Management of CLL in elderly patients asco 2014

Jeffrey P. Sharman, MDMedical DirectorHematology ResearchUS Oncology ResearchEugene, Oregon

Case Discussion 3:Management of Frail Patients With CLL

Image: PR. J. BERNARD/CNRI/Copyright©2014 Science Source. All Rights Reserved

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

Case Presentation

86-yr-old male with good performance status for age

Initially presents with lymphocytosis, lymphadenopathy, splenomegaly, Hb 11 g/dL, platelets 120 cells/mm3

During the next 2 yrs, WBC climbs from 40,000 cells/mL to 170,000 cells/mL, Hb falls to 9 g/dL by age 88

FISH shows trisomy 12 and IgVH unmutated

Let’s Test Your Knowledge


What is your treatment choice?

1. Ibrutinib

2. Alemtuzumab

3. FCR

4. Obinutuzumab + chlorambucil

5. Ofatumumab + chlorambucil

6. Unsure


Which novel therapies have received FDA approval for previously untreated patients with CLL via the “Breakthrough Therapy Designation?”

1. Ibrutinib

2. Idelalisib

3. Obinutuzumab

4. Ofatumumab

5. None

6. Both 1 and 2

7. Both 3 and 4

8. Unsure


Social Security Projections

Exact Age, Yrs Male

Death Probability Number of Lives Life Expectancy

88 0.14 23,222 4.66

89 0.15 20,021 4.33

90 0.17 16,969 4.02

91 0.19 14,112 3.73

Social Security. Acturial Life Tables.


Mortality Following First Therapy

Setting Median Age Regimen 12 Month Mortality

MD Anderson 57 FCR 1%

German CLL8 61 FC vs FCR 4%

Community 74 Any 10%

Connect CLL: The CLL Disease Registry.


Choosing First-line Therapy in 2014

Age and Comorbidity

FCR BR CD20

German CLL10 Study[1] German CLL11 Study[2]

Complement 1 Study[3]

1. Eichhorst B, et al. ASH 2013. Abstract 526. 2. Goede V, et al. N Engl J Med. 2014;370:1101-1110. 3. Hillmen P, et al. ASH 2013. Abstract 528.


In Defense of Chlorambucil

Woyach JA, et al. J Clin Oncol. 2013;31:440-447.

1.0

0.8

0.6

0.4

0.2

00 24 48 72 96 120 144

Mos

Pro

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FS

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0.6

0.4

0.2

00 48 96 144 192 240

Mos

Pro

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f O

S

Interaction test P = .006Interaction test P = .046

F and < 70Ch and < 70F and ≥ 70Ch and ≥ 70

F and < 70Ch and < 70F and ≥ 70Ch and ≥ 70


PFS OS

Eichhorst BF, et al. Blood. 2009;114:3382-3391.

No Benefit of Fludarabine vs Chlorambucil in Elderly Patients With CLL

1.0

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00 12 24 36 48 60 72 84 96

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ival

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0 12 24 36 48 60 72 84 96Mos

Cu

mu

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ival

FludarabineChlorambucil


Chlorambucil Use as Function of Age

Age, Yrs First Line, % Second Line, %

Young than 65 2 0

65-75 4 1

Older than 75 12 8

Sharman J, et al. Ash 2011. Abstract 2864.


Patients withpreviously untreated

CLL (N = 444)

OfatumumabCycle 1 Day 1 300 mg, Day 81000 mg, cycles 2-12 Day 1

1000 mg q28d +

Chlorambucil 10 mg/m2 Days 1-7 every 28 days

Chlorambucil10 mg/m2 Days 1-7 every 28

days

Follow-up: 1 mo past last dose, 3rd mos, then every 3 mos

Minimum 3 cycles or until best response or PD; maximum 12 cycles; no crossover allowed.

Hillmen P, et al. ASH 2013. Abstract 528.

Phase III COMPLEMENT1: Ofatumumab + Chlorambucil vs Chlorambucil Alone

Dose rationale: highest PFS and ORR with the lowest toxicity compared with any other chlorambucil treatment


Ofatumumab + Chlorambucil vs Chlorambucil Alone: PFS*


Ofatumumab + chlorambucil

Median PFS: 22.4 mos

HR: 0.57 (95% CI: 19.0-25.2;

P < .001)

Chlorambucil

Median PFS: 13.1 mos

(95% CI: 10.6-13.8)

Median follow-up: 28.9 mos

*As assessed by an Independent Review Committee.

1.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0

Pro

bab

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f P

FS

Mos Since Randomization

0 524 8 12 16 20 24 28 32 36 40 44 48


Response Chlorambucil(n = 226)

Ofatumumab + Chlorambucil (n = 221)

PFS, mos 13 22

ORR, % 69 82

CR, % 1 14

MRD, % 4 12

COMPLEMENT 1: Chlorambucil ± Ofatumumab



Previously untreatedCLL patients with

comorbidities(CIRS score > 6 and/or

CrCl < 70 mL/min)(N = 781)

Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 118)

Obinutuzumab 1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles

(n = 333)

Rituximab 375 mg/m2 IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles

(n = 330)

28-day cycle

Patients who progress on chlorambucil alone allowed to crossover to obinutuzumab + chlorambucil arm.

Randomized 1:2:2

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

CLL11 Trial: Obinutuzumab + Chlorambucil vs Rituximab + Chlorambucil


Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions


100

80

60

40

20

0

P < .001 P < .001

55.0

22.3

31.4

58.47.3

G-Clb(n = 238)

Clb(n = 118)

R-Clb(n = 233)

Pat

ien

ts W

ith

a R

esp

on

se (

%)

Obinutuzumab-ClbCRPF

ClbCRPR

Rituximab-ClbCRPR


Obinutuzumab + Chlorambucil: Patients With CLL and Coexisting Conditions


100

80

60

40

20

0

100

80

60

40

20

0

P < .001

20.7

57.7

7.0

58.1

Obinutuzumab-Clb(n = 333)

Rituximab-Clb(n = 329)

Pat

ien

ts W

ith

a

Res

po

nse

(%

)

Bone Marrow Blood

P < .001 P < .001

19.5

2.6

37.7

3.3

Pts atRisk, n 26/133 3/114 87/231 8/243

Pat

ien

ts W

ith

a

Neg

ativ

e M

RD

Tes

t (%

)

Obinutuzumab-ClbRituximab-Clb

Obinutuzumab-ClbCRPR

Rituximab-ClbCR PR


0 3 6 9 12 15 18 21 24 27 30 33 36 39

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of

PF

S

Mos

CLL11 Trial: PFS Head-to-Head Comparison

15.2 26.7

Obinutuzumab-chlorambucilRituximab-chlorambucil

Stratified HR: 0.39(95% CI: 0.31-0.49;P < .0001)



CLL11: Overall Survival


1.0

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00 6 12 18 24 30 36

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G-Clb

Clb

Stratified HR for death with G-Clb: 0.41 (95% Cl: 0.23-0.74;P = .002)


Single-Agent Obinutuzumab

Before After

Images courtesy Dr. Jeff Sharman.

Let’s Review the Case Study and Questions


Case Presentation

86-yr-old male with good performance status for age

Initially presents with lymphocytosis, lymphadenopathy, splenomegaly, Hb 11 g/dL, platelets 120 cells/mm3

During the next 2 yrs, WBC climbs from 40,000 cells/mL to 170,000 cells/mL, Hb falls to 9 g/dL by age 88

FISH shows trisomy 12 and IgVH unmutated


What is your treatment choice?

1. Ibrutinib

2. Alemtuzumab

3. FCR

4. Obinutuzumab + chlorambucil

5. Ofatumumab + chlorambucil

6. Unsure


LYN

SYK

BCR

BTK

PLCγ2

PKC

AKT

mTOR

p70s6k elf4E

GSK-3 NF-kβ

pathway

Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies

BCR signaling is required for tumor expansion and proliferation

BCR signaling up-regulated in B-cell malignancies

New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk

IbrutinibAVL-292

┬ ┬IdelalisibIPI-145TGR-1202

┬FostamatinibGS-9973

PI3Kdelta


Ibrutinib Idelalisib/Rituximab

Relapse


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

00 6 12 18 24 30 36 42 48

Wks

Ab

solu

te L

ymp

ho

cyte

Co

un

t (p

er m

m3 )

Idelalisib + rituximab Placebo + rituximab


Relapsed CLL: Idelalisib + Rituximab


125

100

75

50

25

0

-25

-50

-75

-100

Idelalisib + Rituximab Placebo + Rituximab

Changes in the Measured Size of Lymph Nodes From Baseline

Patients

Gre

ates

t P

erce

nt

Ch

ang

e


Idelalisib and Rituximab for Previously Treated Patients With CLL

PF

S (

%)

Idelalisib + rituximabMedian PFS: not reached

Placebo + rituximabMedian PFS: 5.5 mos

HR: 0.15(95% CI: 0.08-0.28;P < .0001)

100

75

50

25

0

0 2 4 6 8 10 12 14 16Mos


OS

(%

)

HR: 0.28(95% CI: 0.09-0.86; P = .018)

100

75

50

25

00 2 4 6 8 10 12 14 16

Mos

Idelalisib + rituximab

Placebo + rituximab

dcameron

Design: could we put this graph and the graph on the next page side by side?

Devin Overbey

figures moved to same slide, side by side.

Andrea Eva Neal

update tick marks to be at intervals of 20: 0, 20, 40, 60, 80, 100

Andrea Eva Neal

update tick marks to be at intervals of 20: 0, 20, 40, 60, 80, 100

Andrea Eva Neal

suggest to restructure this slide so that the legends appear above their graphs per our usual format


Relapsed CLL: Targeting BTK With Ibrutinib

Byrd JC, et al. N Engl J Med. 2013;369:32-42.

100

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0

5246

33

2420 18 18

71716865

54

3921

18 7 5 4 4 4 4

CR + PR

PR with lymphocytosis

SD

0 4 8 12 16 20 24

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(%

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in S

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(%)

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ALC SPD


Targeting BTK With Ibrutinib in Relapsed CLL: OS


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0P = .15 by log-rank test

No 17p or 11q deletions (n = 29)

11q deletion (n = 23)

17p deletion (n = 28)


Targeting BTK With Ibrutinib in Relapsed CLL: PFS


1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30

P = .04 by log-rank test

No 17p or 11q deletions (n = 29)

11q deletion (n = 23)

17p deletion (n = 28)

Pro

bab

ilit

y o

f P

FS


Labeled Indications for Ibrutinib

Ibrutinib is a kinase inhibitor indicated for the treatment of patients with:

– Mantle cell lymphoma who have received at least 1 previous therapy

– CLL who have received at least 1 previous therapy

These indications are based on ORR

Improvements in survival or disease-related symptoms have not been established

Ibrutinib [package Insert].


Ofatumumab or Ibrutinib in Relapsed CLL

Relapsed CLL/SLL, including deletion 17p

N = 350

Ran

dom

ized

1:1

Arm A: Ofatumumab

Wk 1: 300 mg IV initial dose

Wk 2-8: 2000 mg IV/wk

Wks 12, 16, 20, 24: 2000 mg IV

Arm B: Ibrutinib

400 mg orally, once daily continuously until disease progression or unacceptable toxicity

ClinicalTrials.gov. NCT01578707.


Conclusions

Treatment of elderly CLL poses high risk of 12-mo mortality, possibly due in part to toxicity of current treatment regimens

Management of CLL is dynamically changing due to introduction of TKI agents and CD20-based therapy

CD20-based approvals in frontline therapy likely to be joined in near term by TKI-based options

Relapsed disease being transformed by ibrutinib/idelalisib with BCL-2 coming soon

Audience Question and Answer Session

Documents

Management of CLL in elderly patients asco 2014