Tratamiento del LNH folicular en recaída. Madrid, de enero de 2013 Carlos Panizo Servicio de Hematología. Clínica Universidad de Navarra

Transcripción

1 Tratamiento del LNH folicular en recaída Madrid, de enero de 2013 Carlos Panizo Servicio de Hematología. Clínica Universidad de Navarra

2 Bendamustine-Rituximab (BR) Replaces R-CHOP as Standard of Care in the Treatment of Indolent Non-Hodgkin s Lymphoma in German Haematology Outpatients Centres. BR es el tratamiento sistémico utilizado con más frecuencia en LNHi en los centros outpatient en Alemania. El esquema R-CHOP ya no se considera como el standard of care para los pacientes con LNHi. Los resultados de los ensayos clínicos se trasladan con velocidad a la práctica clínica habitual. Knauf W, et al. ASH 2012:Abstract 3666

3 Patterns of Delivery of Chemoimmunotherapy to patients with Follicular Lymphoma in the United States: Results of the National Lymphocare Study. BR es muy poco utilazado en este entorno. Como los esquemas R-CHOP, R-CVP y R- Fludarabina son los más usados en primera línea, BR es una muy buena aproximación para la segunda línea en estos pacientes. Martin P, et al. ASH 2012:Abstract 3702

4 FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan Therapy Predicts Outcome in Relapsed or Refractory Indolent B-Cell Lymphoma. El PET-FDG/CT realizado 2 semanas después de la administración del 90Y Ibritumomab Tiuxetan predice mejor la SLP en LNHi en recaída o refractario Okada M, et al. ASH 2012:Abstract 3648

5 Whole Genome Sequencing in Sequential Biopsies Reveals the Genetic Evolution of Follicular Lymphoma to Transformed Follicular Lymphoma. N: 6 pts con Linfoma Folicular 8 FL, 6 tfl, 6 germline Secuenciación del genoma completo Número de tratameintos: 2-6; Número de recaídas: 1-6 Mediana de tiempo a transformación: 8,6 años Media de mutaciones somáticas/tumor: 72 (range: ) con mayor frecuencia en tfl (mediana: FL 64.8; tfl 83.6), lo que indica evolución genética con la progresión. Todas las biopsias mostraron mutaciones en MLL2 (gen implicado en metilación de histonas) También mutaciones en la vía de NF-kB, receptor de la señal de célula B, desarrollo B, reparación DNA, regulación de apoptosis. Okosun J, et al. ASH 2012:Abstract 145

6 Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with Immunochemotherapy. R-BMD Geltamo 08 Trial N = 60 Peñalver J, et al. ASH 2012: Abstract 1639

7 Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with Immunochemotherapy. R-BMD Geltamo 08 Trial Peñalver J, et al. ASH 2012: Abstract 1639

8 Rituximab, Bendamustine, Mitoxantrone, Dexamethasone (R-BMD) in Patients with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with Immunochemotherapy. R-BMD Geltamo 08 Trial Peñalver J, et al. ASH 2012: Abstract 1639

9 Outcome of BEAM-Autologous and BEAM-Alemtuzumab Allogeneic Transplantation in Relapsed Advanced Stage Follicular Lymphoma Noriega V, et al. ASH 2012:Abstract 2022

10 Remission Duration 12 Months for Early Relapsed and Refractory Follicular Lymphoma Is Predictive of Early Failures Post-High Dose Therapy and Autologous Stem Cell Rescue The management of relapsed/refractory FL remains a clinically complex topic. Remission duration of 12 months prior to re-induction chemotherapy is suggestive of inferior disease control with HDT-ASCR. Given the relatively unfavorable pretransplant characteristics of the allosct cohort, FL appears to be exquisitely sensitive to an allogeneic effect. TRM continues to limit the benefit of allosct Lunning MA, et al. ASH 2012:Abstract 3136

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12 Blood and Lymphatic Microenvironment as Prognostic Factor in Follicular Lymphoma Nesterova ES, et al. ASH 2012:Abstract 2696

13 Rituximab +/- Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute Avastin unión al factor de crecimiento del endotelio vascular (VEGF) Hainsworth JD, et al. ASH 2012:Abstract 2749

14 Lenalidomide Is Effective in Heavily Pretreated Non Hodgkin Lymphoma (NHL): Analysis of a Retrospective Data Collection Rigacci L, et al. ASH 2012:Abstract 3964

15 Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma Pharmacokinetic and Pharmacodynamic Analysis of Ocaratuzumab in 50 Patients with Relapsed Follicular Lymphoma and Low- Affinity FcγRIIIa (CD16a) Polymorphisms) An Open-label, Phase I Study of R-CVP in Combination With Inotuzumab Ozagamicin in Patients With CD22-positive B-cell non- Hodgkin s Lymphoma: Preliminary Safety and Efficacy Data Phase II Safety and Efficacy Study of CT-011, a Humanized Anti-PD-1 Monoclonal Antibody, in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma Bispecific SCORPION Molecules Effectively Redirect T-Cell Cytotoxicity Toward CD19-Expressing Tumor Cells Immunotherapy with LAK Cells and Anti- CD20 Monoclonal Antibodies for Follicular Lymphoma: Enhanced Antibody-Dependent Cell Cytotoxicity of LAK Cells in Association with GA101 Rather Than Rituximab

16 Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma. CD37 tetraspanin presente en la superficie celular en linfocitos B normales y neoplásicos. Miembro de la superfamilia de proteínas transmembrana 4. Co-associada con HLA-DR, CD81 (TAPA- 1), CD82, CD53. Expresada por tumores de células B. Función desconocida Papel en la interacción B/T Posible papel en la proliferación T Posible participación en regulación de producción de IL6 por células dendríticas Gopal AK, et al. ASH 2012:Abstract 3678

17 Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma. ADAPTIR TM (Modular Protein Technology) Targeting CD37 F c F v VH C H 1 VL CL MW 150 kda C H 2 C H 3 Antibody Linker VL VH Hinge hufc TRU-016 MW ~105 kda Bien tolerado: MTD no alcanzada Clínicamente activo: ORR 100% a 20 mg/kg ORR 83% todos los pacientes CR 33% todos los pacientes Gopal AK, et al. ASH 2012:Abstract 3678

18 Pharmacokinetic and Pharmacodynamic Analysis of Ocaratuzumab in 50 Patients with Relapsed Follicular Lymphoma and Low-Affinity FcγRIIIa (CD16a) Polymorphisms. Du M, et al. ASH 2012:Abstract 2750

19 An Open-label, Phase I Study of R-CVP in Combination With Inotuzumab Ozagamicin in Patients With CD22-positive B-cell non-hodgkin s Lymphoma: Preliminary Safety and Efficacy Data Ogura M, et al. ASH 2012:Abstract 1633

20 Phase II Safety and Efficacy Study of CT-011, a Humanized Anti-PD-1 Monoclonal Antibody, in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma La expresión de programmed death (PD)-1, un receptor coinhibidor, está aumentada en las células T intratumorales en LF. CT-011 (pidilizumab), Ac monoclonal anti-pd-1 bloquea la vía PD-1/PD-ligand pudiendo incrementar la función antitumoral de linfoitos T y NK. Rituximab actúa vía ADCC Fase II N=30 LF recaídos (1-4 Ttos previos) RTX sensibles Criterios de inclusión habituales CT mg/kg x4 dosis + RTX CT RTX RTX ORR 66% 40% CR 52% 11% hasta Evaluación Westin JR, et al. ASH 2012:Abstract 793

21 Bispecific SCORPION Molecules Effectively Redirect T-Cell Cytotoxicity Toward CD19-Expressing Tumor Cells Chenault RA, et al. ASH 2012:Abstract 3722

22 % Citotoxicidad Immunotherapy with LAK Cells and Anti-CD20 Monoclonal Antibodies for Follicular Lymphoma: Enhanced Antibody-Dependent Cell Cytotoxicity of LAK Cells in Association with GA101 Rather Than Rituximab LAK cells generated from peripheral blood lymphocytes by culture with IL-2 in patients with LF show a higher cytotoxic activity than naive lymphocytes. The observed cytotoxic capacity of these LAK cells against a CD20 positive cell line (CRL-1596) is enhanced by the addition of anti-cd20 mabs. Interestingly, GA101 was consistently more effective than rituximab in enhancing the cytotoxic capacity of LAK cells. Panizo C, et al. ASH 2012:Abstract 4881

23 A Phase I Trial of the Bruton s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin s Lymphoma (NHL) The Bruton s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non- Hodgkin Lymphoma: Results From a Phase I Study Clinical Safety and Activity in aphase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-,Y, in Patients with Advanced Hematologic Malignancies

24 The Bruton s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma Fase I Búsqueda DMT LNH indolentes recaidos LF N=14 TOXICIDAD: Buena tolerancia. MTD no alcanzada AEs en 25% included: diarrea (50%), fatigue (44%), naúseas (38%), tos (31%) y mialgias (25%). Hubo 1 Grade 4: hypokalemia. Cohort 28-day on/7-day off 28-day on/7-day off 28-day on/7-day off 28-day on/7-day off 28-day on/7-day off Continuous Continuos Ibrutinib dose (mg) orally 1,25 mg/kg 12,5 mg/kg 8,3 mg/kg 560 mg fija EFICACIA: 14 pts con LF, 11 evaluables (>2,5 mg/kg) ORR: 54.5% (3 CRs, 3 PRs) Duración de respuesta (DOR) 12.3 meses. Mediana PFS 13.4 meses. 2 pts siguieron Tto.: +25 y +29 meses Fowler NH, et al. ASH 2012:Abstract 156

25 Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-,Y, in Patients with Advanced Hematologic Malignancies IPI-145 es un potente inhibidor a dosis < 15 mg BID. Dosis mayores potencian la inhibición. SAEs más frecuentes: citopenias, elevación ALT/AST Clínicamente activo: Respuestas en inhl con dosis < 50 mg BID Flinn IW, et al. ASH 2012:Abstract 3663

26 A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/ Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) Abexinostat (S78454 / PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose- Escalation Study in 35 Patients

27 Abexinostat (S78454 / PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non- Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients Morschhauser F, et al. ASH 2012:Abstract 3643

28 A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/ Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) Evens AM, et al. ASH 2012:Abstract 55