clinical advances and research progress in chronic lymphocytic leukemia
TRANSCRIPT
Clinical Advances and Research Progress
in Chronic Lymphocytic Leukemia
Farrukh A. Awan, MD, MS
Associate Professor of Internal Medicine
The Ohio State University Comprehensive Cancer Center
Disclosures
Dr. Awan discloses the following commercial relationships:
◼ Advisory Board: Gilead, Pharmacyclics
◼ Grants/Research Support: Pharmacyclics
Learning Objectives
▶ Evaluate criteria to risk stratify patients with CLL
▶ Describe mechanisms of treatment resistance in CLL
▶ Differentiate emerging data on novel therapeutic approaches
for patients with previously untreated and relapsed/refractory
CLL
CLL = chronic lymphocytic leukemia.
Essential Tests at Initial Presentation:
Beyond the Basics
▶ Diagnostic◼ Peripheral blood-flow cytometry
◼ Bone marrow biopsy– Conventional karyotyping
▶ Prognostic◼ Interphase FISH
◼ IGHV mutational analysis
◼ TP53 mutational analysis
◼ Beta-2-microglobulin
◼ LDH
FISH = fluorescence in situ hybridization; IGHV = immunoglobulin heavy-chain variable;
LDH = lactate dehydrogenase.
Other Considerations
▶ Direct antiglobulin test (Coombs)
▶ Quantitative immunoglobulins
▶ CT scan of the chest/abdomen/pelvis
▶ Infectious serology
CT = computed tomography.
Risk Stratification
Prognostic Markers
▶ Interphase cytogenetics by FISH
▶ IGHV mutational status
Interphase FISH Correlates With OS
OS = overall survival.
Döhner et al, 2000.
17p deletion
11q deletion
12 trisomy
Normal
13q deletion as
sole abnormality
Pa
tie
nts
Su
rviv
ing
(%
)100
80
60
40
20
00 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months
Outcome by Interphase FISH Abnormalities
at Diagnosis
Döhner et al, 2000.
Abnormality Detected by
FISH
Median Time to Treatment (mo)
Median OS (mo)
% of Patients
del(17p) 9 32 7
del(11q) 13 79 18
Trisomy 12q 33 114 16
del(13q) 92 133 55
Normal 49 111 18
Prognostic Markers
▶ Interphase cytogenetics by FISH
▶ IGHV mutational status
Significance of IGHV in CLL
▶ Mutational status of IGHV predicts clinical outcome
Mutated IGHV is defined as <98% sequence homology
to established germline sequence
▶ Unmutated IGHV predicts earlier therapy, poorer
response, inferior survival, and risk for Richter’s
transformation
▶ IGHV correlates with disease positive for CD38 and
ZAP-70
Damle et al, 1999; Pepper et al, 2012.
IGHV Mutational Status Predicts Survival
Hamblin et al, 1999.
0 25 50 75 100 125 150 175 200 225 250 275 300 325
Months
Su
rviv
ing
(%
)
0
10
20
30
40
50
60
70
80
90
100Mutational
Status
Patients
N=84
n (%)
Median
Survival
(mo)
Mutated 46 (54.8) 293
Unmutated 38 (45.2) 117
P=0.001
Mutated
Unmutated
Prognostic Factors in CLL: Summary
▶ Interphase FISH is standard of care at diagnosis
and RELAPSE◼ Chromosomal abnormalities may change with time
◼ Consider repeat interphase FISH prior to starting the next
therapy to assess for clonal evolution
▶ IGHV status does not change with time
▶ CD38 and ZAP-70 correlate with IGHV
Timing of Therapy
Early Treatment Does Not Improve Survival
Clb = chlorambucil; P = prednisolone; Obs = observed; Exp = expected; NS = not statistically significant.
CLL Trialists’ Collaborative Group, 1999.
Start
YearStudy Name Treatment
Death/Patients Immediate Deaths Ratio of Annual Death Rates
Allocated
Immediate
Allocated
Deferred
Obs –
Exp
Variance of
Obs – Exp
1976 CALGB Clb 7/22 9/25 –0.5 2.7
1978 MRC-CLL-1 Clb 31/37 32/41 3.7 15.1
1980 FRE-CLL-80 Clb 175/300 169/307 10.1 85.6
1984 MRC-CLL-2 Clb 76/121 73/118 5.2 36.6
1985 FRE-CLL-85 Clb+P 122/457 126/462 –2.0 62.0
1988 PETHEMA Clb+P 21/77 21/81 0.5 10.4
Total432/1014
(42.6%)
430/1034
(41.6%)16.9 212.3
Heterogeneity between 6 trials: 𝟀𝟓𝟐= 1.7; P>0.1; NS
99% or 95% confidence intervals
1.08 (SD = 0.07)
Immediate Better Deferred Better
Treatment effect P>0.1; NS, adverse
0.0 0.5 1.0 1.5 2.0
Immediate Deferred
Indications for Initiating Therapy
▶ Objective laboratory/radiographic findings:◼ Reminiscent of Rai staging system
◼ Worsening anemia and/or thrombocytopenia– Hemoglobin <11 g/dL
– Platelets <100,000/uL
◼ Spleen ≥6 cm below the left costal margin
◼ Lymph nodes ≥10 cm
▶ Constitutional symptoms:◼ Unintentional weight loss of ≥10% within the previous 6 months
◼ Significant fatigue (ECOG PS 2 or worse)
◼ Fevers >100.5°F for ≥2 weeks without other evidence of infection
◼ Night sweats for >1 month without evidence of infection
ECOG = Eastern Cooperative Oncology Group.
Hallek et al, 2008.
Review of Standard and
Novel Frontline Strategies
Young, Healthy Patients
Age ≤65 Years, Without del(17p)/TP53 Mutation
FC vs FCR: GCLLSG-8 Trial
FC = fludarabine + cyclophosphamide; FCR = FC + rituximab; ORR = overall response rate;
CR = complete remission; PFS = progression-free survival.
Hallek et al, 2010.
N=817
FC
n=409
(%)
FCR
n=408
(%)
ORR 80 90a
CR 22 44a
3-year PFS 45 65a
3-year OS 83 87b
PFS
Pro
po
rtio
n W
ith
ou
t P
rogr
essi
on
(%
) ChemoimmunotherapyChemotherapy
100
0
90
80
70
60
50
40
30
20
10
06 12 18 24 30 36 42 48 54 60 66
FCRFC
aP<0.0001; bP=0.012
FCR vs BR: CLL-10 GCLLSG Trial
BR = bendamustine + rituximab; TRM = treatment-related mortality.
Eichhorst et al, 2016.
FCR
n=282
BR
n=279P Value
ORR (%) 97.8 97.8 NS
CR (%) 40.7 31.5 0.026
Median PFS (mo) 53.7 43.2 0.001
OS at 3 years (%) 90.6 92.2 NS
Severe neutropenia (%) 87.7 67.8 <0.001
Severe infections (%) 39.8 25.4 0.001
TRM (%) 3.9 2.1 —
CLL10 Trial: Minimal Residual Disease
MRD = minimal residual disease; PB = peripheral blood; BM = bone marrow.
Eichhorst et al, 2016; Kovacs et al, 2016.
No. of patients: 72/180 44/156 137/185 107/170 75/129 31/98
100
90
80
70
60
50
40
30
20
10
0
MR
D-N
eg
ati
ve P
ati
en
ts (
%)
Interim PB Final PB Final BM
P=0.023
P=0.024
P<0.001 FCRBR
FCR: A Possible Cure for CLL?
▶ Median PFS was not
reached at 12.8 years in
the IGHV-mutated group
▶ Approximately 50% of
IGHV-mutated patients
achieved MRD negativity
▶ No relapses have been
seen beyond 10 years in
IGHV-mutated patients
▶ FCR vs ibrutinib as
preferred frontline
therapy?
Thompson et al, 2016.
PF
S (
%)
Time (yr)
100
25
50
75
00 1 12 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Patients
(n)
Prog-Free
(n)
IGHV-mutated 88 49
IGHV-unmutated 126 12
P=0.0001
IGHV mutated
IGHV unmutated
Older Patients
Age >65 Years
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 6 12 18 24 30 36 42
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 6 12 18 24 30 36 4842
Chemotherapy for Older Patients
▶ Avoid fludarabine-based regimens
▶ Bendamustine + rituximab◼ Slightly higher toxicity rate but feasible in this population
aAll patients in the intent-to-treat group.
PD = progressive disease.
Fischer et al, 2012; Hillmen et al, 2015.
Cu
mu
lati
ve
Su
rviv
al
(Pro
ba
bil
ity)
Time to New CLL Therapy, PD, or Death (mo) Time to Death (mo)
Cu
mu
lati
ve
Su
rviv
al
(Pro
ba
bil
ity)
Event-Free Survivala Overall Survivala
CLL-11 Trial: Obinutuzumab + Chlorambucil
▶ Obinutuzumab is an engineered anti-CD20 monoclonal antibody
▶ It is well tolerated in patients with comorbidities and median age of 73.
▶ Improved PFS when compared with R + Clb and Clb alone
G-Clb = obinutuzumab/chlorambucil; R-Clb = rituximab/chlorambucil.
Goede et al, 2014.
G-Clb(n=238)
G-ClbP<0.001 P<0.001
P<0.001 P<0.001
G-Clb R-Clb
R-Clb(n=233)
Clb(n=118)
100
90
80
70
60
50
40
30
20
10
0
R-Clb
Clb
Bone Marrow Blood
100
90
80
70
60
50
40
30
20
10
0
22.3
7.3
58.455.0
31.4 19.5
37.7
2.6 3.3
MR
D-N
eg
ati
ve P
ati
en
ts (
%)
Pati
en
ts W
ith
a R
esp
on
se (
%)
PR
CR
PR
PR
CR
CR
Obinutuzumab + Chlorambucil
for Untreated CLL
HR = hazard ratio; CI = confidence interval.
Goede et al, 2014.
R-Clb
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
ba
bilit
y o
f P
FS
Months
15.2 26.7
G-Clb
Stratified HR = 0.39
95% CI: 0.31–0.49
P<0.001
Ibrutinib as Frontline Therapy
All Ages
Targeting Kinases in CLL
BTK = Bruton’s tyrosine kinase; PI3K = phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP3 = phosphatidylinositol—3,4,5,-trisphosphate;
DAG = diacylglycerol; PKC = protein kinase C; GSK = glycogen synthase kinase; NFAT = nuclear receptor of activated T cells.
Awan & Byrd, 2014.
Ibrutinib
▶ Highly potent BTK inhibition at IC50 = 0.5 nM
▶ Administered orally with once-daily dosing, resulting in
24-hour target inhibition
▶ No cytotoxic effect on T cells or NK cells
▶ Promotes apoptosis and inhibits migration and adhesion
in CLL cells
NK = natural killer.
Ibrutinib for High-Risk CLL: PFS Results
Byrd et al, 2015.
1.0
18
0.8
0.6
0.4
0.2
126 3630 42240
CensoredLogrank p=0.0031
0.0
Months From Initiation of Study Treatment
PF
S (
Pro
po
rtio
n)
30-Month
Estimated PFS
del(17p) 48%
del(11q_ 74%
No del(17p) or del(11q)
del(11q)
del(17p)
Ibrutinib vs Chlorambucil (RESONATE-2)
Burger et al, 2015; AbbVie Inc, 2016.
PF
S (
%)
Months
100
90
80
70
60
50
40
30
20
10
00 3 6 9 12 15 18 21 24 27
Ibrutinib
Chlorambucil
Median PFS
(mo)
Chlorambucil 18.9
Ibrutinib NR
HR (95% CI) 0.16 (0.09–0.28)
P= 0.001
▶ Ibrutinib is superior to chlorambucil in patients >65 years with previously
untreated CLL◼ Approval in March 2016 for all untreated CLL patients
Novel Therapy for Relapsed CLL
Kinase Inhibitors
RESONATE Trial: PFS Results
Byrd et al, 2014.
Months
PF
S(%
)
195 183 116 38 7
196 161 83 15 1 0
Ofatumumab
Ibrutinib
0
100
90
80
70
60
50
40
30
20
10
03 6 9 12 15
Censored
Median PFS
(mo)
Ofatumumab 8.1
Ibrutinib NRa
HRb (95% CI) 0.22
(0.15-0.32)
P=0.001 by log-rank test
aNot reached at median follow-up of 9.4
months; bHR for progression or death.
No. at risk
Ibrutinib
Ofatumumab
Months
550
450
350
250
150
50
–50
ALC
0 111 2 3 4 5 6 7 8 9 10
Months
25
0
–25
–50
–75
–100
SPD
0 111 2 3 4 5 6 7 8 9 10
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e i
n A
LC
(%
)
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e i
n S
PD
(%
)
Pattern of Response:
Blood Lymphocytes vs Lymph Nodes
ALC = absolute lymphocyte count; SPD = sum of the products of perpendicular diameters of lymph nodes.
Byrd et al, 2013.
Ibrutinib: Long-Term Follow-up
Byrd et al, 2015.
Months From Initiation of Study Treatment
PF
S (
Pro
po
rtio
n)
1.0
18
0.8
0.6
0.4
0.2
128 36 4224 300
Censored0.0
Relapsed/refractory
Treatment-naive
Ibrutinib Discontinuation and
Richter’s Transformation
Maddocks et al, 2015.
Cu
mu
lati
ve I
ncid
en
ce o
f
Ibru
tin
ib D
isco
nti
nu
ati
on
No. at risk: 308 261 169 135 86 58 34 10 0
Months
30
0 6 12 18 24 30 36 42 48
25
20
15
10
5
0
CLL progression
Richter’s transformation
Other event
Ibrutinib-Related Adverse Events
▶ Disrupts collagen-induced platelet aggregation
▶ vWF binding
vWF = von Willebrand factor.
Lipsky et al, 2015.
Months on Study
Cu
mu
lati
ve I
ncid
en
ce o
f E
ven
ts
Incidence
Confidence intervals
At risk: 85 38 34 20 18 4
On drug: 85 81 70 43 40 4
Management of Ibrutinib Bleeding Issues
▶ Avoid aspirin, NSAIDs, fish oil
▶ Avoid warfarin◼ May consider alternative anticoagulants with caution
NSAIDs = nonsteroidal anti-inflammatory drugs.
Imbruvica® prescribing information, 2017; Lipsky et al, 2015.
Other AEs Associated With Ibrutinib
▶ Bruising
▶ Diarrhea
▶ Fatigue
▶ Upper respiratory tract infection
▶ Rash
▶ Nausea
▶ Arthralgia
▶ Atrial fibrillation
▶ Cytopenias
Treatment discontinuation due to AEs = 6-20%No evidence of cumulative toxicity
AEs = adverse events.
Imbruvica® prescribing information, 2017.
100
12
75
50
25
024 36 480
100
12
75
50
25
024 36 480
Del 17pDel 11 qNeither del 17p nor del 11q Complex karyotypeNo complex karyotype
Ibrutinib Has Inferior PFS in Patients With
Complex Karyotype
Thompson et al, 2015.
Even
t-F
ree S
urv
iva
l(%
)
Time (mo)
Even
t-F
ree S
urv
iva
l(%
)
Time (mo)
P=0.02 P<0.0001
n Event-Free
Neither del 17p nor del 11q 24 18 (75.0%)
del 11q 28 22 (78.6%)
del 17p 34 17 (50.0%)
n Event-Free
No complex karyotype 35 28 (80.0%)
Complex karyotype 21 7 (33.3%)
BTK C481S-Resistant Clones Detected at an
Estimated Median of 9.3 Months Before Relapse
UPN = unique patient number.
Woyach et al, 2017.
Managing Resistance to Ibrutinib
▶ Mechanisms for resistance to ibrutinib have been
identified
▶ Testing not widely available
▶ Management of resistance not clearly defined
▶ Resistance mechanisms for other agents not defined
▶ Referral to a CLL center required
Woyach & Johnson, 2015.
Ibrutinib: Conclusion
▶ Approved frontline therapy for all CLL patients◼ May not be the best frontline choice for patients <65 years
▶ Promising responses ~90%
▶ Low incidence of complete responses (2-7%)
▶ Response deepens over time◼ Median time to response: 4 months
◼ Median time to best response: 12 months
▶ del(17p) responds but PFS is shorter
▶ Use full dose and avoid disruptions
▶ Avoid using with anticoagulation
▶ Follow stopping rules prior to surgical interventions
Targeting Kinases in CLL
Awan & Byrd, 2014.
Idelalisib
▶ Selective PI3K delta inhibitor
▶ Single-agent response rate: 72%◼ 39% PR and 33% PR + L
PR = partial response; PR + L = partial response with treatment-induced lymphocytosis.
Brown et al, 2014.
Idelalisib for Relapsed/Refractory CLL
Brown et al, 2014.
Median PFS: 15.8 months Median OS: not reached
100
75
50
25
00 6 12 18 24 30 36 42
100
75
50
25
00 6 12 18 24 30 36 42
Months From Start of Idelalisib Months From Start of Idelalisib
PFS (N=54) OS (N=54)
PF
S (
%)
OS
(%
)
Time (mo)
PF
S (
%)
Phase III Trial: Idelalisib + Rituximab vs
Placebo + Rituximab for Relapsed CLL
Sharman et al, 2014.
Idelalisib + R
Placebo + R
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Study Arm nMedian PFS
(mo)
Idelalisib + R 110 19.4
Placebo + R 110 7.3
Idelalisib + Rituximab in Relapsed CLL
Furman et al, 2014.
180,000
120,000
60,000
40,000
30,000
20,000
10,000
00 6 12 18 24 30 36 42 48
Weeks
Ab
so
lute
Lym
ph
ocyte
Co
un
t (p
er
mm
3)
Idelalisib + Rituximab Placebo + Rituximab
125
100
75
50
25
-25
-50
-75
-100
0
Idelalisib in del(17p) CLL
Mut = mutation.
Coutre et al, 2014.
Bes
t %
Ch
an
ge in
SP
D
Idelalisib + Rituximab
(n=102)
Placebo + Rituximab
(n=101)
Neither del(17p) or TP53
Mut del(17p) and/or TP53
Mut neither del(17p) or TP53
TP53 mut del(17p) and/or TP53 mut
del(17p)/TP53 Mutation IGHV-Unmutated
Idelalisib OS in High-Risk CLL
Sharman et al, 2014.
Placebo + R
Idelalisib + R Overa
llS
urv
ival
(%)
Time (mo)
100
80
60
40
20
00 2 2624222018161412104 6 8
Time (mo)
Overa
llS
urv
ival
(%)
100
80
60
40
20
00 2 2624222018161412104 6 8
Study Arm nMedian OS
(mo)
Idelalisib + R 46 >18
Placebo + R 49 14.8
P=0.001
Study Arm nMedian OS
(mo)
Idelalisib + R 91 >19
Placebo + R 93 18.1
P=0.0003
Idelalisib + R
Placebo + R
Adverse Events With Idelalisib
▶ Pneumonitis◼ Distinguish from infectious issues
◼ Leading cause of discontinuation
▶ Diarrhea◼ Early onset
◼ Late onset
◼ Colitis (secondary to T-cell activation)
▶ Transaminitis
Zydelig® prescribing information, 2016.
Deciding Between Ibrutinib and Idelalisib
Choose Ibrutinib if
Patient Has:
Choose Idelalisib if
Patient Has:
Allergy to rituximab Need for anticoagulation
Inflammatory bowel disease Atrial fibrillation
Liver problems
Need for
concurrent azoles
(CYP3A inhibitors)
Lung problems
1.00
0.25
0.50
0.75
0.002520151050
1.00
0.25
0.50
0.75
0.002520151050
Sequencing Ibrutinib and Idelalisib
▶ Overall response rate◼ Idelalisib after ibrutinib:
50%
◼ Ibrutinib after idelalisib:
77%
▶ PFS ◼ Alternate KI: not reached
– Median follow-up of 5
months
◼ Non-kinase inhibitor:
7 months
KI = kinase inhibitor; Ibr = ibrutinib; Ide = idelalisib.
Mato et al, 2015.
PFS: Alternate KI Therapy Following Ibr/Ide Discontinuation
PFS: Non-KI Therapy Following Ibr/Ide Discontinuation
Months
Months
Kinase Inhibitor Efficacy
▶ Effective in patients with previously untreated and
relapsed CLL
▶ Effective in patients with otherwise limited therapeutic
options, including those who have progressed on kinase
inhibitors
▶ Effective in patients with conventional high-risk features
Bcl-2 Pathway: Balancing Bcl-2 and BAX
BCR = B-cell receptor; IgL = immunoglobulin light chain; IgH = immunoglobulin heavy chain; BCL = B-cell lymphoma;
CARD11 = caspase recruiting domain-11; IKKa = inhibitor of NF-κB kinase; MALT1 = mucosa-associated lymphoid tissue translocation protein 1;
MAPK = mitogen-activated protein kinase; MAPKK = MAPK kinase; Mcl-1 = myeloid cell leukemia differentiation protein-1; NfκB = nuclear factor κB;
P = phosphorylation; PKCb = protein kinase C beta; SFK = SRC family kinase; SYK = spleen tyrosine kinase; Y = tyrosine.
Cheson, 2014.
Venetoclax (ABT-199)
▶ Highly selective inhibitor of Bcl-2
▶ Bcl-2 is central to the survival of CLL cells◼ Inhibition triggers apoptosis
▶ First in human, phase I dose-escalation study of daily
oral venetoclax with expansion cohort
▶ Relapsed/refractory population
▶ 89% were considered high risk
Roberts et al, 2016.
100
–100
0
–50
50
–100
0
–50
50
200 mg
200 mg
150 mg
800 mg
Expansion
(400 mg)
1,200 mg
300 mg
600 mg
400 mg
200 mg
200 mg
150 mg
800 mg
Expansion
(400 mg)
1,200 mg
300 mg
600 mg
400 mg
Venetoclax for Progressive CLL: Response
Roberts et al, 2016.
▶ Overall response rate was 79% (n = 116)
▶ Complete remissions occurred in 20%
▶ Minimal residual disease negativity was achieved in 5%
▶ Overall response rate did not vary on the basis of the number of
previous therapies or other usual risk factors
Absolute Lymphocyte Count Nodal Mass
Ch
an
ge F
rom
Baselin
e (
%)
Ch
an
ge F
rom
Baselin
e (
%)
100
25
50
75
0
0 302724211815
400-mg group
>400-mg group
<400-mg group
12963
100
25
50
75
0
0 30272421181512963
Venetoclax for Progressive CLL:
PFS Results
▶ Median duration of follow-up was 17 months
▶ 15-month PFS was 69% in the 400-mg group
▶ 51 patients remained on treatment at the time of publication
▶ Richter’s transformation occurred in 16% (n=18)
▶ 2-year overall survival was 84%
Roberts et al, 2016.
PF
S (
%)
MonthP
ati
en
ts W
ith
Resp
on
se (
%)
Month
Partial responseComplete response
Venetoclax for Patients With
del(17p) CLL: PFS Results
▶ Patients with del(17p) had:◼ Overall response rate: 71%
◼ Complete response rate: 16%
▶ Approved for second-line therapy in patients with del(17p) in April 2016
Roberts et al, 2016; FDA, 2016.
PF
S (
%)
Month
Patients without del(17p)
Patients with del(17p)
100
25
50
75
0
0 30272421181512963
Median PFS: 16
months
Venetoclax: Tumor Lysis Syndrome
▶ First three patients received initial dose of 200 mg◼ All three developed TLS
▶ Stepwise ramp-up dosing was developed in response
▶ Amendment to protocol included TLS prophylaxis and
inpatient observation on D1 and D8
▶ Patients with bulky disease required inpatient
observation for all dose escalations
TLS = tumor lysis syndrome.
Roberts et al, 2016.
Dose-Escalation Cohort Expansion Cohort
Day –7
Wk 1Wk 2
Wk 3
Wk 1Wk 2
Wk 3Wk 4
Wk 5
50 mg50 mg
Step-
up
dose
Target
group
dose 20 mg 50 mg100
mg
200
mg
400
mg
Venetoclax: Dose-Limiting Toxicities
aInitial cohort prior to protocol amendment instituting dose ramp-up.bSudden death.
Roberts et al, 2016.
Dose
(mg)
TLS
n (%)
Neutropenia
n (%)
Muscle Spasms
n (%)
Vomiting
n (%)
Thrombocytopenia
n (%)
200a 3 (100) 0 0 0 0
150 0 0 0 0 0
200 0 0 0 0 0
300 1 (14) 0 0 0 0
400 0 0 1 (14) 1(14) 1 (14)
600 0 1(7) 0 0 0
800 0 0 0 0 0
1200 1 (20)b 0 0 0 0
Emerging Data on
Novel Targeted Therapies
Acalabrutinib (ACP-196): In Vitro Data
▶ More selective, second-generation, irreversible BTK
inhibitor
▶ Designed to improve upon the safety and efficacy of first-
generation BTK inhibitors◼ Ibrutinib irreversibly inhibits alternative kinase targets in addition
to BTK: EGFR, TEC, ITK, TXK
◼ Associated with rash, diarrhea, bleeding, atrial fibrillation
EGFR = epidermal growth factor receptor; TEC = tyrosine kinase expressed in hepatocellular carcinoma;
ITK= interleukin-2-inducible T-cell kinase; TXK = T-cell X chromosome kinase.
Byrd et al, 2016.
Adverse Events With Acalabrutinib
URI = upper respiratory infection.
Byrd et al, 2016.
All Grades
(%)
Grades 1/2
(%)
Grades 3/4
(%)
Headache 43 43 0
Diarrhea 39 38 2
Pyrexia 23 20 3
URI 23 23 0
Fatigue 21 18 3
Peripheral edema 21 21 0
Hypertension 20 13 7
Contusion/petechiae 34 34 0
Arthralgia 16 15 2
Acalabrutinib: BTK Occupancy
QD = once daily; BID = twice daily.
Byrd et al, 2016.
▶ Low rates of adverse
events allowed safe
administration of
twice-daily dosing
▶ Full target coverage
may reduce drug
resistance
BTK Occupancy, 100 mg, Twice-Daily Cohort
Cohort
Time of Assessment
BT
K O
ccu
pan
cy (
%)
BT
K O
ccu
pan
cy (
%)
BTK Occupancy, All Cohorts
100
Before
100 mg QD(N = 8)
Median
Median
After
89%
Day 1, 4 hrafter dosing
Day 8, 4 hrafter dosing
Day 2before dosing
Day 8before dosing
Day 28, 4 hrafter dosing
Day 28before dosing
97% 95% 97% 97%99% 99%
99%
Before
175 mg QD(N = 8)
After
87% 99%
Before
250 mg QD(N = 7)
After
92% 100%
Before
400 mg QD(N = 6)
After
95% 100%
Before
100 mg BID(N = 27)
After
97% 100%
90
80
70
6010
0
100
0
5080
90
N = 28 N = 26 N = 27 N = 28N = 27 N = 19
25
–100
0
0
100
200
300
400
500
600
700
–100 –100
–90
–80
–70
–60
–50
–40
–30
–20
–10
0
–75
–50
–25
9876543210
Acalabrutinib: Change in ALC and SPD
▶ Median of 3 previous CLL therapies
▶ 31% with del(17p)
▶ 75% with unmutated IGHV genes
Byrd et al, 2016.
Med
ian
Ch
an
ge F
rom
Baselin
e i
n A
LC
(%
)
Med
ian
Ch
an
ge F
rom
Baselin
e i
n S
PD
(%
)
PatientCycle
ALC (N = 61)
SPD (N = 56)
Max
imu
m C
han
ge
in
SP
D (
%)
Stable
disease
Partial
response
Partial response
with lymphocytosis
100
90
80
70
60
50
40
30
20
10
00
No. at risk:
2 4 6 8 10 12 14 16 18
61 59 59 58 57 48 32 20 16 3Median
follow-up (mo) 14.3 19.2 17.8 16.4 14.6 11.8
20
9080706050403020100
0 0 0 05
100
10
1025
13
Acalabrutinib: Response
▶ Median follow-up of 14.3 months
▶ Overall response rate was 95%
▶ No cases of Richter’s transformation
▶ Only one case of CLL progression has occurred
Byrd et al, 2016.
Best
Resp
on
se (
%)
Cohort Month
PF
S (
% o
f P
ati
en
ts)
Stable
disease
Partial
response
Partial response
with lymphocytosis
(N = 60) (N = 8) (N = 8) (N = 7) (N = 6) (N = 31)
Chimeric Antigen Receptor-Modified T Cells
Porter et al, 2011; Casucci & Bondanza, 2011.
▶ Lentiviral vector
expressing a chimeric
antigen receptor with
specificity for the B-cell
antigen CD19
▶ Coupled with CD137 and
CD3-zeta (costimulatory
receptors in T Cells)
▶ Transduced into
autologous T cells and
reinfused
Proliferation/cytokine production
Survival
Cytotoxicity
1G
CD3
2G 3G
ZAP-70
CD28 PI3K
4-1BB, OX40TRAF2
VH VL
CD34-1BBHinge & TM
Truncated env
Truncated gag/pol
RRE
cPPT/CTS5ʹLTR
pELPS 19-BB-11556 bp
3ʹLTR (truncated)
Amp R
Bovine GH Poly A
Bacterialreplication
origin
FMC63
U3 (truncated)
R region (truncated)
R region
WPRECD19 BB
scFv
Lentiviral Vector
Generations of Chimeric Antigen Receptors
Chimeric Antigen Receptor-Modified T Cells:
Contrast-Enhanced CT Scans
Porter et al, 2011.
Axial Coronal
Before
therapy
1 month of
treatment
3 months of
treatment
Future Directions
▶ Early results with kinase inhibitors are extremely
promising
▶ Similar agents also in clinical development:◼ Monoclonal antibodies
– Ublituximab (CD20)
◼ PI3K inhibitors– TGR 1202
– Duvelisib/IPI145
▶ Novel combinations under investigation:◼ Obinutuzumab + venetoclax (CLL-14)
◼ Bendamustine + rituximab + venetoclax/ibrutinib/idelalisib
Key Takeaways
▶ Interphase FISH is standard of care at diagnosis and
relapse
▶ Early treatment does not improve survival
▶ FCR is effective in young, healthy patients without del
(17p)/TP53 mutation
▶ Kinase inhibitors are effective in patients with previously
untreated and relapsed disease, including those with
high-risk features
▶ As new therapies emerge, cost, prescription coverage,
and long-term side effects will be increasingly important
issues, especially with drug combinations
Case Studies
Case 1: Cal
▶ Cal is a 77-year-old man with del(13q), IGHV-unmutatedCLL who presents for follow-up
▶ Past medical history includes CAD, hypertension, mild CHF, and hyperlipidemia
▶ Previously treated with FCR 6 years ago and achieved a complete remission that lasted for 4 years and with mutated IGHV
▶ Followed with watchful waiting after his relapse until now when he started experiencing progressive fatigue, lymphadenopathy, and splenomegaly
▶ Laboratory evaluation reveals:◼ WBC count: 105,000 cells/µL ◼ Hemoglobin: 10.5 mg/dL ◼ Platelet count: 96,000 cells/µL
CAD = coronary artery disease; CHF = congestive heart failure; WBC = white blood cell.
Case 1 Question
Which of the following therapies would you recommend for
Cal?
a. Chlorambucil
b. Fludarabine + rituximab
c. Fludarabine + cyclophosphamide + rituximab
d. Bendamustine + rituximab
e. Chlorambucil + obinutuzumab
f. Chlorambucil + ofatumumab
g. Idelalisib + rituximab
h. Ibrutinib
Case 1 Question (cont.)
Which of the following therapies would you recommend for
Cal?
a. Chlorambucil
b. Fludarabine + rituximab
c. Fludarabine + cyclophosphamide + rituximab
d. Bendamustine + rituximab
e. Chlorambucil + obinutuzumab
f. Chlorambucil + ofatumumab
g. Idelalisib + rituximab
h. Ibrutinib
Case 2: Fred
▶ Fred is a 57-year-old man who was diagnosed with
del(17p), IGHV-unmutated CLL 6 months ago
▶ Presents with progressive fatigue, lymphadenopathy in
the axillary and inguinal regions, and palpable
splenomegaly of 7 cm below the costal margin while he
is taking ibrutinib
▶ Only significant past medical history is for hypertension,
for which he takes hydrochlorothiazide
▶ Laboratory evaluation reveals:◼ WBC count: 88,000 cells/µL
◼ Hemoglobin: 9.8 mg/dL
◼ Platelet count: 102,000 cells/µL
Case 2 Question
What is the optimal treatment for this patient?
a. Idelalisib
b. FCR
c. Lenalidomide
d. Venetoclax
e. Steroids
Case 2 Question (cont.)
What is the optimal treatment for this patient?
a. Idelalisib
b. FCR
c. Lenalidomide
d. Venetoclax
e. Steroids
Questions?
References
AbbVie Inc (2016). Imbruvica (ibrutinib) approved by U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. Chicago, IL. Available at:
https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm
Awan FT & Byrd JC (2014). New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin Cancer Res, 20(23):5869-5874.
DOI:10.1158/1078-0432.ccr-14-1889
Brown JR, Byrd JC, Coutre SE, et al (2014). Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110ō, for relapsed/refractory chronic lymphocytic
leukemia. Blood, 123(22):3390-3397. DOI:10.1182/blood-2013-11-535047
Burger JA, Tedeschi A, Barr PM, et al (2015). Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med, 373(25):2425-2437.
DOI:10.1056/nejmoa1509388
Byrd JC, Brown JR, O’Brien S, et al (2014). Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med, 371(3):213-223.
DOI:10.1056/nejmoa1400376
Byrd JC, Furman RR, Coutre SE, et al (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med, 369(1):32-42.
DOI:10.1056/nejmoa1215637
Byrd JC, Furman RR, Coutre SE, et al (2015). Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent
ibrutinib. Blood, 125(16):2497-2506. DOI:10.1182/blood-2014-10-606038
Byrd JC, Harrington B, O’Brien S, et al (2016). Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med, 374(4):323-332.
DOI:10.1056/nejmoa1509981
Casucci M & Bondanza A (2011). Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes. J Cancer, 2:378-382.
DOI:10.7150/jca.2.378
Cheson BD (2014). CLL and NHL: the end of chemotherapy? Blood, 123(22):3368-3370. DOI:10.1182/blood-2014-04-563890
CLL Trialists’ Collaborative Group (1999). Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Canc
Inst, 91(10):861-868.
Coutre SE, Furman RR, Sharman JP, et al (2014). Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin
Oncol (ASCO Annual Meeting Abstracts), 32(Suppl 15). Abstract 7012.
Damle RN, Wasil T, Fais F, et al (1999). Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
Blood, 94(6):1840-1847.
References
Döhner H, Stilgenbauer S, Benner A, et al (2000). Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med, 343:1910-1916.
DOI:10.1056/nejm200012283432602
Eichhorst B, Fink AM, Bahlo J, et al (2016). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphmide, and
rituximab in patients with advanced chrnoic lymphocytic leukaemia (CLL10): an internation, -open-label, randomised, phase 3, non-inferiority trial.
Lancet Oncol, 17(7):928-942. DOI:10.1016/s1470-2045(16)30051-1
Food and Drug Administration (2016). FDA approves new drug for chronic lymphocytic leukemia in patients with specific chromosomal abnormality [news
release]. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm495253.htm
Fischer K, Cramer P, Busch R, et al (2012). Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a
multicenter phase II trial of German chronic lymphocytic leukemia study group. J Clin Oncol, 30(26):3209-3216. DOI:10.1200/jco.2011.39.2688
Furman RR, Sharman JP, Coutre SE, et al (2014). Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med, 370(11):997-1007.
DOI:10.1056/nejmoa1315226
Goede V, Fischer K, Busch R, et al (2014). Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med, 370(12):1101-1110.
DOI:10.1056/nejmoa1313984
Hallek M, Cheson BD, Catovsky D, et al (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 111(12):5446-5456.
Hallek M, Fischer K, Fingerle-Rowson G, et al (2010). Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic
leukaemia: a randomised, open-label, phase 3 trial. Lancet, 376(9747):1164-1174. DOI:10.1016/s0140-6736(10)61381-5
Hamblin TJ, Davis Z, Gardiner A et al (1999). Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood,
94(6):1848-1854.
Hillmen P, Robak T, Janssens A, et al (2015). Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic
lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet, 385(99880):1873-1883. DOI:10.1016/S0140-
6736(15)60027-7
Imbruvica® (ibrutinib) prescribing information (2017). Pharmacyclics. Available at: https://www.imbruvica.com/docs/librariesprovider7/default-document-
library/prescribing_information.pdf
References
Kovacs G, Robrecht S, Fink AM, et al (2016). Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic
leukemia (CLL) who achieve partial response: comprehensive analysis of two phase III studies of the German CLL Study Group. J Clin Oncol. [Epub
ahead of print] DOI:10.1200/jco.2016.67.1305
Kumar S, Vij R, Kaufman JL, et al (2015). Phase I interim safety and efficacy of venetoclax (ABT-199/GDC-0199) monotherapy for relapsed/refractory (R/R)
multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts), 33. Abstract 8576.
Lipsky AH, Farooqui MZ, Tian X, et al (2015). Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia
treated with ibrutinib. Haematologica, 100(12):1571-1578. DOI:10.3324/haematol.2015.126672
Maddocks KJ, Ruppert AS, Lozanski G, et al (2015). Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia.
JAMA Oncol, 1(1):80-87. DOI:10.1001/jamaoncol.2014.218
Mato A, Nabhan C, Barr PM, et al (2015). Favorable outcomes in CLL pts with alternate kinase inhibitors following ibrutinib or idelalisib discontinuation: results
from a large multi-center study. Blood (ASH Annual Meeting Abstracts), 126. Abstract 719.
Pepper C, Majid A, Lin TT, et al (2012). Defining the prognosis of early stage chronic lymphocytic leukaemia patients. Br J Haematol, 156(4):499-507.
DOI:10.1111/j.1365-2141.2011.08974.x
Porter DL, Levine BL, Kalos M, et al (2011). Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med, 365(8):725-733.
DOI:10.1056/nejmoa1103849
Roberts AW, Davids MS, Pagel JM, et al (2016). Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med, 374(4):311-322.
DOI:10.1056/nejmoa1513257
Sharman JP, Coutre SE, Furman RR, et al (2014). Second interim analysis of a phase 3 study of idelalisib (Zydelig®) plus rituximab (R) for relapsed chronic
lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood, 124. Abstract 330.
Thompson PA, O’Brien SM, Wierda WG, et al (2015). Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory
chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer, 121(20):3612-3621. DOI:10.1002/cncr.29566
Thompson PA, Tam CS, O’Brien SM, et al (2016). Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-
mutated chronic lymphocytic leukemia. Blood, 127(3):303-309. DOI:10.1182/blood-2015-09-667675
Woyach JA & Johnson AJ (2015). Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood, 126(4):471-477.
DOI:10.1182/blood-2015-03-585075
References
Woyach JA, Ruppert AS, Guinn D, et al (2017). BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol, 35(13):1437-1443.
DOI:10.1200/jco.2016.70.2282
Zydelig® (idelalisib) prescribing information (2016). Gilead Sciences. Available at: https://www.zydelig.com/include/media/pdf/full-prescribing-information.pdf