IV Reunión de la Sociedad Asturiana de Hematología y Hemoterapia

TRATAMIENTO DE LA LLC EN LOS PACIENTES DE EDAD

AVANZADA O CON COMORBILIDADESDr. FRANCESC BOSCH

SERVICIO DE HEMATOLOGÍAHOSPITAL UNIVERSITARIO VALL D’HEBRON

BARCELONA

Soto del Barco, 12 de Marzo de 2011

GE LLCGE LLC

Tratamiento de la LLC El objetivo del tratamiento ha sido siempre paliativo

Historicamente pocos enfermos alcanzaban la RC

Enfermedad de personas de edad avanzada

En los últimos años ha mejorado dramáticamente la tasa

y duración de las respuestas

Los estudios aleatorizados recientes demuestran que

esto se traduce en una mejor supervivencia

LLC: Progreso de la respuesta en los últimos 10 años

Drugs n CR OR Survival

Rai, NEJM 2000

CLBF

181170

4%20%

37%63%

5666

GCLLSG CLL4, 2006

FFC

151148

12%25%

84%95% No

Hallek,CLL8, 2010

FCFC+R

408409

23%45%

85%95% Yes

Rai et al. NEJM 2000;343:1750–1757Eichhorst et al. Blood 2006;107:885–891Hallek et al. Lancet 2010;376:1164–1174

R-FCNuevo estándar de tratamiento en la LLC

Hallek et al., The Lancet 2010, 1164

Principales cuestiones en el tratamiento de la LLC

¿Podemos mejorar los resultados de R-FC? ¿Podemos disminuir la toxicidad con igual eficacia? ¿Podemos curar la enfermedad? ¿Debe ser la erradicación de la ERM el principal objetivo? ¿Qué papel juega el mantenimiento?

¿Cómo tratar a los enfermos de edad avanzada o con comorbilidades?

¿Cómo tratar a pacientes con del17p/p53? ¿Cómo tratar a los pacientes que fracasan al R-FC? ¿Qué nuevos fármacos asoman en el horizonte?

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1980 - 1994 1995 - 2004

> 80

70-79

60-69

50-59

< 50 años

LLC: Enfermedad de pacientes en edad avanzada

Horner M et al. SEER Report 2009, http://seer.cancer.gov/statfacts/html/clyl.html

≥65 años

55–64 años20–54 años

19%11%

70%

Abrisqueta et al., Blood 2009

Pacientes > 70 años en la vida real yen ensayos clínicos

CLL5 protocol of the GCLLSGfor advanced CLL in elderly patients

6 x FF 25 mg/m², day 1–5 i.v.q 28 d

Clb (max. 12 months)Clb 0.4 mg/kg BW p.o.Dose escalation up to 0.8mg/kg BWq 15 d

CLL, 65 years, untreated, Binet stage C or B (with symptoms) or A

with B-symptoms

Eichhorst B et al. Blood 2009;114: 3382–91

CLL5:Progression-free survival and overall survival

time to progression or death908478726660544842363024181260

Cum

Sur

viva

l

1,0

0,9

0,8

0,7

0,6

0,5

0,4

0,3

0,2

0,1

0,0

CLB-censoredF-censoredCLBF

random

p = 0.72 Overall survival in months908478726660544842363024181260

Cum

Sur

viva

l

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

CLB-censoredF-censoredCLBF

random

p = 0.15

Cortesia de B. Eichhorst (Blood 2009)

PFS OS

CLL5Cause of Death

66%3%

25%

6%

CLL related

Treatment related

Secondary disease

Unknown

Clb arm: 32 patients died

54%

10%

31%

5%

CLL relatedTreatment relatedSecondary diseaseUnknown

F arm: 42 patients died

Cortesía de B. Eichhorst (Blood 2009)

CLL5Second line therapy

Clb60 pts (62%)

F34 pts (39%)

regimen pt ORR % pt ORR%F 26 53 4 0F-combination

10 100 9 100

Clb 12 n.e. 2 n.e.

CHOP 2 n.e. 9 75 p = 0.001

Comorbilidades en LLC

100

80

60

40

20

0

SEER Cancer Registry% patients

Age

55–65years

65–74years

>75years

>5

Co-morbidities

4

3

2

1

0

LLC: Impacto de las comorbilidades en la supervivencia

70

60

50

40

30

20

10

00 1 2 3 >4

Number of major co-morbidities

Mor

talit

y (%

)

No documented infectionDocumented infection

1.24.9 6.7

14.7 12.9

28.9 23.8

47.4 38.3

57.4

Kuderer MH, et al. Cancer 2006;106:2258–66 Cortesía de B. Eichhorst (Blood 2009)

Factors affecting the choice of fludarabine Renal insufficiency: debate exists

◦ CrCl 30–70 ml/min: reduce dose

Other contraindications◦ Cardiac insufficiency◦ Recurrent chest infections/bronchiectasis◦ Neurological disorders (pre-existing CNS

disorders or peripheral neuropathy)◦ Hepatitis prophylaxis

Autoimmune haemolysis ◦ During previous exposure to fludarabine◦ De novo autoimmune haemolysis?

Edad y Comorbilidad en LLC

EDAD

COMORBILIDADES

¿RESPUESTA?¿TOXICIDAD?

GCLLSG CLL8: FC + rituximab provides similar efficacy in elderly patients

30% of patients in CLL8 were ≥ 65 years old10% of patients in CLL8 were ≥ 70 years old

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

ORR P-value CR P-valueFCR vs FC in <65yo FCR (n=282) 89%

0.00145%

<0.0001 FC (n=290) 79% 20%FCR vs FC in ≥65yo FCR (n=126) 93%

0.02843%

0.003 FC (n=119) 83% 24%

Inmunoquimioterapia en la LLCRespuesta y toxicidad por edades

NDND57%77%15%48R-FC “Lite”4

57%32%80%84% *20%*70R-FCM3

30%26%43%45% *8%812R- FC (CLL8)2

28%25%71%77%14%223R-FC (MDAKC)1

> 70 yrs< 70 yrs> 70 yrs< 70 yrs

Neutropenia Grade 3/4CR rate% > 70 yearsn=

NDND57%77%15%48R-FC “Lite”4

57%32%80%84% *20%*70R-FCM3

30%26%43%45% *8%812R- FC (CLL8)2

28%25%71%77%14%223R-FC (MDAKC)1

> 70 yrs< 70 yrs> 70 yrs< 70 yrs

Neutropenia Grade 3/4CR rate% > 70 yearsn=

1Tam et al, J Clin Oncol 20082Hallek et al, Lancet 20103Bosch et al, J Clin Oncol 20094Foon et al, J Clin Oncol 2009

Edad y Comorbilidad en LLC

EDAD

COMORBILIDADES

RESPUESTATOXICIDAD

• La valoración de la comorbilidad nos permitiría identificar pacientes que se podrían beneficiar de un tratamiento menos intensivo

• ¿Cuál es la mejor escala de comorbilidad?• CIRS?• Collect? http://www.linfoma.roche.es/

Cumulative illness rating scale (CIRS)

According to Extermann et al., JCO 1998

‘Go-go’• Completely independent• No co-morbidity• Normal life expectancyAggressive

chemotherapy

‘No-go’• Severely handicapped• High co-morbidity• Reduced life expectancyPalliative care

Rituximab-FC is the standard of care

‘Slow-go’ • Some co-morbidity• Impaired organ function• Reduced performance

statusLess aggressive

approach

What is thestandard of care?

Where to draw the line?

¿Alternativas al tratamiento de los pacientes con comorbilidades?

1. Clorambucil control de la enfermedad

2. Nuevas combinaciones adaptadas a estos enfermos◦ Clorambucil + anti-CD20◦ Otras quimioterapias (+ anti-CD20):

Bendamustina Pentostatina

◦ Lenalidomida +/- anti-CD20◦ ....

R-chlorambucil - CLL208 study design:Phase II trial in 100 untreated patients

End-points: Primary = safetySecondary = responses (including MRD), PFS and survival

100 patients from 12 UK Centres between Nov 2007 and Nov 2009

Rituximab (375mg/m2 cycle 1, 500mg/m2 cycles 2–6) Chlorambucil (10mg/m2/day for 7 days)

50m

g/m

2

325m

g/m

2

500m

g/m

2

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: Serious adverse eventsA total of 57 SAEs occurred in 39 patients

Serious adverse event (SAE)

R-chlorambucil (n=100)

No. of eventsFebrile neutropenia 5Neutropenic sepsis 4Infusion related reaction 3Back pain 2Cytokine release syndrome 2Joint swelling 2Pneumonia 3Pyrexia 2Vomiting 2Others 32Total 5713 deaths:– 11 due to progressive disease and 2 considered

treatment-related (neutropenic sepsis and CVA)

CLL208: Response rates

ORR=80% 95% CI 70.8–87.3

12%

68%

17%3%

No patients had an MRD negative remission

CR

PR

SD/PDMissing

Courtesy Dr. P. Hillmen

R-chlorambucil - CLL208: Comparison with 150 chlorambucil patients from LRF CLL4

Age

Binet stage

VH mutational status

11q deletion status byFISH assessment

Each patient from CLL208 was matched using

to 3 patients treated with chlorambucil in CLL4

All well matched except median age: CLL4 - 65yo; ChlorR – 70yo

Matched-pair analysis: Response rates

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]

Chlorambucil 1 200 6% 66% 30% 4% [59.0, 72.5]

1 CLL4, Catovsky et al. Lancet 2007; 370:230–239

Progression-free survival: R-chlorambucilPr

obab

ility

of p

rogr

essi

on-fr

ee s

urvi

val (

%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time in study (months)

Censored observations100

90

80

70

60

50

40

30

20

10

0

Median PFS=23.9 months

(CLL4-UK)

Courtesy Dr. P. Hillmen

Median age (70 yrs) of the patients is more representative of the CLL in clinics

Chlorambucil + Rituximab◦ Low toxic profile in unfit patients (more neutropenia?)◦ Response rates > chlorambucil alone (84% vs 66%)◦ Remissions < R-FC

Chlorambucil + rituximab tested in a phase III trial (German CLL11 Trial)

Rituximab + Chlorambucil. Conclusions

Ofatumumab (300mg + 1000mg cycle 1, 1000mg cycles 2–12) Chlorambucil (10mg/m2/day for 7 days)

300m

g

1000

mg

CLL7: GSK Registration Study for ofatumumab (Complement-1 Trial)

3 cycles beyond maximum response (up

to 12 cycles)7 days 7 days 7 days21 days 21 days

7 days 7 days 7 days21 days 21 days

Chlorambucil (10mg/m2/day for 7 days)

Primary end-point = Progression Free Survival

Patients with CLL requiring

therapy (n=444)

R

BO21004 (CLL11) Trial: 1st Line Therapy of Patients with Comorbidity

Chlorambucil (Clb)

ChlorambucilRituximab

(R-Clb)RCIRS > 6

ChlorambucilGA101 (G-Clb)GE LLCGE LLC

Chemical structure of bendamustine

CH3

N

N

CH2

H2C CH2

COOH

NH2C

CH2

Cl

Cl

CH2

N

CH

CH2

H2C

Cl

Cl

COOH

NH2CH2

N

CH2

CH2

H2C

Cl

Cl

CH2

COOH

P

HN

ON

CH2

H2C

Cl

ClO

Cyclophosphamide FludarabineChlorambucil

Nitrogen mustard:DNA alkylation

moiety

Butyric acid group

Benzimidazole ring

Mecanismo de acción único y dual Aprobada en primera línea para los pacientes con

contraindicación para fludarabina

Tratamiento intravenoso (oral 2013)

◦ Primera línea: 90 mg/m2/día, días 1+2

◦ Segunda línea: 70 mg/m2/día, días 1+2

Aclaramiento hepático a través del citocromo P450

No modificación de dosis por fracaso renal (CrCl >10ml/min)

BENDAMUSTINA EN LLC

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

0 60 120 180 240 300 360 420 480

Bendamustine concentration (ng/mL)

0

2000

4000

6000

8000

10,000

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

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

European Phase III ‘Intergroup’ CLL Study: sub-analysis of progression-free survival by age

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

0.0

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prog

ress

ion-

free

surv

ival

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

Progression-free survival by treatment group and age

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

CLL2M

R B B R B B R B B R B B R B B R B B

B = Bendamustine 90 mg/m2 day 1-2, cycle 1-6, q4wks

R = Rituximab 375 mg/m2 day 0, cycle 1, 500 mg/m2 cycle 2-6, q4wks

CLL2MTREATMENT SCHEDULE

Fischer et al. ASH 2009

CLL2MPATIENTS CHARACTERISTICS I

Number of pts N %

Total 117 100

Male 84 71.8

Female 33 28.2

Age Years

Median 64

Age categories N %

< 65 60 51.3

≥ 65 < 70 27 23.1

≥ 70 30 25.6

CLL2M PATIENTS CHARACTERISTIC

* N=110 (7 pts not yet evaluable)

Phase II CLL2M: Best Response

Response N %ORR 100 90.9 CR 36 32.7 nPR 3 2.7 PR 61 55.5SD 10 9.1PD - -

Fischer et al. ASH 2009; Abstract 205.

CLL2M RESPONSE

PCRA good option for older patients

PCR◦ Pentostatin 2 mg/m2 day 1◦ Cyclophosphamide 600 mg/m2 day 1◦ Rituximab 375 mg/m2 day 1

No differences in hte number of cycles administered in pts older than 70 yrs.

OR: 90% CRs: 27%

Shanafelt et al, Cancer 2007, 2291

Lenalidomide

Thalidomide analogueImmunomodulatory drug (IMiD)

3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

Lenalidomide in CLL:Currrent status Lenalidomide is a new therapeutic approach in CLL

targeting the microenvironment Lenalidomide is active in:

◦ relapsed or refractory CLL ◦ “Poor-risk” CLL, including unmutated IgVH / High

ZAP-70 and del17p / del 11q Time to response is prolonged, best responses seen after

6-9 months Myelosuppression is frequent, requires dose reduction Synergistic with Rituxmab

Clinical Trials with Lenalidomide in CLL

MDACC• Lenalidomide as salvage [44*]• Lenalidomide as initial treatment elderly [60*]• Lenalidomide + rituximab as salvage [59*]• Lenalidomide + ofatumumab as salvage [27/36]• Lenalidomide as consolidation [15/52]

Published/Reported• Chanan-Khan lenalidomide as salvage • Christine Chen lenalidomide as initial treatment [IWCLL 2009]• Jennifer Brown FR + lenalidomide [ASH 2009]• Alexander Egle FR+ len [ASH 2009]• Adrian Wiestner lenalidomide as salvage [ASH 2009]• Javier Pinilla lenalidomide and rituximab [ASH 2010]• Thomas Kipps (CRC) lenalidomide + rituximab initial therapy [ASH 2010]• CLL001 lenalidomide as salvage [ASH 2010]

Lenalidomide as Initial Treatment of Elderly Patients

Phase II, 60 patients Frontline patients with standard indications for

treatment age 65 or older 5 mg p.o.daily for 56 days, 5 mg/28 days (max

25 mg daily)Allopurinol 300 mg day 1 -14 as tumor lysis

syndrome prophylaxis

Badoux, X et al. (submitted)

Lenalidomide in Elderly CLL: Response (2008 NCI-WG Criteria)

N = 60 NCI Responsen patients %

CR* 6 10 CRi* 3 5 Nodular PR 3 5 PR 25 42ORR 37 62

*4 patients (8%) with flow cytometry negative CR

Badoux, X et al. (submitted)

Lenalidomide in Elderly CLL: Overall and Progression-free Survival

Badoux, X et al. (submitted)

Lenalidomide in Elderly CLL: Improvement in Serum Igs (n=37)

• 8 / 16 (50%) patients with IgG<600mg/dl → normalized serum IgG

* p<0.001

Cycles of therapy Cycles of therapy

Badoux, X et al. (submitted)

Lenalidomide and Rituximab as Salvage in Relapsed CLL: Pre-clinical Experience

IMiDs ↑ rituximab-mediated cytotoxicity1

Lenalidomide ↑ NK-cell and ADCC in rituximab-treated NHL and CLL2

Lenalidomide ↑ NK-cell function, alter cytokine production and ↓ angiogenesis enhancing rituximab-mediated anti-

tumor activity in lymphoma3

Lenalidomide and rituximab ↑ NK-cell mediated cytotoxicity in MCL4

Lenalidomide ↓CD20 expression and antagonizes direct and ADCC cytotoxicity of rituximab in CLL cells5

1 Hernandez-Ilizaliturri et al, Clin Cancer Res; 11:5984-92, 20052 Wu, L. Blake Bartlett J. et al. Clin Cancer Res;14:4650-57,20083 Reddy N. Br J Haematol. Jan;140(1):36-45, 2008

4 Zhang L. and Wang M. Am. J. Hematol. E-pub, 2009 5 Lapalombella, R., Byrd J. et al. Blood;112:5180-9, 2008

Lenalidomide and Rituximab in Relapsed CLL: Doses and Schedule

Allopurinol 300 mg day 1 -14 of cycle 1No antibiotic or anti-viral prophylaxis No DVT prophylaxis

1 8 15 22 281 8 15 22 281 8 15 22 28

Cycle 1 Cycle 2 Cycles 3-12Rituximab 375 mg/m2

Day 9 Lenalidomide 10 mg daily until progression

Days

R

Lenalidomide and Rituximab in Relapsed CLL: Responses (ITT)

N = 59 NCI Response

n patients %

CR 5 8

CRi/u 3 5

Nodular PR 7 12

PR 23 39

ORR 38 64

Rituximab + GM-CSF Treatment Plan

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Week 1 Week 2 Week 3 Week 4

Rituximab 375mg/m2 i.v.GM-CSF 250 mcg s.c.

29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56

Week 5 Week 6 Week 7 Week 8

Day

Day

Response Rituxan + GM-CSF Untreated CLL Age > 70

Total patients: 32

CR 2 ( 6%)

nPR 2 ( 6%)

PR 18 (56%)

Fail 10 (32%)

Treatment of elderly CLLCOMBINATION GOAL

Fit for fludarabine< 70-75 yo (?)

FCR, R-FCM Responses

Unfit for fludarabine< 75 yo (?)Low comorbidities (?)

R-BendamustineChlorambucil + Anti-CD20PCR

Responses / QoL

Comorbidities Chlorambucil + Anti-CD20(Lenalidomide + R)

QoL

No-go Chlorambucil(R+GM-CSF)

Palliation

17p- AlemtuzumabCamPredCamDex(Lenalidomide)

QoL

COMORBIDITY ASSESSMENT?

N. VillamorP. AbrisquetaM.J. TerolE. González-BarcaM. GonzálezC. FerraE. AbellaJ. DelgadoJA. García-MarcoY. GonzálezF. CarbonellS. FerrerE. MonzóI. JarqueA. MuntañolaM. ConstantsL. EscodaE. Montserrat

Peter HillmenJ.A. García-MarcoTait ShanafeltAbraham M VargheseBarbara Eichhorst

GE LLCGE LLC