Avances en Leucemia Mieloide Aguda Miguel A. Sanz Coordinador del Grupo PETHEMA Hospital Universitario La Fe Valencia, España X Reunión Científica de la Sociedad Castellano-Manchega de Hematología y Hemoterapia Pastrana, Guadalajara (abril de 2011) 1

Lowenberg B. N Engl J Med 2008;358:1960-1962 Los días en que el microscopio era la principal herramienta para clasificar las diversas formas de LMA y predecir la respuesta de los pacientes parecen haber pasado. Lowenberg B. N Engl J Med 2008;358:1960-1962 2

Avances en la LMA De la morfología a las alteraciones genómicas El descubrimiento de mutaciones y alteraciones en la expresión génica, que determinan el fenotipo de las células leucémicas e influyen en la respuesta al tratamiento, ha cambiado no sólo el papel del microscopio en el diagnóstico de las leucemias sino también el manejo de estas enfermedades. Lowenberg B. N Engl J Med 2008;358:1960-1962 3

Alteraciones Genómicas en la LMA Integración en el algoritmo de decisión Es preciso clarificar el significado pronóstico de todas las alteraciones genómicas que se encuentran en la LMA e integrar este conocimiento en un algoritmo de decisión clínicamente útil que incluya los tradicionales marcadores citogenéticos. Lowenberg B. N Engl J Med 2008;358:1960-1962 4

Alteraciones Genómicas en la LMA Esquema de la presentación De la LMA como entidad única a las entidades nosológicas específicas. Impacto de las alteraciones genómicas en el algoritmo terapéutico: del tratamiento único al tratamiento dirigido a dianas, pasando por la terapia adaptada al riesgo 5

Morfología y Citoquímica Clasificación FAB 6

Diagnóstico Integrado

Estudio Inicial de una Leucemia Citometría de flujo multiparamétrica Paneles de anticuerpos monoclonales empleados para el estudio inicial de las LAs (FITC/ PE/ ECD/ PC5/ PC7) cMPO/ cCD79a/ CD45/ cCD3 nTdT/ cIgM/ CD45/ CD34 CD45/ CD4/ CD8/ CD3/ CD19 CD10/ CD20/ CD45/ CD34/ CD19 CD38/ CD22/ CD45/ HLADR/ CD19 CD15/ CD13/ CD45/ CD33/ CD19 KOR-SA/ 7.1/ CD45/ CD24/ CD19 IP (DNA)/ pan-B CD45/ CD4/CD8/ CD3/ CD19 CD7/ CD34/ CD3/ HLADR/ CD5 CD7/ CD1a/ CD45/ CD33/ CD56 CD7/ CD13/ CD45/ CD10/ CD2 CD38/ TCR/ CD45/ TCR/ CD3 LLA de fenotipo B LLA de fenotipo T INMUNOFENOTIPOS LEUCÉMICOS LMA CD15/ CD13/ CD45/ CD33/ CD34 CD7/ CD117/ CD45/ CD34/ CD56 CD65/ CD135/ CD45/ CD2/ CD34 CD64/ CD11b/ CD45/ CD14/ CD16 HLADR/ CD235a/ CD45/ CD34/ CD41

Enfermedades Oncohematológicas Clasificación WHO (2008)

Tratamiento Dirigido a Dianas Cambios en la Estrategia Terapéutica De la terapia única la terapia dirigida en la LMA Terapia Única “one size fits all” Tratamiento Adaptado (edad, linaje morfológico, citogenética) “Tailored Therapy” Tratamiento Dirigido a Dianas “Targeted Therapy” 10

Fases del Tratamiento de la LMA INDUCCIÓN A LA REMISIÓN Esquema “3 + 7” TERAPIA POSTREMISIÓN Consolidación Intensificación QT intensiva TPH 11

Inducción a la Remisión de la LMA Esquema estándar (‘3 + 7’) Daunorubicina, 45 mg/m2/día x 3 + Ara-C, 100 mg/m2/día x 7 Rai KR et al. Blood 1981; 58: 1203-12 Yates J et al. Blood 1982; 60: 454-62 Preisler H et al. Blood 1987; 69: 1441-9 Dillman RO et al. Blood 1991; 78: 2520-6 12

Quimioterapia en LMA Una revisión sistemática 129 artículos (39.557 pacientes) 1 meta-análisis 18 estudios retrospectivos 51 estudios aleatorizados 29 otros estudios 39 estudios prospectivos 13

Inducción a la Remisión de la LMA Esquema estándar actual (‘3 + 7’) Idarrubicina, 12 mg/m2/día x 3 (Daunorubicina, 60 mg/m2/día x 3) + Ara-C, 100 – 200 mg/m2/día x 7 Tasas de RC: 60-80% 14

Original Article Anthracycline Dose Intensification in Acute Myeloid Leukemia Hugo F. Fernandez, M.D., Zhuoxin Sun, Ph.D., Xiaopan Yao, Ph.D., Mark R. Litzow, M.D., Selina M. Luger, M.D., Elisabeth M. Paietta, Ph.D., Janis Racevskis, Ph.D., Gordon W. Dewald, Ph.D., Rhett P. Ketterling, M.D., John M. Bennett, M.D., Jacob M. Rowe, M.D., Hillard M. Lazarus, M.D., and Martin S. Tallman, M.D. N Engl J Med Volume 361(13):1249-1259 September 24, 2009

Study Overview Patients with AML who were between 17 and 60 years of age were randomly assigned to receive induction therapy with the standard dose of daunorubicin or twice the standard dose; the two groups also received a standard dose of cytarabine Rates of complete remission and overall survival were best in the high-dose group, especially among patients with a favorable or an intermediate cytogenetic risk profile Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Hazard Ratios for Death by Subgroup AML 17- 60 years Hazard Ratios for Death by Subgroup Figure 1. Hazard Ratios for Death, According to Subgroup. All hazard ratios are for patients who received a 90-mg dose of daunorubicin (high-dose group), as compared with those who received a 45-mg dose (standard-dose group). A univariate Cox proportional-hazards model was used to estimate hazard ratios and the significance of the comparison for overall survival. The horizontal lines represent 95% confidence intervals for the ratios. The box size is proportional to the inverse of the standard error of the hazard-ratio estimates. Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Kaplan-Meier Estimates of Overall Survival AML 17- 60 years Kaplan-Meier Estimates of Overall Survival Figure 2. Kaplan-Meier Estimates of Overall Survival. Data from the intention-to-treat analysis are shown for survival of all patients (Panel A), those with a favorable or an intermediate cytogenetic profile (Panel B), and those with an unfavorable cytogenetic profile (Panel C). Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Kaplan-Meier Estimates of Overall Survival AML 17- 60 years Kaplan-Meier Estimates of Overall Survival Figure 2. Kaplan-Meier Estimates of Overall Survival. Data from the intention-to-treat analysis are shown for survival of all patients (Panel A), those with a favorable or an intermediate cytogenetic profile (Panel B), and those with an unfavorable cytogenetic profile (Panel C). Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Kaplan-Meier Estimates of Overall Survival AML 17- 60 years Kaplan-Meier Estimates of Overall Survival Figure 2. Kaplan-Meier Estimates of Overall Survival. Data from the intention-to-treat analysis are shown for survival of all patients (Panel A), those with a favorable or an intermediate cytogenetic profile (Panel B), and those with an unfavorable cytogenetic profile (Panel C). Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Fernandez HF et al. N Engl J Med 2009;361:1249-1259 AML 17- 60 years Kaplan-Meier Estimates of Overall Survival, According to Mutation Status Figure 3. Kaplan-Meier Estimates of Overall Survival, According to Mutation Status. Data are shown for the overall survival of patients with the FLT3-ITD mutation (Panel A), those without the FLT3-ITD mutation (Panel B), those with the MLL-PTD mutation (Panel C), and those without the MLL-PTD mutation (Panel D). Also shown are survival curves for patients who received high-dose daunorubicin (90 mg per square meter of body-surface area per day), according to the presence or absence of the FLT3-ITD genotype (Panel E). ITD denotes internal tandem duplication, and PTD partial tandem duplication. Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Fernandez HF et al. N Engl J Med 2009;361:1249-1259 AML 17- 60 years Kaplan-Meier Estimates of Overall Survival, According to Mutation Status Figure 3. Kaplan-Meier Estimates of Overall Survival, According to Mutation Status. Data are shown for the overall survival of patients with the FLT3-ITD mutation (Panel A), those without the FLT3-ITD mutation (Panel B), those with the MLL-PTD mutation (Panel C), and those without the MLL-PTD mutation (Panel D). Also shown are survival curves for patients who received high-dose daunorubicin (90 mg per square meter of body-surface area per day), according to the presence or absence of the FLT3-ITD genotype (Panel E). ITD denotes internal tandem duplication, and PTD partial tandem duplication. Fernandez HF et al. N Engl J Med 2009;361:1249-1259

Conclusion In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose

Original Article High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia Bob Löwenberg, M.D., Gert J. Ossenkoppele, M.D., Wim van Putten, M.Sc., Harry C. Schouten, M.D., Carlos Graux, M.D., Augustin Ferrant, M.D., Pieter Sonneveld, M.D., Johan Maertens, M.D., Mojca Jongen-Lavrencic, M.D., Marie von Lilienfeld-Toal, M.D., Bart J. Biemond, M.D., Edo Vellenga, M.D., Marinus van Marwijk Kooy, M.D., Leo F. Verdonck, M.D., Joachim Beck, M.D., Hartmut Döhner, M.D., Alois Gratwohl, M.D., Thomas Pabst, M.D., Gregor Verhoef, M.D., for the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON), German AML Study Group (AMLSG), and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group N Engl J Med Volume 361(13):1235-1248 September 24, 2009

Study Overview Patients with acute myeloid leukemia (AML) who were more than 60 years of age received treatment to induce a complete remission that consisted of cytarabine and daunorubicin; the latter was given at a dose of either 45 mg per square meter of body- surface area (the conventional dose of the drug) or 90 mg per square meter As compared with patients who received the conventional dose of daunorubicin, those who received the high dose had a significantly higher rate of complete remission without an increase in toxic effects

Lowenberg B et al. N Engl J Med 2009;361:1235-1248 Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia Figure 1. Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia. Patients were randomly assigned for their first induction cycle of combination chemotherapy to receive daunorubicin at a dose of 45 mg per square meter of body-surface area (conventional-dose group) or 90 mg per square meter (escalated-dose group) on 3 successive days. The top row of panels shows data for all patients, the second row, data for patients 60 to 65 years of age; the third row, data for patients older than 65 years of age; and the bottom row, data for patients with abnormalities in core-binding factors (CBF). Lowenberg B et al. N Engl J Med 2009;361:1235-1248

Lowenberg B et al. N Engl J Med 2009;361:1235-1248 Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia Figure 1. Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia. Patients were randomly assigned for their first induction cycle of combination chemotherapy to receive daunorubicin at a dose of 45 mg per square meter of body-surface area (conventional-dose group) or 90 mg per square meter (escalated-dose group) on 3 successive days. The top row of panels shows data for all patients, the second row, data for patients 60 to 65 years of age; the third row, data for patients older than 65 years of age; and the bottom row, data for patients with abnormalities in core-binding factors (CBF). Lowenberg B et al. N Engl J Med 2009;361:1235-1248

Lowenberg B et al. N Engl J Med 2009;361:1235-1248 Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia Figure 1. Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia. Patients were randomly assigned for their first induction cycle of combination chemotherapy to receive daunorubicin at a dose of 45 mg per square meter of body-surface area (conventional-dose group) or 90 mg per square meter (escalated-dose group) on 3 successive days. The top row of panels shows data for all patients, the second row, data for patients 60 to 65 years of age; the third row, data for patients older than 65 years of age; and the bottom row, data for patients with abnormalities in core-binding factors (CBF). Lowenberg B et al. N Engl J Med 2009;361:1235-1248

Lowenberg B et al. N Engl J Med 2009;361:1235-1248 Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia Figure 1. Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukemia. Patients were randomly assigned for their first induction cycle of combination chemotherapy to receive daunorubicin at a dose of 45 mg per square meter of body-surface area (conventional-dose group) or 90 mg per square meter (escalated-dose group) on 3 successive days. The top row of panels shows data for all patients, the second row, data for patients 60 to 65 years of age; the third row, data for patients older than 65 years of age; and the bottom row, data for patients with abnormalities in core-binding factors (CBF). Lowenberg B et al. N Engl J Med 2009;361:1235-1248

Lowenberg B et al. N Engl J Med 2009;361:1235-1248 Conclusion In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects Lowenberg B et al. N Engl J Med 2009;361:1235-1248

Tratamiento Estándar de la LMA Avances en resultados Tasas de RC con esquemas clásicos: 65% a 85% Figure 1. Estimates of overall survival overall ≤ 55 years > 55 years Tallman, M. S. et al. Blood 2005;106:1154-1163 Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Estrategia terapéutica Caracterización Genética de la LMA Primera alteración citogenética específica LMA LPA LMA  t(15;17)  Estrategia terapéutica “one size fits all” Estrategia terapéutica “tailored therapy”  “targeted therapy” 32

De una entidad a múltiples entidades nosológicas Caracterización Genética de la LMA Principales alteraciones citogenéticas (11q23) De una entidad a múltiples entidades nosológicas 33

Avances en el Pronóstico de la LMA Valor pronóstico de la citogenética Citogenética normal y favorable Citogenética normal y desfavorable Grimwade et al. Blood 1998;92(7):2322-2333. 34

Avances en el Pronóstico de la LMA Valor pronóstico de la citogenética Citogenética normal y favorable Citogenética normal y desfavorable Grimwade et al. Blood Online First Edition 2010 35

Avances en el Pronóstico de la LMA Valor pronóstico de la citogenética Citogenética normal y favorable Citogenética normal y desfavorable Grimwade et al. Blood Online First Edition 2010 36

Avances en el Pronóstico de la LMA Impacto en el algoritmo terapéutico Citogenética favorable Estrategia terapéutica “adaptada al riesgo”  No TPH alogénico (disbalance riesgo/beneficio) AD/Ara-C (2-3 ciclos) Excepciones: 1) Mutaciones C-KIT; 2) > 1 ciclo de inducción; 3) ERM por CF >0,1% (postinducción ) 37

Avances en el Pronóstico de la LMA Impacto en el algoritmo terapéutico Estrategia terapéutica “adaptada al riesgo”  Citogenética desfavorable TPH alogénico Tratamientos investigacionales 38

Avances en el Pronóstico de la LMA Impacto en el algoritmo terapéutico Estrategia terapéutica “adaptada al riesgo”  Citogenética normal 39 ?

Caracterización Genética de la LMA Mutaciones y alteraciones de expresión génica FLT3, NPM1, CEBPA, MLL1, WT1, NRAS, PTPN11, CBL, … (11q23) Expresión génica alterada ERG, MN1, EVI1, BAALC, WT1, ... Cambios epigenéticos Metilación Acetilación histonas miRNA 40

Schlenk RF et al. N Engl J Med 2008;358:1909-1918 Caracterización Genética de la LMA Mutaciones recurrentes en CN y pronóstico Schlenk RF et al. N Engl J Med 2008;358:1909-1918 41

Caracterización Genética de la LMA Mutaciones recurrentes en CN y pronóstico NPM1= 53% FLT3-ITD = 31% FLT3-TKD = 11% CEBPA = 13% MLL-PTD = 7% 42

Caracterización Genética de la LMA Mutaciones recurrentes en CN y pronóstico FLT3 NPM1 CEBPA MLL-PTD Döhner K. et al., Blood 2005 43

Relapse-free survival Mutaciones NPM1, FLT3-ITD y CEBPA Impacto pronóstico según el genotipo en CN Relapse-free survival Overall survival "Other genotypes" is defined as the FLT3-ITD genotype and the triple-negative genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. Schlenk RF et al. N Engl J Med 2008;358:1909-1918

Mutaciones NPM1, FLT3-ITD y MLL RFS con aloTPH según el genotipo en CN Excluyendo mutaciones de CEBPA Schlenk RF et al. N Engl J Med 2008;358:1909-1918

Algoritmo Diagnóstico Riesgo estándar NPM+ FLT3-ITD- CEBPA+ NPM- CN CEBPA- FLT3-ITD+ Riesgo alto

Avances en el Pronóstico de la LMA Impacto en el algoritmo terapéutico Citogenética favorable Citogenética normal Citogenética desfavorable NPM1+ FLT3- CEBPA Otros genotipos No TPH alogénico (disbalance riesgo/beneficio) AD/Ara-C (2-3 ciclos) TPH alogénico Tratamiento investigacional Dirigido a diana No dirigido a diana 47

Esquema Terapéutico del PETHEMA Tratamiento post-remisión adaptado al riesgo Edad Citogenética Biología molecular Enfermedad residual 48

Explorar Demetilantes Explorar HDAi Ara-C AD 2 ciclos Auto-TPH BEA ¿Mantenimiento? CBF EMR– (<0,1%) CN/NPM1+/FLT3- Explorar Demetilantes Explorar HDAi ARA-C 100 + GO 2 ciclos > 60 años Hermano HLA-idéntico IDA+ Ara-C Alo-TPH No Hermano HLA-idéntico IDA+ Ara-C + GO EMR- (<0,1%) CN/NPM1-/FLT3- Auto-TPH BEA Ara-C AD IDA + Ara-C (‘3 + 7’) INDUCCIÓN: CANDIDATO A QUIMIOTERAPIA INTENSIVA TERAPIA POST-REMSIÓN > 60 años (valorar mini-alo) ARA-C 100 + GO 2 ciclos Explorar Lenalidomida en -5/del(5q) Donante IDA+ Ara-C Alo-TPH EMR+ (>0,1%) CN/FLT3+ CAR t(8;21)/c-kit+ Auto-TPH BEA No Donante IDA+ Ara-C + GO Ara-C AD > 60 años (valorar mini-alo) ARA-C 100 + GO 2 ciclos Explorar TKi Flt3i 49

Tratamiento Dirigido a Dianas Cambios de Estrategia en la LMA De la terapia única la terapia dirigida Terapia Única “one size fits all”” Tratamiento Adaptado (edad, linaje morfológico, citogenética) “Tailored Therapy” Tratamiento Dirigido a Dianas “Targeted Therapy” 50

CALGB 10603/RATIFY INTERGROUP STUDY NCIC EORTC CALGB AMLSG OSHO ECOG SAL CETLAM GIMEMA SWOG PETHEMA Brazil

RATIFY: Study Schema Primary endpoint: overall survival Cytarabine (200 mg/m2/day, Days 1–7) + Daunorubicin (60 mg/m2/day, Days 1–3) + Midostaurin (50 mg, bid, Days 8–21) High-dose cytarabine (3 g/m2/day BID Days 1, 3, and 5) + Midostaurin (50 mg, bid, Days 8–21) Midostaurin (50 mg, bid, Days 1–28) Midostaurin group CR Treatment-naïve AML patients with activating Flt-3 mutations Induction (1–2 cycles) Consolidation (4 cycles) Continuation (12 cycles) Randomization (n = 513) Cytarabine (200 mg/m2/day, Days 1–7) + Daunorubicin (60 mg/m2/day, Days 1–3) + Placebo (bid, Days 8–21) High-dose cytarabine (3 g/m2/day BID Days 1, 3, and 5) + Placebo (bid, Days 8–21) Placebo (bid, Days 1–28) Control group CR Primary endpoint: overall survival Study drug is given on Days 8-21 after each course of chemotherapy, and Days 1-14 of each 28 day Maintenance cycle.

RATIFY: Study Schema R A N D O M I Z E DNR ARA-C PKC412 R E G I S T MAINTENANCE 12 months PKC412 CR HiDAC PKC412 X 4 FLT3 ITD or TKD DNR ARA-C PLACEBO HiDAC PLACEBO MAINTENANCE 12 months PLACEBO CR X 4 Central Lab Study drug is given on Days 8-21 after each course of chemotherapy, and Days 1-14 of each 28 day Maintenance cycle. Not on study: FLT3 wild type 53

Tratamiento de la LMA Nuevas terapias 54 Litzow. Curr Opin Hematol, 2007 54 54

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