DIANÓSTICO E CLASSIFICAÇÃONOVOS CONCEITOS
SÍNDROMES MIELODISPLÁSTICAS
Silvia M M MagalhãesUniversidade Federal do Ceará
Myelodysplastic syndrome is a heterogeneous group of bone marrow neoplasms characterized by ineffective hematopoiesis, peripheral blood
cytopenias and a significant risk of progression to acute myeloid leukemia
Neukirchen J et al Leuk Res 2015; 39: 679.
The improvement of the prognosis was restricted to high-riskMDS patients diagnosed between 2002 and 2014 in comparisonto the patient group diagnosed between 1982 and 2001(19 vs. 13 months, p < 0.001).
The prognosis of low-risk MDS patients did not changesignificantly.
Dusseldorf - Germany
1982 - 2001
2002 - 2014
MDS – OVERALL SURVIVAL
Gangat N et al. Blood Cancer J 2016 Apr; 6: e414.
2004 AZACITIDINE2005 LENALIDOMIDE2006 DECITABINE
Platzbecker U et al Haematologica 2016; 101: 891
•NEW CONCEPTS
•PHISIOPATHOLOGY
• TREATMENT
•Classificação de acordo com displasias e % de blastos
•10% de displasia: critério para diagnóstico de SMD
•Exclusão de causas não-clonais
Citopenias•são condição necessária para o diagnóstico•citopenias específicas têm pouco impacto na classificação• não podem ser previstas a partir da linhagem displásica
Arber DA et al Blood 2016 May; 127: 2391.
•Definição de citopenia como definido pelo IPSS (1997)
Hb< 10 g/dL
neutrófilos < 1.800/mm3
plaquetas <100.000/mm3
Arber DA et al Blood 2016 May; 127: 2391.
IPSS (1997) PadrãoHEMOGLOBINA g/dL 10 12(M); 13 (H)NEUTROFILOS /mm3 1.800 1.800PLAQUETAS /mm3 100.000 <150.000
•Citopenia: sine qua non para o diagnóstico (WHO)
•Categorização para avaliação prognóstica (não diagnóstica)
•Avaliação do banco de dados IPSS-R: 7.012 pacientes
•23% não teriam citopenia e não classificados como SMD!
Greenberg P et al Blood Aug 17 [Epub ahead of print}
•Eliminados os termos:anemia refratárianeutropenia refratáriatrombocitopenia refratária
Steensma D Leuk Res 2016 Oct ; 51: 22.
SMD com sideroblastos em anel
marcador molecular
• ≥ 15% sideroblastos em anel (SA)
• ≥ 5% SA na presença de mutação SF3B1
displasia em única linhagem
displasia em múltiplas linhagens
Leucemia mielóide aguda
• Definição WHO 2008: LMA “the 50% rule”≥50% precursores eritróides≥20% blastos na população não eritróide
• Definição WHO 2016:≥20% blastos na população de células nucleadas da medula óssea: LA<20% blastos na população de células nucleadas da medula óssea - SMD
BLASTOS: 4 % do total de células nucleadas
“the 50% rule”
BLASTOS: 13% (4/30) do total de células nãoeritróides em paciente com 70% de precursoreseritróides
AR AREB-2
Bennett JM et al Leuk Res 2016 Aug; 47: 63.
•In a series of MDS patients 15.7% of cases have 50% or more erythroid precursors.
•The “50% rule” does not enhance the prognostic impact of the classifications on survival or time to transformation.
•This method of classification is no longer recommended.
Arenillas L et al J Clin Oncol 2016 Sep; 34: 3284.
3,692 patients in the Spanish MDS registry
Improved prognostic prediction after multivariable adjustment whenNEC was used as the denominator for the marrow blast percentage
calculation, rather than TNC
THE IMPORTANCE OF ERYTHROID ENUMARATION IN MYELOID NEOPLASIA
Zeidan AM et al Ann Hematol 2016 Oct [Epub ahead of print]
•Investigators: to combine datasets to analyze question more carefully
•Morphologists: to be clear about the method used for blast calculation
SMD com del(5q)
marcador molecular• A presença de del(5q) isolada ou associada a uma alteração
citogenética adicional exceto -7 ou del(7q)• WHO 2016 recomenda pesquisa de mutação TP53: define
pior resposta à lenalidomida e pior prognóstico
Jadersten M et al. J Clin Oncol . 2011, 29:1971.
Saft L et al Haematologica. 2014; 99: 1041.
This study validates p53 immunohistochemistry as a strong and useful predictive tool in patients with lower-risk del(5q) MDS
Strong p53 expression in ≥1% of bone marrow progenitor cells (35% of patients) was significantly associated with:
•higher acute myeloid leukemia risk (p=0.0006)•shorter overall survival (p=0.0175)•lower cytogenetic response rate (p=0.009)
p53
Saft L et al Haematologica. 2014; 99: 1041.
Strong p53 expression in ≥1% of bone marrow progenitor cells
p53
p53
McGraw KL et al Haematologica. 2016 Aug;101: e320
cellular TP53 mutation burden (next-generation sequencing) was strongly correlated with strength of p53 expression
Belickova M et al Oncotarget 2016 Jun 14; 7: 36266
high correlation in the mutational data from cells of the peripheral blood and those of the bone marrow: peripheral blood is a reliable source for
mutation monitoring
HEALTH CHIP CCUS MDS
Moyo TK et al Curr Hematol Malig Rep 2016 Oct 12. [Epub ahead of print]
DIAGNOSIS - WHAT IS THE ROLE OF MOLECULAR TESTING?
identification of genetic mutations cannot lead to a diagnosis of MDS if morphologic criteria are not met
MOLECULAR TESTING IN PATIENTS WITH SUSPECTED MYELODYSPLASTIC
SYNDROMES
Moyo TK et al Curr Hematol Malig Rep 2016 Oct [Epub ahead of print]
IPSS-RM
the prognostic overlap between the genomic and clinical data highlights the challenge in
combining clinical and mutational data
Papaemmanuil E et al Blood 2013; 122: 3616.Haferlach T et al Leukemia 2014; 28: 241.
508 MDS treated patients (primary, secondary and CMML)
•training cohort: 333
•validation cohort: 175
Nazha A et al Leukemia 2016 Nov; 30: 2214.
The addition of mutational data to the IPSS-R makes itdynamic, increases the C-index substantially andenhances its predictive ability in treated MDS patientsregardless of their initial or subsequent therapies (C-index 0.73)
Independent significant prognostic factors for survivalincluded age, IPSS-R, EZH2, SF3B1 and TP53
Nazha A et al Leukemia 2016 Nov; 30: 2214.
Nazha A et al Leukemia 2016 Nov; 30: 2214.
Nazha A et al Leukemia 2016 Nov; 30: 2214.
Validation in a larger cohort from a multi-institutional data set to confirm this result andassure the translation of this model into the clinicis currently underway through the InternationalWorking Group (IWG-PM) .
UNIVERSIDADE FEDERAL DO CEARÁHospital Universitário Walter Cantídio
Serviço de Hematologia
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