when to consider cit in first line therapy of cll? · when to consider cit in first line therapy of...
TRANSCRIPT
Disclosures
Speaker’s Bureau: Janssen, Roche, Takeda, Abbvie, BMS
Educational Support: Janssen, Takeda, Roche, Abbvie
Advisory Board: Janssen, Abbvie, Astra Zeneca
Research: Janssen, Millenium, Merck, Alnylam
Slides will be presented in English for bettercomprehension of invited speakers
CIT has proved value in CLL
• Hallek et al, 2010: – CLL 8 Ph3 trial with 817 patients randomized between FC x FCR for 6
cycles
– Exclusion criteria: ClCr<70, ECOG>1
Hallek M et al, Lancet 2010
Not everyone benefits from CIT in CLL8
No Benefit in del17p
Fischer K, et al. Blood. 2016;127:208-215.
X
Not everyone tolerated CIT in CLL8
Hallek M et al, Lancet 2010
26% did not received planned 6 cycles47% needed reduction >10%
Seminal Study of FCR in Treatment-Naive Pts With CLL
Thompson PA, et al. Blood. 2016;127:303-309.
1614120 2 4 6 8 10
100
75
50
25
0
PF
S (
%)
Yrs
IGHV mutated
IGHV unmutated
n Pts Tested, %
88
4
1
126
5
9
P < .0001
CIT x IGVH Status – CLL8
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
CLL10 Study: FCR VS BR in Front-line
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)
FCRFludarabine 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
Eichhorst B et al, Lancet Oncol 2016
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
Eichhorst B et al, Lancet Oncol 2016
CLL10 Study: FCR VS BR in Front-Line
ITT Progression-free survival = Primary endpoint
PFS 41·7 months vs 55·2 months HR 1·643 [90·4% CI 1·308–2·064] p=0·0003
Eichhorst B et al, Lancet Oncol 2016
CLL10 Study: FCR VS BR in Front-Line
PFS in IGHV Status(n=398: FCR= 201; BR =197)
Eichhorst B et al, Lancet Oncol 2016
IGHVm: FCR NR vs 55·4m BR (p=0·089)
IGHVunm: FCR 42·7m vs 33·6m BR (p=0·017)
CLL10 Study: FCR VS BR in Front-line
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
Eichhorst B et al, Lancet Oncol 2016
Can Ibrutinib overcome the impactof IGHV Status?
14
15
Who benefits from FCR?
Sharman et al: <20% of patients satisfy age, renal clearance and fitness profile of inclusion criteria from CLL8 and CLL10, DESPITE molecular features that exclude FCR as Treatment
Young fit patients with active CLL- Age <65- no del17p- IgHV mutated patients
7% estimate byOpat et al
Eligibility:• Previously untreated CLL • Requires treatment • Age <70• ECOG 0-2• CrCL >40 • Able to tolerate FCR• No deletion 17p by FISH
(Planned Accrual: 519)
Ran
do
miz
atio
n 2
:1
Dis
ea
se
Pro
gre
ss
ion
Study Design E1912
CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; FISH, Fluorescence in situ hybridization; IV, intravenous; IWCLL, International Workshop on Chronic Lymphocytic Leukemia; ITT, intent-to-treat: PO, oral.
Primary Endpoint: PFSSecondary Endpoint: OS
FCR (n=175)
Fludarabine (25 mg/m2 IV, D1-3, Cycles 1-6)Cyclophosphamide (250 mg/m2 IV, D1-3, Cycles 1-6 )Rituximab (50 mg/m2 IV, D1C1, 325 mg/m2
IV, D2C1,500 mg/m2 IV, D1 Cycles 2-6)
IR (n=354)
Ibrutinib (420 mg PO daily) until disease progression
C2-7: Rituximab (50 mg/m2 IV, D1C2, 325
mg/m2 IV, D2C2,500 mg/m2 IV, D1 Cycles 3-
7
Stratification: • Age <60 yrs. vs >/= 60 yrs• ECOG 0, 1, vs. 2• Stage 3 /4 vs 1/ 2• Del11q vs other
Median follow-up
33.6 m (0 -51.1)
Shanafelt T, et al. ASH 2018.
*Tested in 437 (82%) patients.
Baseline characteristicsIR
(n=354)FCR
(n=175)Total
Age, median, years 58 57 58
Age ≥60, % 41.0 40.0 40.6
Female, % 33.3 31.4 32.7
ECOG=0, % 63.8 62.3 63.3
Rai stage 0, % 3.1 5.1 3.8
Rai stage I-II, % 52.8 53.7 53.1
Rai stage III-IV, % 44.1 41.1 43.1
FISH, %
11q deletion 22.0 22.3 22.2
Trisomy 12 19.8 15.4 18.3
13q deletion 34.2 33.1 33.8
B2M >3.5 mg/L, % 51.9 48.0 50.6
IGHV Unmutated*, % 75.0 61.7 71.1
Baseline characteristics of the studied cohort
Shanafelt T, et al. ASH 2018.
IR in front line reduces in 65% the risk of DP or death compared to FCR
0 1 2 3 4
0.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
ba
bili
ty
IR (37 events/ 354 cases)
FCR (40 events/ 175 cases)
Number at risk
354 339 298 148 16
175 147 112 50 0
HR = 0.35 (95% CI 0.22−0.56)
One−sided p = 1.62 ´ 10-6
Shanafelt T, et al. ASH 2018.
In unmutated IGHV, IR reduces in 74% the risk of DP or death compared to FCR
0 1 2 3 40.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
ba
bili
ty
IR (8 events/ 70 cases)
FCR (6 events/ 44 cases)
Number at risk
70 67 59 25 2
44 38 31 18 0
HR = 0.44 (95% CI 0.14−1.36)
One−sided p = 7.08 ´ 10-2
0 1 2 3 4
0.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
ba
bili
ty
IR (20 events/ 210 cases)
FCR (21 events/ 71 cases)
Number at risk
210 203 177 90 12
71 64 43 14 0
HR = 0.26 (95% CI 0.14−0.50)
One−sided p = 7.51 ´ 10-6
Shanafelt T, et al. ASH 2018.
IGHV Unmutated IGHV Mutated
Front line treatment with IR reduces in 82% the risk of death
IGHV Unmutated IGHV MutatedIntent to Treat
0 1 2 3 4
0.0
0.2
0.4
0.6
0.8
1.0
Years
Pro
ba
bili
ty
IR (4 events/ 354 cases)
FCR (10 events/ 175 cases)
Number at risk
354 347 318 166 18
175 155 130 58 1
HR = 0.17 (95% CI 0.05−0.54)
One−sided p = 3.22 ´ 10-4
HR = 0.17 (95% CI 0.05-0.54)
One sided p<0.0003
Shanafelt T, et al. ASH 2018.
Ibrutinib and rituximab were well tolerated in patients ≤70 years of age
Grade 3-5 adverse events (AEs)IR (%)
(n= 352)FCR (%)(n=158)
P Value
Neutropenia 22.7 43.7 <0.001
Anemia 2.6 12.0 <0.001
Thrombocytopenia 2.9 13.9 <0.001
Any Infection 7.1 19.0 <0.001
Infection 5.4 8.2 0.24
Neutropenic fever 2.3 15.8 <0.001
Atrial fibrillation 2.9 0.0 0.04
Bleeding 1.1 0.0 0.32
Hypertension 7.4 1.9 0.01
Diarrhea 2.6 0.6 0.19
Any Grade ≥3 AE 58.5 72.1 0.004
Shanafelt T, et al. ASH 2018.
Causes of Death in ECOG ACRIN
Shanafelt T, et al. ASH 2018.
Cause of Death IRN=354
FCRN=175
CLL 1 6*
Unexplained/unwitnessed 1 2
Other: Acute/chronic respiratoryfailure, lung adenocarcionoma
1 0
Acute respiratory failure 1 0
Metastatic Colon Cancer 0 1
Drug Overdose 0 1
Total 4 10
What about unfit patients?
Previously untreated
CLL patients with
comorbidities
(CIRS score > 6 and/or
CrCl < 70 mL/min)
(N = 780)
Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles
(n = 118)
Obinutuzumab 1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles
(n = 333)
Rituximab 375 mg/m2 IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles
(n = 330)
28-day cycleRandomized 1:2:2
Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014 [Epub ahead of print]
CIT as standard therapy: CLL11
CLL11 Trial:
Obinutuzumab + Chl v Rituximab + Chl
Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014 [Epub ahead of print]
CLL11 Trial:
Obinutuzumab + Chl v Rituximab + Chl
Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]
CLL11 Update EHA
CLL11 – EHA 2018
Resonate-2
Burger JA, et al. N Engl J Med. 2015
PFS Ibr vs Chl: Resonate-2
Resonate-2: OS
Study Design ALLIANCE
Key Eligibility Criteria
• ≥65 years old
• Previously untreated CLL
• Requiring treatment
• ECOG PS 0-2
Primary Endpoint: PFS
Secondary Endpoints: OS and safety
Bendamustine* + Rituximab (n=183)
B: 90 mg/m2 D1-2 of C1-6
R: 375 mg/m2 C1D0 then 500 mg/m2 D1 of
C2-6
Ra
nd
om
ize
d 1
:1:1
Ibrutinib (n=182)
420 mg daily until disease progression ]]
Ibrutinib + Rituximab (n=182)I: 420 mg daily until disease progression
R: 375 mg/m2 weekly x 4 starting C2D1, thenD1 of C3-6
Disease
progression†
N=547
*At the investigator’s discretion, the cycle 1 dose of bendamustine
could be 70 mg/m2.
†Patients on BR who progressed could cross
over to single-agent ibrutinib within 1 year after
progression. (n=30 crossed over to single-agent
ibrutinib)
Stratification:
• Rai stage (intermediate vs high)
• ZAP70 methylation (unmethylated [<20%] vs methylated
[≥20%])
• Del(17p13.1) or del(11q22.3) on local FISH analysis
(absent vs present) Woyach J, et al. ASH 2018.
Baseline characteristics of the studied cohort
Woyach J, et al. NEJM 2018.
PFS: Ibrutinib-containing regimens x BR
PFS was significantly longer with I vs BR HR 0.39, 95% CI: 0.26-0.58
(P <0.001)
PFS was significantly longer with IR vs BRHR 0.38, 95% CI: 0.25-0.59
(P <0.001)
No significant difference in PFS between the IR and
I HR 1.00, 95% CI: 0.62-1.62
(P = 0.49)
Arm C (IR)Arm B (I)
Arm A (BR)
% A
live a
nd
Pro
gre
ssio
n-F
ree
0 6 12 18 24 30 36 42 48 52
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 52
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
Censor
32/170Arm C (IR)
34/178Arm B (I)
68/176Arm A (BR)
Events/TotalArm
Patients-at-Risk176 140 129 122 103 88 57 26 11 0178 165 154 147 136 120 78 45 22 0170 159 145 138 132 115 74 40 20 0
Arm N 24 Month Estimate
BR 176 74% (95% CI: 66-80%)
I 178 87% (95% CI: 81-92%)
IR 170 88% (95% CI: 81-92%)
Rituximab does not improve PFS over ibrutinib alone in the frontline setting for older CLL patients
Woyach J, et al. ASH 2018.
PFS: Ibrutinib-containing regimens vs BR: Subgroup analysis
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)Mehtylated: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Methylated: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Methylated: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Unmethylated: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Unmethylated: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Unmethylated: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Zap-70
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Present: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Present: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Present: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Absent: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Absent: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Absent: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
del(17p) or del(11q)
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
High: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
High: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
High: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Intermediate: IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Intermediate: IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Intermediate: I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
Rai Stage
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
IR vs I
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
IR vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
I vs BR
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
All Patients
N
365
365
364
167
168
167
198
197
197
263
265
266
102
100
98
191
191
192
173
173
172
Events
105
106
69
53
49
32
52
57
37
70
72
52
35
34
17
61
68
35
43
37
34
HR
0.37
0.40
1.06
0.44
0.32
0.73
0.33
0.50
1.44
0.44
0.50
1.11
0.26
0.24
0.90
0.19
0.31
1.57
0.81
0.58
0.72
95% CI
(0.25-0.56)
(0.27-0.60)
(0.66-1.70)
(0.25-0.78)
(0.17-0.59)
(0.36-1.46)
(0.18-0.60)
(0.29-0.85)
(0.75-2.76)
(0.27-0.72)
(0.31-0.80)
(0.65-1.92)
(0.12-0.56)
(0.11-0.53)
(0.35-2.32)
(0.11-0.35)
(0.18-0.51)
(0.80-3.09)
(0.45-1.48)
(0.30-1.12)
(0.36-1.43)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Hazard Ratio
Rituximab does not improve PFS over ibrutinib alone in the frontline setting for older CLL patients
Woyach J, et al. ASH 2018.
Del17
p
PFS in High Risk Subgroups
PFS was longer with Ibrutinib-containing regimens than with BR,
Particularly in patients with Del17p, complex and no complex Karyotype
Woyach J, et al. ASH 2018.
OS: Ibr x R – Ibr x BR
Arm C (IR)Arm B (I)
Arm A (BR)
% A
live
0 6 12 18 24 30 36 42 48 52
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 52
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
Censor
22/182Arm C (IR)
24/182Arm B (I)
20/183Arm A (BR)
Events/TotalArm
Patients-at-Risk183 166 163 160 153 143 98 53 23 1182 175 166 161 156 146 100 62 26 1182 172 169 165 161 147 100 55 24 1
Arm
N 24 Month Estimate
BR 183 95% (95% CI: 91-98%)
I 183 90% (95% CI: 85-94%)
IR 182 94% (95% CI: 89-97%)
Median Follow-up: 38 months
Rituximab does not improve OS over ibrutinib alone in the frontline setting for older CLL patients
(Short follow-up of study – 38 months)
Woyach J, et al. ASH 2018.
Response Rates and Minimal Residual Disease
• No significant differences in Overall Response Rates–BR: 81% (95% CI: 75 - 87%)
–Ibrutinib: 93% (95% CI: 88 - 96%)
–IR: 94% (95% CI: 89 - 97%)
• Higher Complete Response Rates with BR–BR: 26% (95% CI: 20 - 33%)
–Ibrutinib: 7% (95% CI: 4 - 12%)
–IR: 12% (95% CI: 8 - 18%)
• Higher MRD neg in marrow at 9 months with BR–BR: 8% (95% CI: 5 - 13%)
–Ibrutinib: 1% (95% CI: <1 - 3%)
–IR: 4% (95% CI: 2 - 8%)
Lower MRD negative reached with Ibrutinib-Containing Regimens
Woyach J, et al. ASH 2018.
Grade 3, 4, or 5 Adverse Events during treatment or follow-up
Woyach J, et al. ASH 2018.
Patients (N=229)
• Previously untreated CLL/SLL
• Requiring treatment
• Age ≥65 years or <65 years old with ≥1
coexisting condition:
CIRS >6
CrCl <70 mL/min
del(17p) or TP53 mutation
Study Design iLLUMINATE (PCYC-1130)
Ran
do
miz
ati
on
(1:1
)
IG (n=113)
Ibrutinib 420 mg PO once daily, continuously, until PD or
unacceptable toxicity
+
Obinutuzumab 100 mg IV on C1D1, 900 mg on C1D2,
1,000 mg on C1D8 & C1D15, then D1 of Cycles 2-6
GC (n=116)
Chlorambucil 0.5 mg/kg PO Days 1, 15 each Cycle, for 6
Cycles
+
Obinutuzumab 100 mg IV on C1D1, 900 mg on C1D2,
1,000 mg on C1D8 & C1D15, then 1,000 mg D1 of Cycles 2-6
Stratification:
• ECOG status (0-1 vs 2)
• Cytogenetics (del17p ± del11q vs del11q without del17p vs neither)
After IRC-confirmed PD, patients
were allowed to receive single-
agent ibrutinib (n=46)
Moreno et al. ASH 2018
Primary Endpoint: PFS assessed by an IRC
Secondary Endpoint:IRC-assessed PFS in high-risk population(e.g., del17p, TP53 mutation, del11q, or unmutatedIGHV)Undetectable MRDORROSInfusion-related reactionsSafety
Median follow-up:
31.3 m (0.2–36.9)
(40% cross-over)
Baseline characteristics of the studied cohort
CharacteristicIbrutinib-obinutuzumab
N=113
Chlorambucil-
obinutuzumab
N=116
Median age (range), years
Age ≥65 years, n (%)
70 (47–87)
91 (81)
72 (40–86)
92 (79)
ECOG performance status, n (%)
0
1
2
57 (50)
52 (46)
4 (4)
53 (46)
56 (48)
7 (6)
Advanced stage disease (Rai III or IV), n (%) 60 (53) 59 (51)
Bulky disease ≥5 cm, n (%) 30 (27) 44 (38)
High-risk population: unmutated IGHV, del(11q), del(17p) or mutTP53, n (%)
Unmutated IGHV
Del(11q)a
Del(17p) and/or mutTP53
Del(17p)
mutTP53
73 (65)
66/107 (62)
13 (12)
18 (16)
14 (12)
13/112 (12)
75 (65)
57/107 (53)
22 (19)
23 (20)
18 (16)
16/110 (15)
CIRS score >6, n (%) 37 (33) 36 (31)
CrCl <60 mL/min, n (%) 26 (23) 38 (33)
CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy-chain variable region; mutTP53, TP53 mutation. aWithout del17p (hierarchical categories according to Dohner classification).
Moreno et al. ASH 2018
Superior Progression-Free Survival with Ibrutinib-Obinutuzumab
IRC Assessment
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0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Pro
gre
ssio
n-f
ree
su
rviv
al (
%)
Months
Ibrutinib-obinutuzumab (N=113)Chlorambucil-obinutuzumab (N=116)
Median (mo)0.231 (0.145–0.367);
P<0.0001Hazard ratio (95% CI)
Ibrutinib-obinutuzumab
Chlorambucil-obinutuzumab
NR 19.0
| | | | | | | || |
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|
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||
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Pro
gre
ssio
n-f
ree
su
rviv
al (
%)
Months
Ibrutinib-obinutuzumab (N=113)Chlorambucil-obinutuzumab (N=116)
Median (mo)0.260 (0.163–0.415);
P<0.0001Hazard ratio (95% CI)
Ibrutinib-obinutuzumab
Chlorambucil-obinutuzumab
NR 21.9
PFS at 30 months: 79% with I-G vs. 31% with Clb-G
Moreno et al. ASH 2018
Ibrutinib-G led to 77% reduction in risk of progression or death compared to Clb–G
Superior Progression-Free Survival with Ibrutinib-Obinutuzumab in High-Risk CLL (unmutated IGHV, del(11q), del(17p) and/or TP53 mutation)
85% reduction in risk of progression or deathwith I-G in high-risk population
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Pro
gre
ssio
n-f
ree
su
rviv
al (
%)
Months
Ibrutinib-obinutuzumab (n=73)
Chlorambucil-obinutuzumab (n=75)
Median (mo)0.154 (0.087–0.270);
P<0.0001Hazard ratio (95% CI)
Ibrutinib-obinutuzumab
Chlorambucil-obinutuzumab
NR 14.7
Moreno et al. ASH 2018
84% reduction in risk of progression or deathwith I-G among high-risk CLL patients withoutdel(17p)
85% reduction in risk of progression or deathwith I-G among unmutated IGHV patientswithout del(17p)
Prolonged Time to Next Treatment with Ibrutinib-Obinutuzumab
40% of patients randomized to Clb-G crossed over to receive single-agent ibrutinib
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 39
Ov
era
ll s
urv
iva
l (%
)
Months36
Ibrutinib-obinutuzumab (N=113)
Chlorambucil-obinutuzumab (N=116)
Median (mo)0.921 (0.479–1.722);
P=0.81Hazard ratio (95% CI)
Ibrutinib-obinutuzumab
Chlorambucil-obinutuzumab
NR NR
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 39T
ime
-to
-ne
xt-
tre
atm
en
t (%
)
Months
Ibrutinib-obinutuzumab (N=113)
Chlorambucil-obinutuzumab (N=116)
36
Median (mo)0.063 (0.023–0.175);
P<0.0001Hazard ratio (95% CI)
Ibrutinib-obinutuzumab
Chlorambucil-obinutuzumab
NR NR
94% reduction in risk for need of second-line therapy with I-G
Moreno et al. ASH 2018
Salvage treatment for relapsed disease required in 4% of patients treated in first-line with I-G vs. 44% with G-Clb
Improved ORR and CR rates with Ibrutinib-Obinutuzumab
CR, complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; ORR, overall response rate; PR, partial response; SD, stable disease.
IRC Assessment
In the high-risk population:
ORR: I-G 90% vs. G-Clb 68%
CR/CRi rates: I-G 14% vs. G-Clb 4%
Pat
ien
ts(%
)
CR
CRi
nPR
PR
Response SD Response SD
Ibrutinib-obinutzumab Chlorambucil-obinutuzumab
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
42%
61%
12%
8%
3%
4%
37% 16%
ORR 91%
ORR 81%
1%
2%
16% CR/CRi41% CR/CRi
Pat
ien
ts(%
)
CR
CRi
nPR
PR
Response SD Response SD
Ibrutinib-obinutzumab Chlorambucil-obinutuzumab
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
65% 66%
4%
19%
8%
21%
1%
19% CR/CRi
ORR 88%
ORR 73%
8% CR/CRi
6%
Moreno et al. ASH 2018
ORR and CR/Cri rates were significantly improved with IG treatment, specially in the high risk population
Conclusions
• Which patients with CLL should receive CIT?– In MY opinion, NO ONE.
• Fit Patients: Ibrutinib+ R improves PFS and OS in ITT population• Benefit is superior in unmIGVH• You can still defend FCR for mutIGVH, but until when?
• Unfit: Ibrutinib improves PFS– Follow up too short for OS
• BTKi should be the backbone of new trials in CLL (single agent withmost activity)
• Time to change the discussion: – Costs– Access– Finite Therapy
CLL Survival x Matched Population
