role of targeted therapies in the management of...

Role of Targeted Therapies in the Management of

Chronic Lymphocytic Leukemia: From Clinical Data to Individualized Care

Ryan Jacobs, MD Department of Hematology

Levine Cancer Institute

Carolinas Health Care System

Charlotte, NC

Clinical Assistant Professor of Medicine

UNC-Chapel Hill School of Medicine

Chapel Hill, NC

Disclosures

• During the course of this lecture, Dr. Jacobs may mention the use of medications for both FDA-approved and non-approved indications.

• Dr. Jacobs has no relevant financial relationships to disclose.

Learning Objectives

• Review disease-risk stratification and the use of a prognostic nomogram for estimating time to treatment.

• Examine the first-line management of patients with chronic lymphocytic leukemia (CLL) to maximize adherence while minimizing associated adverse events.

• Discuss the current treatment options for patients with relapsed/refractory CLL and associated limitations.

• Explain the late-stage, clinical trial data for emerging therapies in relapsed/refractory CLL.

Essential Tests at Initial Presentation of CLL: 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

CLL = chronic lymphocytic leukemia; FISH = fluorescence in situ hybridization; IGHV = immunoglobulin heavy-chain variable (region genes); Tp53 = gene providing instructions for making tumor protein p53; LDH = lactate dehydrogenase.

Other Notable Considerations

CT = computed tomography; CAP = chest/abdomen/pelvis.

• Direct anti-globulin test

• Quantitative immunoglobulins

• CT scan of CAP

• Infectious serology

Prognostic Markers in CLL

Prognostic Markers

• Interphase cytogenetics by FISH

• IGHV mutational status

Interphase FISH Correlates With OS

Döhner H et al. N Engl J Med. 2000;343:1910-1916.

17p deletion 11q deletion 12 trisomy Normal 13q deletion as sole abnormality

Pat

ien

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

OS = overall survival.

Outcome by Interphase FISH Abnormalities (At Diagnosis)

Döhner H et al. N Engl J Med. 2000;343:1910-1916.

Abnormality detected by

FISH

Median Time to Treatment

(months)

Median OS (months)

Percentage 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

• Mutational status of IGHV predicts clinical outcome in CLL.

• Mutated IGHV is defined as <98% sequence homology to established germline sequence.

• Unmutated IGHV predicts earlier therapy, poorer response, inferior survival, and risk of transformation.

• IGHV correlates with CD38 and ZAP70+ disease.

Damle RN et al. Blood. 1999:94:1840-1847.

IGHV Mutational Status Predicts Survival

Hamblin TJ et al. Blood. 1999;94:1848-1854.

0 25 50 75 100 125 150 175 200 225 250 275 300 325

Months

Surv

ivin

g (%

)

0

10

20

30

40

50

60

70

80

90

100

Patients

N = 84

n (%)

Median

Survival

(months)

Mutated 46 (54.8) 293

Unmutated 38 (45.2) 117

P=0.001

Mutated

Unmutated

Prognostic Factors in CLL: Summary

• Interphase-FISH cytogenetic analysis is standard of care at diagnosis and RELAPSE.

– Chromosomal abnormalities may change with time.

– Repeat FISH and cytogenetics prior to starting the next therapy to assess for clonal evolution.

• IGHV status does not change with time.

• CD38 and ZAP70 correlate with IGHV.

Timing of Therapy

Early Treatment Does Not Improve Survival

J Natl Cancer Inst. 1999;91:861-868.

Start

Year Study 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

Total 432/1014

(42.6%)

430/1034

(41.6%) 16.9 212.3

Heterogeneity between 6 trials: χ2 = 1.7; P>0.1; NS 5

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

Clb = chlorambucil; P = prednisolone; Obs = observed; Exp = expected; NS = not statistically significant.

Immediate Deferred

Indications for Initiating Therapy

Objective laboratory/radiographic findings

• Worsening anemia and/or thrombocytopenia

– Hemoglobin <11g/dL

– Platelets <100,000/uL

• Spleen ≥6cm below the left costal margin

• Lymph nodes ≥10cm

Hallek M et al; NCI-IWCLL. Blood. 2008;111:5446-5456.

Indications for Initiating Therapy (Continued)

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

Hallek M et al; NCI-IWCLL. Blood. 2008;111:5446-5456.

ECOG = Eastern Cooperative Oncology Group.

Review of Standard and Novel Front-Line Strategies

Young, Healthy Patient

(Age ≤65 Years, Non-del 17p/Tp53 Mutated)

FC vs FCR in GCLLSG-8

Hallek M et al. Lancet. 2010;376:1164-1174.

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 Pr

ogr

ess

ion

(%

) 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

FC = fludarabine + cyclophosphamide; FCR = FC + rituximab; ORR = overall response rate; CR = complete remission; PFS = progression-free survival.

FCR vs BR—CLL-10 GCLLSG Trial

Eichhorst B et al. Blood. 2014;124(21): abstract 19. (Available at www.bloodjournal.org/content/124/21/19.full.pdf)

FCR

n = 282

BR

n = 279

P-value

ORR (%) 98 98 NS

CR (%) 41 32 0.026

Median PFS (months) 54 43 0.001

OS at 3 years (%) 91 92 NS

Severe neutropenia (%) 88 68 <0.001

Severe infections (%) 40 25 0.001

TRM (%) 4 2 —

BR = bendamustine + rituximab; TRM = treatment-related mortality.

CLL10 Trial: Minimal Residual Disease

Eichhorst B et al. Blood. 2014;124(21): abstract 19. (Available at www.bloodjournal.org/content/124/21/19.full.pdf)

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

ega

tive

pat

ien

ts (

%)

Interim PB Final PB Final BM

P=0.023

P=0.024

P<0.001 FCR BR

MRD = minimal residual disease; PB = peripheral blood; BM = bone marrow.

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 front-line therapy?

Thompson PA et al. Blood. 2016;127:303-309.

PFS

(%

)

Time (years)

100

25

50

75

0 0 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Patients

n

PFS

n

IGHV mutated 88 49

IGHV unmutated 126 12

P=0.0001

IGHV mutated

IGHV unmutated

Elderly 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 48 42

Chemotherapy Options in Elderly Populations

• Avoid fludarabine-based regimens

• Bendamustine + rituximab

– Slightly higher toxicity rate but feasible in this population

Fischer K et al. J Clin Oncol. 2012;30:3209-3216.

*All patients in the intent-to-treat group.

Cu

mu

lati

ve s

urv

ival

(p

rob

abili

ty)

Time to new CLL therapy, PD, or death (months) Time to death (months)

Cu

mu

lati

ve s

urv

ival

(p

rob

abili

ty)

Event-free survival* Overall survival*

PD = progression of disease.

Obinutuzumab Plus Chlorambucil (CLL-11 Trial)

• Obinutuzumab is an engineered anti-CD20 monoclonal antibody.

• It is well tolerated in patients with co-morbidities and median age of 73.

• Improved PFS when compared with R + Clb and Clb alone

Goede V et al. N Engl J Med. 2014;370:1101-1110.

G-Clb (N = 238)

G-Clb P<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 mar r o w Blood

100

90

80

70

60

50

40

30

20

10

0

22.3

7.3

58.4 55.0

31.4 19.5

37.7

2.6 3.3

Pat

ien

ts w

ith

ne

gati

ve M

RD

te

st (

%)

Pat

ien

ts w

ith

a r

esp

on

se (

%)

G-Clb = obinutuzumab + chlorambucil; R-Clb = rituximab + chlorambucil.

PR

CR

PR

PR

CR

CR

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

PFS

Months

15.2 26.7

G-Clb

Stratified HR = 0.39 95% CI: 0.31–0.49 P<0.001

Obinutuzumab Plus Chlorambucil

Goede V et al. N Engl J Med. 2014;370:1101-1110.

HR = hazard ratio; CI = confidence interval.

R-Clb

Ibrutinib as Front-Line Therapy in CLL

(All Ages)

Targeting Kinases in CLL

Awan FT, Byrd JC. Clin Cancer Res. 2014;20:5869-5874.

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.

Ibrutinib

• Highly potent BTK inhibition at IC50 = 0.5 nM

• Ibrutinib is administered orally with once-daily dosing, resulting in 24-hour target inhibition.

• No cytotoxic effect on T cells or NK cells

• It promotes apoptosis and inhibits migration and adhesion in CLL cells.

NK = natural killer.

Ibrutinib PFS in High-Risk Disease

1.0

18

0.8

0.6

0.4

0.2

126 3630 42240

CensoredLogrank p=0.0031

0.0

Byrd JC et al. Blood. 2015;125:2497-2506.

Months from initiation of study treatment

PFS

(P

rop

ort

ion

)

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)

• Ibrutinib is superior to chlorambucil in patients older than 65 years of age with previously untreated CLL.

Burger JA et al. N Engl J Med. 2015;373:2425-2437. FDA approval (http://abbvie.mediaroom.com/2016-03-04-IMBRUVICA-ibrutinib-Approved-by-U-S-FDA-for-the-First-line-Treatment-of-Chronic-Lymphocytic-Leukemia)

• FDA approval on 3/4/16 for all untreated CLL patients

PFS

(%

)

Months

100

90

80

70

60

50

40

30

20

10

0 0 3 6 9 12 15 18 21 24 27

Ibrutinib

Chlorambucil

Median PFS

(months)

Chlorambucil 18.9

Ibrutinib NR

HR (95% CI) 0.16 (0.09–0.28)

P=0.001

Front-Line Therapy Summary

CLL or SLL stage II-IV

Observe No indication

Indication present

Del17p or TP53 mutation (any age)

Ibrutinib

Elderly/fit (>65 years)

• Ibrutinib (preferred)

• Bendamustine + rituximab

Young/fit (<65 years)

• Consider FCR (preferred for IGHV mutated)

• Ibrutinib

Treatment?

Elderly + comorbidities

• Ibrutinib (preferred)

• Obinutuzumab + chlorambucil

SLL = small lymphocytic lymphoma.

Novel Treatment of Patients With Relapsed Disease

Kinase Inhibitors

RESONATE Trial

Byrd JC et al. N Engl J Med. 2014;371:213-223.

Months

PFS

(%

)

195 183 116 38 7

196 161 83 15 1 0

Ofatumumab

Ibrutinib

0

100

90

80

70

60

50

40

30

20

10

0 3 6 9 12 15

Censo r ed

Median PFS

(months)

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 11 1 2 3 4 5 6 7 8 9 10

Months

25

0

–25

–50

–75

–100

SPD

0 11 1 2 3 4 5 6 7 8 9 10

Me

dia

n c

han

ge f

rom

bas

elin

e in

ALC

(%

)

Me

dia

n c

han

ge f

rom

bas

elin

e in

SP

D (

%)

Pattern of Response: Blood Lymphocytes vs Lymph Nodes


ALC = absolute lymphocyte count; SPD = sum of the products of perpendicular diameters of lymph nodes.

Ibrutinib—Long-Term Follow-up


Months from initiation of study treatment

PFS

(p

rop

ort

ion

)

1.0

18

0.8

0.6

0.4

0.2

12 8 36 42 24 30 0

Censo r ed 0.0

Relapsed/refractory

Treatment-naïve

Ibrutinib Discontinuation and Richter’s Transformation (RT)

Maddocks KJ et al. JAMA Oncol. 2015;1:80-87.

Cu

mu

lati

ve in

cid

en

ce o

f d

isco

nti

nu

atio

n o

f ib

ruti

nib

th

era

py

(%)

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

RT

Other event

Issues With Ibrutinib

• Disrupts collagen-induced platelet aggregation

• vWF binding

Lipsky AH et al. Haematologica. 2015;100:1571-1578.

Months on study

Cu

mu

lati

ve in

cid

en

ce o

f ev

en

ts

Incidence Confidence intervals

vWF = von Willebrand factor.

At risk: 85 38 34 20 18 4 On drug: 85 81 70 43 40 4

Management of Bleeding Issues With Ibrutinib

• Avoid aspirin, NSAIDs, fish oil

• Avoid warfarin

• Can consider alternate anti-coagulants with caution

Ibrutinib (Imbruvica®) prescribing information. Available at www.imbruvica.com

NSAID = non-steroidal antiinflammatory drug.

Other Issues With Ibrutinib

• Diarrhea

• Fatigue

• Upper respiratory tract infection

• Rash

• Nausea

• Arthralgia

• Atrial fibrillation

• Cytopenias

• Treatment discontinuation due to AEs = 6%

• No evidence of cumulative toxicity or long-term safety

AEs = adverse events.

Ibrutinib (Imbruvica® ) prescribing information. Available at www.imbruvica.com

100

12

75

50

25

0 24 36 48 0

100

12

75

50

25

0 24 36 48 0

del(17p) del(11q) Neither del(17p) nor del 11q) Complex karyotype No complex karyotype

Ibrutinib Has Inferior PFS in Patients With Complex Karyotype

Thompson PA et al. Cancer. 2015;121:3612-3621.

Eve

nt-

fre

e s

urv

ival

(%

)

Time (months) Ev

en

t-fr

ee

su

rviv

al (

%)

Time (months)

P=0.02 P<0.0001

N Event-free

Neither del(17p) nor del(11p) 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%)

Ibrutinib—Conclusion

• Now approved front-line therapy for all CLL patients

– May not be the best front-line choice for patients aged <65 years

• Promising responses ~90%

• Low incidence of complete responses, ie, 2–7%

• Response deepens over time.

– Median time to response: 4 months

– Median time to best response: 12 months

• Del17p responds, but PFS is shorter.

• Use full dose, and avoid disruptions.

• Avoid using ibrutinib with anticoagulation.

• Follow stopping rules prior to surgical interventions.

Idelalisib

• Selective PI3-K delta inhibitor

• Single-agent response rate of 72%

• 39% PR and 33% PR+L

Brown JR et al. Blood. 2014;123:3390-3397.

PR = partial response; PR+L = partial response with treatment-induced lymphocytosis.

Idelalisib in Relapsed/Refractory CLL

Brown JR et al. Blood. 2014;123:3390-3397.

Median PFS: 15.8 months 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

Months from start of idelalisib Months from start of idelalisib

PFS (N = 54) OS (N = 54)

PFS

(%

)

OS

(%)

Time (months)

Pro

gre

ssio

n-f

ree

su

rviv

al (

%)

Phase III Idelalisib and Rituximab for Previously Treated Patients With CLL

Sharman JP et al. Blood. 2014;124(21): abstract 330.

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

N

Median PFS

(Months)

Idelalisib + R 110 19

Placebo + R 110 7

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

Weeks

Ab

solu

te ly

mp

ho

cyte

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 Disease

Coutre SE et al. J Clin Oncol. 2014;32(5 suppl): abstract 7012.

Need to be redrawn by Martin

Be

st %

ch

ange

in S

PD

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

Mut = mutation.

Del(17p)/TP53 mutation (either) IGHV unmutated

Idelalisib OS in High-Risk Disease

Sharman JP et al. Blood. 2014;124(21): abstract 330.

Placebo + R

Idelalisib + R

Ove

rall

surv

ival

(%

)

Time (months)

100

80

60

40

20

0 0 2 26 24 22 20 18 16 14 12 10 4 6 8

Time (months) O

vera

ll su

rviv

al (

%)

100

80

60

40

20

0 0 2 26 24 22 20 18 16 14 12 10 4 6 8

Study Arm

N

Median OS

(Months)

Idelalisib + R 46 >18

Placebo + R 49 14.8

P=0.001

Study Arm

N

Median OS

(Months)

Idelalisib + R 91 >19

Placebo + R 93 18.1

P=0.0003

Idelalisib + R

Placebo + R

Issues with Idelalisib

• Pneumonitis

– Distinguish from infectious issues

– Leading cause of discontinuation

• Diarrhea

– Early onset

– Late onset

– Colitis—secondary to T-cell activation

• Transaminitis

Idelasib (Zydelig™) prescribing information (www.zydelig.com/include/media/pdf/full-prescribing-information.pdf)

How to Choose Between Ibrutinib and Idelalisib

Ibrutinib Idelalisib

Patients allergic to

rituximab Patients on anti-coagulation

Inflammatory bowel

disease Atrial fibrillation

Liver problems Patients on concurrent azoles

(CYP3A Inhibitors)

Lung problems

1.00

0.25

0.50

0.75

0.00 25 20 15 10 5 0

1.00

0.25

0.50

0.75

0.00 25 20 15 10 5 0

What Next?

Mato A et al. Blood. 2015;126(23): abstract 719.

• 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

PFS: Alternate KI therapy following Ibr/Ide discontinuation

PFS: Non-KI therapy following Ibr/Ide discontinuation

Months

Months

KI = kinase inhibitor; Ibr = ibrutinib; Ide = idelalisib.

Summary of Kinase-Inhibitor Efficacy in Relapsed Disease

• Kinase inhibitors are effective in patients with untreated and relapsed disease.

• Kinase inhibitors are effective in patients who otherwise would have limited therapeutic options.

– This includes patients who have progressed on kinase inhibitors.

• Kinase inhibitors are effective in patients with conventional high-risk features.

Relapsed High Risk Patients

(All ages, Del 17p/Tp53 Mutated)

Bcl-2 Pathway

Cheson BD. Blood. 2014;123:3368-3370.

Idelalisib

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.

Venetoclax (ABT-199)

Roberts AW et al. N Engl J Med. 2016;374:311-322.

• 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.

Venetoclax—Tumor Lysis Syndrome (TLS)


• First three patients received 200mg as the initial dose.

– All three developed tumor lysis.

• Stepwise ramp-up dosing was developed in response.

• Amendment to protocol included TLS prophylaxis and inpatient observation for D1 and D8 for all patients.

• Patients with bulky disease required inpatient observation for all dose escalations.

Dose-escalation cohort Expansion cohort

Day –7

Wk 1 Wk 2

Wk 3

Wk 1 Wk 2

Wk 3 Wk 4

Wk 5

50 mg 50 mg

Step-up dose

Target group dose 20 mg 50 mg 100 mg 200 mg 400 mg

Venetoclax—Dose-Limiting Toxicities


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

aInitial cohort prior to protocol amendment instituting dose ramp up; b sudden death.

100

–100

0

–50

50

–100

0

–50

50

200 mg

200 mg

150 mg

800 mg

Expansion (400 mg)

1200 mg

300 mg

600 mg

400 mg

200 mg

200 mg

150 mg

800 mg

Expansion (400 mg)

1200 mg

300 mg

600 mg

400 mg

Venetoclax (ABT-199)—Response


• 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

ange

fro

m b

ase

line

(%

)

Ch

ange

fro

m b

ase

line

(%

)

100

25

50

75

0

0 30 27 24 21 18 15

400 mg g r oup

>400 mg g r oup

<400 mg g r oup

12 9 6 3

100

25

50

75

0

0 30 27 24 21 18 15 12 9 6 3

Venetoclax (ABT-199) —Response (Continued)


• Median duration of follow-up was 17 months. • 15-month PFS was 69% in the 400mg group. • 51% of patients remain on treatment at the time of publication. • Richter’s transformation occurred in 16% (n = 18). • 2-year overall survival was 84%.

Pro

gre

ssio

n-f

ree

su

rviv

al (

%)

Month P

atie

nts

wit

h r

esp

on

se (

%)

Month

Partial response

Complete response

Venetoclax (ABT-199)—Response (17p Deletion)


Patients with 17p deletion had: • Overall response rate: 71% • Complete response rate: 16% • Approved by the FDA for second line therapy in patients with 17p

deletion on 4/11/16

PFS

(%

)

Month

Patients without del(17p)

Patients with del(17p)

100

25

50

75

0

0 30 27 24 21 18 15 12 9 6 3

Median PFS: 16 months

Emerging Data on New Targeted Therapies

Acalabrutinib (ACP-196)


• More selective, second-generation, irreversible BTK inhibitor

• Designed to improve on the safety and efficacy of first-generation BTK inhibitors.

• Ibrutinib irreversibly inhibits alternative kinase targets in addition to BTK.

– EGFR, TEC, ITK, TXK

– Responsible for rash, diarrhea, bleeding, afib.

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; afib = atrial fibrillation.

Adverse Events With Acalabrutinib

Adapted from Byrd JC et al. N Engl J Med. 2016;374:323-332.

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

URI = upper respiratory infection.

Acalabrutinib (ACP-196)—BTK Occupancy


• Low rates of adverse events allowed safe administration of twice-daily dosing.

• Full target coverage may reduce drug resistance.

BTK occupancy, all cohorts

BTK occupancy, 100 mg, twice-daily cohort

Cohort

Time of assessment

BTK

occ

up

ancy

(%

) B

TK o

ccu

pan

cy (

%)

100

Before

100 mg QD (N = 8)

Median

Median

After

89%

D a y 1, 4 hr a ft er dosing


D a y 2

b e f o r e dosing

D a y 8

b e f o r e dosing


D a y 28

b e f o r e 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

60 10

0

100

0

50 80

90

N = 28 N = 26 N = 27 N = 28 N = 27 N = 19

QD = once daily; BID = twice daily.

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

9 8 7 6 5 4 3 2 1 0

Acalabrutinib (ACP-196)—Change in ALC and SPD

• Median of three previous therapies for CLL

• 31% had chromosome 17p deletion.

• 75% had unmutated immunoglobulin heavy-chain variable genes.


Me

dia

n c

han

ge f

rom

bas

elin

e in

ALC

(%

)

Me

dia

n c

han

ge f

rom

bas

elin

e in

SP

D (

%)

Patient Cycle

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

0 0

No. at risk:

2 4 6 8 10 12 14 16 18

61 59 59 58 57 48 32 20 16 3

Median follow-up(mo) 14.3 19.2 17.8 16.4 14.6 11.8

20

90 80 70 60 50 40 30 20 10

0 0 0 0 0

5

100

10

10 25

13

Acalabrutinib (ACP-196)—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.


Be

st r

esp

on

se (

%)

Cohort Month

PFS

(%

of

pat

ien

ts)

Stable disease

Partial response

Partial response with lymphocytosis

(N = 60) (N = 8) (N = 8) (N = 7) (N = 6) (N = 31)

Entospletinib (GS-9973)

Sharman J et al. Blood. 2015;125:2336-2343.

• Oral, selective inhibitor of spleen tyrosine kinase (Syk)

– Syk is a cytoplasmic protein that is predominantly expressed in cells of hematopoietic lineage.

– Syk signaling elicits a range of diverse biologic functions, including cellular development, function, proliferation, differentiation, and adhesion.

• Multicenter phase II

– 41 patients, relapsed/refractory CLL

Entospletinib (GS-9973)—Response


• Overall response rate: 61%

• Nodal response: 7.3% • No complete responses • Only one patient with

refractory disease (2.4%)

• No difference in ORR between subgroups

• Median follow-up of 7.7 months

Subgroup No. Objective Response Rate with 95% CI

Overall 41 0.61 (0.45-0.76)

Gender

Male 28 0.68 (0.48-0.84)

Female 13 0.46 (0.19-0.75)

Age

<65 7 0.57 (0.18-0.90)

≥65 34 0.62 (0.44-0.78)

No. of Prior Therapies

<4 28 0.61 (0.41-0.78)

≥4 13 0.62 (0.32-0.86)

IGHV

Mutated 8 0.63 (0.24-0.91)

Unmutated 31 0.61 (0.42-0.78)

17p Del or TP53 Mutation

Either 10 0.40 (0.12-0.74)

Neither 29 0.69 (0.49-0.85)

0 0.25 0.50 0.75 1.00

Be

st %

ch

ange

in S

PD

Subjects (N = 39)

100

-100

25

-50

75

0

-25

-75

50

With 17p deletion and/or TP53 mutation With 11q deletion With NOTCH1 and/or SF381 mutation None of the above deletion or mutation Undetermined

100

25

50

75

0

0 2 4 6 8 10 12 14 16 18

100

25

50

75

0

0 2 4 6 8 10 12 14

Entospletinib (GS-9973 )—PFS and DoR

• Median PFS was 13.8 months.

• Median duration of response has not been reached.


PFS

(%

)

Co

nti

nu

ed r

esp

on

se %

) Months from start of entospletinib

Months from response

Median DoR is not reached. 75% of subjects with DoR ≥6.5 months

Median PFS is 13.8 months.

DoR = duration of response.

Otlertuzumab (TRU-016)


• Novel humanized anti CD-37 protein

• CD-37 is involved in the regulation of B-Cell function

– Present in high levels of B-cell leukemias and lymphomas

• Phase I dose escalation study with expansion cohort

• Administered weekly x 8 weeks, followed by monthly

• Patients with relapsed/refractory CLL

Otlertuzumab (TRU-016)—Response


• Median number of prior therapies: 4 in dose-escalation group and 1 in expansion group

• 25 patients (30%) had deletion 17p. • Lymphocyte reduction of ≥50% was observed in 76% of patients. • Lymph-node reduction of ≥50% was observed in 20% of patients.

-100

100

-90 -80 -70

Dose G r oup 0.03mg 1.0mg 0.3mg 0.1mg 3.0mg 15mg 10mg 6.0mg 20mg Nai v e

20mg 30mg

-60 -50 -40 -30 -20 -10

10 20 30 40 50 60 70 80 90

0

Red

uct

ion

(%

)

-100

100

-90 -80 -70 -60 -50 -40 -30 -20 -10

10 20 30 40 50 60 70 80 90

0

1.0mg 15mg

Dose G r oup 0.03mg 3.0mg 0.3mg 10mg 6.0mg 20mg Nai v e 20mg

30mg

Red

uct

ion

(%

)

ALC SPD

Chimeric Antigen Receptor-Modified T Cells

• 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

Porter DL et al. N Engl J Med. 2011;365:725-733. Casucci M, Bondanza A. J Cancer. 2011;2:378-382.

Proliferation/cytokine production

Survival

Cytotoxicity

1G

CD3

2G 3G

ZAP70

CD28 PI3K

4-1BB, OX40 TRAF2

V H V L

CD3 4-1BB Hinge & TM

Truncated env

Truncated gag/pol

RRE

cPPT/CTS 5ʹLTR

pELPS 19-BB- 11556 bp

3ʹLTR (truncated)

Amp R

Bovine GH Poly A

Bacterial replication

origin

FMC63

U3 (truncated)

R region (truncated)

R region

WPRE CD19 BB

scFv

Lentiviral vector

Generations of chimeric antigen receptors

Chimeric Antigen Receptor-Modified T Cells (Contrast-Enhanced CT Scans)

Porter DL et al. N Engl J Med. 2011;365:725-733.

Axial Coronal

Before therapy

1 month of treatment

3 months of treatment

Pembrolizumab

Ding W et al. Blood. 2015;126(23): abstract 834.

• MC1485 trial: phase II trial in relapsed/refractory CLL

• 16 patients (5 with Richter’s transformation)

• 5 patients had progressed on ibrutinib.

• 4/5 patients with Richter’s transformation had a response.

– 1 complete response

– Immature PFS data

• 2 non-Richter’s patients had stable disease and continued on therapy at the last follow-up.

Summary

• Early results with kinase inhibitors are extremely promising.

• Similar agents are also in clinical development.

– Monoclonal antibodies

• Ublituximab (CD20)

– PI3K inhibitors

• TGR 1202

• Duvelisib/IPI145

• Novel combinations are being tested.

– Obinutuzumab + venetoclax (CLL-14)

– Bendamustine + rituximab + (venetoclax/ibrutinib/idelalisib)

• Cost and prescription coverage and long-term side effects may be issues, especially with combinations.

Case Studies

Case 1—Cal

• Cal is a 77-year-old male with 13q deleted, IGHV-unmutated CLL, who presents for follow-up for his CLL.

– He also has CAD, hypertension, mild CHF, and hyperlipidemia.

• He was previously treated with FCR 6-years ago and achieved a complete remission that lasted for 4 years. He was followed with watchful waiting after his relapse until now when he started having progressive fatigue, lymphadenopathy, and splenomegaly.

• His lab 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

What is the best choice of therapy 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 male who was diagnosed with del17p, IGHV-unmutated CLL 6 months ago.

• He now presents with progressive fatigue, lymphadenopathy in the axillary and inguinal regions, and palpable splenomegaly of 7cm below the costal margin.

• His only significant past medical history is for hypertension, for which he takes hydrochlorothiazide.

• His lab evaluation reads:

– WBC count: 88,000 cells/µL

– Hemoglobin: 9.8 mg/dL

– Platelet count: 102,000 cells/µL

Case 2—Question 1

• You decide to start Fred on ibrutinib.

• Ibrutinib places Fred at increased risk for all of the following EXCEPT ___?

A. Diarrhea

B. Atrial fibrillation

C. Bruising

D. Bleeding

E. Colitis

F. Nausea

G. Rash

Case 2—Question 1

• You decide to start the patient on ibrutinib.

• Ibrutinib places this patient at increased risk for all of the following EXCEPT ___?

A. Diarrhea

B. Atrial fibrillation

C. Bruising

D. Bleeding

E. Colitis

F. Nausea

G. Rash

Questions and Answers

role of targeted therapies in the management of...

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