Management of CLL in elderly patients asco 2014

Jeffrey P. Sharman, MD
Medical Director
Hematology Research
US Oncology Research
Eugene, Oregon
Case Discussion 3:
Management of Frail Patients
With CLL
Image: PR. J. BERNARD/CNRI/Copyright©2014 Science Source. All Rights Reserved

clinicaloptions.com/oncology
How 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

What is your treatment choice?
1. Ibrutinib
2. Alemtuzumab
3. FCR
4. Obinutuzumab + chlorambucil
5. Ofatumumab + chlorambucil
6. Unsure

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

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.

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.

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.

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
0
0 24 48 72 96 120 144
Mos
ProbabilityofPFS
1.0
0.8
0.6
0.4
0.2
0
0 48 96 144 192 240
Mos
ProbabilityofOS
Interaction test P = .006Interaction test P = .046
F and < 70
Ch and < 70
F and ≥ 70
Ch and ≥ 70
F and < 70
Ch and < 70
F and ≥ 70
Ch and ≥ 70

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
0
0 12 24 36 48 60 72 84 96
Mos
CumulativeSurvival
1.0
0.8
0.6
0.4
0.2
0 12 24 36 48 60 72 84 96
Mos
CumulativeSurvival
Fludarabine
Chlorambucil

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.

Patients with
previously
untreated
CLL
(N = 444)
Ofatumumab
Cycle 1 Day 1 300 mg, Day 8
1000 mg, cycles 2-12 Day 1
1000 mg q28d
+
Chlorambucil 10 mg/m2
Days 1-7 every 28 days
Chlorambucil
10 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

Ofatumumab + Chlorambucil vs
Chlorambucil Alone: PFS*
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
ProbabilityofPFS
Mos Since Randomization
0 524 8 12 16 20 24 28 32 36 40 44 48

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

Previously untreated
CLL 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

Obinutuzumab + Chlorambucil: Patients
With CLL and Coexisting Conditions
100
80
60
40
20
0
P < .001 P < .001
55.0
22.3
31.4
58.4
7.3
G-Clb
(n = 238)
Clb
(n = 118)
R-Clb
(n = 233)
PatientsWithaResponse(%)
Obinutuzumab-Clb
CR
PF
Clb
CR
PR
Rituximab-Clb
CR
PR

Obinutuzumab + Chlorambucil: Patients
With CLL and Coexisting Conditions
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)
PatientsWitha
Response(%)
Bone Marrow Blood
P < .001 P < .001
19.5
2.6
37.7
3.3
Pts at
Risk, n 26/133 3/114 87/231 8/243PatientsWitha
NegativeMRDTest(%)
Obinutuzumab-Clb
Rituximab-Clb
Obinutuzumab-Clb
CR
PR
Rituximab-Clb
CR
PR

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
ProbabilityofPFS
Mos
CLL11 Trial: PFS Head-to-Head
Comparison
15.2 26.7
Obinutuzumab-chlorambucil
Rituximab-chlorambucil
Stratified HR: 0.39
(95% CI: 0.31-0.49;
P < .0001)

CLL11: Overall Survival
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 36
Mos
ProbabilityofOS
G-Clb
Clb
Stratified HR for
death with G-Clb: 0.41
(95% Cl: 0.23-0.74;
P = .002)

Single-Agent Obinutuzumab
Before After
Images courtesy Dr. Jeff Sharman.

Let’s Review the Case Study and
Questions

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
Ibrutinib
AVL-292
┬
┬
Idelalisib
IPI-145
TGR-1202
┬
Fostamatinib
GS-9973
PI3K
delta

Ibrutinib Idelalisib/Rituximab

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
0
0 6 12 18 24 30 36 42 48
Wks
AbsoluteLymphocyteCount(permm3
)
Idelalisib + rituximab Placebo + rituximab

Relapsed CLL: Idelalisib + Rituximab
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
GreatestPercentChange

Idelalisib and Rituximab for Previously
Treated Patients With CLL
PFS(%)
Idelalisib + rituximab
Median PFS: not reached
Placebo + rituximab
Median 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 16
Mos
OS(%)
HR: 0.28
(95% CI: 0.09-0.86; P = .018)
100
75
50
25
0
0 2 4 6 8 10 12 14 16
Mos
Idelalisib + rituximab
Placebo + rituximab

Relapsed CLL: Targeting BTK With
Ibrutinib
Byrd JC, et al. N Engl J Med. 2013;369:32-42.
100
80
60
40
20
0
52
46
33
24
20 18 18
7171
6865
54
39
21
18 7 5 4 4 4 4
CR + PR
PR with lymphocytosis
SD
0 4 8 12 16 20 24
Mos
PatientsWithaResponse(%)
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
MedianChangeFromBaselineinALC(%)
200
100
0
MedianChangeFromBaselineinSPD(%)
Mos
ALC SPD

Targeting BTK With Ibrutinib in Relapsed
CLL: OS
1.0
0.8
0.6
0.4
0.2
0 5 10 15 20 25 30
ProbabilityofOS
0
P = .15 by log-rank test
No 17p or 11q deletions (n = 29)
11q deletion (n = 23)
17p deletion (n = 28)

Targeting BTK With Ibrutinib in Relapsed
CLL: PFS
1.0
0.8
0.6
0.4
0.2
0
0 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)
ProbabilityofPFS

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].

Ofatumumab or Ibrutinib in Relapsed CLL
 Relapsed CLL/SLL, including deletion 17p
 N = 350
Randomized1:1
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.

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

Management of CLL in elderly patients asco 2014

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