Madrid, 26-27 de enero de 2013

Carlos Panizo

Servicio de Hematología. Clínica Universidad de Navarra

Tratamiento del LNH folicular en recaída

Bendamustine-Rituximab (BR) Replaces R-CHOP as “Standard of

Care” in the Treatment of Indolent Non-Hodgkin’s Lymphoma in

German Haematology Outpatients Centres

.

Knauf W, et al. ASH 2012:Abstract 3666

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.

Patterns of Delivery of Chemoimmunotherapy to patients with

Follicular Lymphoma in the United States: Results of the National

Lymphocare Study

.

Martin P, et al. ASH 2012:Abstract 3702

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.

FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan

Therapy Predicts Outcome in Relapsed or Refractory

Indolent B-Cell Lymphoma .

Okada M, et al. ASH 2012:Abstract 3648

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

• 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

Whole Genome Sequencing in Sequential Biopsies Reveals the Genetic

Evolution of Follicular Lymphoma to Transformed Follicular Lymphoma

.

Okosun J, et al. ASH 2012:Abstract 145

Media de mutaciones somáticas/tumor:

72 (range: 41-143) 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.

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

N = 60

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

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

Outcome of BEAM-Autologous and BEAM-Alemtuzumab Allogeneic

Transplantation in Relapsed Advanced Stage Follicular Lymphoma

Noriega V, et al. ASH 2012:Abstract 2022

Lunning MA, et al. ASH 2012:Abstract 3136

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 pre-

transplant characteristics of the alloSCT

cohort, FL appears to be exquisitely

sensitive to an allogeneic effect. TRM

continues to limit the benefit of alloSCT

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

Blood and Lymphatic Microenvironment as Prognostic Factor in

Follicular Lymphoma

Nesterova ES, et al. ASH 2012:Abstract 2696

Rituximab +/- Bevacizumab for Patients with Previously Treated Follicular

Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon

Research Institute

Hainsworth JD, et al. ASH 2012:Abstract 2749

Avastin

unión al factor de crecimiento del endotelio vascular (VEGF)

Lenalidomide Is Effective in Heavily Pretreated Non Hodgkin Lymphoma

(NHL): Analysis of a Retrospective Data Collection

Rigacci L, et al. ASH 2012:Abstract 3964

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

Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination

with Rituximab and Bendamustine in Relapsed Indolent Lymphoma

.

Gopal AK, et al. ASH 2012:Abstract 3678

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

Phase 1b Study of TRU-016, an Anti-CD37 SMIPTM Protein, in Combination

with Rituximab and Bendamustine in Relapsed Indolent Lymphoma

.

Gopal AK, et al. ASH 2012:Abstract 3678

Bien tolerado: MTD no alcanzada

Clínicamente activo:

ORR 100% a 20 mg/kg

ORR 83% todos los pacientes

CR 33% todos los pacientes

F

c

F

v VL

VH

CL

CH2

CH3

CH1

MW 150

kDa

VL

VH

Hinge

Linker

TRU-016 MW ~105

kDa

Antibody

huFc

ADAPTIRTM (Modular Protein Technology)

Targeting CD37

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

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

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

Westin JR, et al. ASH 2012:Abstract 793

● Fase II

● N=30 LF recaídos (1-4 Ttos previos) RTX sensibles

● Criterios de inclusión habituales

CT-011 3 mg/Kg x4 dosis + RTX

1 4 8

Evaluación

32 28 24 20 16 12 2

… hasta 12

CT-011 + RTX RTX

ORR 66% 40%

CR 52% 11%

• 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

Bispecific SCORPION™ Molecules Effectively Redirect T-Cell Cytotoxicity

Toward CD19-Expressing Tumor Cells

Chenault RA, et al. ASH 2012:Abstract 3722

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

Panizo C, et al. ASH 2012:Abstract 4881

% C

ito

toxic

ida

d

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.

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

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)

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

The Bruton’s Tyrosine Kinase Inhibitor

Ibrutinib (PCI-32765) Is Active and Tolerated

in Relapsed Follicular Lymphoma

The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and

Tolerated in Relapsed Follicular Lymphoma

Fowler NH, et al. ASH 2012:Abstract 156

● Fase I

● Búsqueda DMT

● LNH indolentes recaidos

● LF N=14

Cohort Ibrutinib dose (mg)

orally

28-day on/7-day off 1,25 mg/kg

28-day on/7-day off

28-day on/7-day off

28-day on/7-day off

28-day on/7-day off 12,5 mg/kg

Continuous 8,3 mg/kg

Continuos 560 mg fija

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.

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

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

Flinn IW, et al. ASH 2012:Abstract 3663

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

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

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

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