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iFCG regimen in IGHV mutated CLL

Chronic Lymphocytic
Leukemia
Relapsed CLL Treatment
Nitin Jain, MD
Department of Leukemia
MD Anderson Cancer Center
Houston, TX
March 2018

Financial Disclosures
Research Funding
Pharmacyclics, Abbvie, Genentech, Infinity, BMS,
Pfizer, ADC Therapeutics, Seattle Genetics, Incyte,
Celgene, AstraZeneca, Servier, Verastem, Cellectis,
Adaptive Biotechnologies
Advisory Board
Pharmacyclics, Novartis, ADC Therapeutics, Pfizer,
Servier, Novimmune, Abbvie, Verastem, Adaptive
Biotechnologies, Janssen

Current Standard Rx of CLL
Meets IWCLL criteria for treatment

NO

YES

Watch and Wait

Treatment-naïve

Relapsed/Refractory

‘Age’, Comorbidities, FISH status

<65-70 yr and no
major comorbidities

>65-70 yr old,
major comorbidities

del(17p)

FCR

Ibrutinib

Ibrutinib

1. Ibrutinib
2. Venetoclax
3. Idelalisib + R

Jain N, O'Brien S. Blood Rev. 2016;233-44.

1

iFCG regimen in IGHV mutated CLL

Presentation Outline
• Approved therapies in R/R CLL
–BTK inhibitor Ibrutinib
–PI3K inhibitor Idelalisib + Rituximab
–BCL2 inhibitor Venetoclax

• Combination therapies in R/R CLL
• CART therapy in CLL

Targeting Key Signaling
Pathways in CLL
Membrane-bound immunoglobulin

Obinutuzumab

B-cell receptor

CD20

Fostamatinib
GS-9973

Lyn

Ibrutinib
ACP-196
BGB-3111

PI3K/Akt
pathway

Syk

CD20

Btk
NF-κB
pathway

571300080995
MAPK
pathway

Bcl-2

Idelalisib
IPI-145
TGR-1202

Venetoclax
Cell survival
Normal B-cell activation and proliferation
Malignant B-cell initiation and progression

Friedman DR, Weinberg JB. The Hematologist. 2013.

IBRUTINIB

BTK Inhibitor

2

iFCG regimen in IGHV mutated CLL

Ibrutinib (PCI-32765)
A Selective Inhibitor of BTK
• Forms a specific bond with cysteine481 in BTK
O

• Highly potent BTK inhibition at
IC50 = 0.5 nM
• Orally administered with once daily
dosing resulting in 24-hr target
inhibition

NH2
N

N
N

N

• In chronic lymphocytic leukemia
(CLL) cells promotes apoptosis and
inhibits CLL cell migration and
adhesion

N
O

Advani, R. et al, J Clin Oncol. 2012;42:7906.
Honigberg LA et al, Proc Natl Acad Sci U S A.2010;107:13075.
Herman SEM et al, Blood.2011;117: 6287-6296.
Ponader, et al, ASH Meeting Abstracts. 2010; 116:45.

5-Year Experience With Ibrutinib Monotherapy
PCYC-1102/1103 Phase 2 Study Design
Phase 2 (PCYC-1102)
N=132

Extension Study
(PCYC-1103)

Treatment Naïve (TN)
≥65 years
n=31

Patients with CLL/SLL
treated with
oral, once-daily ibrutinib
(420 or 840 mg/day)

≥SD

Long-Term
Follow-Up

Relapsed/Refractory*
(R/R)
n=101
*

R/R includes patients with high-risk CLL/SLL,
defined as progression of disease <24 months after
initiation of a chemoimmunotherapy regimen or
failure to respond

O’Brien et al. ASH 2016, Abstract 233

5-Year Experience With Ibrutinib Monotherapy
Best Response

100%

TN (n=31)

R/R (n=101)

Total (N=132)

87%

89%

89%

10%

14%

80%
29%

CR
PR
PR-L

60%
76%

40%

71%

55%

20%
0%
Median DOR, months
(range)
Median follow-up,
months (range)

3%

3%

3%

NR (0.0+ to 65.5+)

56.8 (0.0+ to 65.5+)

NR (0.0+ to 65.5+)

62 (1–67)

49 (1+–67)

56 (1+–67)

O’Brien et al. ASH 2016, Abstract 233

9

3

iFCG regimen in IGHV mutated CLL

5-Year Experience With Ibrutinib Monotherapy
Survival Outcomes: Overall Population
Progression-Free Survival

TN (n=31)
R/R (n=101)

Median PFS

5-year PFS

NR
52 mo

92%
43%

Overall Survival

Median OS

5-year OS

NR
NR

92%
57%

TN (n=31)
R/R (n=101)

O’Brien et al. ASH 2016, Abstract 233

5-Year Experience With Ibrutinib Monotherapy
Survival by FISH in R/R Patients*
Progression-Free Survival

Overall Survival

Median PFS

5-year PFS

Median OS

5-year OS

Del17p (n=34)

26 mo

19%

Del17p (n=34)

57 mo

32%

Del11q (n=28)

55 mo

33%

Del11q (n=28)

NR

61%

Trisomy 12 (n=5)

NR

80%

Trisomy 12 (n=5)

NR

80%

Del13q (n=13)
No abnormality** (n=16)

NR
NR

91%
66%

Del13q (n=13)
No abnormality** (n=16)

NR
NR

91%
83%

*Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population.
**No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q.

O’Brien et al. ASH 2016, Abstract 233

RESONATE™ Phase 3 Study Design

R
A
Patients with N
previously D
O
treated
M
CLL/SLL
I
Z
E

▪
▪
▪

Oral ibrutinib 420 mg once
daily until PD or
unacceptable toxicity
n=195

1:1
IV ofatumumab initial dose
of 300 mg followed by 2000
mg x 11 doses over 24
weeks
n=196

Cross over to ibrutinib
420 mg once daily after
IRC confirmed PD (n=57)

Primary Endpoint: PFS
Stratification according to:
– Disease refractory to purine analog chemoimmunotherapy (no response or <12 months)
– Presence or absence of 17p13.1 (17p del)
At time of interim analysis, median time on study was 9.4 months
Byrd J et al. NEJM 2014

4

iFCG regimen in IGHV mutated CLL

Progression-Free Survival
Progression-Free Survival (%)

100
90

Ofatumumab Ibrutinib
8.08
NR

Median
time (mo)
Hazard
ratio
(95% CI)

80
70
60

0.215
(0.146-0.317)

50

Log-rank
P value

40

< 0.0001

30

NR, not reached

20
Ibrutinib
Ofatumumab

10
0
0

3

6

195
196

183
161

116
83

9

12

15

7
1

0

Months

No. at risk
Ibrutinib:
Ofatumumab:

38
15

Byrd J et al. NEJM 2014

Overall Survival

Ibrutinib (n=195, 16 events)
Ofatumumab (n=196, 33 events)
First patient cross over

Median time (mo)
Hazard ratio
(95% CI)
Log-rank P value

Ofatumumab Ibrutinib
NR
NR
0.434
(0.238-0.789)
< 0.0049

NR, not reached

Byrd J et al. NEJM 2014

Pattern of Response:
Blood Lymphocytes vs. Lymph Nodes
25

550

Lymph
node
burden

ALC
450
0

350
-25
250
-50
150

-75
50

-100

-50
0

1

2

3

4

5

6

Month

7

8

9

10

11

0

1

3
2

4

5

6

7

8

9

10

11

Month

5

iFCG regimen in IGHV mutated CLL

IDELALISIB
PI3K-δ Inhibitor

Idelalisib, A Novel Small Molecule Inhibitor
Class I PI3K
g
a
b
d
Isoform
Expression Ubiquitous Ubiquitous Leukocytes Leukocytes
EC50 (nM)

>10,000

1,419

2,500

9

• Targeted, highly selective, oral inhibitor of
PI3K-delta (δ)
• Inhibits proliferation and induces apoptosis
in CLL cells
• Inhibits homing and retention of CLL cells in
lymphoid tissues reducing cell survival
Coutre et al. EHA 2014:S704

Phase 3 Trial of Idelalisib + Rituximab in Relapsed CLL:
Subgroup Analysis of High-Risk Groups
Primary Study 116
Double-Blind
Initial Therapy

Arm B
N=110

Placebo (BID)

Blinded
Dose

Disease
Progression

Arm A
N=110

Rituximab (6 mo)

Extension Study 117

Double-Blind
Continuous
Therapy

Idelalisib (150 mg BID)

Screen

Open-Label

Idelalisib (300 mg BID)

Idelalisib (150 mg BID)

Rituximab (6 mo)

Randomization/
Stratification

Blinded,
Independent
Review

Interim
Analyses and
Unblinding

Independent
Review

Median Follow-up, months
IDELA + R

PBO + R

1st Interim Analysis

4

4

DMC halted trial (Furman NEJM 2014)

2nd Interim Analysis

6

5

Blind ended (Coutre ASCO 2013)
• Arm A continues
• Arm B crosses over

Update

13

11

PFS, OS by subgroup analysis

Sharman et al., ASH 2014, Abstract 330

6

iFCG regimen in IGHV mutated CLL

PFS, Including Extension Study*
Idelalisib + R vs Placebo + R
All Patients
P ro g re s s io n -fre e S u rv iv a l (% )

100

80

Idelalisib + rituximab approved for
- R/R CLL
60

40

20

Idelalisib + R (n=110)

Placebo + R (n=110)

0
0

N at risk
IDELA + R
PBO + R

2

4

6

8

10

95
66

92
58

83
51

64
33

12

14

16

18

20

22

24

26

12
0

7
-

1
-

1
-

0
-

T im e ( m o n t h s )

110 102
110 86

43
15

Median PFS (95% CI)
IDELA + R

19.4 mo (16.6, ‒)

PBO + R

7.3 mo (5.5, 8.5)

26
5

19
1

HR (95% CI)

p-value

0.25 (0.16, 0.39)

<0.0001

*Placebo + R includes those patients who received open-label idelalisib after unblinding without prior progression (n=42).

Sharman et al., ASH 2014, Abstract 330

Serious Adverse Events In ≥2 Patients On IDELA + R
SAE, n (%)
Patients with any SAE
Pneumonia
Pyrexia
Febrile neutropenia
Sepsis
Pneumonitis
Pneum. jirov. pneumonia
Diarrhea
Hypercalcemia
Abdominal pain
Hypoxia
Colitis
Deep vein thrombosis
Sepsis syndrome
Neutropenia
Neutropenic sepsis
Lung infection
Transient ischemic attack

IDELA + R (N=110)

Placebo + R (N=108)

54 (49)
10 (9)
10 (9)
5 (5)
5 (5)
4 (4)
3 (3)
3 (3)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)

41 (38)
11 (10)
3 (3)
5 (5)
3 (3)
1 (1)
1 (1)
0
2 (2)
1 (1)
1 (1)
0
0
0
0
0
0
0

Colitis with PI3K-δ Inhibition
WT

p110δ D910A/D910A

p110δ D910A/D910A
- IBD like picture
- Mucosal hyperplasia
- Crypt abscess

Clinical Management
- Late event (>6mos)
- Drug hold
- Oral/IV steroids

Okkenhaug et al. Science 2002.

7

iFCG regimen in IGHV mutated CLL

Idelalisib Summary
▪Approved for patients with relapsed CLL
in combination with rituximab
▪Immune-mediated colitis, transaminitis,
pneumonitis
▪EMA/FDA Advisory (March 2016)
– Increased deaths due to infections in Phase
III trials of idelalisib vs. placebo
– All patients PCP prophylaxis
– CMV monitoring

VENETOCLAX
(ABT-199)
Bcl-2 Inhibitor

Bcl-2 in CLL
▪ Bcl-2 expression is uniformly high in CLL
NO2 H
N

▪ ABT-199 is a selective, potent, orally bioavailable
Bcl-2 inhibitor

O

O2S
NH

O

O
N
N

▪ ABT-199 binds Bcl-2 with high affinity and with
substantially lower affinity to Bcl-xL, Bcl-w and
MCL-1

N
H

N

Cl

ABT-199

Souers et al. Nature Med. 2013
24

8

iFCG regimen in IGHV mutated CLL

Venetoclax
CRR and ORR Rates by Subgroups
Variable

No.

ORR %

CR %

All patients

116

79

20

17p deletion

31

71

16

Unmutated IGHV

46

76

17

Flu - refractory

70

79

16

Prior Rx ≥ 4

56

73

16

Age ≥ 70

34

71

21

Nodes > 5 cm

67

78

8

Roberts et al N. Engl J Med 2016; 374; 311-22

Best Percent Change from Baseline in Blood
Lymphocyte Count and Nodal Mass by CT Scan
Blood Lymphocytes (n=60)
•

Nodal Mass by CT Scan (n= 93)

Median Time to 50% reduction: 14 days, range [1 – 49]

•

The median time to 50% reduction 1.4 months, range [0.65 –
13.7]*

•

78 (84%) evaluable patients had at least a 50% reduction in sum
of the product of diameters (SPD) of nodal masses

Cohort Dose (mg)

Cohort Dose (mg)

150

200

300

400

Data represents patients with lymphocyte count >5 x 109/L at
baseline
25

600
26

800

1200

400 Safety Expansion

*coincides with first protocol specified CT scan at 6 weeks.
26

Seymour et al. EHA 2014, Abstract S702

% Change from Baseline

0

-25

-50

Best Percent Change from Baseline in Bone
Marrow Infiltrate (n=51)

-75

• Median time to 50% reduction: 5.5 months, range [1.9 – 17.4]*
• 46/51 (90%) evaluable patients have had at least a 50% reduction.
-100

# Patient

had 70% infiltrate at baseline and at Week 24
^Patient did not have CLL infiltrate at baseline.

Anti-tumor activity of ABT-199 was observed in all tumor compartments.
27

9

iFCG regimen in IGHV mutated CLL

Relapsed CLL
Combination Therapy: Future?

BCRi
+/BCL2i
+/CD20 mAb

Combined Venetoclax and Ibrutinib
for Patients with Previously
Untreated High-Risk CLL, and
Relapsed/Refractory CLL
A Phase II Trial

Nitin Jain, Philip Thompson, Alessandra Ferrajoli, Jan Burger, Gautam
Borthakur, Koichi Takahashi, Prithviraj Bose, Zeev Estrov, Elias Jabbour,
Marina Konopleva, Yesid Alvarado, Tapan Kadia, Musa Yilmaz, Courtney
DiNardo, Maro Ohanian, Jorge Cortes, Rashmi Kanagal-Shamanna, Keyur
Patel, Naveen Garg, Xuemei Wang, Nina Fru, Nichole Cruz, Varsha Gandhi,
William Plunkett, Hagop Kantarjian, Michael Keating, William Wierda
Department of Leukemia, MDACC
ASH 2017, Abstract 429

VEN + IBR in CLL, ASH 2017

BCR vs. BCL2 Inhibitors

Response

BCR Inhibitor
(Ibrutinib)

BCL2 Inhibitor
(Venetoclax)

Blood ++
LN +++
Marrow +

Blood +++
LN ++
Marrow +++

Lymphocytosis +++

-

CR in R/R CLL

10%

20-25%

AE profile

Atrial fibrillation,
neutropenia, bleeding

TLS, neutropenia

10

iFCG regimen in IGHV mutated CLL

VEN + IBR in CLL, ASH 2017

Ibrutinib + Venetoclax Clinical Trial
• Investigator-initiated phase II trial
• Patients with a diagnosis of CLL/SLL
• Cohort 1: relapsed/refractory CLL

• Cohort 2: untreated with at least one
high-risk feature
•
•
•
•

del(17p) or mutated TP53
del(11q)
unmutated IGHV
≥65 yrs

VEN + IBR in CLL, ASH 2017

Response: R/R Cohort
100
90

3

80

42

70

69

77

60

80

50

91
40
30

58
40

20

31

23

10

8

0

0

3 mo IBR

3 mo VEN+IBR

PR%
n=34

13

n=26

6 mo VEN+IBR

CR/CRi %
n=16

15

9 mo VEN+IBR

20
12 mo VEN + IBR

BM MRD neg %
n=13

n=5

Seymour, JD et al. ASH 2017, Abstract LBA-2

11

iFCG regimen in IGHV mutated CLL

12

iFCG regimen in IGHV mutated CLL

JCAR014 CART in High-risk R/R CLL
• 24 pts with R/R CLL
• No of prior therapies 5
• Ibrutinib refractory 79%
• Venetoclax refractory 25%
• FDG-avid PET 93%
• Documented RT/PLL 33%
• Response at 4 weeks (JCAR014 + Cy/Flu)
• ORR 74%, CR 21%
• PET+ disease CR 64%
• Bone marrow disease 88% MRDneg
Turtle C et al. ASH 2016

13

iFCG regimen in IGHV mutated CLL

Conclusions
• Targeted therapies – great future in CLL
– Ibrutinib – Approved for CLL
– Idelalisib – Approved for R/R CLL
– Venetoclax – Approved for R/R del(17p) CLL

• Combination therapies are the future

Thank you!

njain@mdanderson.org

14

2/28/2018

Ibrutinib intolerance and resistance
in CLL
Alexey V. Danilov MD, PhD
Associate Professor of Medicine

Oregon Health & Science University
Danilov@ohsu.edu

1

Disclosures for Danilov
▪ Research funding:
▪ Leukemia & Lymphoma Society
▪ Lymphoma Research Foundation
▪ NCI/SWOG
▪ Takeda Oncology
▪ Gilead Sciences
▪ Genentech
▪ Consultancy/Honoraria:
▪ Genentech
▪ Verastem
▪ TG Therapeutics
▪ Astra Zeneca
▪ Juno Therapeutics
▪ Gilead Sciences
2

Post-ibrutinib world
▪Ibrutinib intolerance
– Role of other BTK inhibitors (acalabrutinib)
– Alternative pathway medications
– Factors predicting poor ibrutinib outcomes

▪Ibrutinib resistance
– Mechanisms (in CLL)
– What to do?

3

1

2/28/2018

Ibrutinib clinical trials experience
TN
(n=31)

R/R
(n=101)

62
(1–67)

49
(1–67)

Patients remaining on ibrutinib therapy, n (%)

20 (65%)

30 (30%)

Primary reason for discontinuation, n (%)
Progressive disease
Adverse event
Consent withdrawal
Investigator decision
Lost to follow-up

1 (3%)
6 (19%)
3 (10%)
0
1 (3%)

33 (33%)
21 (21%)
5 (5%)
11 (11%)
1 (1%)

Disposition
Median time on study, months (range)

O’Brien, Furman et al, ASH 2016

4

Ibrutinib ‘real world’ experience
d/c rate = 42% after median f/u of 17 months
Toxicity: 50%
Disease progression: 10-20%

Mato AR et al, ASH 2016

5

Mato AR et al, ASH 2016

6

Reasons for Discontinuation
Front Line (%)

Relapsed (%)

arthralgias (42)

atrial fibrillation (12.3)

Afib (25)

Infection (11)

Rash (16)

Pneumonitis (10)
Bleeding (9)
Diarrhea (7)

Median Time to Discontinuation
Bleeding

8 months

Diarrhea

7.5 months

Atrial fibrillation

7 months

infection

6 months

arthralgia

5 months

pneumonitis

4.5 months

rash

3.5 months

2

2/28/2018

Outcomes following ibrutinib failure

Mato et al, 2017

7

Outcomes following ibrutinib failures

OS 4 months (Richters)
OS 22 months (progression)

Woyach et al, 2017

8

Richters syndrome on novel agents:
The median OS for the entire cohort was 3.3 months

With a median follow-up 10.6 months, none of the 7 patients who achieved CR had died
Presented by: Matthew S. Davids, MD, MMSc

3

2/28/2018

Medical comorbidities assessed by CIRS negatively
impact survival in the era
of targeted therapies in CLL: a multicenter
retrospective analysis
Max J. Gordon MD1, Stephen M. Amrock MD SM 1, Xavier Rivera3, Spencer James MD MPH 2, Sudhir Manda
MD FACP2, Stephen E. Spurgeon MD1, Daniel Persky 3,Alexey V. Danilov MD PhD1
1Oregon

Health & Science University, Portland, OR 2Geisel School of Medicine at Dartmouth, Hanover, NH
3University of Arizona, Tucson, AZ

Tolerance of ibrutinib
Dose reduction (n=21)
80

≥1

60

0

60

D/C therapy (n=24)

Yes
No

40

40
20

20

0

0
CIRS<7

CIRS<7

CIRS≥7

Relative risk

P=

CIRS ≥7

11.9

<0.001

CIRS 3-4

4.6

0.01

CIRS≥7

Relative risk

P=

CIRS ≥7

2.5

0.02

CIRS 3-4

3.8

0.005

Outcomes with ibrutinib

➢ Median 37 vs 23 months

➢ OS at 24 months 100 vs 79%

4

2/28/2018

Ibrutinib is a CYP3A4 substrate

Black dots – ibrutinib alone
White dots – ibrutinib PLUS

De Jong et al, 2015

Acalabrutinib Monotherapy in Patients With
Ibrutinib Intolerance: Results From the Phase
1/2 ACE-CL-001 Clinical Study
Farrukh T. Awan,1 Anna Schuh,2 Jennifer R. Brown,3 Richard R. Furman,4 John M. Pagel,5 Peter Hillmen,6
Deborah M. Stephens,7 Ahmed Hamdy,8 Raquel Izumi,8 Priti Patel,8 Min Hui Wang,8 John C. Byrd1
Ohio State University Comprehensive Cancer Center, Columbus, OH; 2University of Oxford, Oxford, UK;
3Dana-Farber Cancer Institute, Boston, MA; 4Weill Cornell Medical College, New York Presbyterian Hospital,
New York, NY; 5Swedish Medical Center, Seattle, WA; 6St. James’s University Hospital, Leeds, UK; 7University
of Utah Huntsman Cancer Institute, Salt Lake City, UT; 8Acerta Pharma, Redwood City, CA

1The

14

Awan F, et al. ASH 2016

Acalabrutinib (ACP-196)
• Acalabrutinib is a highly selective, potent BTK inhibitor
• Minimal off-target effects on TEC, EGFR, or ITK signaling in vitro
Kinase Selectivity Profiling at 1 mol/L1
Acalabrutinib

Ibrutinib

Larger red circles represent stronger inhibition

1

Kinase Inhibition IC50 (nmol/L)1
Kinase

Acalabrutinib

Ibrutinib

BTK

5.1

1.5

TEC

93

7.0

BMX

46

0.8

TXK

368

2.0

ERBB2

~1000

6.4

EGFR

>1000

5.3
4.9

ITK

>1000

JAK3

>1000

32

BLK

>1000

0.1

Covey AACR 2015. Abstract 2596.

15

5

2/28/2018

Awan F, et al. ASH 2016

ACE-CL-001: Acalabrutinib Monotherapy in CLL
– ACE-CL-001 is an ongoing, multinational, phase 1/2 study designed to evaluate
acalabrutinib monotherapy in patients with CLL/SLL.
– Previously reported ORR with acalabrutinib monotherapy:
• Relapsed/refractory: 95% (85% PR, 10% PRL; n = 60).1
• Treatment-naïve: 97% (87.5% PR; 10% PRL; n = 72).2
– Data are presented for 33 patients in the ibrutinib-intolerant cohort with data cut on
01 September 2016.

1

Byrd JC, et al. N Engl J Med. 2016;374(4):323-332. 2 Byrd JC, et al. ASCO 2016 [poster presentation].

16

Awan F, et al. ASH 2016

Patient Disposition
Disposition, n (%)
Treated

33 (100)

Discontinued treatment

9 (27)

Progressive disease

3 (9)

Adverse eventa

3 (9)

Physician decisionb

1 (3)

Otherc

2 (6)

On treatment

24 (73)

aStroke

(hemorrhagic) and fungal infection led to death (n = 1 patient each); metastatic endometrial
cancer (n = 1).
bConcurrent hemophilia.
cIncrease in BTK C481S mutation frequency in peripheral blood and central nervous system involvement
(n = 1 patient each).

• Median time on treatment: 12.2 months (range, 0.2-23.6 months)
17

Awan F, et al. ASH 2016

Recurrence of Prior Ibrutinib-Related AEs
Grade Change in Severity on Acalabrutinib vs on Ibrutinib
Adverse Event
Arthralgia (n = 1)
Atrial fibrillation (n = 1)
Contusion (n = 1)

Increased

Rash (n = 3)

Unchanged

2→1
2→2
1 → 2a

Diarrhea (n = 2)
Ecchymosis (n = 1)
Fatigue (n = 3)
Muscle spasms (n = 1)
Myalgia (n = 1)
Peripheral edema (n = 1)
Panniculitis (n = 1)

Decreased

1 → 2a

2→1
3→1
2 → 1a
2→1

1→1
1→1
1→1
1→1

3 → 2a
3 → 1*

1→1
1 → 1a

Multiple occurrences of the same AE for a given patient were counted once for each Preferred Term.
by investigator as related to acalabrutinib.
a Determined

18

6

2/28/2018

Awan P, et al. ASH 2016

Key Findings
• Acalabrutinib was well tolerated in ibrutinib-intolerant patients.
– A total of 12 of 33 (36%) patients experienced AE recurrence, most of which were
decreased or the same severity.

• No patients discontinued because of a recurrent AE.

• Acalabrutinib has promising activity in ibrutinib-intolerant patients.
– ORR: 79%
– 81% of responding patients have a duration of response (PRL or better) ≥12 months.
– Median PFS has not been reached.

• Acalabrutinib efficacy in ibrutinib-intolerant patients is being evaluated in an
ongoing phase 2 trial (NCT02717611).
19

Ibrutinib RESISTANCE

Woyach et al, 2014
Burger J et al, 2016

20

Mutations in BTK/PLCγ precede ibrutinib
RESISTANCE

Woyach et al, 2017

21

7

2/28/2018

After ibrutinib – what’s next?
▪Acalabrutinib (ibrutinib-intolerant only)
▪Alternative BTK inhibitors which do not bind C481S:
– GDC-0853
– SNS-062
– ARQ-531

▪Venetoclax
▪Idelalisib (Duvelisib, Umbralisib)
▪Other: PD-1; CART; CDK inhibitors (dinaciclib, voruciclib)

22

Venetoclax: Selective BCL-2 Inhibitor
1

An Increase in BCL-2
Expression Allows the
Cancer Cell to Survive

Pro-apoptotic
Proteins
(BAX, BAK)

2

Venetoclax Binds to and
Inhibits Overexpressed BCL-2

3

Apoptosis is Initiated
Active
Caspase

Apoptosome
Venetoclax

Anti-apoptotic
Proteins
(BCL-2)

APAF-1
Cytochrome c

BH3-only

Procaspase
BAX
BAK

Mitochondria

BCL-2

BCL-2

Mitochondria

Mitochondria

▪ Venetoclax is a potent, orally bioavailable agent with a BCR-independent
mechanism of action and substantial activity in heavily pre-treated CLL
(Roberts AW et al, NEJM 2015)

23

Venetoclax Dosing Schedule

Week 3
Week 1 Week 2
20 mg 50 mg 100 mg

Week 4
200 mg

Week 5
400 mg

400 mg venetoclax

Until
progression
or
unacceptable
toxicity

▪ All patients
– had tumor burden assessment by imaging for nodal size and absolute
lymphocyte count at enrollment
– received prophylaxis for tumor lysis syndrome (TLS) with uric acid reducers
and hydration
▪ Patients with high tumor burden were hospitalized prior to dosing to facilitate TLS
prophylaxis
▪ Laboratory values were monitored for evidence of tumor lysis for at least 24 hours
after the first dose at each dose level
24

8

2/28/2018

Venetoclax in IBRUTINIB resistance

Jones J et al, 2018

25

Jones J et al, 2018

26

Jones J et al, 2018

27

Venetoclax after ibrutinib therapy

Venetoclax after ibrutinib therapy

9

2/28/2018

Venetoclax after ibrutinib therapy

42% blood MRD-negative;
5/13 bone marrow MRD-negative

Jones J et al, 2018

28

Failed ibrutinib – what to do?

Mato et al, 2017

29

Summary
▪Ibrutinib intolerance and resistance is becoming a
common problem
▪Ibrutinib does not ‘protect’ from Richter’s
transformation
▪Second-generation BTK inhibitors may be a good option
for patients intolerant of ibrutinib
▪Venetoclax > PI3K in patients resistant to ibrutinib

30

10

3/1/2018

An update on Richter
Transformation
Dr. Philip Thompson
The University of Texas M.D. Anderson Cancer Center,
Department of Leukemia

Disclosures
•
•
•
•

Pharmacyclics: Research support, Consultancy
AbbVie: Research support, Consultancy
Genentech: Consultancy
Amgen: Research support, Consultancy

Background
• Richter Transformation (RT) is a transformation of
CLL to an aggressive lymphoma, most commonly
DLBCL and less commonly classical Hodgkin
Lymphoma.1
• Rare cases of transformation to plasmablastic
lymphoma, histiocytic sarcoma and other
uncommon lymphomas2
• Occurs in 2-10% of patients with CLL (0.5-1% per
year).
1Rossi,

Blood 2011 2Jain, P, Oncology 2012.

1

3/1/2018

Risk factors for transformation
• Tends to be associated with high-risk CLL biology:
1. Unmutated IGHV1
2. Del(17p), del(11q), trisomy 122
3. Mutations in NOTCH1, which disrupt the PEST
domain3
• Possible association with fludarabine-based
chemotherapy.

1Rossi

Blood 2011 2Strati CLML 2015 3Rossi Blood 2012.

Clinical features of transformation
•
•
•
•

Non-specific.
Fevers, drenching night sweats, weight loss.
Rapidly enlarging lymph nodes.
Elevated LDH. Sometimes hypercalcemia.

PET/CT as a screening tool

2

3/1/2018

PET/CT as a screening/prognostic tool
• 332 MDA patients had PET/CT and subsequent biopsy.
Biopsy results classified as RT, histologically-aggressive CLL
(HAC) and histologically-indolent CLL (HIC).1
• SUVmax strongly correlated with histology: median 17.6 vs
6.8 vs 3.7 in RT vs HAC vs HIC, respectively.
• SUVmax ≥5 had NPV of 92% but only 38% PPV for RT. PPV
improved by cut-off of ≥10 SUVmax ≥10 had the optimal
discriminatory power for survival by ROC analysis. Median
OS was 56.7mo if SUVmax <10 and 6.9mo if ≥10.
• Interestingly, the negative prognostic impact of SUVmax ≥10
was identical, regardless of the histology.
• PET/CT also very useful in identifying optimal biopsy site
1Falchi,

Blood 2014

Why biopsy?
• Not all that is hot on PET/CT is RT.
• Multiple other entities may mimic RT:
i) “Accelerated CLL” Important to distinguish as
treatment is different1
ii) EBV-driven lymphomas (eg. after treatment of CLL
with alemtuzumab, post-alloSCT. In contrast, RT is
usually EBV negative.2
iii) Herpetic lymphadenitits3, CMV, EBV.
iv) Nocardiosis, fungal infection (esp. histoplasmosis).
v) Granulomatous diseases (eg. TB).

1Gine

Haematologica 2010 2Asano Blood 2009 3Joseph AJH 2001

RT DLBCL Histology

From: Warnke RA, Weiss LM, Chan JK, et al. Tumors of the lymph nodes and spleen. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 14, 1995, Washington, DC. Armed
Forces Institute of Pathology.

3

3/1/2018

Genomic features of RT
• Clonal relationship to underlying CLL: 80% of
DLBCL-RT arise from underlying CLL clone1,2
through acquisition of additional mutations.
• Genomically less complex than de novo DLBCL and
molecularly distinct:
1. RT frequently associated with TP53 mutations,
inactivating mutations in CDKN2A/B, MYC
overexpression, mutations in the PEST domain of
NOTCH1, stereotyped B-cell receptor.
2. De novo DLBCL frequently associated with BCL2
and BCL6 translocations (not seen in RT).

1.

Rossi, Blood 2011. 2. Chigrinova, Blood 2013

Major genomic aberrations in RT

Chigrinova Blood
2013

Patients with ECOG >1 and TP53 disruption have poor outcomes.

Davide Rossi et al. Blood 2011;117:3391-3401

4

3/1/2018

Loss of functional p53 is a key prognostic marker,
regardless of the mechanism

Davide Rossi et al. Blood 2011

Clonally-unrelated “RT” should be thought
of as a different disease

Davide Rossi et al. Blood 2011;117:3391-3401

RT is still a frequent event during
targeted therapies for R/R CLL
•
•
•
•

Ibrutinib ~5%.1,2
Venetoclax up to 16%.3
Transformation in these studies was an early event.
Likely driven by disease biology rather than
treatment per se. These early phase studies were
enriched for patients with biologically high-risk
disease.

1Maddocks,

JAMA Oncol 2015; 2Jain, Blood 2015; 3Roberts NEJM 2016

5

3/1/2018

Ibrutinib discontinuations over time

Maddocks, K et al. JAMA Oncology. 2015;1:80

Cumulative incidence of discontinuation

MDA Data on ibrutinib discontinuation
30
25

Toxicity
Progression

20

Richters
15
10
5
0

0

6

12

18

24
30
36
Time (Months)

42

48

54

60

Jain, P Cancer 2017

Prognosis of RT with chemoimmunotherapy
Study

Regimen

n

Median
age
(years)

ORR CRR

Median OS

67%

7%

27 months

Results

Anthracycline-containing Regimens
Jenke et al, 2011
R-CHOP

15

69 (N/A)

Dabaja et al, 2001

29

61 (36-75) 41%

38%

10 months

59 (27-79) 43%

18%

8.5 months

HyperCVAD

Rituximab and GM-CSF with
Tsimberidou et al, 2003 alternating hyperCVAD & 30
MTX/cytarabine
Platinum-containing Regimens
Tsimberidou et al, 2008 OFAR1

20

59 (34-77) 50%

20%

8 months

Tsimberidou et al, 2013 OFAR2

35

63 (40-81) 43%

8.6%

6.6 months

12

59 (49-74) 45% N/A

17 months

15

62 (42-74) 5%

5%

2.2 months

7

56 (44-70) 0%

0%

N/A

Fludarabine-containing Regimens
Giles et al, 1996

PFA or CFA

Tsimberidou et al, 2002 FACPGM
Radio-Immunotherapy
Tsimberidou et al, 2004

90Y-ibritumomab

6

3/1/2018

Hematopoetic stem cell
transplantation
• Durable responses achieved in patients who have
achieved an objective response after
chemoimmunotherapy (CIT).
• 3y OS 75% compared to 27% without transplant.1
• Prolonged survival also achieved after autoSCT.2
• Consolidative transplant should be offered to
patients who respond to CIT, with the exception of
patients who haven’t received treatment for CLL
and achieve CR with CIT.
1Tsimberidou,

JCO 2006 2Cwynarski JCO 2012.

Treatment of Hodgkin variant
• Generally treated similarly to de novo HL (eg. ABVD
or BEACOPP).
• Outcome better than for DLBCL-RT, but worse than
for de novo HL.1,2

1Tsimberidou,

Cancer 2006 2Brecher Am J Clin Pathol 1990

Novel therapeutic
strategies for RT

7

3/1/2018

Acalabrutinib
•
•
•
•
•

2nd generation BTK inhibitor.
29 patients with RT.
Median 4 prior therapies.
21% del(17p).
ORR 38% (14% CR). Median duration of response
5.7mo.
• Median PFS of 3mo.

Hillmen, P. ASH 2016.

Pembrolizumab
• A phase II trial of pembrolizumab in relapsed and
transformed CLL included 9 patients with RT; ORR
in these patients was 44% (CR 11%, PR 33%).1
• For RT patients, the median progression-free and
overall survival was 5.4 months and 10.7 months
respectively.
• 0/16 patients with CLL responded.
• PD-L1 expression on RT cells: potentially useful
biomarker for response.

1Ding

Blood 2017

Novel therapeutics – ibrutinib + nivolumab
• Encouraging activity.
• Approximately 40% response rate in the first 15
patients1
• Rapid responses in RT.

1Jain,

N. ASH 2017.

8

3/1/2018

Pre-treatment

Post-1m nivolumab

Post-3m nivolumab/2m
ibrutinib

Blinatumomab
• CD3x19 bispecific antibody, approved in ALL.
• In R/R DLBCL, overall response rate of 43% (CRR
19%), using high-dose therapy (max 112mcg/d).
• 1 of first 3 patients achieved CR.

75M, developed RT on ibrutinib. Failed CIT, obinutuzumab and ibrutinib + nivolumab

9

3/1/2018

EPOCH-R + venetoclax.
• Multi-center study (DFCI, OSU, UCSD, us) of 20
patients.
• Addition of venetoclax to R-EPOCH.
• Some single-agent activity with venetoclax, but of
limited duration. Combination of bcl-2 inhibitor
with chemoimmunotherapy may prevent BCL2mediated resistance to chemotherapy-induced
apoptosis.

CAR T-cells
• KiTE CD19 CAR-T highly active in DLBCL. With in the
group of DLBCL patients in ZUMA-1 study, ORR was 79%
and CRR 52%. 3 patients had therapy-related death.
• Major toxicity. Grade 3 CRS in 13 cases. 28%
neurotoxicity (all reversible). 3 treatment-related
deaths.
• Despite the toxicity, this represents a major advance.
• Potential to be tested in RT.
• Turtle et al. reported 24 patients with CLL treated in
Seattle. Mostly ibrutinib-refractory. Many also
venetoclax refractory. ORR 74% (21% CR).
• Possibility to combine with checkpoint inhibition.

Khan and Thompson, Annals of Oncology 2017

10
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