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DIANÓSTICO E CLASSIFICAÇÃONOVOS CONCEITOS

SÍNDROMES MIELODISPLÁSTICAS

Silvia M M MagalhãesUniversidade Federal do Ceará

DECLARAÇÃO DE CONFLITO DE INTERESSE

Nenhum conflito de interesse

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

OUTCOME OF MDS PATIENTS

Steensma DP Leuk Lymphoma 2016; 57: 17.

NOVOS CONCE

FAB 1982

OMS 2001

OMS 2008

OMS 2016

CLASSIFICAÇÃO

Arber DA et al Blood 2016 May; 127: 2391.

•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.

Greenberg P et al Blood. 2016 Aug 17 [Epub ahead of print]

IWG-PM

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.

1,448 patients in the Dusseldorf MDS registry

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

McGraw KL et al Haematologica. 2016 Aug;101: e320

p53

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

INDOLENT MYELOID HEMATOPOIETIC DISORDERS

ICUS

IDUSCHIPCCUS

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]

Moyo TK et al Curr Hematol Malig Rep 2016 Oct 12. [Epub ahead of print]

Malcovati L et al Blood 2014; 124: 1513.

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.

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

[email protected]