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- 1. Anemia aplásica Estado del Arte 01 de junio de 2022 Modulo: Patología de la célula tallo. Dr. Alejadro Pérez González, Residente de hematología Asesor: Dr. Moisés Xolotl Castillo
- 2. Agenda • Introducción • Fisiopatología y diferencias con otros diagnósticos de falla medular. • Diagnóstico. • Tratamiento • Trasplante MO vs SP. • Alogénico vs haploidentico. • GAT H vs GAT R. • TPO RA
- 3. Historia 1988: Paul Ehrlich ‘’anemia aplastique’’. 1904: Características clínicas por Henri Vazquez. Inicios de siglo XX: Richard C. Cabot y colaboradores hacen descripción histopatológica. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 4. Historia ‘’Enfermedad aguda y escalofriante que lleva a la muerte de personas jovenes’’. Actualmente considerada una enfermedad con buen pronóstico si es tratada adecuadamente. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 5. Definición Se usa el término anemia, ya que el conteo del hematocrito es la manifestación clinica más evidente. Aplasia, se refiere a la falla de la médula ósea de formar sangre total. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 6. Definición • Falla hematopoyética Anemia aplásica Síndrome mielodisplásico HPN Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 7. Definición • Falla hematopoyética Anemia aplásica Síndrome mielodisplásico HPN Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 8. Fisiopatología Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 9. Fisiopatología Síndromes constitucionales Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 10. Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica [Internet]. 2016;101(11):1343–50. Available from: http://dx.doi.org/10.3324/haematol.2016.149476
- 11. Fisiopatología Síndrome constitucionales 1990 - 2012. Genes de insuficiencia de la médula ósea/síndrome mielodisplásico en el 5,1 % (5/98) de los pacientes con anemia aplásica y en el 13,6 % (15/110) de los pacientes con síndrome mielodisplásico Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica [Internet]. 2016;101(11):1343–50. Available from: http://dx.doi.org/10.3324/haematol.2016.149476
- 12. Fisiopatología Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 13. Fisiopatología Anemia aplásica inmune Lamayoría de los casos esporádicos son por esta causa. Mejoría con el uso de de terapias inmunosupresoras. Células T citotóxicas Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 14. Fisiopatología Anemia aplásica inmune Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 16. Fisiopatología Hematopoyesis Déficit profundo de células hematopoyéticas y progenitoras. ¿Expansión clonal? Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 17. Fisiopatología Telómeros Cortos por un aumento en la demanda mitótica. La longitud de los telómeros al diagnóstico se relaciona a repuesta a tratamiento, evolución a SMD y LMA. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 18. Diagnóstico Biopsia de médula ósea. Tamizaje de sindromes constitucionales en: •Niños y adolescentes. •Falla a IST. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 19. Diagnóstico Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 20. Diagnóstico diferencial. Sindrome mielodisplásico hipoplásico vs Anemia aplásica. Megacariocitos dispoyéticos. Citometría de flujo para fenotipos anómalos. Secuenciación para mutacion de espleciosomas o genes característicos de SMD. Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica [Internet]. 2009
- 21. DECISION M A KING A ND PROBLEM SOLVING Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach John M. Bennett,1 and Attilio Orazi2 1 James P. Wilmot Cancer Center, University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, Rochester, NY; 2 Weill Medical College of Cornell University, Department of Pathology and Laboratory Medicine, New York, NY, USA ABST RACT Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica [Internet]. 2009 Síndrome mielodisplásico hipoplásico vs Anemia aplásica
- 22. Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica [Internet]. 2009 • Estudio retrospectivo en periodo de 2 años, 63 pacientes. • 38 SMD hipocelular. • 14 H AML. • 11 AA. 1. Blastos en SP. 2. Neutrófilos hipogranulares, pseudo Pelger >10%. 3. 1-20% blastos en MO. 4. Displasia de megacariocitos. Síndrome mielodisplásico hipoplásico vs Anemia aplásica
- 23. Criteria for hypocellular MDS and hypocellular AML eria published for the AML and H-MDS have nd compared to AA by attempt at establishing series of publications number of cases exam- d applied to a series of ps (Table 1). impact of age llows for a more repro- d H-AML has been to ake an appropriate cor- ecording the degree of e ta l .6 In that paper the ularity published by t a large data base of ercent of patients with below the lower range as abnormal and inconsistent with AA. Erythroid dys- plasia had to be moderate to severe, if the sole finding (bi or trinucleated forms, numerous Howell-Jolly bodies, 10 T able 1. G uidelines for diagnosis. Major recommendations P eripheral bloodfilm:count at least 100cellswherever possible. A numeratedysplasiaof granulocytes A ssessfor presenceof blasts Bonemarrowaspirate P erforma500cell differential if possible Examinefor dysplasiaof erythroidprecursors,granulocytesand megakaryocytes P erformanironstainfor ringsideroblast assessment Bonemarrowbiopsy A ssessfor cellularity A ssessfor presenceof A LIP(supplement withimmunostainsfor C D34,117,myeloperoxidase) P erformareticulinstain A dditional studies S tandardcytogenetics/interphaseFIS H Flowcytometry P NHscreeningbyasensitiveflowor molecular screeningtechnique F o u n d a t i o n • AA concordancia 10/11 casos. • SMD concordancia 100%. Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica [Internet]. 2009 Síndrome mielodisplásico hipoplásico vs Anemia aplásica
- 24. Síndrome mielodisplásico hipoplásico vs Anemia aplásica • La presencia de DMT3A o ASXL1 no altera el diagnóstico de AA o su respuesta al tratamiento. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 25. Síndrome HPN + AA HPN >50% de clona. Clona grande, puede indicar la necesidad de uso de eculizumab para evitar manifestaciones trombóticas. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 26. Tratamiento Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 27. Tratamiento El trasplante de médula ósea es curativo. Limitado por complicaciones, EICH y ausencia de donadores. Trasplante de donador relacionado e histocompatible con respuesta hasta de 90% en niños. Adultos 50 % en mayores de 40 años. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 28. Tratamiento Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 29. Tratamiento Las respuestas son mejores cuando: La fuente es médula ósea. GAT se usa en el regimen de acondicionamiento. El tiempo entre el diagnóstico y el trasplante es corto. Niños. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 30. M.O. vs S.P. TRANSPLANTATION Brief report Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia Hubert Schrezenmeier,1 Jakob R. Passweg,2 Judith C. W. Marsh,3 Andrea Bacigalupo,4 Christopher N. Bredeson,5 Eduardo Bullorsky,6 Bruce M. Camitta,5 Richard E. Champlin,7 Robert Peter Gale,8 Monika Fuhrer,9 John P. Klein,10 Anna Locasciulli,11 Rosi Oneto,4 Antonius V. M. B. Schattenberg,12 Gerard Socie,13 and Mary Eapen10 1Institute of Clinical Transfusion Medicine and Immunogenetics, University of Ulm, Germany; 2Hopitaux Universitaires, Geneva, Switzerland; 3St George’s Hospital Medical School, London, United Kingdom, 4Ospedale S. Martino, Genova, Italy; 5Medical College of Wisconsin, Milwaukee; 6Hospital Britanico, Buenos Aires, Argentina; 7M. D. Anderson Cancer Center, Houston, TX; 8Center for Advanced Studies in Leukemia, Los Angeles, CA; 9Universitat Munchen, Munich, Germany; 10The Statistical Center, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee; 11Ospedale S. Camillo-Forlanini, Rome, Italy; 12University Medical Center, Nijmegen, the Netherlands; 13St Louis Hospital-1, Paris, France We analyzed the outcome of 692 pa- tients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were pe- tients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of plantations, respectively. Correspond- ing probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts Downloaded from http://ashpublications Blood. 2007;110:1397-1400
- 31. MO vs SP Blood. 2007;110:1397-1400
- 32. Tratamiento Trasplante haploidéntico Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 33. Tratamiento Trasplante haploidéntico Tratamiento de primera línea en China en niños. Europa: sobrevivencia a 1 año 74%, recomendado por EBMT como terapia segunda línea. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 34. Tratamiento Terapia inmunosupresora GAT + Ciclosporina respuesta en 1/3. Young NS. Aplastic anemia. N Engl J Med [Internet]. 2018;379(17):1643–56. Available from: http://dx.doi.org/10.1056/NEJMra1413485
- 36. Terapia inmunosupresora Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 37. Terapia inmunosupresora – GAT La GAT de conejo: Superior en la prevención de rechazo de trasplante renal. Efectiva como tratamiento de segunda línea. Mejor depleción linfocítica. Induce la diferenciación de Treg.
- 38. Terapia inmunosupresora GAT Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 39. Terapia inmunosupresora GAT Obejtivo primario: respuesta hematológica a los 6 meses. Objetivos secundarios: • Magnitud de la respuesta. • Recaída. • Respuesta a los 3 meses y al año. • Evolución clonal. • Sobrevivencia global. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 40. Terapia inmunosupresora GAT H-ATG: 40 mg/kg de peso por 4 días. RATG: 3.5 mg/kg de peso por 5 días. Ambas con: • Ciclosporina 10 mg/kg/día divididos en en dos dosis, para mantener niveles terapeuticos 200-400 ng/ml Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 41. Terapia inmunosupresora GAT Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 42. Terapia inmunosupresora GAT Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 43. Terapia inmunosupresora GAT Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 44. Terapia inmunosupresora GAT Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med [Internet]. 2018;378(25):2450. Available from: http://dx.doi.org/10.1056/NEJMx180020
- 45. Estimulación de la célula madre hematopoyética Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med [Internet]. 2022;386(1):11–23. Available from: http://dx.doi.org/10.1056/NEJMoa2109965
- 46. Estimulación de la célula madre hematopoyética Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med [Internet]. 2022;386(1):11–23. Available from: http://dx.doi.org/10.1056/NEJMoa2109965
- 47. Estimulación de la célula madre hematopoyética Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med [Internet]. 2022;386(1):11–23. Available from: http://dx.doi.org/10.1056/NEJMoa2109965
- 48. Estimulación de la célula madre hematopoyética • La incidencia acumulada de una primera respuesta a los 3 meses fue del 25 % (IC 95 %, 16 a 33) en el Grupo A y del 53 % (IC 95 %, 43 a 63) en el Grupo B; a los 6 meses, las incidencias fueron del 45 % (IC 95 %, 35 a 54) y del 68 % (IC 95 %, 58 a 77). Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med [Internet]. 2022;386(1):11–23. Available from: http://dx.doi.org/10.1056/NEJMoa2109965
- 49. Estimulación de la célula madre hematopoyética Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica [Internet]. 2019;104(6):1112–23. Available from: http://dx.doi.org/10.3324/haematol.2018.212845
- 51. Conclusiones • Enfermedad previamente considerada letal, ahora con potencial curativo. • Paciente jóvenes decartar sindromes constitucionales. • El trasplante de médula ósea es curativo. • GAT de conejo mejor linfodepleción, menor sobrevida global. • TPO con acción e diferentes sitios, lo que implica una mejor respuesta cuando se unen trasnmembrana.
Notas del editor
- most often sudden in onset and occurring in young persons, can now be successfully treated in almost all patients. An understanding of the pathophysiology of aplastic anemia, gained in the research laboratory, has guided the development of effective therapies. Marrow failure syndromes have been linked to viral infection and environmental toxins, inherited and acquired genetic mutations, early events in leukemogenesis, and the hematopoiesis of normal aging.
- Yet a seemingly “empty” bone marrow may be entirely capable of supporting normal hematopoiesis. Conversely, bone marrow failure can occur without low marrow cellularity, as in the myelodysplastic syndromes and paroxys- mal nocturnal hemoglobinuria (PNH).
- Daño directo a la médula ósea: iatrogenico por quimioterapia o radioación, exposición al benceno. Síndromes constitucionales:
- Fanconi anemia (replication-dependent removal of interstrand DNA cross-links)5 and dyskeratosis congenita (telomere maintenance and repair) syndromes affecting im- mune regulation, such as in those due to cyto- toxicT-lymphocyte–associatedantigen4(CTLA-4) mutations8 and deficiency of adenosine deami- nase 2 (DADA2).9 Constitutional syndromes are classically manifested in childhood, often with characteristic physical anomalies; typically, mul- tiple organs are involved. The family history may disclose affected relatives. However, genetic and genomic testing has revealed that genetic defi- ciencies can appear in adults, who may present without these typical features. Recognition of a germline cause is critical for guiding therapy and has consequences for family members. Fatal graft rejection has followed inadvertent use of a graft from an affected sibling10 and persistent marrow failure after transplantation in patients with mutations in the gene encoding the growth factor thrombopoietin.11 Results of published surveys from specialty clinics are influenced by referral patterns and case definitions. In a study involving 98 children and adults with aplastic anemia, 5% had genetic mutations on screening
- atal graft rejection has followed inadvertent use of a graft from an affected sibling10 and persistent marrow failure after transplantation in patients with mutations in the gene encoding the growth factor thrombopoietin.11 Results of published surveys from specialty clinics are influenced by referral patterns and case definitions. In a study involving 98 children and adults with aplastic anemia, 5% had genetic mutations on screening.12 Of 173 patients with bone marrow failure of suspected inherited origin, most of whom were under 18 years of age, about 50% had muta- tions.13 At the National Institutes of Health, among children and adults referred for protocol treatments, unexpected pathogenic mutations were very unusual in patients with severe aplastic anemia but were much more prevalent in those with moderate bone marrow failure (Rodrigues F: personal communication).
- 1990 y 2012 de niños y adultos jóvenes. con anemia aplásica o síndrome mielodisplásico trasplantado en el Centro de Investigación del Cáncer Fred Hutchinson. Se encontraron mutaciones en los genes hereditarios de insuficiencia de la médula ósea/síndrome mielodisplásico en el 5,1 % (5/98) de los pacientes con anemia aplásica y en el 13,6 % (15/110) de los pacientes con síndrome mielodisplásico.
- The Venn diagram in Panel A highlights the overlap of aplastic anemia, both diagnostically and pathophysiologically, with paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, and constitutional marrow failure syndromes. Many clinical and pathophysiolog- ical features of aplastic anemia parallel those of other immune-mediated diseases in which a single organ is targeted
- Almost all sporadic cases of aplastic anemia, especially when severe and acute, appear to be immune-mediated. The strongest, most relevant evidence for an immune mechanism is improve- ment in blood counts after a variety of immuno- suppressive therapies and dependence of adequate counts after recovery on a maintenance calci- neurin inhibitor (usually cyclosporine) Aplastic anemia is associated with immunologic diseases (particularly seronegative hepatitis,15 eosinophilic fasciitis,16 and thymoma17), but most cases do not have a clear cause and have been labeled idiopathic.
- . Panel B shows the spectrum of immune cytopenias. The dominant immune effectors are delineated on the y axis; for example, autoimmune destruction of peripheral-blood cells is mainly antibody-mediated, whereas T cells have been implicated in marrow destruction. However, the immune response is almost certainly complex in all these diseases. (For schematic purposes, the circles in each Venn diagram have been scaled to the relative numbers of PubMed citations.)
- Exposición antigénica no identificadaprovoca una expansión policlonal de CD4+, con una sobreproducción de citocinas inflamatorias cmo inteferon alfa, factor de ncrosis tumoral. Expansión oligoclonal de CD8+. Aumento de Th17, las cuales producen IL-17 El nivel de Th17 se correlaciona al nicel de IFN y y de manera negativa con Treg. CD8+CD57+ Dominance of a Treg B subpopulation, defined in part by higher expression of specifically human leukocyte antigen (HLA)-DR, FOXP3, CD95, and CCR4, lower expression of CD45RA, and expression of the interleukin-2 (IL-2)/STAT5 pathway were found in AA patient with response to IST cquired, somatic mu- tations in the signal transducer and activator of transcription 3 (STAT3) signaling pathway may be pathogenic in some cases of aplastic anemia, as they are in large granular lymphocytosis, producing constitutively activated T cells.24 Regulatory T (Treg) cells are decreased in patients with aplastic ane- mia and increase with a hematologic response.25,26 Aplastic anemia is associated with specific histocompatibility antigens.27 The presence of “escape clones” (granulocytes with loss of the region of chromosome 6 that encompasses HLA alleles) in 10 to 15% of patients is striking28,29; cells selected because of the absence of HLA, acquired by 6p loss of heterozygosity (LOH) or somatic mutations, sustain hematopoiesis by means of clonal expansion.30 Immune escape has also been hypothesized to explain clonal expan- sion of “PNH cells” in aplastic anemia; red cells and white cells deficient in glycosylphosphoino- sitol (GPI)–anchored proteins originate from a stem cell with an acquired mutation in PIGA (phosphatidylinositol glycan class A)
- Clonal populations may be easier to detect in patients with marrow failure than in healthy persons with many more active stem cells. Mutated clones need not be malig- nant. In aplastic anemia, benign clonal popula- tions of granulocytes deficient in GPI-anchored proteins or lacking HLA expression are com- mon, presumably selected for their survival un- der immune attack. Indeed, healthy persons have tiny numbers of leukocytes with PIGA mutations, and chromosomal clonal mosaicism is present in many normal tissues. Clonal evolution in aplas- tic anemia is development of the myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), usually characterized by aneuploidy, es- pecially loss of all or a portion of chromosome 7. Abnormalities of chromosome 7 are a feature of both acquired39 and constitutional40 aplastic ane- mia, suggesting that the environment of marrow failure itself confers a predisposition to their selection. With next-generation sequencing, clonality is detected in leukocytes with a mutation in a spe- cific gene. In most targeted genomic studies, mutations are queried in about 50 “candidate” genes (i.e., genes known to be recurrently mu- tated in MDS and AML). (These mutations are acquired, not inherited, and are present in a hematopoietic stem cell and its progeny.41) Such clonal populations are present in about one third of patients with aplastic anemia, but in contrast to MDS and AML, a very limited set of genes (DNMT3A, ASXL1, and BCOR) is involved, and the clone size (variant allele fraction) is small.42,43 Mutated clones are associated with prognosis (favorable with BCOR and PIGA and unfavorable with DNMT3A and ASXL1).42 Clones containing mutations in these genes can be stable over a period of many years,42 and mutated clones in- frequently appear to drive evolution to a myeloid cancer.44,45
- Tamizaje en niños y adolescentes y en aquellos donde la IST falló.
- Hypocellular MDS may be suggested from the appearance of the bone marrow, espe- cially dyspoietic megakaryocytes,51 and a normal or increased number of CD34 cells is not consis- tent with aplastic anemia. Flow cytometry enu- merates CD34 cells and identifies anomalous phenotypes indicating aberrant differentiation.52 Genomic testing may be useful, since spliceo- some gene mutations and multiple mutated genes are characteristic of MDS but not of aplastic anemia.5 However, the genomic pattern of hypo- plastic MDS — involvement of specific genes, the likelihood of a single gene mutation, and clone size — is both similar to the pattern in aplasticanemiaanddistinctfromthatintypical persons and patients with normocellular and hypercellular types of MDS.54 The finding of a DNMT3A- or ASXL1-mutated clone does not alter the diagnosis of aplastic anemia or the likeli- hood of a response to therapy. Sindrome mielodisplasico entradentro de las anemias refractarias, sin un conteo de blastos. La displasia unicamente se observa en SMD Three workshops were held by members of the French-American-British (FAB) Cooperative Leukemia Working Group over a two year period with 63 cases reviewed. These included 38 cases of hypocellular MDS (diagnosed at one center and previously published),2 14 cases of hypocellular AML1 and 11 cases of AA (provid- ed from the files of two of the members). All cases had bone marrow cellularity of <20%. The materials reviewed included peripheral blood smears, bone marrow aspirate smears, iron stains to identify ring sideroblasts and cytochemical peroxidase stains to identify myeloid precursors. Conventionally processed bone marrow biopsies were also reviewed. All cases were coded and laboratory/clinical information was made available only after the initial diagnoses were recorded. The following approaches were agreed upon; (i) the presence of unequivocal blasts in the peripheral blood was considered indicative of MDS or AML. Because of significant leukopenia, a precise determination of blast percentage was often impossible, but an effort was made to count at least 100 cells, including lymphocytes; (ii) hypogranular neutrophils or pseudo-Pelger neu- trophils were considered indicative of either MDS or AML if more than 10% were identified. Fewer numbers raised the suspicion but were not felt to be definitive; (iii) the presence of >1% to 20% blasts in the marrow aspirates was considered diagnostic of MDS if dysplasia was recognized; (iv) morphological marrow dysplasia of either granulocytes or megakaryocytes was considered
- Three workshops were held by members of the French-American-British (FAB) Cooperative Leukemia Working Group over a two year period with 63 cases reviewed. These included 38 cases of hypocellular MDS (diagnosed at one center and previously published),2 14 cases of hypocellular AML1 and 11 cases of AA (provid- ed from the files of two of the members). All cases had bone marrow cellularity of <20%. The materials reviewed included peripheral blood smears, bone marrow aspirate smears, iron stains to identify ring sideroblasts and cytochemical peroxidase stains to identify myeloid precursors. Conventionally processed bone marrow biopsies were also reviewed. All cases were coded and laboratory/clinical information was made available only after the initial diagnoses were recorded. The following approaches were agreed upon; (i) the presence of unequivocal blasts in the peripheral blood was considered indicative of MDS or AML. Because of significant leukopenia, a precise determination of blast percentage was often impossible, but an effort was made to count at least 100 cells, including lymphocytes; (ii) hypogranular neutrophils or pseudo-Pelger neu- trophils were considered indicative of either MDS or AML if more than 10% were identified. Fewer numbers raised the suspicion but were not felt to be definitive; (iii) the presence of >1% to 20% blasts in the marrow aspirates was considered diagnostic of MDS if dysplasia was recognized; (iv) morphological marrow dysplasia of either granulocytes or megakaryocytes was considered
- The finding of a DNMT3A- or ASXL1-mutated clone does not alter the diagnosis of aplastic anemia or the likeli- hood of a response to therapy.
- Screening for PNH is performed by means of flow cytometry, which precisely measures the proportion of GPI-anchored, protein-deficient erythrocytes and leukocytes. In classic hemolytic PNH, the PNH clone is large, above 50% and sometimes approaching representation of all circulating cells from the mutated clone. A large clone correlates with an increased risk of cata- strophic venous clot and is an indication for anticomplement therapy with eculizumab, which corrects intravascular hemolysis and is effective prophylaxis against thrombosis. Clones are gen- erally small in aplastic anemia, requiring moni- toring but not treatment. Clinical PNH usually does not develop from tiny clones or in the ab- sence of a clone at diagnosis.
- and a relative risk of death that is almost three times as high for older adults as it is for chil- dren in registry data.71 Black patients also have poorer outcomes than white patients.
- Outcomes are better when marrow is transplanted rather than blood cells, ATG is included in the conditioning regimen, donors are young, and the interval between diag- nosis and transplantation is short.77,79 Outcomes have been so good in children that some experts have advocated for first-line use of transplants from unrelated donors,8
- Marrow is the preferred source, since the risk of GVHD is higher with the use of peripheral blood.73,74 Rabbit antithymocyte globulin (ATG) is often added to the conditioning regimen,64
- We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were pe- ripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus- host disease (GVHD) were similar after PBPC and BM transplantations regard- less of age at transplantation. Intients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P .002) and overall mortality (RR 2.04; P .024) were higher after transplanta- tion of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM trans- plantations, respectively. Correspond- ing probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA- matched sibling donor transplantation for SAA. (Blood. 2007;110:1397-1400) Aunque la mediana del tiempo hasta la recuperación de neutrófilos (13 días frente a 18 días) y la recuperación de plaquetas (19 días frente a 25 días) fue más rápida después del trasplante de PBPC en comparación con BM, las probabilidades de recuperación de neutrófilos en el día 28 (89 % frente a 85 %) y la recuperación de plaquetas en el día 100 (80 % frente a 85 %) fueron similares. La proporción de pacientes con falla primaria del injerto (9 % frente al 9 %) y falla secundaria del injerto (6 % frente al 7 %) fue similar después del trasplante de PBPC y BM, respectivamente. ates of grades 2 to 4 acute GVHD were similar after PBPC and BM transplantations (RR, 1.42; 95% CI, 0.59-3.39; P .436; and RR, 1.03; 95% CI, 0.60-1.79; P .909) in patients 20 years old and younger and older than 20 years, respectively. The day-100 probabilities of acute grades 2 to 4 GVHD in younger patients were 10% and 14%, after BM and PBPC transplantations, respectively. Corresponding probabilities in older patients were 20% and 19%. Chronic GVHD rates were higher after PBPC transplantations than after BM transplantations in patients 20 years old and younger (RR, 2.82; 95% CI, 1.46-5.44; P .002; Figure 1A). In those older than 20 years, rates were similar after PBPC and BM transplanta- tions (RR, 1.14; 95% CI, 0.71-1.85; P .589). This differs from some reports where chronic GVHD rates were higher with PBPC grafts regardless of age.19-21 Notably, the significant difference in chronic GVHD rate after PBPC and BM transplantations was most evident with follow-ups of more than 6 to 7 years.
- Haploidentical transplantation has been advocated in China as first-line treat- ment for children.92 In Europe, with an average 1-year survival rate of about 74%, haploidentical transplantation is recommended as second-line therapy.93
- Combined with cyclo- sporine, ATG leads to hematologic responses in about two thirds of patients.
- We hypothesized that rabbit ATG would result in a higher response rate than horse ATG as a first treatment, for several reasons. First, in com- parison trials, rabbit ATG was superior to horse ATG in preventing and reversing acute renal- allograft rejection.13,14 Second, in patients with severe aplastic anemia, rabbit ATG has been ef- fective as salvage therapy for refractory disease or relapse after initial therapy with horse ATG.15,16 Third, in comparison with horse ATG, rabbit ATG more efficiently depletes lymphocytes in vivo and is more cytotoxic on a weight basis in vitro. rabbit ATG but not horse ATG induces the development of regulatory T cells from nor- mal T cells in tissue culture, which should be beneficial in suppressing a harmful immune re- sponse.18,19
- . Assignment of treat- ment was performed with the use of a block ran- domization scheme in a 1:1 ratio, with the as- signment probability remaining fixed over the course of the trial. The randomization schedule was based on a table of random numbers devel- oped by the pharmacy department at the clinical center. The study’s primary end point was hemato- logic response at 6 months, defined as no longer meeting the criteria for severe aplastic anemia; this end point strongly correlates with trans- fusion independence and long-term survival.6,12 Secondary end points included robustness of hema- tologic recovery, relapse, response rate at 3 months and yearly, clonal evolution, and overall survival.
- Horse ATG (ATGAM, Pfizer) was administered at a dose of 40 mg per kilogram of body weight per day for 4 days and rabbit ATG (Thymoglobulin, Genzyme) at a dose of 3.5 mg per kilogram per day for 5 days, as previously described.12,16 Cyclo- sporine was administered at a dose of 10 mg per kilogram per day (15 mg per kilogram per day for children under 12 years of age), given in divided doses every 12 hours from day 1 and continued for at least 6 months in both the horse-ATG and rabbit-ATG groups, with the dose adjusted to main- tain trough blood levels of 200 to 400 ng per milliliter
- Romiplostim is a peptibody that binds directly and competitively at the TPO binding site, where- as eltrombopag is a small molecule which binds at a trans- membrane site. There are also differences in the activation of other signaling pathways in megakaryocytes (MK) such as STAT3, ERK and AKT (Table 1).6-8 Furthermore, romi- plostim mostly stimulates mature precursors, while eltrombopag appears to act earlier in the pathway, stimu- lating MK precursor cells and MK differentiation.4,6 In addition to differences in TPO-receptor activation, eltrombopag also has off-target effects. For example, eltrombopag chelates both extra- and intra-cellular calci- um and iron and can shuttle iron out of cells.9 The iron- chelating action of eltrombopag causes anti-proliferative effects on leukemic cells lines,10 and a TPO-independent effect on stimulating stem cells and MK precursors in vivo. TPO-RA have also been described to have immunomodulatory effects, with increased regulatory T- and B-cell effects in patients on TPO-RA.13 This effect has been suggested to be mediated by TGF-B, a major cytokine involved in T-regulatory (Treg) cell development, and found in abundance in MK and platelets.