GeneticsTier 1Medical Sciences concept

Cytogenetic abnormalities and prognosis in myelodysplastic syndrome/leukaemia

Core concept

Karyotype (and now the mutation panel) is the dominant prognostic variable in MDS and AML - it outweighs blast count and morphology
Two broad biologies:
- Balanced translocations -> fusion gene, chimeric transcription factor -> younger, de novo, better prognosis
- Unbalanced loss (-5/-7, complex, TP53) -> genomic instability -> older, therapy-related, chemoresistant

AML - ELN 2022 genetic risk

Risk	Findings
Favourable	t(8;21) RUNX1::RUNX1T1, inv(16)/t(16;16) CBFB::MYH11 (the "core-binding factor" leukaemias), NPM1 mutated WITHOUT FLT3-ITD, bZIP in-frame CEBPA
Intermediate	FLT3-ITD (any allelic ratio, +/- NPM1), t(9;11) KMT2A::MLLT3, anything not otherwise classified
Adverse	Complex (>=3 abnormalities), monosomal karyotype, -5/del(5q), -7, -17/abn(17p), inv(3)/t(3;3) GATA2-MECOM, t(6;9) DEK::NUP214, t(9;22), other KMT2A rearrangements, TP53, and ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2

ELN 2022 removed the FLT3-ITD allelic ratio (unstandardisable between labs) - FLT3-ITD is now intermediate whatever the ratio and whatever NPM1 does
t(15;17) PML::RARA = APL and is classified and treated separately - ATRA + arsenic trioxide, chemotherapy-free in non-high-risk disease; the emergency is the coagulopathy, not the count
Core-binding factor AML -> add gemtuzumab ozogamicin; high cure rate with cytarabine consolidation

MDS

Cytogenetics	Prognosis
Isolated del(5q)	Very good - "5q- syndrome": macrocytic anaemia, normal/high platelets, hypolobated megakaryocytes, F>M -> lenalidomide
Normal, -Y, del(11q), del(20q)	Good
-7/del(7q), inv(3), complex (3)	Poor
Complex (>3), TP53 multi-hit	Very poor

IPSS-R = cytogenetics + blasts + Hb + platelets + neutrophils, 5 categories
IPSS-M adds 31 gene mutations and reclassifies ~half of patients (mostly upward) - it discriminates overall survival and leukaemic transformation better than IPSS-R
- SF3B1 (ring sideroblasts) favourable -> luspatercept; ASXL1, RUNX1, EZH2, NRAS, TP53 adverse
- TP53 multi-hit (biallelic) is the single worst variable and is now its own disease entity

Risk score determines intent, not just prognosis
- Lower-risk MDS - transfusion support, ESA if EPO <500 and low transfusion need, luspatercept for SF3B1/ring sideroblasts, lenalidomide for del(5q)
- Higher-risk MDS - azacitidine, and allogeneic transplant is the only curative option - refer early while fit
Therapy-related myeloid neoplasm
- Alkylating agents -> latency 5-7 yr, -5/-7, complex, TP53, preceded by MDS
- Topoisomerase II inhibitors -> latency 1-3 yr, balanced 11q23 KMT2A translocations, no MDS phase
Send karyotype + FISH + NGS panel at diagnosis and again at progression - clonal evolution changes the category
Cytopenias with an MDS-defining cytogenetic abnormality can establish the diagnosis even when morphological dysplasia is not convincing

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