chronic lymphocytic leukemia · the ohio state university comprehensive cancer center – arthur g....
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CHRONIC LYMPHOCYTIC LEUKEMIA
Farrukh Awan, MD Associate Professor of Medicine
Division of Hematology
The Ohio State University
Jun 2015
cll.osu.edu
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Definition of CLL IWCLL - 2008
Small, clones of mature B-cells
Atleast 5,000/ul B-cells
Co-express CD5 and CD23
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Prognostic Markers
Interphase cytogenetics and FISH
IGHV Mutational Status
CD38
ZAP-70 methylation
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Interphase FISH correlates with Survival
17p deletion
11q deletion
12 trisomy
Normal
13q deletion as
sole abnormality
Pati
en
ts s
urv
ivin
g (
%)
100
80
60
40
20
0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months Dohner, et al. N Engl J Med. 2000
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Outcome by Interphase FISH Abnormalities
Abnormality detected by
FISH
Median Time to Treatment (months)
Median Overall Survival (months)
Percentage of Patients (%)
Del 17p 9 32 7
Del 11q 13 79 18
Trisomy 12 33 114 16
Del 13q 49 133 55
Normal 92 111 18
Dohner, et al. N Engl J Med. 2000
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
IGHV Mutational Status predicts Survival
Hamblin et al. Blood. 1999
Median Survival
293 months (Mutated)
117 months (Unmutated)
0 25 50 75 100 125 150 175 200 225 250 275 300 325
Months
(P=0.001)
Su
rviv
ing
(%
)
0
10
20
30
40
50
60
70
80
90
100 All patients (N=84)
Mutated (55%)
Unmutated (46%)
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CD38 expression correlates with IGHV mutational status
Damle, et al, Blood, 1999
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
ZAP-70 Methylation
loss of methylation at a specific single CpG dinucleotide in the ZAP-70 5’ regulatory sequence is a highly predictive and reproducible biomarker of poor prognosis in this disease
Claus et al. J Clin Oncol 2012
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Other Prognostic Markers
Favorable Outcome Un-Favorable Outcome
LDH Low or Normal Elevated
Lymphocyte Doubling Time > 12 months < 12 months
Thymidine Kinase Activity Low or Normal Elevated
Beta-2 Microglobulin Low or Normal Elevated
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Prognostic factors in CLL: Summary
Interphase-FISH cytogenetic analysis is standard of care
Chromosomal abnormalities may change with time
IGHV status does not change with time
CD38 and ZAP-70 methylation correlates with IGHV
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
So is stage of the cancer important in CLL
Rai/Binet Staging system has been used for a long time
Newer molecular methods are much more useful
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
What do we do at Initial Presentation?
All patients undergo
History and Physical
CBC with diff
CMP
Direct Anti-Globulin Test*
Quantitative Immunoglobulins
Infectious Serology*
Peripheral Blood Flow cytometry
+/- CT scan CAP*
+/- Bone Marrow Biopsy*
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
What do we do at Initial Presentation?
Prognostic Markers
Interphase FISH
Conventional karyotyping
IGHV mutational analysis
ZAP-70 Methylation
Beta-2 microglobulin
LDH
Lymphocyte doubling time
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Timing of Therapy
Constitutional symptoms – How you feel
Unintentional weight loss of >10% within the previous 6 mos
significant fatigue (ECOG PS 2 or worse)
fevers >100.5°F for >2 wks without other evidence of infection
night sweats for >1 month without evidence of infection
NCI-IWCLL recommendations, Blood, 2008
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Timing of Therapy
Worsening or steroid resistant anemia and/or thrombocytopenia
Spleen >6cm below the left costal margin
Lymph Nodes >10cm
Lymphocyte doubling time (LDT) of <6 months
NCI-IWCLL recommendations, Blood, 2008
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Don’t Treat
Hypogammaglobulinemia
Monoclonal or oligoclonal paraproteinemia
Elevated leukocyte count
NCI-IWCLL recommendations, Blood, 2008
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Early Treatment Does not improve Survival
J Natl Cancer Inst, 1999
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
But treatments have changed ……
Early treatment can be considered if
treatment is well tolerated
doesn’t have too many side effects
and works well
Early intervention trial of ibrutinib available at OSU soon for patients who don’t need treatment per conventional criteria
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Infectious Complications
Infections are the leading cause of death in CLL
Most common infections are sinus, throat and chest
It generally results from low immunoglobulin levels and defective immune system
Intravenous immunoglobulins (IVIg) can help in some patients
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
How to prevent infections?
Pneumococcal vaccine every 2-5 years (PCV13)
Flu vaccine every year
Avoid live virus vaccines including
Shingles
Nasal flu
Oral polio
Yellow fever
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Secondary Cancers
Patients with CLL are at a high risk of getting secondary cancers
Colonoscopy every 5 years
Skin exam by dermatologist every year
Mammogram every year
Pap smear every year
PSA every year
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Issues with Supplements
Metabolism uncertain
Side effects not well characterized
Efficacy not proven in clinical trials
Interaction with other drugs not known
Please tell your doctor about the type of supplement that you take
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
babili
ty o
f P
FS
Mos
15.2 26.7
Obinutuzumab-chlorambucil
Rituximab-chlorambucil
Stratified HR: 0.39
(95% CI: 0.31-
0.49;
P < .0001)
Obinutuzumab plus Chlorambucil
Goede, et al. Nejm 2014
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ofatumumab + chlorambucil
mPFS: 22.4
(95% CI: 19.0-25.2)
HR 0.57; P < .001
Chlorambucil
mPFS: 13.1
(95% CI:
10.6,13.8)
Median follow-up: 28.9 mos
1.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
Pro
ba
bil
ity o
f P
FS
Mos Since Randomization
0 52 4 8 12 16 20 24 28 32 36 40 44 48
Ofatumumab plus Chlorambucil
Hillmen P, et al. ASH 2013. Abstract 528.
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Targeting kinases in CLL
Awan F, et al, CCR 2014
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ibrutinib
Forms a specific bond with cysteine-481 in BTK
Highly potent BTK inhibition at IC50 = 0.5 nM
Orally administered with once-daily dosing resulting in 24-hr target inhibition
No cytotoxic effect on T cells or NK cells
Promotes apoptosis and inhibits migration and adhesion in CLL cells
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
PCYC-1102-CA: Phase IB/II in CLL/SLL
PCYC-1102-CA
Total enrollment 117 patients
Dates enrolled 20th May 10 –
27th Jul 11
Relapsed/Refractory 420 mg/d (n=27)
Median follow-up 17.5 months
Treatment Naïve ≥ 65 yrs 420 mg/d (n=26)
Median follow-up 14.4 months
Relapsed/Refractory 840 mg/d (n=34)
Median follow-up 13.8 months
High-risk Relapsed/Refractory 420 mg/d (n=25)
Median follow-up 7.4 months
Treatment Naïve ≥ 65 yrs 840 mg/d (n=5)
Median follow-up 7.4 months Co-leaders: J Byrd and S O’Brien
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Phase II CLL Patient Characteristics
Modest toxicity in phase II study similar to phase I study
NEJM 2013
Lancet Oncology
TN ≥65 yrs (N=31) R/R + HR (N=85)
Age, years ≥ 70 years, (%)
74%
35%
ECOG Status 0, 1, 2
Median Prior Therapies
74%, 26%, 0%
N
41%, 56%, 2%
4 (1-12)
Rai Stage III/IV at Baseline 48% 65%
Prognostic Markers, % IGHV unmutated
del(17p13.1) del(11q22.3)
55% 7% 3%
85% 35% 39%
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Byrd JC, et al. N Engl J Med. 2013;369:32-42.
Mo
550
450
350
250
150
50
-50
ALC
0 11 1 2 3 4 5 6 7 8 9 10
Mo
25
0
-25
-50
-75
-100
SPD
0 11 1 2 3 4 5 6 7 8 9 10
Media
n C
hange F
rom
Baselin
e in A
LC
(%
)
Media
n C
hange F
rom
Baselin
e in S
PD
(%
)
Pattern of Response: Blood Lymphocytes vs Lymph Nodes
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Phase II Response and Progression-free Survival
R/R + High-Risk R/R (n=85)
Est. PFS at 26 mo is 75%
Treatment Naïve (n=31)
Est. PFS at 26 mo is 96%
Months on Study 0 5
20 25
1.0
0.8
0.6
0.4
0.2
0.0
PF
S P
rob
ab
ilit
y
71% ORR (10% CR)
71% ORR (2% CR)
NEJM 2013
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
PFS by FISH: Relapse Cohort
Months on Study
del17p (n=28) Est. PFS at 26 mo is 57%
del11q (n=23) Est. PFS at 26 mo is 73%
No del17p or del11q (n=29) Est. PFS at 26 mo is 93%
1.0
0.8
0.6
0.4
0.2
0.0
PF
S P
rob
ab
ilit
y
0 10 15 20 25 p=0.0437
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
0 6 12 18 24 30 36 42 48
Months from first OSU Treatment
0.0
0.2
0.4
0.6
0.8
1.0
Pro
gre
ssio
n-f
ree S
urvi
val P
robabili
ty
Ibrutinib (n = 27)
CDKi (n = 58)
Other (n = 88)
P < 0.0001 by log-rank test
IB vs O: P < 0.0001
CDKi vs O: P < 0.0001
IB vs CDKi: P = 0.002
Ibrutinib (n = 27)
Early Results Of Impact: Outcome of
Treatment of del(17p13.1) CLL at OSU
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
PR-L is not associated with inferior PFS compared with PR/CR at 12 months
Woyach J et al: Blood 2014
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ibrutinib and Rituximab
Burger J et al: Lan Onc 2014
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Idelalisib
Selective PI3-K delta inhibitor
Single agent response rate of 72%
39% PR and 33% PR+L
Penumonitis, colitis, transaminitis
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Idelalisib in relapsed/refractory CLL
Brown JR, et al. Blood. 2014 May 29;123(22):3390-7
Median PFS: 17.1 mos Median OS: not reached
100
75
50
25
0 0 6 12 18 24 30 36 42
100
75
50
25
0 0 6 12 18 24 30 36 42
Mos From Start of Idelalisib Mos From Start of Idelalisib
PFS (N = 54) OS (N = 54)
PF
S (
%)
OS
(%
)
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Phase III Idelalisib and Rituximab for Previously Treated Patients With CLL
Idelalisib + rituximab
Median PFS: not reached
Placebo + rituximab
Median PFS: 5.5 mos HR: 0.15
(95% CI: 0.08-0.28;
P < .0001)
PF
S (
%)
100
75
50
25
0 0 2 4 6 8 10 12 14 16
Mos
Furman R, et al. N Engl J Med. 2014
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Summary
CLL is a disease with varied presentation
Comprehensive diagnostic and prognostic workup is important for optimal management at the time of diagnosis
Multiple treatment options exist including chemotherapy and non-chemotherapy approaches
Prognosis is generally excellent and improving every day