Post on 07-May-2015
Jeffrey P. Sharman, MDMedical DirectorHematology ResearchUS Oncology ResearchEugene, Oregon
Case Discussion 3:Management of Frail Patients With CLL
Image: PR. J. BERNARD/CNRI/Copyright©2014 Science Source. All Rights Reserved
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Case Presentation
86-yr-old male with good performance status for age
Initially presents with lymphocytosis, lymphadenopathy, splenomegaly, Hb 11 g/dL, platelets 120 cells/mm3
During the next 2 yrs, WBC climbs from 40,000 cells/mL to 170,000 cells/mL, Hb falls to 9 g/dL by age 88
FISH shows trisomy 12 and IgVH unmutated
Let’s Test Your Knowledge
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
What is your treatment choice?
1. Ibrutinib
2. Alemtuzumab
3. FCR
4. Obinutuzumab + chlorambucil
5. Ofatumumab + chlorambucil
6. Unsure
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Which novel therapies have received FDA approval for previously untreated patients with CLL via the “Breakthrough Therapy Designation?”
1. Ibrutinib
2. Idelalisib
3. Obinutuzumab
4. Ofatumumab
5. None
6. Both 1 and 2
7. Both 3 and 4
8. Unsure
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Social Security Projections
Exact Age, Yrs Male
Death Probability Number of Lives Life Expectancy
88 0.14 23,222 4.66
89 0.15 20,021 4.33
90 0.17 16,969 4.02
91 0.19 14,112 3.73
Social Security. Acturial Life Tables.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Mortality Following First Therapy
Setting Median Age Regimen 12 Month Mortality
MD Anderson 57 FCR 1%
German CLL8 61 FC vs FCR 4%
Community 74 Any 10%
Connect CLL: The CLL Disease Registry.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Choosing First-line Therapy in 2014
Age and Comorbidity
FCR BR CD20
German CLL10 Study[1] German CLL11 Study[2]
Complement 1 Study[3]
1. Eichhorst B, et al. ASH 2013. Abstract 526. 2. Goede V, et al. N Engl J Med. 2014;370:1101-1110. 3. Hillmen P, et al. ASH 2013. Abstract 528.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
In Defense of Chlorambucil
Woyach JA, et al. J Clin Oncol. 2013;31:440-447.
1.0
0.8
0.6
0.4
0.2
00 24 48 72 96 120 144
Mos
Pro
bab
ilit
y o
f P
FS
1.0
0.8
0.6
0.4
0.2
00 48 96 144 192 240
Mos
Pro
bab
ilit
y o
f O
S
Interaction test P = .006Interaction test P = .046
F and < 70Ch and < 70F and ≥ 70Ch and ≥ 70
F and < 70Ch and < 70F and ≥ 70Ch and ≥ 70
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
PFS OS
Eichhorst BF, et al. Blood. 2009;114:3382-3391.
No Benefit of Fludarabine vs Chlorambucil in Elderly Patients With CLL
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96
Mos
Cu
mu
lati
ve S
urv
ival
1.0
0.8
0.6
0.4
0.2
0 12 24 36 48 60 72 84 96Mos
Cu
mu
lati
ve S
urv
ival
FludarabineChlorambucil
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Chlorambucil Use as Function of Age
Age, Yrs First Line, % Second Line, %
Young than 65 2 0
65-75 4 1
Older than 75 12 8
Sharman J, et al. Ash 2011. Abstract 2864.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Patients withpreviously untreated
CLL (N = 444)
OfatumumabCycle 1 Day 1 300 mg, Day 81000 mg, cycles 2-12 Day 1
1000 mg q28d +
Chlorambucil 10 mg/m2 Days 1-7 every 28 days
Chlorambucil10 mg/m2 Days 1-7 every 28
days
Follow-up: 1 mo past last dose, 3rd mos, then every 3 mos
Minimum 3 cycles or until best response or PD; maximum 12 cycles; no crossover allowed.
Hillmen P, et al. ASH 2013. Abstract 528.
Phase III COMPLEMENT1: Ofatumumab + Chlorambucil vs Chlorambucil Alone
Dose rationale: highest PFS and ORR with the lowest toxicity compared with any other chlorambucil treatment
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Ofatumumab + Chlorambucil vs Chlorambucil Alone: PFS*
Hillmen P, et al. ASH 2013. Abstract 528.
Ofatumumab + chlorambucil
Median PFS: 22.4 mos
HR: 0.57 (95% CI: 19.0-25.2;
P < .001)
Chlorambucil
Median PFS: 13.1 mos
(95% CI: 10.6-13.8)
Median follow-up: 28.9 mos
*As assessed by an Independent Review Committee.
1.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
Pro
bab
ilit
y o
f P
FS
Mos Since Randomization
0 524 8 12 16 20 24 28 32 36 40 44 48
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Response Chlorambucil(n = 226)
Ofatumumab + Chlorambucil (n = 221)
PFS, mos 13 22
ORR, % 69 82
CR, % 1 14
MRD, % 4 12
COMPLEMENT 1: Chlorambucil ± Ofatumumab
Hillmen P, et al. ASH 2013. Abstract 528.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Previously untreatedCLL patients with
comorbidities(CIRS score > 6 and/or
CrCl < 70 mL/min)(N = 781)
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 cycle
Patients who progress on chlorambucil alone allowed to crossover to obinutuzumab + chlorambucil arm.
Randomized 1:2:2
Goede V, et al. N Engl J Med. 2014;370:1101-1110.
CLL11 Trial: Obinutuzumab + Chlorambucil vs Rituximab + Chlorambucil
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions
Goede V, et al. N Engl J Med. 2014;370:1101-1110.
100
80
60
40
20
0
P < .001 P < .001
55.0
22.3
31.4
58.47.3
G-Clb(n = 238)
Clb(n = 118)
R-Clb(n = 233)
Pat
ien
ts W
ith
a R
esp
on
se (
%)
Obinutuzumab-ClbCRPF
ClbCRPR
Rituximab-ClbCRPR
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions
Goede V, et al. N Engl J Med. 2014;370:1101-1110.
100
80
60
40
20
0
100
80
60
40
20
0
P < .001
20.7
57.7
7.0
58.1
Obinutuzumab-Clb(n = 333)
Rituximab-Clb(n = 329)
Pat
ien
ts W
ith
a
Res
po
nse
(%
)
Bone Marrow Blood
P < .001 P < .001
19.5
2.6
37.7
3.3
Pts atRisk, n 26/133 3/114 87/231 8/243
Pat
ien
ts W
ith
a
Neg
ativ
e M
RD
Tes
t (%
)
Obinutuzumab-ClbRituximab-Clb
Obinutuzumab-ClbCRPR
Rituximab-ClbCR PR
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
0 3 6 9 12 15 18 21 24 27 30 33 36 39
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
bab
ility
of
PF
S
Mos
CLL11 Trial: PFS Head-to-Head Comparison
15.2 26.7
Obinutuzumab-chlorambucilRituximab-chlorambucil
Stratified HR: 0.39(95% CI: 0.31-0.49;P < .0001)
Goede V, et al. N Engl J Med. 2014;370:1101-1110.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
CLL11: Overall Survival
Goede V, et al. N Engl J Med. 2014;370:1101-1110.
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36
Mos
Pro
bab
ilit
y o
f O
S
G-Clb
Clb
Stratified HR for death with G-Clb: 0.41 (95% Cl: 0.23-0.74;P = .002)
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Single-Agent Obinutuzumab
Before After
Images courtesy Dr. Jeff Sharman.
Let’s Review the Case Study and Questions
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Case Presentation
86-yr-old male with good performance status for age
Initially presents with lymphocytosis, lymphadenopathy, splenomegaly, Hb 11 g/dL, platelets 120 cells/mm3
During the next 2 yrs, WBC climbs from 40,000 cells/mL to 170,000 cells/mL, Hb falls to 9 g/dL by age 88
FISH shows trisomy 12 and IgVH unmutated
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
What is your treatment choice?
1. Ibrutinib
2. Alemtuzumab
3. FCR
4. Obinutuzumab + chlorambucil
5. Ofatumumab + chlorambucil
6. Unsure
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
LYN
SYK
BCR
BTK
PLCγ2
PKC
AKT
mTOR
p70s6k elf4E
GSK-3 NF-kβ
pathway
Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies
BCR signaling is required for tumor expansion and proliferation
BCR signaling up-regulated in B-cell malignancies
New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk
IbrutinibAVL-292
┬ ┬IdelalisibIPI-145TGR-1202
┬FostamatinibGS-9973
PI3Kdelta
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Ibrutinib Idelalisib/Rituximab
Relapse
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Relapsed CLL: Idelalisib + Rituximab
Furman RR, et al. N Engl J Med. 2014;370:997-1007.
180,000
120,000
60,000
40,000
30,000
20,000
10,000
00 6 12 18 24 30 36 42 48
Wks
Ab
solu
te L
ymp
ho
cyte
Co
un
t (p
er m
m3 )
Idelalisib + rituximab Placebo + rituximab
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Relapsed CLL: Idelalisib + Rituximab
Furman RR, et al. N Engl J Med. 2014;370:997-1007.
125
100
75
50
25
0
-25
-50
-75
-100
Idelalisib + Rituximab Placebo + Rituximab
Changes in the Measured Size of Lymph Nodes From Baseline
Patients
Gre
ates
t P
erce
nt
Ch
ang
e
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Idelalisib and Rituximab for Previously Treated Patients With CLL
PF
S (
%)
Idelalisib + rituximabMedian PFS: not reached
Placebo + rituximabMedian PFS: 5.5 mos
HR: 0.15(95% CI: 0.08-0.28;P < .0001)
100
75
50
25
0
0 2 4 6 8 10 12 14 16Mos
Furman RR, et al. N Engl J Med. 2014;370:997-1007.
OS
(%
)
HR: 0.28(95% CI: 0.09-0.86; P = .018)
100
75
50
25
00 2 4 6 8 10 12 14 16
Mos
Idelalisib + rituximab
Placebo + rituximab
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Relapsed CLL: Targeting BTK With Ibrutinib
Byrd JC, et al. N Engl J Med. 2013;369:32-42.
100
80
60
40
20
0
5246
33
2420 18 18
71716865
54
3921
18 7 5 4 4 4 4
CR + PR
PR with lymphocytosis
SD
0 4 8 12 16 20 24
Mos
Pa
tie
nts
Wit
h a
Re
sp
on
se
(%
)
0 2 4 6 8 10 12 14 16 18
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
700
600
500
400
300
-100
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e i
n A
LC
(%
)
200
100
0
Me
dia
n C
ha
ng
e F
rom
Ba
se
line
in S
PD
(%)
Mos
ALC SPD
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Targeting BTK With Ibrutinib in Relapsed CLL: OS
Byrd JC, et al. N Engl J Med. 2013;369:32-42.
1.0
0.8
0.6
0.4
0.2
0 5 10 15 20 25 30
Pro
bab
ilit
y o
f O
S
0P = .15 by log-rank test
No 17p or 11q deletions (n = 29)
11q deletion (n = 23)
17p deletion (n = 28)
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Targeting BTK With Ibrutinib in Relapsed CLL: PFS
Byrd JC, et al. N Engl J Med. 2013;369:32-42.
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30
P = .04 by log-rank test
No 17p or 11q deletions (n = 29)
11q deletion (n = 23)
17p deletion (n = 28)
Pro
bab
ilit
y o
f P
FS
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Labeled Indications for Ibrutinib
Ibrutinib is a kinase inhibitor indicated for the treatment of patients with:
– Mantle cell lymphoma who have received at least 1 previous therapy
– CLL who have received at least 1 previous therapy
These indications are based on ORR
Improvements in survival or disease-related symptoms have not been established
Ibrutinib [package Insert].
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Ofatumumab or Ibrutinib in Relapsed CLL
Relapsed CLL/SLL, including deletion 17p
N = 350
Ran
dom
ized
1:1
Arm A: Ofatumumab
Wk 1: 300 mg IV initial dose
Wk 2-8: 2000 mg IV/wk
Wks 12, 16, 20, 24: 2000 mg IV
Arm B: Ibrutinib
400 mg orally, once daily continuously until disease progression or unacceptable toxicity
ClinicalTrials.gov. NCT01578707.
clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape
Conclusions
Treatment of elderly CLL poses high risk of 12-mo mortality, possibly due in part to toxicity of current treatment regimens
Management of CLL is dynamically changing due to introduction of TKI agents and CD20-based therapy
CD20-based approvals in frontline therapy likely to be joined in near term by TKI-based options
Relapsed disease being transformed by ibrutinib/idelalisib with BCL-2 coming soon
Audience Question and Answer Session