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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