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LLA Phi-Like: Características y Tratamiento
- 1. LLA Phi- Like Julio/2017 Carlos Avendaño Hospital Barros Luco
- 2. Características •Subtipo de LLA-B de mal pronostico •Su incidencia aumenta con la edad •Mayor recuento de leucocitos •Mayor EMR al final de la inducción •Peor pronostico •Phi like es un factor pronostico independiente. Roberts et al N Engl J Med 2014; 371: 1005-1015
- 3. N Engl J Med 2014; 371: 1064-1066. Herold, T. & Gökbuget, N. Curr Oncol Rep (2017) 19: 31 Generan un perfil de expresión molecular (GEP) similar a las LLA-B phi (+) Sin la proteina de fusion BCR-ABL1 Receptor de citoquinas (no kinasa) y JAK Tirosinas kinasas DESREGULACION
- 4. Roberts et al N Engl J Med 2014; 371: 1005-1015
- 5. Roberts et al N Engl J Med 2014; 371: 1005-1015
- 6. Roberts et al N Engl J Med 2014; 371: 1005-1015
- 7. Roberts et al N Engl J Med 2014; 371: 1005-1015
- 9. LLA Phi (+) y Phi like: asociacion con IKZF1 IKZF1: ikaros Factor de transcripcion Mutaciones: perdida de acción supresora de tumores LLA Phi (+) LLA Phi like Raetz Blood 2014 123: 1626-162
- 10. Subtipos de phi like Roberts et al N Engl J Med 2014; 371: 1005-1015 cytokine receptor like factor 2
- 11. El peor grupo de phi -like es aquel que tiene alteración de IKZF1 Roberts et al N Engl J Med 2014; 371: 1005-1015
- 12. Y del grupo que no tiene ikaros mutado es JAK2/EPOR
- 15. COMO Y A QUE PACIENTE ESTUDIAR??? Xinyan Lu. Blood 2016 128: 2915;
- 16. COG Todos los pacientes LLA-B alto riesgo >10 años >5omil blancos al Dx Diseñaron un Low density array
- 17. Herold, T. & Gökbuget, N. Curr Oncol Rep (2017) 19: 31
- 18. Tratamiento
- 20. Tratamiento
- 21. También hay estrategias de inmunoterapia. ◦ blinatumomab anticuerpo CD3 / CD19 ◦ inotuzumab anticuerpo anti-CD22 Herold, T. & Gökbuget, N. Curr Oncol Rep (2017) 19: 31
- 22. CONCLUSIONES •Aun sabemos poco y faltan estudios que realmente confirmen beneficio de estas dianas de tratamiento •Importante identificar pctes con phi-like: representar la gran mayoría de los pcts que tienen todos los demás rearreglos negativos quedando subtratados - clasificados como riesgo estándar siendo realmente de alto riesgo. •Idealmente adicionar a los paneles de citometria de flujo detección de sobreexpresión de CRLF2 en: • LLA-B al Dx, o al menos en MDR + tras la inducción.
- 23. •Lo otro interesante es poder identificar a que grupo de alteraciones corresponden para poder elegir tto, mas que definir un perfil génico completo de la leucemia. • Receptores de citoquinas no quinasa y jak: ruxolutinib • Tirosinas kinasas: dasatinib
- 24. Gracias
Notas del editor
- En total fueron 264 para un % de 15,3%
- Estructura de Ikaros. La porción N-terminal de Ikaros contiene un dominio de unión a ADN con motivos dedo de 4 zinc. Hay 2 motivos dedo de zinc en el extremo C-terminal que son esenciales para la formación de homodímeros Ikaros. Ikaros se une directamente al ADN para positivamente (verde) o negativamente (rojo) regular la expresión de genes diana. Deleciones internas en los exones 4 a 7 son alteraciones comunes que atenúan la capacidad de unión a ADN de Ikaros, y estas deleciones producen una isoforma dominante negativo que resulta en pérdida de la función supresora de tumores del alelo WT, de modo que se pierde la actividad transcripcional (exones no dibujados a escala real). 7
- CRFL2: cytokine receptor like factor 2
- Wild type: tipo salvaje o tipo normal o natural a diferencia del mutado.
- En resumen lo que hace es estudiar todoslos pctes nuevos y recaidos y e iniciar el estudio con CRLF2 por citometria de flujo, si es (+) realizan el fish para ver que tipo de reareglo tiene y si es postivo se para, si es negativo se amplia el panel Abstract Introduction: Philadelphia chromosome-like (Ph-like) B acute lymphoblastic leukemia (B-ALL) is characterized by a specific gene expression profile similar to that of Ph positive B-ALL, but lacks the BCR-ABL1 fusion. Ph-like B-ALL is known to frequently carry translocations and/or point mutations in various kinases and/or the cytokine receptor CRLF2 that activate a multi-kinase cascade and is often associated with poorer clinical outcomes. Recent reports have shown that patients with Ph-like B-ALLs respond to ABL1 or JAK2 inhibitors. However, timely diagnosis of Ph-like B-ALL cases remains clinically challenging. Methods: A panel of seven fluorescence in situ hybridization (FISH) probes targeting CRLF2, ABL1, ABL2, JAK2, PDGFRB, CSF1R and EPORwere designed and validated for the detection of rearrangements in Ph-like B-ALL. Of these, FISH for CRLF2was performed on both metaphase and interphase cells and the results were correlated with levels of CRLF2 expression assessed by multiparameter flow cytometry (MFC). Additional comprehensive analysis of fusion transcripts was conducted by PCR based testing. DNA copy number analyses were assessed using SNP microarray and/or MLPA and technologies. Results: For the initial validation, CRLF2 FISH was tested in 10 relapsed and 5 de novo B-ALL cases with CRLF2 overexpression by MFC and 100% concordance was achieved. FISH validation of other probes was successful in detecting known positive rearrangements. Using this panel, we tested a cohort of 57 B-ALL cases with a median age of 31 years old (range 13-81) and unknown Ph-like status, including 14 relapsed and 43 de novo. CRLF2 FISH was positive in all 17 (29.8%) MFC CRLF2 positive cases including 3 co-existing with the BCR-ABL1 fusion, showing 100% concordance. Of the 17 CRLF2 positive cases, five of nine cases tested (55.6%) were positive for JAK2 mutation. IGH-CRLF2fusion was the most prevalent seen in 10 (58.9%) by metaphase FISH whereas P2RY8-CRLF2 was seen in two (11.8%) cases by metaphase FISH and/or SNP array analysis. One case had a novel fusion PAX5/ZCCHC7-CRLF2 detected by metaphase FISH analysis and the remaining 4 cases showed unknown fusion partners. In 40 (70.2%) CRLF2 negativecases, five (5/57, 8.8%) were positive with our FISH panel including two with CSF1R/PDGFRB, one with JAK2 and one with EPOR rearrangements, while one with NUP214-ABL1fusion was detected by PCR. Conclusions: Using the integrated MFC, FISH and Molecular testing, we demonstrated Ph-like B-ALL in 38.6% (22/57) of unselected B-ALL cases, including 17 CRLF2, 2 CSF1R/PDGFRB, 1 JAK2, 1 EPOR and 1 ABL1 rearrangements. Based on our clinical experience, we further implemented a clinical testing algorithm (Figure 1) for the diagnosis of Ph-like B-ALL. It is noteworthy that BCR-ABL1 fusion and CRLF2 rearrangement are not mutually exclusive and all B-ALL patients should be screened for both rearrangements simultaneously. Download figure Open in new tab Download powerpoint Figure 1 Disclosures Mullighan: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Loxo Oncology: Research Funding. Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain: Servier: Consultancy, Honoraria; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; ADC Therapeutics:Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. ↵* Asterisk with author names denotes non-ASH members. © 2016 by The American Society of Hematology
- Low: es como estuio genetico pero de pocos genes. Esto para escrenning de todos los pactines. Para seleccionar los que podrian ser BCR-abl o phi like
- A) Expression of RCSD1-ABL1 (110 kDa), RCSD1-ABL2 (100 kDa), SSBP2-CSF1R (87 kDa), PAX5-JAK2 (59 kDa) and Ik6 (32 kDa) in murine interleukin-7 dependent Arf-/- primary pre-B cells. B) Proliferation of Ba/F3 cells in the absence of cytokine and C) in the presence of dasatinib.
- CUANDO HAY REARREGLOS DE JAK DEO EPOR ESTAS CELULAS SE MUEREN CON EL USO DE RUXOLUTINIB. Figure S17. Treatment of Ph-like ALL xenografts with tyrosine kinase inhibitors A) Ex vivo cytotoxicity assays of human leukemic cells harboring ATF7IP-JAK2 or IGH-EPOR. Both were sensitive to ruxolitinib, whilst imatinib had no effect on cell proliferation. B) Ex vivo cytotoxicity assay of human leukemic cells harboring ETV6-NTRK3 harvested from xenografted mice treated with crizotinib and imatinib. C) In vivo response of ETV6-ABL1 xenograft to dasatinib (20mg/kg/day 5 days per week) with a significant reduction in circulating human CD45+ leukemic cells and spleen weight. ***, P