Inmunoterapia aplicada a la leucemia mieloide cró .Inmunoterapia aplicada a la leucemia mieloide

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  • Inmunoterapia aplicada a la leucemia mieloide crnica

    Francisco Cervantes

    Servicio de Hematologa, Hospital Clnic, Barcelona

    Barcelona, Junio 2016

  • Esquema de la presentacin

    Limitaciones del tratamiento actual de la LMC

    Papel del sistema inmune en el control de la LMC

    Nuevas estrategias de inmunoterapia en la LMC

  • 50%

    50%

    Fase crnica

    F. aceleracin

    Crisis blstica

    Historia natural de la LMC

    (2/3 mieloide,1/3 linfoide)

  • BCR-ABL promotes the progression of CML by inducing genomic instability

    BCR-ABL

    Decreased apoptosis

    Increased cell proliferation(telomere shortening)

    Deficiencies inDNA repair

    Mutagenesis via reactive oxygen species

    N

    NN

    N

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    N NN

    NN N

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    N

    N

    N

    N

    N

    N

    N

    NN

    N

    N

    NN

    N

    Ph+

    Ph+

    Ph+

    Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+

    Ph+

    Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+ Ph+Ph+

    Ph+Ph+

    Ph+

    Ph+ Ph+

    Ph+Ph+

    Ph+ Ph+ Ph+ Ph+ Ph+ Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+Ph+

    Ph+

    Ph+Ph+

    Ph+

    Ph+Ph+

    Ph+

    Ph+

    Ph+Ph+

    Ph+

    Ph+Ph+

    Ph+

    Ph+Ph+

    Ph+

    Ph+

    Ph+

    Ph+

    Ph+

    N = normal cells

    1 2 3 4 5

    Years from diagnosis

  • IRIS 8-Year UpdateOverall Survival (ITT) Imatinib Arm

    Estimated overall survivalat 8 years was 85%

    (93%, considering onlyCML related deaths)

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    0 12 24 36 48 60 72 84 96 108

    M onths Since Randomization

    Survival: deaths associated with CM LOverall Survival

    % A

    live

    Deininger et al., ASH 2009 Poster presentation

  • Dianas moleculares de los ITC en la LMC

    IMATINIBGlivec

    NILOTINIBTasigna

    DASATINIBSprycel

    BOSUTINIBBosulif

    PONATINIBIclusig

    BCR-ABL + ++ +++ ++ +++

    BCR-ABL(T315I)

    - - - - +++

    PDGFR + + +++ - +++

    c-KIT + + ++ - ++

    SRC - - ++ ++ ++

    Otras cinasas DDR1 DDR1

    BTKTECEPH

    FGFR2VEGFR FGFRTIE2

  • Approved Drugs for CML

    Imatinib

    Dasatinib

    Nilotinib

    1st line 2nd line 3rd line T315I mut.

    Dasatinib

    Nilotinib

    Bosutinib

    Ponatinib *

    Nilotinib

    Dasatinib

    Bosutinib **

    Ponatinib *

    Ponatinib

    * Might be considered in resistance, not in intolerance

    ** Preferred drug in intolerance to the 2nd generation TKIs

  • Imatinib, dasatinib, nilotinibSe necesitan ms frmacos para la LMC?

    Algunos pacientes se diagnostican en fases avanzadas o su enfermedades primariamente resistente a los ITCs.

    A medio plazo, slo ~60% de los pacientes contina recibiendo el ITCinicial y slo ~30% mantiene el ITC de 2 lnea.

    Un 30-50% de pacientes alcanza una respuesta que permite suspender elITC. La mitad de ellos recaen dentro de los 6 primeros meses tras lasuspensin. Ello sugiere que las clulas madre leucmicas quiescentesson resistentes a los ITCs, lo que impedira la curacin de la enfermedad.

  • Inmunoterapia en LMC:1) Trasplante alognicoEfecto antileucmico del sistema inmune en el Alo-TPH

    Pavlu J, et al. Blood 2011;117:755-763

    Trasplante autlogo (n=87)

    Trasplante alognico familiar(n=200)

  • Respuesta inmune especfica por linfocitos T activados frente a antgenos de las clulas leucmicas

    Greiner J & Schmitt M. Eur J Haematol 2008;80:461-68

    WT1PRAME

    PR3

    Feng X, et al. Trends Immunol 2008;29(12):624-32

  • Expresin de antgenos asociados a la leucemia y riesgo de recada post-trasplante alognico en la LMC

    Yong AS et al. Blood 2007;110:770-5

  • Biernacki MA, et al. Cancer Res 2010;70:906-15

    Respuesta inmune especfica por linfocitos B frente a antgenos de las clulas leucmicas

  • Adapted from R. Hehlmann, German CML Study Group.SCT, stem-cell transplantation

    Year after diagnosis

    Surv

    ival

    pro

    babi

    lity

    0 2 64 8 10 16 18 20 2212 140.0

    0.2

    0.1

    0.5

    0.6

    0.7

    0.8

    0.9

    1.0

    0.3

    0.4 IFNa or SCT, 1995-2008 (CML III) 5 years 63%

    IFNa, 1986-2003 5 years 53%

    Busulfan, 1983-1994 5 years 38%

    Hydroxyurea, 1983-1994

    IFNa or SCT + 2nd line imatinib, 1997-2008 (CML IIIA) 5 years 71%

    Primary imatinib, 2002-2008 (CML IV) 5 years 93%

    Inmunoterapia en LMC: 2) Interfern

  • Supervivencia libre de recada tras suspensin del interfern

    Mahon FX. et al. JCO 2002;20(1):214-20

  • Poblaciones linfocitarias en pacientes con LMC en respuesta mantenida tras la suspensin del interfern

    Kreutzman A. et al. Plos One 2011;6(8):e23022

  • FRENCH SPIRIT:BCR-ABL/ABL 0.01% at 24 mos

    N= 636 (ITT)

    46%

    Preudhomme C, et al. NEJM 2010;363(26):2511-21

    GERMAN CML-IV STUDY

    Hehlmann R, et al. JCO 2011;29(12):1634-42

  • Inmunoterapia en LMC:3) Vacunas

    Bocchia M et al. Int J Hematol 2014;99:107-16

  • T CellsNK Cells

    MDSC

    TregImmune effectorImmune suppressor

    Effect of TKI onthe immune system

    Inmunoterapia en LMC:4) Inhibidores de BCR-ABL

    Modificado de Hughes et al., ASH 2015

  • Dasatinib: movilizacin de linfocitosis T/NK

    Mustjoki S. et al. Leukemia 2013;27:914-24

  • Dasatinib: linfocitosis durante el tratamiento

    Schiffer CA, et al. , Cancer 2016; 122:1398-1407

    Table 2. Incidence, Timing, and Duration of Lymphocytosis During Treatment With DasatinibDASISIONa CA180-034b CA180-035b

    Variable CML-CP, n=258 CML-CP, n=662 CML-AP, n=316 CML-MBP, n=148Incidence, % 35 32 35 34

    Time to onset: Median (range), mo 5.2 (1.0-35.9) 3.2 (1.0-72.0) 3.5 (1.0-25.1) 2.6 (1.0-16.3)

    On-treatment follow-up: Median (range), mo 60.5 (0-72.7) 29.8 (0.1-92.9) 6.1 (0-67.0)

    Lymphocyte counts in those with lymphocytosis at the time of initial detection and maximal lymphocyte count: Median (range),103/L

    At initial detection 4.2 (3.6-8.7) 4.2 (2.8-1350.0)e 4.5 (3.6-32.9)e 5.1 (3.6-25.3)e

    Maximal 5.4 (3.7-29.1)e 5.7 (3.7-5226.0)e 6.9 (3.9-215.6)e 9.5 (3.9-66.2)e

    Duration of lymphocytosis: Median (range), moc 33.8 (28.3-37.2+)

    d 12.9 (11.7-15.1+)d 8.4 (4.9-12.2+)d 1.4 (0.6-2.9+)d

    Lymphocytosis duration>12 mo, %d 77 52 42 18

    http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0013http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0014http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0014http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0017http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0015http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0016http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0016http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0016http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0016http://onlinelibrary.wiley.com/doi/10.1002/cncr.29933/full#cncr29933-note-0016
  • Cervantes F, et al. Blood 1996; 87:2476-85

  • Cervantes F, et al. Blood 1996; 87:2476-85

    Co-cultivo de clulas NK activadas y progenitoreshemopoyticos de pacientes con LMC

  • Cervantes F, et al. Blood 1996; 87:2476-85

    ANK from CML patients suppress autologous malignant progenitors but not benign progenitors

    Autologous ANK did not suppress normal CFC or LTCIC.In contrast, ANK from eight patients with CML with potent cytotoxicity against NK-sensitive(K5621 and NK-resistant (Raji) tumor targets exhibited an ANK dose-dependentsuppression of both CFC and LTCIC

  • STIM Study: Kaplan-Meier estimates of CMR after discontinuation of imatinib (n= 100)

    The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29-48)

    Molecular relapse occurred in 61 pts with 58 relapses occurring during the first 7 months 3 late relapses at month 19, 20 and 22, respectively

    Mahon et al., ASH 2011

  • Non-relapsing= patients without treatment for over 12 monthsEarly relapse= relapse before 6 monthsLate relapse= relapse after 6 months

    Clulas NK y suspensin del tto. con ITCs

    Non-relapsing patients have more NK cells

    Ilander M et al., ASH 2015

  • Inmunogentica y riesgo de recada tras suspensin ITCKIR2DL3+ and KIR2DL2+ genotypes are favorable to successful discontinuation

    Ilander M et al., ASH 2015

  • Fenotipo clulas NK en pacientes con LMC tratados con ITCs (evolucin fenotpica)

    ****Cytotoxicity

    Maturation

    ****

    Hughes et al., ASH 2015

  • Natural Killer