steven e. coutre, md professor of medicine department of hematology stanford university school of...

Steven E. Coutre, MDProfessor of Medicine Department of HematologyStanford University School of MedicineStanford, California

How to Treat CLL in 2014: Overview of CLL

This activity is supported by educational grants from Infinity Pharmaceuticals Inc.; Janssen Biotech Inc., Pharmacyclics Inc.; TG Therapeutics.

clinicaloptions.com/oncologyHow to Treat CLL in 2014: Making Sense of the Changing Landscape

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Faculty Disclosures

Steven E. Coutre, MD, has disclosed that he has received funds for research support from AbbVie, Celgene, Gilead Sciences, and Pharmacyclics and has served on advisory boards for AbbVie, Celgene, Gilead Sciences, and Janssen Biotech, and Pharmacyclics.


Initial Diagnosis: Questions You Will Need to Consider What is the prognosis?

– Should you do additional prognostic testing?

When should treatment start?

– Is watch and worry still appropriate for many patients?

What type of therapy should you choose?

What is your goal of therapy?


Risk Assessment

Stage (Rai, Binet)

Age

“Fitness”

– Performance status

– CIRS


Prognostic factor: predicts an event (eg, progression) in untreated patients

Predictive factor: anticipates response to a given event

Prognostic vs Predictive Factors


Prognostic Factors

Traditional

– Advanced stage, older age, males

– Short lymphocyte doubling time, increased 2m

Newer

– Increased CD38, ZAP70

– Cytogenetic (FISH) abnormalities

– IGVH mutational status


ZAP-70 Expression and Prognosis

Crespo M, et al. N Engl J Med. 2003;348:1764-1775.

Yrs After Diagnosis Yrs After Diagnosis

Risk of Disease Progression Likelihood of Survival

20% ZAP-70–positive cells

< 20% ZAP-70–positive cells 20% ZAP-70–positive cells

< 20% ZAP-70–positive cells

P = .009 P = .01

% o

f C

ells

% o

f C

ells

100

80

60

40

20

00 2 4 6 8 10 12 14 16

100

80

60

40

20

00 4 8 12 16 20 24 28 32 36


IgVH Mutation Status and Prognosis:Pts With Mutated vs Unmutated VH Genes

1. Damle RN, et al. Blood. 1999;94:1840-1847. 2. Hamblin TJ, et al. Blood. 1999;94:1848-1854.

Su

rviv

ing

(%

)

All Patients (N = 84) Patients With Stage-A CLL (n = 62)

Su

rviv

ing

(%

)

0 50 100 150 200 250 3000

20

40

60

80

100

Mos

P = .0008

Mos

P = .001

0 50 100 150 200 250 3000

20

40

60

80

100

Mutated

UnmutatedUnmutated

Mutated

Median survival 8-9 yrs in “unmutated” vs > 24 yrs in mutated


0 12 24 36 48 60 72 84 96 108120132 144156 168 180

Pat

ien

ts T

reat

ed (

%)

Mos

100

80

60

40

20

0

17p deletion11q deletion12q trisomyNormal13q deletion assole abnormality

Probability of Disease Progression

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


Rossi D, et al. Expert Rev Hematol. 2012;5:593-602.

Mutation Prevalence, % P53 ~ 10

NOTCH1 ~ 10

SF3B1 ~ 9

BIRC3 ~ 5

MYD88 ~ 3

Point Mutations May Carry Prognostic Significance, but Are Not Assessed by FISH


1. Wang L, et al. N Engl J Med. 2011;365:2497-2506. 2. Rossi D, et al. Expert Rev Hematol. 2012;5:593-602. 3. Vallamor N, et al. Semin Hematol. 2013;50:286-295.

Notch1 Mutations Occur in ~ 10% Cases


Jeromin S, et al. Leukemia. 2014;28;108-117.

Time to Treatment Overall Survival

Notch1 Mutations and Prognosis

Tim

e to

Tre

atm

ent

100

90

80

70

60

50

40

30

20

10

00 2 6 10 14 18 224 8 12 16 20 2624

Yrs

P < .001

wt (n = 644)

mut (n = 93)

Ove

rall

Su

rviv

al

100

90

80

70

60

50

40

30

20

10

00 2 6 10 14 18 224 8 12 16 20 2624

Yrs

P = .016

wt (n = 648)

mut (n = 101)


Time to Rx (+12 Cohort)

Jeromin S, et al. Leukemia. 2014;28;108-117.

Overall Survival (+12 Cohort)

Notch1 Mutations and Prognosis

Tim

e to

Tre

atm

ent

100

90

80

70

60

50

40

30

20

10

000 2 6 10 14 18 224 8 12 16 20 2624

Yrs

P = .002

NOTCH1wt (n = 69)

NOTCH1mut (n = 29)

Ove

rall

Su

rviv

al

100

90

80

70

60

50

40

30

20

10

00 2 6 10 14 18 224 8 12 16 20 2624

Yrs

P = .155

NOTCH1wt (n = 69)

NOTCH1mut (n = 31)


Treatment Selection

Age

“Fitness”

– Performance status

– CIRS, renal function


R

Fludarabine + Cyclophosphamide (FC)

FC + Rituximab (Anti-CD20) (FCR)

Pt Population Physically fitCIRS ≤ 6 Normal CrClN = 817

Fischer K, et al. ASH 2012. Abstract 435. Cramer P, et al. Leuk Lymphoma. 2013;54:1821-1822.

Phase III CLL8 Trial

First-line FC ± rituximab in previously untreated CLL


Shanafelt T. Hematology 2013;2013:158-167.

Efficacy vs Toxicity

PFS/TFS

% Grade 3+ Adverse Event

Efficacy

Toxicity

FCR1

58 mos PCR2; FR2 42 mos BR2; FC1

34 mos

Fludarabine1; bendamustine1

alemtuzumab1 20-23 mos

Chlor-rituximab1;

16 mos Chlorambucil1; 12 mos

FCR1; FR2 76%

BR2; FC2 64% to

65%

PCR2 Chlor-

rituximab1 46% to

47%

Chlorambucil1 Fludarabine1

40%

Alemtuzumab1 27%

Rituximab2 11%

1 Phase III data. 2 Phase II data.


Prognostic vs Predictive Factors

Prognostic factor: predicts an event (eg, progression) in untreated patients

Predictive factor: anticipates response to a given event


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

FCR

Poor Prognostic Impact of 11q- May Be Overcome by Addition of Rituximab

Pro

po

rtio

n S

urv

ivin

g (

%)

100

90

80

70

60

50

40

30

20

10

00

Mos Since Randomization

6 12 18 24 30 36 42 48 54 60 66

+12q13q-single11q-Not 17p-/11q-/+12q/13q-


0.4

0.2

0.4

Del Poeta G, et al. 2013 EHA. Abstract P102

Notch1 Mutations May Confer Lack of Benefit to Anti-CD20 mAb Therapy 123 CLL symptomatic patients homogeneously treated with first-line fludarabine

followed by consolidation rituximab in responding patients

NOTCH1mut

S̶ Significant associations with trisomy 12 (P = .03) and unmutated IGHV (P = .0001)

S̶ 20 of 123 pts (16.3%).

S̶ Associated with inferior response rates, PFS

Cu

mu

lati

ve

Pro

po

rtio

n

Pro

gre

ss

ing

1.0

0.8

0.6

0.2

00 24 7248 96 144120 168

Mos From the End of Induction Therapy

n = 20

n = 103

P = .00004

NOTCH1 wild typeNOTCH1 mutated

Cu

mu

lati

ve

Pro

po

rtio

n

Pro

gre

ss

ing

1.0

0.8

0.6

00 24 7248 96 144120 168

Mos From the End of Induction Therapy

n = 21

n = 49

P = .0007

UnconsolidatedConsolidatedNOTCH1 wtConsolidatedNOTCH1 mutn = 10

P = .004

Response Duration by NOTCH1 MutationsResponse Duration by Unconsolidated vs

NOTCH1 wt and NOTCH1 Mut Consolidated Pts


Diagnosis Performance status?

Chlorambucil (del)17p?

Alemtuzumab

Allo-SCT

Fludarabine,cyclophosphamide,

and rituximab (FCR)

“iwCLL active disease”

Poor

No

Good/moderate

Yes

Gribben JG. Blood. 2010;115:187-197.

Frontline Treatment of CLL: Past


Frontline Treatment Algorithm for CLL Pts

Stage Fitnessdel(17p)p53mut

Therapy

Binet A-B, Rai 0-II, inactive

Irrelevant Irrelevant None

Active disease or Binet C or Rai III-IV

Go goNo FCR

Yes Allo-SCT

Slow goNo CLB + anti-CD20-mAb

Yes Al, HD R or O

Hallek M. Hematology. 2013;2013:138-150.

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