chronische lymphatische leukämie

Michael Hallek

Chronische lymphatische Leukämie

Themen

• Wandel der Prognose

• CLL8 Follow up

• CLLM1

• Neue Substanzen

– Ibrutinib

– CAL101

• CLL-Therapie 2013

• Studien der DCLLSG

Cancer 1981

Clinical Stage and Prognosis of CLL in 2001 (Barcelona data)

Years

0,0

0,5

1,0

4 8 12 16 20 24 28

Binet A

Binet B

Binet C

Binet A 15.5 y

Binet B 5.5 y

Binet C 3 y

Courtesy of Emili Montserrat et al.

Improved survival of advanced CLL – 1981 versus 2011

Binet stage A

Survival after 5

years: 87.8%

Binet stage B

Survival after 5 years:

74.0%

HR: 2.7 (95% CI: 2.042

– 3.484)

Binet stage C

Survival after 5 years:

72.8%

HR: 2.6 (95% CI: 1.927 –

3.582)

6

Overall survival and clinical stage updated results of several gCLLSG Trials, 2011 (N= 1948) Jasmin Bahlo, Natali Pflug Abstract 4.13, IWCLL 2011 Abstract book, Page S225

Binet stage A

Survival after 5 years:

87.8%

Binet stage B

Survival after 5 years: 74.0%

HR: 2.7 (95% CI: 2.042 – 3.484)

Binet stage C

Survival after 5 years: 72.8%

HR: 2.6 (95% CI: 1.927 – 3.582)

Kirsten Fischer, MD, Jasmin Bahlo, Anna-Maria Fink, MD, Raymonde Busch, Sebastian Böttcher, MD, Jiri Mayer, MD, Peter Dreger, MD, Christian Maurer,

Anja Engelke, Michael Kneba, MD, PhD, Hartmut Döhner, MD, Barbara F. Eichhorst, MD, Clemens-Martin Wendtner, MD, Stephan Stilgenbauer, MD,

and Michael Hallek, MD

435 EXTENDED FOLLOW UP OF THE CLL8 PROTOCOL, A RANDOMIZED PHASE-III TRIAL OF THE GERMAN CLL

STUDY GROUP (GCLLSG) COMPARING FLUDARABINE AND CYCLOPHOSPHAMIDE (FC) TO FC PLUS RITUXIMAB (FCR) FOR PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC

LYMPHOCYTIC LEUKEMIA (CLL)

54th Annual Meeting of the American Society of Hematology (ASH), Atlanta, December 10, 2012

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

C1 C2 C3 C4 C5 C6

Updated results of the 3rd analysis, July 2010 Median observation time 47,4 months.

Hallek et al., Lancet 2010; 376: 1164–74

Patient Characteristics (N=817)

Hallek M et al. Lancet 2010

FC (N=408) FCR (N=409)

Median age 61 61

Binet stage

A 5% 4%

B 63% 64%

C 31% 31%

Cytogenetic abnormalities

17p- 10% 7%

11q- 22% 27%

Mutational status

IGHV unmutated 63% 63%

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Progression free survival (PFS)* 2009

Hallek M et al.

Lancet 2010

HR 0.56,

95% CI 0.46 – 0.69

p < 0.0001

Median PFS

FCR 52 months

FC 33 months

Median observation time

3.2 years

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Progression free survival (PFS)* 2012

*Fischer K et al.

ASH 2012

Median observation time

5.9 years

Median PFS

FCR 57 months

FC 33 months

HR 0.59,

95% CI 0.5-0.7

p < 0.0001

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Binet stage A Binet stage B Binet stage C

Progression free survival (PFS)* 2012

*Fischer K et al.

ASH 2012

Median PFS

FCR not reached

FC 34 months

Median PFS

FCR 58 months

FC 32 months

Median PFS

FCR 43 months

FC 33 months

p < 0.0001 p = 0.07 p = 0.02

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Overall survival (OS)* 2009

Hallek M et al.

Lancet 2010

Median observation time

3.2 years

HR 0.66,

95% CI 0.475-0.914

p=0.013

FCR 85.0% alive

Median not reached

FC 80.0% alive

Median not reached

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Overall survival (OS)* 2012

*Fischer K et al.

ASH 2012

Median observation time

5.9 years

FCR 69.4% alive

Median not reached

FC 62.3% alive

Median 86 months

HR 0.68,

95% CI 0.535-0.858

p=0.001

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

** Courtesy of

Stilgenbauer S.

N Pts

alive,

%

Median

OS,

months

+12q 24 79.2 NR

13q- 105 81.0 NR

11q- 80 71.2 NR

Not** 80 62.5 NR

17p- 22 36.4 33.1

Overall survival (OS) in genetic subgroups of FCR patients*

2012

** not 17p- / 11q- /

+12q / 13q- acc. to

Döhner et al. NEJM

2000

Neutropenias

N % p value

FCR 136 34 < 0.0001

FC 83 21

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Toxicities during treatment (N=800)* 2009

Hallek M et al.

Lancet 2010

Infections

N % p value

FCR 103 25 0.2

FC 85 21

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Toxicities after end of treatment (N=800)* 2012

Late neutropenias

2 months after

end of treatment

N % p value

FCR 67 16.6 0.007

FC 35 8.8

Late neutropenias

12 months after

end of treatment

N % p value

FCR 16 3.9 0.7

FC 15 3.7

*Fischer K et al.

ASH 2012

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Toxicities after end of treatment (N=800)* 2012

Secondary

malignancies** N % p value

FCR 40 9.9 0.4

FC 48 12.1 0.4

Secondary

malignancies** N %

Solid tumor 46 5.7

Richters`

transformation 33 4.1

AML or MDS 12 1.5

*Fischer K et al.

ASH 2012

** Mean time to

onset, 2.4 years

(range 2.0 days –

7.4 years)

ADDITION OF RITUXIMAB TO

FLUDARABINE AND CYCLOPHOSPHAMIDE

Solid tumor N % p value

FCR 26 5.0 0.4

FC 20 6.6 0.4

Richters`

transformation N % p value

FCR 12 3.0 0.1

FC 21 5.3 0.1

AML or MDS N % p value

FCR 9 2.2 0.1

FC 3 0.8 0.1

Late toxicities after end of treatment (N=800)* 2012

*Fischer K et al.

ASH 2012

CLL8: DEFINITION OF HIGH RISK AFTER FCR

(= PATIENTS RELAPSING WITHIN 2 YEARS) (FINK ET AL., ASH AND IWCLL 2011)

• MRD levels >10-2 or

• MRD levels >10-4 -<10-2 combined with del(17p) or TP53 mutation or unmutated IGHV

CLL8 SHORT PFS IS RELATED WITH SHORT OS

Total n=143, HR n=40, LR n=103

median OS High risk 57 months Low risk not reached (HR 5.758, 95%CI: 2.799-11.844, p<0.0001)

Physically fit and previously untreated patients with treatment requiring disease

CLLM1-STUDY DESIGN

Firstline investigator‘s choice (FCR, BR, FR

(FC)

Arm A L-maintenance

133 patients

Arm B Placebo

67 patients

200 patients 2:1 randomization

Double blind

High Risk Of

Early PD

Follow up

Start Q3/2012~700

Screening patients

A phase 3, multicenter, randomized,

double-blind, placebo-controlled, study

of the efficacy and safety of lenalidomide

as maintenance therapy for high-risk

patients with chronic lymphocytic

leukemia following first-line therapy

25. Arbeitstreffen der DCLLSG, Petersberg, Königswinter 14. September 2012

Die Zukunft

Therapeutic modulation of B-cell receptor-dependent signaling in CLL

pre-BCR

Ig Ig

P P Lyn

CD19

PI3K P Syk

Btk P

PLC-

PLC- P

PIP2 IP3

DAG

Ca2+

IKK PKCβ

NF-κB ERK

Ibrutinib

CAL-101, GS-1101, idelalisib

189 The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR)

Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study

John C. Byrd, MD1, Richard R. Furman, MD2, Steven Coutre, MD3, Ian W. Flinn, MD, PhD4,5, Jan A. Burger, MD, PhD6, Kristie A. Blum, MD7*, Jeff P. Sharman, MD8*, Barbara Grant, MD9*, Jeffrey A. Jones, MD, MPH7, William G. Wierda,

MD, Ph.D.10, Weiqiang Zhao, MD PhD11*, Nyla A. Heerema, PhD11, Amy J. Johnson, PhD12, Anh Tran13*, Fong Clow, ScD14*, Lori Kunkel, MD15, Danelle F.

James, M.D13 and Susan O'Brien, MD16*

Patient cohorts

Cohort Population Dose mg/day

Group Size

1 relapsed/refractory 420 27

2 treatment-naïve; aged ≥ 65 years

420 26

3 relapsed/refractory 840 34

4 High Risk - relapsed or refractory

420 24

5 treatment-naïve; aged ≥ 65 years

840 5a

Patients in the 3 Cohorts Study Population

(N=116) Treatment naive , age >=

65yrs (cohort 2 & 5) Relapsed or

Refractory (cohort 1 & 3)

High risk (cohort 4)

Number of pts 31 61 24 Median f/u, months (range)

16.6 (1.4, 23.2) 17.3 (0.3, 22.4) 10.3 (1.1, 11.5)

Age (range) 71 (65, 84) 64 (40, 81) 68 (37, 82) Median # prior Tx (range)

0 4 (1,12) 4 (1,11)

Hgb <11 g/dl OR Plt <100,000 µL

61% 57% 63%

b2M >3 mg/L 8/ 31 (26%) 30/ 57 (53%) 9/ 23 (39%) IgVH unmutated (UM)

17/ 31 ( 55%) 50/ 58 (86%) 19/ 23 ( 83%)

del 17p 2/ 30 ( 7%) 21/ 57 ( 37%) 7/ 23 ( 30%) del 11q 1/ 30 ( 3%) 23/ 57 ( 40%) 8/ 23 ( 35%)

Treatment response Study

Population (N=116)

Treatment naive , age >= 65yrs (cohort

2 & 5)

Relapsed or Refractory

(cohort 1 & 3)

High risk (cohort

4)

Number of pts 31 61 24

IWCLL ORR (CR + PR)

71% 67% 50%

CR 10% 3% 0

PR 61% 64% 50%

PR with lymphocytosis

10% 20% 29%

SD 13% 5% 8%

PD 0 2% 4%

Not evaluable 6% 7% 8%

191 Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab

and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

(CLL): Results From a Phase I Study

Steven E. Coutre, MD1, John P. Leonard, MD2, Richard R. Furman, MD2, Jacqueline C. Barrientos, MD3, Sven de Vos, MD, PhD4*, Ian W. Flinn, MD,

PhD5, Marshall T. Schreeder, MD, MPH6*, Nina D. Wagner-Johnston, MD7, Jeff P. Sharman, MD8*, Thomas E. Boyd, MD9*, Nathan H Fowler, MD10, Leanne M.

Holes11*, Brian J. Lannutti, PhD11, Dave M. Johnson11, Langdon L Miller, MD11* and Thomas M. Jahn, MD/PhD11 *

Parameter

Regimen

GS-1101/R N=19

GS-1101/B N=17

GS-1101/BR N=15

Age, median [range], years 65 [40-84] 59 [38-81] 59 [48-76]

Sex, males/females, % 68/32 41/59 60/40

Patients with bulky adenopathy, % 58 65 67

Prior therapies

Median [range], n 2 [1-8] 3 [1-9] 4 [1-10]

Patients with prior R/B, % 100/47 94/41 100/40

Pts with refractory disease, % 37 71 47

GS-1101 doses

Pts at 100 mg/dose BID, n 4 4 n/a

Pts at 150 mg/dose BID, n 15 13 15

Patients

Parameter Regimen

GS-1101/R N=19

GS-1101/B N=17

GS-1101/BR N=15

GS-1101 minimum follow-up, weeks 64 40 48

Pts with Grade ≥3 adverse events, %

Anemia 5 35 20

Neutropenia 32 76 67

Febrile neutropenia 11 12 7

Thrombocytopenia 21 35 27

Infections 11 18 0

Pneumonia/pneumonitis 21 29 0

Rash 5 6 13

Diarrhea 5 12 7

Hepatic transaminase elevation 5 18 0

Side effects

Parameter Regimen

GS-1101/R N=19

GS-1101/B N=17

GS-1101/BR N=15

Pts with decrease in adenopathy, % 95 93 100

Max. decrease in adenopathy, median -78 -74 -85

Pts with lymph node response (decrease ≥50%), %

84 82 87

Best on-treatment response rate2, CRu3/PR/SD/PD/NE, %

0/78/11/11/0

0/82/6/0/12

7/80/0/0/13

Intent-to-Treat ORR, % 78 82 87

1-Year PFS, % 74 88 87

Response

Therapiestandard

2013

Ersttherapie der CLL

Stage 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 go No FCR

Yes Allo-SCT

Slow go

No CLB + anti-CD20-

Mab (R oder GA-101)

Yes Al, HD R or O

Rezidivtherapie der CLL Response to First-Line Therapy

Fitness Therapy

Standard Alternatives (trials)

Refractory or progress within 2 years

Go go Al-Dex, FA, FCRAllo SCT

Lenalidomide, BR, BR2

Combination with kinase inhibitors

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

Rezidiv

Max. 3

Vortherapien

Bendamustin

Lenalidomid

Rituximab

Rezidiv

Mind. 1

Vortherapie

Ibrutinib plus

Bendamustin

plus Rituximab

CLL2P CLLR1

Re

zid

ivth

era

pie

CLLR2

Rezidiv

Slow Go (oder

tox. KM-

Insuff.)

Rituximab plus

CAL101 vs.

Rituximab plus

Placebo

Go Go High

Risk

Lenalidomid-

Erhaltung

vs. Placebo

Go Go

Bendamustin

Lenalidomid

Rituximab

Go Go

CLLM1 CLL2P CLL13 P

rim

ärt

he

rap

ie

Binet C, behandlungsbedürftiges Binet B und A

Re

gis

ters

tud

ie

Risk of Early

Progression

Ibrutinib vs.

Placebo

Low Risk

w&w

CLL12

Binet A

CLL14

Slow Go

Nic

ht

behandlu

ngsbedürf

tig

CLLR3

Rezidiv

Max. 3

Vortherapien

FC-GA101 vs.

B-GA101 plus

GA101-

Erhaltung

Tra

nspla

nta

tion

Firstline und

Rezidiv

FCM+ Cam,

gefolgt von

Cam-

Erhaltung

T-PLL2

T-P

LL

CLLX4

Slow Go

Allo TX in

High Risk

Ofatumumab

in Induktion

und Erhaltung

Th

rom

bo

pe

nie

Bei Thrombo-

penien

Eltrombopag

0-3

Vortherapien

CLL2S Register

Langzeit-

beobachtung

CLL, SLL, B-

PLL, T-PLL,

LGL, Richter

Syndrom

W&W

Inactive Binet A Active disease

CLL12 CLLM1 CLL11

Go go

Slow go

Which is the best score to

define high risk?

yes no

CLB CLB + R

L W&W treat W&W

Disease (MRD) eradication Longer survival

Symptom control Longer disease-free survival

CLB + GA101

Trials of the GCLLSG, Generation 3.1: Risk, Stage and Fitness Adapted

BR/FR/FCR

MRD+ High risk

W&W

Inactive Binet A Active disease

CLL12 CLL13 CLL14

Go go Slow go Definition of a biological &

genetic risk score

High, very high

Low, intermed

iate B + GA101

treat W&W

Disease (MRD) eradication Longer survival

Long-term disease-control with minimal side effects

CLB + GA101

Trials of the GCLLSG, Generation 4.0: Risk, Stage and Fitness Adapted

BR BR+TKI

(B+)TKI GA101