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Dr. FRANCESC BOSCH SERVICIO DE HEMATOLOGÍA HOSPITAL UNIVERSITARIO VALL D’HEBRON BARCELONA

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.

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Dr. FRANCESC BOSCH SERVICIO DE HEMATOLOGÍA HOSPITAL UNIVERSITARIO VALL D’HEBRON BARCELONA

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  1. IV Reunión de la SociedadAsturiana de Hematología y HemoterapiaTRATAMIENTO 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

  2. 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

  3. LLC: Progreso de la respuesta en los últimos 10 años Rai et al. NEJM 2000;343:1750–1757 Eichhorst et al. Blood 2006;107:885–891 Hallek et al. Lancet 2010;376:1164–1174

  4. R-FCNuevoestándar de tratamiento en la LLC Hallek et al., The Lancet 2010, 1164

  5. Principalescuestiones 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? • ¿Cómotratar a los enfermosde edadavanzada o con comorbilidades? • ¿Cómotratar a pacientes con del17p/p53? • ¿Cómotratar a los pacientesquefracasan al R-FC? • ¿Quénuevosfármacosasoman en el horizonte?

  6. LLC: Enfermedadde pacientes en edadavanzada Horner M et al. SEER Report 2009, http://seer.cancer.gov/statfacts/html/clyl.html Abrisqueta et al., Blood 2009

  7. Pacientes > 70 años en la vida real yen ensayosclínicos

  8. CLL5 protocol of the GCLLSGfor advanced CLL in elderly patients CLL,  65 years, untreated, Binet stage C or B (with symptoms) or A with B-symptoms 6 x F F 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 BW q 15 d Eichhorst B et al. Blood 2009;114: 3382–91

  9. CLL5:Progression-freesurvivalandoverallsurvival OS PFS Cortesia de B. Eichhorst (Blood 2009)

  10. CLL5Cause of Death Clb arm: 32 patients died F arm: 42 patients died Cortesía de B. Eichhorst (Blood 2009)

  11. CLL5Second line therapy  p = 0.001

  12. Comorbilidades en LLC

  13. LLC: Impacto de las comorbilidades en la supervivencia Cortesía de B. Eichhorst (Blood 2009) Kuderer MH, et al. Cancer 2006;106:2258–66

  14. 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?

  15. Edad y Comorbilidad en LLC COMORBILIDADES ¿RESPUESTA? ¿TOXICIDAD? EDAD

  16. GCLLSG CLL8: FC + rituximab provides similar efficacy in elderly patients 30% of patients in CLL8 were ≥ 65 years old 10% of patients in CLL8 were ≥ 70 years old Hallek M, et al.Lancet 2010; 376: 1164 - 1174.

  17. Inmunoquimioterapia en la LLCRespuestaytoxicidad por edades 1Tam et al, J Clin Oncol 2008 2Hallek et al, Lancet 2010 3Bosch et al, J Clin Oncol 2009 4Foon et al, J Clin Oncol 2009

  18. Edad y Comorbilidad en LLC COMORBILIDADES RESPUESTA TOXICIDAD EDAD • La valoración de la comorbilidad nos permitiríaidentificar pacientesque se podrían beneficiar de un tratamientomenosintensivo • ¿Cuál es la mejor escala de comorbilidad? • CIRS? • Collect?  http://www.linfoma.roche.es/

  19. Cumulative illness rating scale (CIRS) According to Extermann et al., JCO 1998

  20. ¿Alternativas al tratamiento de los pacientes con comorbilidades? 1. Clorambucil  control de la enfermedad 2. Nuevascombinacionesadaptadasa estos enfermos • Clorambucil + anti-CD20 • Otrasquimioterapias (+ anti-CD20): • Bendamustina • Pentostatina • Lenalidomida +/- anti-CD20 • ....

  21. R-chlorambucil - CLL208 study design:Phase II trial in 100 untreated patients Rituximab (375mg/m2 cycle 1, 500mg/m2 cycles 2–6) Chlorambucil (10mg/m2/day for 7 days) 50mg/m2 325mg/m2 500mg/m2 21 days 21 days 21 days 21 days 21 days 7 days 7 days 7 days 7 days 7 days 7 days Further 6 cycles chlorambucil alone if patient not in CR and continuing to respond 21 days 21 days 21 days 21 days 21 days 7 days 7 days 7 days 7 days 7 days 7 days • End-points: • Primary = safety • Secondary = responses (including MRD), PFS and survival • 100 patients from 12 UK Centres between Nov 2007 and Nov 2009

  22. CLL208: Serious adverse eventsA total of 57 SAEs occurred in 39 patients 13 deaths:– 11 due to progressive diseaseand 2 consideredtreatment-related (neutropenicsepsisand CVA)

  23. CLL208: Response rates Missing CR SD/PD 3% 12% 17% ORR=80% 95% CI 70.8–87.3 68% PR No patients had an MRD negative remission Courtesy Dr. P. Hillmen

  24. R-chlorambucil - CLL208: Comparison with 150 chlorambucil patients from LRF CLL4 Each patient from CLL208 to 3 patients treated with chlorambucil in CLL4 was matched using Age Binet stage VH mutational status 11q deletion status byFISH assessment All well matched except median age: CLL4 - 65yo; ChlorR – 70yo

  25. Matched-pair analysis: Response rates 1 CLL4, Catovsky et al. Lancet 2007; 370:230–239

  26. Progression-free survival: R-chlorambucil Censored observations 100 90 80 70 60 50 40 30 20 10 0 Median PFS=23.9 months Probability of progression-free survival (%) (CLL4-UK) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time in study (months) Courtesy Dr. P. Hillmen

  27. Rituximab + Chlorambucil. Conclusions • 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 > chlorambucilalone (84% vs 66%) • Remissions < R-FC • Chlorambucil + rituximabtested in a phase III trial (German CLL11 Trial)

  28. CLL7: GSK Registration Study for ofatumumab (Complement-1 Trial) Ofatumumab (300mg + 1000mg cycle 1, 1000mg cycles 2–12) Chlorambucil (10mg/m2/day for 7 days) 3 cycles beyond maximum response (up to 12 cycles) 1000 mg 300mg 21 days 21 days 21 days 21 days Patients with CLL requiring therapy (n=444) 7 days 7 days 7 days 7 days 7 days 7 days R Chlorambucil (10mg/m2/day for 7 days) Primary end-point = Progression Free Survival

  29. BO21004 (CLL11) Trial: 1st Line Therapy ofPatientswithComorbidity Chlorambucil (Clb) Chlorambucil Rituximab (R-Clb) R CIRS > 6 Chlorambucil GA101 (G-Clb)

  30. Chemical structure of bendamustine Cl CH2 Cl COOH H2C N H2C CH2 CH2 N N CH3 Benzimidazole ring Butyric acid group Nitrogen mustard: DNA alkylation moiety Cyclophosphamide Chlorambucil Fludarabine

  31. BENDAMUSTINA EN LLC • Mecanismo de acciónúnico y dual • Aprobada en primeralíneapara los pacientes con contraindicaciónparafludarabina • Tratamientointravenoso (oral 2013) • Primeralínea: 90 mg/m2/día, días 1+2 • Segundalínea: 70 mg/m2/día, días 1+2 • Aclaramientohepático a través del citocromo P450 • No modificación de dosisporfracaso renal (CrCl >10ml/min)

  32. Phase I study in patients with MM and renal disease: bendamustine pharmacokinetics Bendamustine concentration (ng/mL) 10,000 8000 Patients with normal renal function (n=12) 6000 Patients with impaired renal function/dialysis-dependent (n=12) 4000 2000 0 0 60 120 180 240 300 360 420 480 Preiss R et al. Hematology J;2003:4(Suppl 1):Abs 394 and associated poster

  33. European Phase III ‘Intergroup’ CLL Study: sub-analysis of progression-free survival by age Progression-free survival by treatment group and age 1.0 Age <65 years – Bendamustine (n=87; median=20.9) 0.9 Age <65 years – Chlorambucil (n=68; median=8.7) Age 65 years – Bendamustine (n=74; median=21.3) 0.8 Age 65 years – Chlorambucil (n=79; median=9.4) 0.7 0.6 0.5 Progression-free survival 0.4 0.3 0.2 0.0 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Months Knauf W et al. Blood 2009;114: Abs 2367 and accompanying poster

  34. R R R R R R B B B B B B B B B B B B CLL2M TREATMENT SCHEDULE R = Rituximab 375 mg/m2 day 0, cycle 1, 500 mg/m2 cycle 2-6, q4wks B = Bendamustine 90 mg/m2 day 1-2, cycle 1-6, q4wks Fischer et al. ASH 2009

  35. CLL2M PATIENTS CHARACTERISTIC PATIENTS CHARACTERISTICS I

  36. CLL2M RESPONSE Phase II CLL2M: Best Response * N=110 (7 pts not yet evaluable) Fischer et al. ASH 2009; Abstract 205.

  37. PCRA goodoption for olderpatients • PCR • Pentostatin 2 mg/m2day 1 • Cyclophosphamide 600 mg/m2day 1 • Rituximab 375 mg/m2day 1 • No differences in htenumber of cyclesadministered in ptsolderthan 70 yrs. • OR: 90% CRs: 27% Shanafelt et al, Cancer 2007, 2291

  38. Lenalidomide Thalidomide analogue Immunomodulatory drug (IMiD) 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

  39. 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 unmutatedIgVH/ High ZAP-70 and del17p / del 11q Time to response is prolonged, best responses seen after 6-9 months Myelosuppressionis frequent, requires dose reduction Synergistic with Rituxmab

  40. 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 Wiestnerlenalidomide as salvage [ASH 2009] • Javier Pinillalenalidomide and rituximab [ASH 2010] • Thomas Kipps (CRC) lenalidomide + rituximab initial therapy [ASH 2010] • CLL001 lenalidomide as salvage [ASH 2010]

  41. 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)

  42. Lenalidomide in Elderly CLL: Response (2008 NCI-WG Criteria) *4 patients (8%) with flow cytometry negative CR Badoux, X et al. (submitted)

  43. Lenalidomide in Elderly CLL: Overall and Progression-free Survival Badoux, X et al. (submitted)

  44. Lenalidomide in Elderly CLL: Improvement in Serum Igs (n=37) *p<0.001 Cycles of therapy Cycles of therapy • 8 / 16 (50%) patients with IgG<600mg/dl → normalized serum IgG Badoux, X et al. (submitted)

  45. 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, 2005 2Wu, L. Blake Bartlett J. et al. Clin Cancer Res;14:4650-57,2008 3 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

  46. Lenalidomide and Rituximab in Relapsed CLL: Doses and Schedule Allopurinol 300 mg day 1 -14 of cycle 1 No antibiotic or anti-viral prophylaxis No DVT prophylaxis Cycle 1 Cycle 2 Cycles 3-12 Rituximab 375 mg/m2 R Days 1 8 15 22 28 1 8 15 22 28 1 8 15 22 28 Day 9 Lenalidomide 10 mg daily until progression

  47. Lenalidomideand Rituximab in Relapsed CLL: Responses (ITT)

  48. Rituximab + GM-CSF Treatment Plan Week 1 Week 2 Week 3 Week 4 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 Day Week 5 Week 6 Week 7 Week 8 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 Day GM-CSF 250 mcg s.c. Rituximab 375mg/m2 i.v.

  49. Response Rituxan + GM-CSF Untreated CLL Age > 70 Total patients: 32 CR 2 ( 6%) nPR 2 ( 6%) PR 18 (56%) Fail 10 (32%)

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