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IV Reunión de la Sociedad Asturiana de Hematología y Hemoterapia TRATAMIENTO DE LA LLC EN LOS PACIENTES DE EDAD AVANZADA O CON COMORBILIDADES. Dr. FRANCESC BOSCH SERVICIO DE HEMATOLOGÍA HOSPITAL UNIVERSITARIO VALL D’HEBRON BARCELONA Soto del Barco, 12 de Marzo de 2011. - PowerPoint PPT Presentation
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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