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Linfoma de manto. Primera línea de tratamiento en pacientes jóvenes..

Linfoma de manto. Primera línea de tratamiento en pacientes jóvenes. Dr. Andrés Borda Hematología Hospital Universitario 12 de octubre. 2013. Cause-specific survival of the main B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland, 1980-2006.

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Linfoma de manto. Primera línea de tratamiento en pacientes jóvenes..

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  1. Linfoma de manto.Primera línea de tratamiento en pacientes jóvenes.. Dr. Andrés Borda Hematología Hospital Universitario 12 de octubre. 2013

  2. Cause-specific survival of the main B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland,1980-2006.

  3. Overall survival for patients with mantle cell lymphoma according to age

  4. Pacientes candidatos a trasplante.

  5. Primera linea de tratamiento en pacientes jovenes con Linfoma de manto. Pocos datos solidos. Hasta la fecha es una entidad incurable. Estudios fase II. Ghielmini M, Zucca E (2009) How I treatmantlecelllymphoma.Blood 114(8):1469–1476

  6. “WatchfulWaiting” El enfoque “ watchful waiting” no es recomendado como tratamiento de primera linea en pacientes jovenes con Linfoma de manto. • Curso clínico agresivo. • No parámetros clínicos o biológicos de predicción. Ghielmini M, Zucca E (2009) How I treatmantlecelllymphoma.Blood 114(8):1469–1476 Dreyling M, Hiddemann W, for The European MCLN (2009)Current treatment standards and emerging strategies in mantlecelllymphoma. Hematology 2009(1):542–551

  7. Primera línea de tratamiento. Linfoma de manto localizado Linfoma de manto avanzado Quimioterapia convencional. Tratamiento intensificado.

  8. Linfoma de manto localizado. • < 20%. • Compromiso de uno a tres territorios adyacentes al momento del diagnostico. • 3 a 4 ciclos de QT • RDT Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R,Connors JM (2003) Limited-stage mantle-cell lymphoma. AnnOncol 14(10):1555–1561

  9. Abstract Mantle-cell lymphoma (MCL) is a rare cancer, with the majority of patients (pts) presenting in stage III-IV and the outcomes are poor. To determine the curability of localized MCL, we examine stage I-II pts at our institution between 1990-2007. 26 pts with stage I (38%) and stage II (62%) were referred. Sites involved were head and neck in 73%. Five had a blastoid variant. Five patients were treated with palliative intent. Analysis was focused on pts treated with a curative intent (21 pts): 17 CT+RT, 2 RT, 2 CT followed by ASCT. 13 patients received CHOP, 5-RCHOP, 1-CVP; most received 6 cycles. The RT median dose was 35Gy and IFRT for the majority. For 21 pts treated with a curative intent, median follow up was 5.8 years. The overall response rate was 95%. Among the 19 CR/CRu pts, 9 relapsed for a 5-year relapse rate of 46%. Relapses were mainly observed at distant sites, 3 were in GI tract, 1 had both local and distant relapse. Median PFS and OS were 3.2 and 6.4 years, respectively. 5-year OS was 62%. In univariate analysis, blastoid variant and stage II were prognostic factors for PFS. Multivariate analysis could not be performed due to the small sample size. With a treatment approach using combined CT+RT for stage I-II MCL, local control was achieved in 94%. Systemic relapse remains a significant problem, especially for stage II and blastoid variant. Radiotherapy should remain part of curative treatment plan in stage I-II MCL. Bernard Met al. Limited-stage mantle cell lymphoma: treatment outcomes at the Princess Margaret Hospital. Leuk Lymphoma. 2013 Feb;54(2):261-7.

  10. Quimioterapia convencional. Estudiosretrospectivos. OS media de 5 a 7 años Respuesta total 90% RC 40% PFS 2 años Agentesalquilantes. Fludarabina / Bendamustina +/- rituximab.

  11. Rituximab en la terapia de inducción. Agente simple con rituximab. ORR 30% Duración media de la respuesta 6 meses. hazard ratio, 0.60; 95 % CI, 0.37–0.98 GhielminiJ Clin Oncol 23(4):705–711 SchulzHet al . J NatlCancerInst 99(9):706–714 Heterogeneidad grande entre los estudios, asicomo los resultados no son conclusivos. Dada la bajatoxicidad del rituximab y eleefectobenefico en RC y posiblemente en OS, Se recomienda en el esquema de inducción.

  12. CRR(%) 25 - 40 ORR (%) 80 a 95 PFS/EFS (m) 7 a 20) Ann Hematol (2013) 92:1151–1179

  13. Overall survival for patients treated with CVP or chlorambucil, with or without rituximab

  14. Distribution of chemotherapy regimens for mantle cell lymphoma 2000 – 2011. Blood. 2014 May 23

  15. Papel de citarabina (ara-C) DHAP Citarabina es muy activo en el tratamiento del linfoma de manto. Mejora de la calidad y duración de la respuesta. Integración a esquemas de primera línea. Dosis altas de ara-C Alta toxicidad. Muerte x toxicidad 5%. Infección severa 15%. Trombocitopenia severa 30%

  16. 29 % no completaron los ciclosportoxicidad. MD Anderson. OS 8 años < 65 años o > 65 años (68 vs 33%) 2-year PFS of 63 % European Mantle Cell Lymphoma Network (MCL net). Fase III .

  17. La conclusión de los resultados de fase II, sugiere que altas dosis de citarabina , deben ser parte de la terapia de inducción en pacientes jóvenes. La alta dosis de metotrexate es más toxico que efectivo, y la citarabina tiene un gran impacto en la tasa de RC. Damon LE(2009) J Clin Oncol 27(36) GeislerCH (2010) Haematologica95(8)

  18. Fase III. • European MCL Network. • R-CHOP x6 vs R-CHOP x 3/ R-DHAPx3 • stem cell mobilization with DexaBEAM • TASPE acondicionamiento (12 Gy TBI+2×60 mg/kg Cyclophosphamide in arm A vs. 10 GyTBI+4×1.5 g/m2 Ara-C+140 mg/m2 melphalan in arm B) PottC et al . (2010) Blood 116 (21 ASH Annual Meeting Abstracts):965

  19. Seguimiento 51 meses. • CR and CR / CRu rates in arm B (25 vs 36 % (p=0.012) and 40 vs 54 % (p=0.0003), respectively). • R-DHAP patients showed longer median time to treatment failure (46 vs. 88 months, p=0.0382; HR, 0.68) and longer median OS (82 months vs. not reached, p= 0.045). • El resultado de este ensayo sugiere que el cuidado estandar en pacientes jovenes con linfoma de manto podría incluir un regimen de inducción que contiene citarabina alta dosis. Hermine O et al. (2012) Blood 120 (21 ASH Annual Meeting Abstracts):151

  20. TASPE Tratamiento de inducción. (esquema basado en ara-C) Mejor EFS y OS comparado con controles históricos. Solo hay un estudio aleatorizado ( resultados no conclusivos) Consolidación. TASPE. • Todos los datossugieren que un plateau de EFS no esalcanzado y pro lo tantoprobablementetodos los pacientes eventualmenterecaen. • El gruponordico, los resultados a 10 años de seguimientos, muestran que persite el riesgo de recaída.

  21. Protocolo nordico. Fase III.

  22. EFS a 10 años 42% Duración de la respuesta 54% a 10 años

  23. Rituximab en la inducción y acondicionamiento tiene mayor PFS que en pacientes que no lo recibieron. • Las diferencias se observaron 2 añosdespués del trasplante. 2009 113: 4144-4152

  24. Purging in vivo con QT en combinación con rituximab. Alta eficacia de purging in vivo con quimioterapia en combinación con rituximab Gianni AM, Blood102(2):749–755 Geisler CH, (2008). Blood 112(7):2687–2693 Howard OM, (2002). J Clin Oncol 20(5):1288–1294

  25. Remisión molecular como objetivo terapéutico en linfoma de manto • Alcanzar la remisión molecular es un predictor independiente y fuerte de resultados en clinicos en MCL Younger Trial. • Es superior al estatus MIPI, tipo de tratamiento. • Papel del tratamiento “Pre-emptive” Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptivetreatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J ClinOncol. 2009;27(26):4365-4370

  26. Response duration according to MRD status in peripheral blood and/or BM after induction immunochemotherapy in the EuropeanMCL Younger Trial.

  27. Clinical response duration in patients with a molecular marker who were candidates for pre-emptive therapy with rituximab for solelymolecular relapse. Mol Rel, molecular relapse.

  28. GEL/TAMO SpanishCooperativeGroup Ann Hematol (2013) 92:1151–1179

  29. Protocolo nordico.

  30. Protocolo Nordico.

  31. 2008 112: 2687-2693

  32. (Blood. 2008;112:2687-2693)

  33. (Blood. 2008;112:2687-2693)

  34. (Blood. 2008;112:2687-2693)

  35. (Blood. 2008;112:2687-2693)

  36. (Blood. 2008;112:2687-2693)

  37. (Blood. 2008;112:2687-2693)

  38. La sobrevida media no alcanzada, pero persiste un patron continuo de recaída, particularmente en el grupo de alto riesgo. Overall and event-free survival (EFS), and response duration in allpatients.

  39. 6 cycles are given in total with alternating R‐maxiCHOP (no rituximab on cycle 1) and high dose Cytarabine every 3 weeks. This is should be consolidated with BEAM PBSCT. Stem cells can be mobilised off the back of a cycle 6 of R‐HD‐Cytarabine.

  40. 2004-2010 • N: 497 pacientes. • (Germany, France, Poland, Belgium). • overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and CR/CRu rates were significantly higher in arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). • After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median FU of 51 months, TTF was longer in Arm B (46m vs 88m; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/PR (n= 81 vs 40). • The rate of ASCT-related death in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49m vs 84m; p=0.0001). • At the time of final analysis, OS was superior in Arm B (NR vs 82m, p=0.045) Conclusiones Con un seguimiento prolongado, se confirma que altas dosis de ara-C en adicción a R-CHOP incrementa significativamente la tasa de respuesta completa, TTF y OS sin relevancia clinica que incremente la toxicidad. Por lo tanto, el regimen de inducción que contiene altas dosis de ara-C seguido de ASCT debeser el estandar en primeralinea de tto para linfoma de manto en < 65 años.

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