune Dysfunction and Leukemia Development in

a Mouse Model of Chronic Lymphocytic Leukemia

Bola Hanna

PhD student

German Cancer Research Center

December 8th 2014


PAge5025.02.2014 |

Author

Division

Myeloid

cells PD-L1

PD-L1

PD-1

Inhibitory ligands(Ramsay et al. Blood 2012)

Chronic activation(Riches et al. Blood 2013,

Brusa et al. Haematologica 2013)

MDSCs and TAMs(Jitschinet al. Blood 2014,

Hanna et al. manuscript in preparation)

PD-1/PD-L1 axis as key inducer of

CLL-associated immune defects

CLL

cells

T cells

(Topalian at al. NEJM, 2012)

Significant anti-tumor response of PD-1

blocking antibodies in solid tumors

PAge5125.02.2014 |

Author

Division

PD-L1 blockade controls disease in

blood and secondary lymphoid organs

isotype

aPD-L1

all graphs show median with IQR, *** p<.0001, ** p<.001, * p<.05

Spleen weight and tumor load

Tumor load in PB and other lymphoid organs

Prevents

T-cell subset changes

CD4:CD8 ratioRestores T-cell cytokine production

and proliferation levels

Prevents “exhaustion” phenotype

and restores T-cell functions

??Therapy for immune failure and autoimmunity in CLL??

The distinct compartments of CLL

Peripheral Circulation

• Mainly quiescent (non-

proliferating cells)

Lymph node microenvironment• Receive survival signals

• Proliferative

Lymph node microenvironment

The biology underlying CLL cell survival/proliferation

Targeting the biology of CLL cell proliferation

• Idelalisib

• HDAC Inhibitors

• Syk/Akt

Inhibitors

Ibrutinib

CAR-T

cells

Interference

Imids

Anti-CD40 Abs

CXCR4 Antagonists

Invitation to Sydneyiw CLL 2015

6-9th September, 2015

iwCLL Sydney 2015

6th September Young Investigator Meeting

6th September CLL Education Forum

7-9th September iwCLL Program

Day 1 The B-Cell Receptor

Day 2 Patient related issues

Day 3 CLL cell related issues

CLL in Asia Session

Invitation to Sydneyiw CLL 2015

6-9th September, 2015

Documents

9 stephen mulligan