I FCR th t d d thI FCR th t d d thIs FCR the standard therapy for older cancer patients withIs FCR the standard therapy

for older cancer patients withfor older cancer patients with chronic lymphocytic

for older cancer patients with chronic lymphocytic

leukemia?leukemia?Véronique LEBLOND

Hôpital PITIE-SALPETRIEREPARISPARIS

FRANCE

How to treat chronic lymphocytic leukaemia ?y p y

FCR Fludarabine: 25mg m2 IV D1-3Fludarabine: 25mg m2 IV D1 3Cyclophosphamide 250mg/m2 IV D1-D3Rituximab: Cycle 1: 375 mg/m2, d 0Cycles 2 6: 500 mg/m2 d 1Cycles 2-6: 500 mg/m2, d 1

•FCR induces the highest remission rates ever reported

FCR h th t l f CLL• FCR may change the natural course of CLL

• FCR should be the treatment of first choice in• FCR should be the treatment of first choice in patients considered fit enough

Adverse events CTC grade 3 and 4

FC FCR ppTotal number of patients with ≥ 1 grade 3/4 event

248 (62.9%) 309 (76.5%) < 0.0001

Hematological toxicity 39 6% 55 7 % < 0 0001Hematological toxicity 39.6% 55.7 % < 0.0001

Neutropenia 21.0% 33.7% < 0.0001

Leukocytopenia 12.1% 24.0% < 0.0001

Thrombocytopenia 11.1% 7.4% 0.07

Anemia 6.8% 5.4% 0.42

I f i 21 5% 25 5% 0 18Infection 21.5% 25.5% 0.18

Tumor lysis syndrome 0.5% 0.2% 0.55

Cytokine release syndrome 0.0% 0.2% 0.32Cytokine release syndrome 0.0% 0.2% 0.32

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

How to treat chronic lymphocytic leukaemia ?

• Only 11% of the patients were over 70 yearsy p y

• All others may receive Chlorambucil

So, do we need something else ?

Median age of patients in pivotal phase III CLL trialsphase III CLL trialsMedian age of diagnosis = 72

yrs)

F

CamFC

F

Age (

1. Goede V and Hallek M. Drugs Aging. 2011;28(3):163‐76

2. Hallek M, et al. Lancet. 2010;376: 1164–74

3. Robak T, et al. J Clin Oncol. 2010;28(10):1756‐65

Professional experience required to “tailor” CLL therapy: characteristics at presentationtherapy: characteristics at presentation

● Median age at diagnosis: 72 years1

● Elderly patients may be fit or have comorbidities

Age at CLL diagnosis (years)

Patients1(%)

Mean comorbidities2(all cancer types, 

Mean no. of co‐morbidities

n/a (years)  n)

≤ 54 11 n/a55–64 20 2.9

2.94.2

/

55 64 20 2.965–74 27 3.675+ 43 4.23.6

1. Altekruse SF, et al. SEER Cancer Statistics Review, 1975‐2007, National Cancer Institute. Bethesda, MD, HYPERLINK "/csr/1975_2007/"http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.

2. Yancik R, Cancer 1997; 80:1273–1283.

Who may not be eligible for fludarabine based therapy?fludarabine based therapy?

• Impaired renal function: debate exists: CrCl• Impaired renal function: debate exists: CrCl 30–70 ml/min mandates reduced dose

• Physically unfit (co morbidities, geriatric assessment)

• Risk for infection

Other chemoimmunotherapy combinations may allow therapy to be adapted tomay allow therapy to be adapted to 

individual patients’ needs

‘Go-go’• Completely independent• No co-morbidity

‘No-go’• Severely handicapped• High co-morbidity

‘Slow-go’ • Some co-morbidity• Impaired organ functionNo co morbidity

• Normal life expectancy Aggressive

chemotherapy

High co morbidity• Reduced life expectancy Palliative care

Impaired organ function• Reduced performance

status Less aggressive

approachpp

Where to draw

What is thestandard of care?

Rituximab-FC is the standard of care to draw

the line?

FC vs FC lite :to target ederly/unfit CLL populationto target ederly/unfit CLL population 

Standard FC FC‐lite

MDACC2005

Eichh.2006

US IG2007

CLL42007

Cazin2008

Foon2009

Forconi2008

Marotta2000

n=224 n=180 n=141 n=196 n=76 n=50 n=26 n=20

Age (y) 57 5842‐64

6139‐86

6540‐86

5737‐66

5836‐84

7065‐80

7561‐87

Rai 0‐II 67% 7% 54% 25% 0% 84% 15% 0%

Min R funct 2 mg/dL NA 40 ml/min

NA « good » 1.8 mg/dL « twofold » « nl »

CIRS NA NA NA NA NA NA 1 (1‐3) NACIRS NA NA NA NA NA NA 1 (1 3) NA

d d d lMedian age:  FC standard 59,6 y vs FC lite 67,6 y

CLL trials in the elderly and/or unfitCLL trials in the elderly and/or unfitStudy Treatment No. of patients CR (%) ORR (%) PFS (months) Comments

Chl b il 100 0 51 18Eichhorst et al, 2009 

GCLLSG CLL5

Chlorambucil

Fludarabine

100

93

0

7

51

72

18

19

65 – 80 years of ageNo sig diff in PFS or OSMedian age  70‐71 yearsKnauf et al, 2009

Multicentre phase III

Chlorambucil

Bendamustine

157

162

2

31

31

68

8.3

21.6

Median age 64 years

No sig diff in ORR in <65 and >65 year olds

(BEN 71 6% 63 5% 0 3 CLB 28 4% 32 5%162 31 68 21.6 (BEN 71.6% vs 63.5%, p>0.3; CLB 28.4% vs 32.5%, p>0.06)

PFS not influenced by age >65 yearsHillmen et al, 2010

CLL208Chlorambucil + Rituximab

100 9 82 23.5

Hillmen et al, 2010

Median age 70 years (range 43–86)

F l 2010

Ph IICLB‐R +/‐ R 

maintenance*54 20.4 81.4 NR

Foa et al, 2010

Median age 70.5 years (range 61–84)

NR = not reported * Interim analysis measuring tumour response at end of induction phase on ITT

GCLLSG CLL5: Phase III Trial of Fludarabine vs Chlorambucil in Elderly (>65yo) CLLvs Chlorambucil in Elderly (>65yo) CLL

OS0.91.0

0.8l

PFS

19

0.91.0

0 70.8

al

Fludarabine

64 mos

0.50.60.70.8

Cum

Sur

viva

Fludarabine

ChlorambucilP = .7019 mos

0.40 3

0.5

0.7

Cum

Sur

viva

Chlorambucil

0.6

P = .1546 mos0.3

0.20 12 964836

0.4

24 60 72 84C

12

18 mos0.2

00 964836

0.3

24 60 72 84

C

0.1

No significant difference seen in either OS or PFS between arms

Mos 0 12 96483624 60 72 8412

Mos 0 96483624 60 72 84

No significant difference seen in either OS or PFS between arms

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

Is chlorambucil an effective therapy s c o a buc a e ect e t e apyfor elderly/unfit patients with CLL?

• Outcome varies by dose and duration of treatment– Higher doses and longer duration of therapy lead to:

• Overall response rates >70% and CR rates 5‐10%• Median PFS ~18 months in front‐line CLLM di ll i l >5• Median overall survival >5 years

• Can we improve on chlorambucil?– alternative chemotherapy ?alternative chemotherapy ?– addition of monoclonal antibodies ?

European Phase III FrontEuropean Phase III Front‐‐linelineCLL Study: progressionCLL Study: progression free survivalfree survivalCLL Study: progressionCLL Study: progression‐‐free survivalfree survival

1.0

0 60.70.80.9

Median age ~ 63 years old!Median age ~ 63 years old!

Bendamustine (n=162)

0.30.40.50.6

Chlorambucil (n=157)0.00.10.2

Median PFS: bendamustine 21.6 months;

0 6 12 18 24 30 36 42 48 54 60Time (months)

Median PFS: bendamustine 21.6 months; chlorambucil 8.3 months; p<0.0001

Knauf W et al. J Clin Oncol 2009;27:4378–84

European Phase III ‘Intergroup’ CLL Study: sub‐analysis by age

Progression‐free survival by treatment group and age

0.8

0.9

1.0Age <65 years – Bendamustine (n=87; median=20.9)Age <65 years – Chlorambucil (n=68; median=8.7)Age 65 years – Bendamustine (n=74; median=21.3)

0 5

0.6

0.7

free

 survival Age 65 years – Chlorambucil (n=79; median=9.4)

censored observations

0 2

0.3

0.4

0.5

rogression

‐f

0.0

0.0

0.2P

0 6 12 18 24 30 36 42 48 54 60 66Months

Knauf W et al. Blood 2009;114: Abs 2367 and accompanying poster 

Relative PFS for Relative PFS for chlorambucilchlorambucil and and

100

bendamustinebendamustine1.0

750.7

0.8

0.9

50

FS

Bendamustine (n=162)

0 4

0.5

0.6

25

% P

Chl0.2

0.3

0.4

0 1 2 3 4 50

Years

Chlorambucil (n=157)0.0

0.1

0 6 12 18 24 30 36 42 48 54 60Years

Time (months)LRF CLL4 TrialLRF CLL4 Trial European Phase III TrialEuropean Phase III Trial

Catovsky D, et al. Lancet 2007;370(9583):230-9Knauf W et al J Clin Oncol 2009;27:4378 84

Phase I study in patients with MM and renal disease: bendamustinerenal disease: bendamustine 

pharmacokineticsBendamustine* concentration (ng/mL)Bendamustine concentration (ng/mL)

8000

10,000

6000

8000

Patients with normal renal function (n=12)Patients with impaired renal function/dialysis-

2000

4000

p ydependent (n=12)

0

2000

Preiss R et al. Hematology J;2003:4(Suppl 1):Abs 394 and associated poster

0 60 120 180 240 300 360 420 480

* Each patient received 120mg/m2 d1+2 q4w

RR‐‐chlorambucil in firstchlorambucil in first‐‐line CLL:line CLL:Study designStudy designy gy g

• Final analysis of UK CLL208 study– Single arm, Phase II study– R‐chlorambucil for first‐line CLL patients (N = 100)

• Primary endpoint: safety– Efficacy measures (response rate, PFS) included as 

d d isecondary endpointsMabThera: 500 mg/m2 (375 mg/m2 cycle 1)

Chlorambucil: 10 mg/m2/day for 7 days

mg/

m2

mg/

m2

375

500

7 days 7 days 7 days 7 days 7 days 7 days21 days 21 days 21 days 21 days 21 days

7 days 7 days 7 days 7 days 7 days 7 days21 days 21 days 21 days 21 days 21 days

Further 6 cycles chlorambucil alone if patient not in CR and continuing to respond

CLL208: Response ratesCLL208: Response ratesC 08: espo se atesC 08: espo se ates

CRCRMi iMi i

O %O %12%17%

3%CRCRSD/PDSD/PD

MissingMissing

ORR=80% ORR=80% 95% CI 70.895% CI 70.8––87.3 87.3

68%Median PFS: 23 months

N ti t h d MRD ti i i

PRPR23 months

No patients had an MRD negative remission

Hillmen P, presented at ASH 2010

MatchedMatched‐‐pair analysis: Response ratespair analysis: Response rates

95% CI for %

Trial  N CR ORR SD/PD Not evaluable 

95% CI for % of patients achieving

at least a PR 

R‐chlorambucil 100 12%  80%  17%  3%  [70.8, 87.3] 

Chlorambucil1 200 6%  66%  30%  4%  [59.0, 72.5] 

Median PFS: 18months

Hillmen P, presented at ASH 20101CLL4, Catovsky et al. Lancet 2007; 370:230–239

New monoclonal antibodies

GA101• CD20 monoclonal• CD20 monoclonal

• Glyco-engineered

• Humanized, type II

Ofatumumab

•CD20 monoclonal

•Humanized, type I

Ongoing CLL studies in the unfit and/or elderlyOngoing CLL studies in the unfit and/or elderlyStudy Phase Previous therapy Treatment RecruitmentStudy Phase Previous therapy Treatment Recruitment

MaBLe

(Roche)IIIb No and yes

Chlorambucil‐R

Bendamustine‐ROngoing

ChlorambucilCLL‐11

(Roche)III No

Chlorambucil

Chlorambucil‐R

Chlorambucil‐GA101

Ongoing

Complement‐1III N

ChlorambucilO i

(GSK)III No

Chlorambucil‐OOngoing

RIAltO(GSK)

III NoChlorambucil‐O

Bendamustine‐OPlanned

Origin(Celgene)

III NoChlorambucil

LenalidomideOngoing

GOELAMS and FCGCLL/WM

III No FCR +/‐ R maintenance OngoingFCGCLL/WM

GOELAMS and II N

Chlorambucil

Fludarabine+ cyclophosphamide lite

B d ti O Pl dFCGCLL/WM

II No Bendamustine‐O

Ofatumumab

Fludarabine‐O

Planned

Conclusion: CLL in Older Patients, Conclusion: CLL in Older Patients, a Problem in Search of Solutionsa Problem in Search of Solutionsa Problem in Search of Solutionsa Problem in Search of Solutions

• FCR improves survival and is the “gold-standard” for all patients p g pconsidered fit enough for therapy

• Evaluation of comorbidities and geriatric assessment • We need a validated, simple-to-use CLL comorbidity and fitness

scale• The most appropriate therapy for those unfit for FCR could be :The most appropriate therapy for those unfit for FCR could be :

– Chlorambucil monotherapy (appropriate dosing!!)• Combinations that are being tested include:g

– Chlorambucil + anti-CD20 (Rituximab, ofatumumab, GA-101)

C– Alternative chemotherapy Bendamustine + anti CD20 – FCR lite

Fitness status and treatment selection in front‐line CLL

MRD‐/OS Symptom control/ palliation

Durable remission

?FCR‐lite?B +R Clb‐R?

FC R Chlorambucil +/‐ R

Clb‐R?Ofatumumab

V fi V fiVery fit Very unfit