Dianas terapeúticas en hematología: ser o no ser, esa es la cuestión Dra Dolores Caballero

Servicio de Hematología. Hospital Universitario de Salamanca Linfomas No Hodgkin

Síndromes mieloproliferativos leucemia mieloide crónica. Imatinib

Primera linea

Time cover, 28th May 2001 Druker B. Blood 2008; 112: 4808-4817. Evolución Supervivencia Global

n = 3682 (CML IV) Imatinib, 2002 – 2012 (CML IV) 5-year survival 90% 10-year survival 83% (CML IIIA) IFN or SCT, 1997 – 2004 (CML IIIA) 5-year survival 71% 10-year survival 61%

(CML III) IFN or SCT, 1995 – 2001 (CML III) 5-year survival 63% 10-year survival 48%

IFN, ± HU, 1986 – 1994

Survival probability Survival (CML I, II) 5-year survival 53% 10-year survival 27%

Hydroxyurea, 1983 – 1994, 5 yr surv. 44%, 10 yr surv. 18%

Busulfan, 1983 – 1994, 5-year survival 38%, 10-year survival 11%

Years after diagnosis

Hehlmann R. German CML study Group, Updated 2016 Via de JAK/STAT en SMP Ph neg

Primera linea Ruxolitinib

Javier Pinilla-Ibarz.Oncotargets 2016 Revised risk stratification of patients with AML on the basis of integrated genetic analysis.

Patel et al, N Engl J Med,2012, 366:1079-89

Leucemia promielocítica aguda

• Clasificación FAB M3 • 23% de LMA en España* • Mayoría <60 años • Coagulapatía de consumo • t(15;17)(q32;q11-12) – Gen de fusión PML/RARα **,variantes • Tratamiento basado en ATRA-antraciclinas.*** *Chillon et al. Haematologica 2001;86:162-166 (Tríóxido de Arsénico-ATO-) ** deThe et al . Nature 1990; 347:558-561 ***Sanz et al. Blood 2009;113:1875-1891 Leucemia promielocítica aguda

Ácido retinoico (ATRA) y Trióxido de Arsénico (ATO). Mecanismos de acción

de Thé et al, J.Cell Biol, 201211 Event-free Survival Primera linea Primary endpoint

97.1% 85.6%

p = 0.02 ATRA+ATO ATRA+Chemo free survival probability survival - free Event

Months from diagnosis

Lo Coco, New Engl Journal Med 2013 TJ Ley et al, 2013; 368:2059-74

Significantly mutated genes, n:23

leucemia Aguda Mieloblástica

Neoplasias linfoides Diferenciacin B

19 Anticuerpos en neoplasias linfoides

Rituximab CD20 CD19 CD22 Inotuzumab ozagamicin

Milatuzimab CD74 CD79b Polatuzumab Apolizumab B cell SLAMF7 CD38 (Plasma Cell)

Mepatumumab GaliximabbCD80 TRAIL Lexatumumab

Alemtuzumabb CD52 CD40 Dacetumumab CD30

Kindly provided by Miguel Canales and adapted Leucemia Aguda Linfoblástica Leucemia Linfoblástica

• Primer tumor en la infancia • Mas del 80% de los niños se curan con quimioterapia convencional • En el adulto pronóstico desfavorable • Tto en adulto: quimioterapia y trasplante alogénico • Avances en los últimos años: • Inhibidores de TK si Ph positivo • Nuevos Ac Mo Ac Mo en LLA

Inotuzumab

Aprobado en LLA. Pendiente precio

Suresh et al. Journal of Hematology & Oncology 2014, Neoplasias linfoides maduras New drugs and mechanisms of action in

MM CS-1 Elotuzumab CD38 Daratumumab / MoAb IPH2101 PD1/PDL1 / / Pidilumab

IL-6 Lymph. Ras NK cell

Raf PI3K IMIDs ME Akt Thalidomide K Lenalidomide Alkylators Pomalidomide mTORC mTORC Melphalan 1 MAP 2 Cyclophosphamide K Bendamustine

Proteasome DACi Inh. Bortezomib Panobinostat Carfilzomib Hsp-90 Inh. Ixazomib

Approved Ocio, Leukemia 2014. Updated Daratumumab (Anti-CD38): Background

• Human CD38 IgGκ

• Direct and indirect anti- myeloma activity1-5

• Depletes CD38+ immunosuppres sive regulatory cells5

• Promotes T-cell expansion and activation5

1. Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474. 2. Jansen JMH, et al. Blood. 2012;120:Abstract 2974. 3. de Weers M, et al. J Immunol. 2011;186:1840-8. 4. Overdijk MB, et al. MAbs. 2015;7:311-21. 5. Krejcik J, et al. Blood. 2016. Epub ahead of print. Pollux: Len-Dex +/- Daratumumab: PFS

1.0 12-month 18-month PFS* PFS* 83% 78% 0.8 DRd

60% 0.6 52%

0.4 Rd Median PFS: 18.4 months progression without surviving Proportion 0.2

HR: 0.37 (95% CI, 0.27-0.52; P <0.0001) 0 0 3 6 9 12 15 18 21

No. at risk Months

Rd 283 249 206 179 139 36 5 0 DRd 286 266 248 232 189 55 8 0

63% reduction in the risk of disease progression or death for Dimopoulos, EHA 2016 DRd vs Rd CLL: The most common leukaemia in the Western world1

 Annual incidence of 4.2/100,000  Male:female ratio of ~2  Median age is 72 years  B mature CD5/CD19 + cells  1/3 of patients will never need treatment  1/3 will be treated at diagnosis  1/3 during evolution

1. Eichhorst B, et al. Ann Oncol 2015; 26(Suppl 5):v78–v84. a Diffuse large B-cell lymphoma accounts for 60% of B-cell 2. Yang SM, et al. Blood Rev 2015; 29:205–213. lymphomas in Eastern Asia4 3. Shahjahani M, et al. Cell Oncol (Dordr) 2015; 38:93–109. CLL: chronic lymphocytic leukaemia 4. Chen Y, et al. Am J Clin Pathol 2010; 133:305–313. Comparison of FDA-approved Anti-CD20 Antibodies Ofatumumab Obinutuzuma b Type I I II Apoptosis + -/+ ++ ADCC ++ +/- +++ Complement fixation ++ +++ +/- Obinutuzumab binding site

Rituximab

Cheson BD, et al. J Clin Oncol. 2010;28:3525-3530. Niederfellner G, et al. Blood. 2011;118:358-367. Obinutuzumab/Chlorambucil vs Rituximab/Chlorambucil in CLL: Updated PFS and OS Results

PFS OS

Goede V, et al. Leukemia. 2015;29:1602-1604. BCR signalling pathway and its importance for B cells. Idela lisib e Ibrutinib

IGL Ibrutinib IGH

BCR PIP3 PIP2 CD19 CD79A CD79B P Cell P membrane LYN P Y Y P LYN P13K LYN Y Y Y SYK P P SYK P IP3 DAG

↑CA2+

PKCβ AKT/mTOR activation

NFAT ERK IKK

NFxB

B-cell Adapted from: Herrera Proliferation, Nucleus AF, Jacobsen ED. Differentiation, Clin Res And survival 2014;20:5365–71. Idelalisib mas Rituximab en LLC refractaria incluyendo 17 p-

32 Ibrutinib vs Ofatumumab en LLC refractaria o 17 p-

33 Venetoclax is a Second Generation BCL-2 inhibitor

Navitoclax Venetoclax

Combination Mono- /combination efficacy in Bcl-X Bcl-2 Efficacy in lymphoid solid tumors L Platelet Lymphocyte malignancies Survival Survival

Thrombocytopenia Lymphopenia

Dual Bcl-2 / Bcl-xL inhibition dictates therapeutic index Venetoclax is specific Bcl-2 (Efficacy / Toxicity) of inhibitor navitoclax

Leverson JD, et al. Sci Transl Med. 2015;7:279ra40. Venetoclax in Patients with CLL refractory or relapsingVenetoclax after in IbrutiR/R CLL:/Idela DoR

PD

PD PD-RT PD PD

Ibrutinib arm

Duration of Response (Pts) Response of Duration PD Idelalisib arm Discontinued

0 2 4 6 8 10 12 14 Mos on Venetoclax Jones J, et al. ASCO 2016. Abstract 7519. Reprinted with permission. Slide credit: clinicaloptions.com Tr

Ibrutinib en MGW. Primer fármaco aprobado RELINF.Distribution by histological subtypes

12% 12% 6% 8%

30% 19%

5%

N=2986 Linfoma B Difuso de Célula Grande

Camicia et al. Molecular Cancer (2015) 14:207 Impacto del perfil genético en los LBDCG

Origen celular en LBDCG

Scott, ASCO Ed Book 2015 Key signalling pathways implicated in ABC DLBCL with targeted novel agents in clinical development

Roschewski, M. et al. Nat. Rev. Clin. Oncol. 11, 12–23 (2014) Lenalidomida en linfomas

Gribben et al .J Clin Oncol 2015 R2-CHOP (Mayo Clinic study) Comparison with R-CHOP control cohort

Nowakowski et al, J Clin Oncol 2014 Key signalling pathways implicated in ABC DLBCL with targeted novel agents in clinical development

Roschewski, M. et al. Nat. Rev. Clin. Oncol. 11, 12–23 (2014)

Offner et al, Blood 2015 Key signalling pathways implicated in ABC DLBCL with targeted novel agents in clinical development

Roschewski, M. et al. Nat. Rev. Clin. Oncol. 11, 12–23 (2014)

Wilson et al, Blood 2013, Ed Book RELINF.Distribution by histological subtypes

12% 12% 6% 8%

30% 19%

5%

N=2986 Nuevas dianas terapeúticas en el Linfoma Folicular refractario

RELINF.Distribution by histological subtypes

12% 12% 6% 8%

30% 19%

5%

N=2986

Eficacia: PFS (IRC)

ITT population Median follow-up: 20 months

56 Dreyling M et al. Lancet 2015; Dec 7 RELINF.Distribution by histological subtypes

12% 12% 6% 8%

30% 19%

5%

N=2986

• .

• 102 patients • 47% of patients in CR ,progression free after a mfu of 53 months. • Prognostic factors for longer PFS: • Younger age ,less functional impairment, • Low disease burden at baseline Gopal A et al.Blood. 2015;125(8):1236-1243 • 59

Brentuximab vedotin

• The European Medicines Agency (EMA) approved ADCETRIS in October 2012 for the following indications:4 - the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): - following autologous stem cell transplant (ASCT) or Internalization - following at least two prior therapies when ASCT or multi-agent is not MMAE a treatment option released inside - the treatment of adult patients with relapsed or target cell refractory systemic anaplastic large cell lymphoma (sALCL).

1. Younes A, et al. J Clin Oncol 2012; 30: 2183 – 2189. 2. Pro B, et al. J Clin Oncol 2012; 30: 2190 -2196. 3. ADCETRISTM U.S. Package Insert, January 2012. 4. ADCETRIS SmPC, January, 2014.

60 61 Composition of the B cell lymphoma microenvironment.

La importancia de la célula T en la respuesta inmune tumoral

63 Estructura genómica de PD1 y PDL1

Shi et al. Journal of Hematology & Oncology 2013, 6:74

64 Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma

Green Blood 2010 65 Interacciones entre la célula T y la célula de RS a traves de PD-1

66 Lancet Oncol 2016 Volume 17, No.9, p1283–1294

Se excluyeron aquellos que habían recibido brentuximab antes del TASPE y los que habíar recaído en los primeros 90 días

67 Engert et al. Haematologica June 2016 101: 793 68 Chimeric Antigen Receptor (CAR) T cell therapy

• Hasta 75 % de respuestas en pacientes con LLA refractaria

Porter et al., ASH 2014; abstract 1982, 1983 (poster presentations) Lugar de las dianas terapeúticas en enfermedades hematológicas

• Primera línea • Pacientes en recaída o refractarios • Ya incorporadas en la terapia convencional • Acaban de llegar • En investigación • Dianas • QT convencional 5/96 patients

Ahn Blood 2016 Comentarios finales

• Muchas dianas terapeúticas en hemopatías • Algunas funcionan como fármaco aislado • Otras demostrada eficacia en combinación a terapia convencional • Nuevas moléculas, algunas orales eficaces como fármco aislado,pero no suficiente…..deben ser investigadas en combinación

Comentarios finales

• Los farmacos orales precentan muchas ventajas…pero no son absolutamente indefensos¡¡¡¡ • Cómo van a ser combinados ? • Diseño de nuevos ensayos para contestar a ls preguntas con el menor coste • Seremos capaces de hacer una medicina personalizada en enfermedades tan heterogéneas en las que las dians seran múltiples??

Gracias¡¡¡¡¡