AML

Definitie: heterogene ziekte gekenmerkt door (oligo)klonale maligne hematopoëse met een blokkade in de differentiatie en daardoor een excessieve toename van leukemische blasten.

Epidemiologie: AML komt meer voor op hogere leeftijd, > 75% van de AML-patiënten is >60 jaar. 

WHO 2022: The classification of AML is re-envisioned to emphasize major breakthroughs over the past few years in how this disease is understood and managed. 


Acute myeloid leukaemia with DEFINING GENETIC ALTERATIONS (20% blast count is not required except for CEBPA en BCR-ABL) --> 85% of all AML


NB. 86% of patiënts have more than 1 driver mutation. Bij relapse ook altijd MoDi herhalen. 


Acute myeloid leukaemia, defined by DIFFERENTIATION --> 15% of AML diagnosis

*AML with BCR::ABL1 and AML with CEBPA mutation are the only disease types with a defined genetic abnormality that require at least 20% blasts for diagnosis. The blast cutoff requirement is needed for the former to avoid overlap with CML. Distinguishing AML with BCR::ABL1 from initial myeloid blast phase of CML can be challenging, and additional evidence continues to be needed to better characterize this AML type. There is insufficient data to support any change in the blast cutoff criterion for AML with CEBPA mutation. 

#Several changes were introduced to the entity formerly designated AML with myelodysplasia-related changes, now called AML, myelodysplasia-related (AML-MR). This AML type is defined as 

Key changes include: (1) removal of morphology alone as a diagnostic premise to make a diagnosis of AML-MR; (2) update of defining cytogenetic criteria; and, (3) introduction of a mutation-based definition based on a set of 8 genes – SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, STAG2, > 95% of which are present specifically in AML arising post MDS or MDS/MPN. The presence of one or more cytogenetic or molecular abnormalities listed in the table and/or history of MDS or MDS/MPN are required for diagnosing AML-MR.

AML defined by differentiation

This AML family includes cases that lack defining genetic abnormalities. It is anticipated that the number of such cases will diminish as discoveries provide novel genetic contexts for their classification. Notwithstanding, categorizing AML cases lacking defining genetic abnormalities based on differentiation offers a longstanding classification paradigm with practical, prognostic, and perhaps therapeutic implications.

WHO 2022 indeling (vervolg)


Acute leukemia of ambiguous lineage (ALAL) and mixed phenotype acute leukaemia (MPAL) are grouped under a single category in view of their overlapping clinical and immunophenotypic features, which in recent studies have been shown to also share common molecular pathogenic mechanisms.


Here too, a framework for a molecular classification is laid by

separating ALAL/MPAL with defining genetic abnormalities from

those that are defined based on immunophenotyping only.

European LeukemiaNet (ELN) risico classificatie 2022 voor intensieve behandeling

ELN in Ven-HMA

Link: Dohner et al. Blood 2022

ELN 2017 risk groups, based on younger patients who received IC regimens, are not prognostic in patients receiving Ven+Aza. This exploratory analysis suggests little OS distinction between favorable and intermediate risk groups. Furthermore, adverse risk ELN groups can be further refined to determine mutationally-defined cohorts with more favorable outcomes. 

Risico classificatie voor venetoclax-HMA

Link: Dohner et al. Blood 2022

Background

Molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This mPRS classification uses N/KRAS, FLT3–internal tandem duplication (ITD), and TP53 mutations to stratify patients into 3 groups (higher, intermediate, and lower-benefit). With this simple 4-gene approach, the authors demonstrated clear segregation of 3 prognostic cohorts of patients with AML with different response rates and outcomes that appeared to perform better than ELN22. 

Link: Bataller et al. Blood advances 2024

Prognosis

Overall response rate: 71% 

Median overall survival (OS) and event-free survival (EFS) 

2-year cumulative incidence of relapse 

Overall survival AML

Diagnostiek AML

Cup-like blast cell (CLB-cell), often in NPM1 or FLT3 associated AML

Intensieve remissie-inductie chemotherapie

NB dag 15-21 responsevaluatie, indien geen CR doorstart maken kuur 2. Het is hierbij goed zich te realiseren dat van het absolute percentage patiënten dat in remissie komt, ongeveer 20% deze remissie pas bereikt na twee intensieve chemokuren.

NB als patiënten in CR waren na 1e kuur, wordt na 2e kuur gefereerd vanaf dag 20 en N>0.5

Venetoclax azacitidine

Cyclus 1: VEN + AZA tenminste 21 dg

Op dag +14-21 BM, indien in MLFS staken ven en start G-CSF

-       Cyclus 2: conform MD Anderson: 

-Als > 5% na C1 meteen door: 21 dagen.

-Als <5% blasten na C1 wachten op repopulatie +/- G-CSF: CR: 21 dagen, CRi of delay kuur > 35 dagen: 14 dagen.

-       Cyclus 3 en verder: conform MD Anderson: 14 dagen, cyclusduur 28-35 dagen.

-       Wanneer besluiten dat behandeling niet effectief is? Hierover gezien nog onvoldoende ervaring nog geen consensus.

Profylaxe: indien neutropeen, posa en ciproxin


Lokale afspraken AMC: 'Upscaling' risico

Complex karyotype

Complex karyotype geeft nog slechter risico dan TP53, de combinatie van beide is uiterst slecht.

De optimale post-remissieconsolidatie is afhankelijk van het risicoprofiel van de ziekte, de respons op de behandeling en de te verwachten toxiciteit van de verschillende behandelstrategieën.

Onderhoud

Specifieke overwegingen behandeling

CNS lokalisatie

Epidemiologie: CNS-betrokkenheid bij AML is relatief laag (≈1%)

Diagnostische LP indien: 

Beleid: 

Refractaire/recidief AML

FLAMSA: literature: Schmid et al. JCO 2005. 2-y overleving 40%, terwijl bij hypomethylerende therapie 10-20%

Nieuwe diagnose AML

Anamnese

Lichamelijk onderzoek: 

Aanvullend onderzoek:

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