Updates on Classification of Myeloid

Neoplasms – MDS and AML

Sanam Loghavi, MD
Department of Hematopathology
MD Anderson Cancer Center

@sanamloghavi
 Conflicts of Interest
• No relevant financial COI
• Co-author on WHO 2022

@sanamloghavi
 Goals of my talk today
• Review new classifications and guidelines – Focus
on MDS and AML
– World Health Organization (WHO)-2022
– International Consensus Classification (ICC) -2022
– European Leukemia Net (ELN)- Dx and management of
AML -2022
• Introduce new terminology you will start seeing
in path reports
• Generate discussion – Please provide input
• Explore potential opportunities for improvement
– Where differences exist

@sanamloghavi
 Two New Classifications for Myeloid Neoplasms-
Molecularly driven

WHO

Leukemia. 2022 Jul;36(7):1703-1719

ICC

Blood. 2022 Jun 29;blood.2022015850. @sanamloghavi

 The beta version of the WHO book is
now online

https://tumourclassification.iarc.who.int/home @sanamloghavi
 ● Clonal hematopoiesis (CH) is recognized as a
precursor to myeloid neoplasms
● CHIP and CCUS are formally defined
Cytopenia Hb <13 g/dL in males & <12 g/dL in females; ANC <1.8 ×109 ; platelets <150 ×109

Clonal Clonal outgrowth of hematopoietic cells from affected stem or progenitor cells regardless of cause
Hematopoiesis (CH) or disease state. CH is used as a synonym for ARCH.

Age-related Clonal CH detectable in blood or BM and associated with aging without a diagnosed hematologic
Hematopoiesis disorder or cytopenia. No specific gene alteration or quantitative criteria reflecting clonal
(ARCH) abundance have been established.

Clonal hematopoiesis CH with somatic mutations of myeloid malignancy-associated genes detected in the blood or BM
of indeterminate at a variant allele fraction of ⩾2% in individuals without a diagnosed hematologic disorder or
potential unexplained cytopenia.
(CHIP)

Clonal cytopenia of CH + one or more persistent cytopenias that are otherwise unexplained by hematologic or non-
undetermined hematologic conditions and that do not meet diagnostic criteria for defined myeloid neoplasms
significance (CCUS) (e.g. MDS, MDS/MPN, etc.).

Idiopathic Sustained and unexplained cytopenia without evidence of blood cancer-associated driver
cytopenias of mutations.
unknown
significance (ICUS)

WHO 5th (ICC , same) @sanamloghavi

Boundaries between CCUS (other
clonal cytopenias) MDS and AML

Dysplasia (10%) Blasts ; genetically defined

CCUS
VEXAS
MDS AML
AA
PNH

Clonal cytopenias

@sanamloghavi
The blast count…softer but still there!

@sanamloghavi
Myelodysplastic neoplasm (MDS) WHO 5th ed

For now not AML defining in WHO

may be regarded as AML-equivalent for therapy and

clinical trials when appropriate

Enriched (~50%)for TP53m- Loghavi et al.Br J Haematol. 2015 Oct;171(1):91-9

Morphologic dysplasia qualifier now omitted; unclassifiable is omitted @sanamloghavi
Myelodysplastic syndrome (MDS)- ICC

WHO, CCUS?

@sanamloghavi
Myeloid neoplasms with mutated TP53-
ICC

Blasts Genetics
MDS with mutated TP53 0-9% BM/blood Multi-hit TP53 or TP53
mutation (VAF >10%) and
complex karyotype (often
with del(17p)
MDS/AML with mutated 10-19% BM/blood Any somatic TP53
TP53 mutation (VAF>10%)
AML with mutated TP53 ≥20% BM or blood or Any somatic TP53
meets criteria for pure mutation (VAF>10%)
erythroid leukemia

@sanamloghavi
Classification dilemmas

@sanamloghavi
Bone marrow aspirate

@sanamloghavi
15% ring sideroblasts

@sanamloghavi
 How do I classify this case?
• SF3B1 K700E mutation; 3% VAF

WHO: MDS with SF3B1 mutation ICC: MDS NOS with multilineage dysplasia

@sanamloghavi
 Prognostic and therapeutic impacts of mutant
TP53 VAF in ND-AML

Short NJ. Blood Adv. 2020 Nov24;4(22):5681-5689

 TP53 Allelic State Demarcates Outcomes MDS

Elsa Bernard, PhD

Versus P=6x 10-18 TP53 state WT (n = 497) 1mut (n = 22) Multi (n = 119)

Versus P = .04 Versus P = 4 x 10-4

Versus P = .6
Probability of OS

Probability of OS
Versus
P = .5

Time Since HMA, y

Time, y

TP53 state WT (n = 69) 1mut (n = 10) Multi (n = 16) TP53 state WT (n = 265) 1mut (n = 7) Multi (n = 24)

Versus P = 3 x 10-5 Versus P = .1

Probability of OS

Probability of OS

Time Since Lenalidomide, y Time Since HSCT, y

Elli Papaemmanuil, PhD

Bernard E et al. Nat Med. 2020;26:1549-1556.

 Multi-hit TP53 alterations –
Essentially means loss of both TP53 copies

One mutation
+ del17p
One mutation
More than
+ cn-LOH*
one TP53
(VAF>50% is
mutation
surrogate)

Multi-hit
TP53
alterations

El Hussein S. and Loghavi S. Cancers (Basel). 2022 Nov; 14(22): 5690. @sanamloghavi
 IPSS-M

E Bernard et al. NEJM Evidence ;

Molecular International Prognostic Scoring System for Myelodysplastic Syndromes, DOI: (10.1056/EVIDoa2200008)
IPSS-M Risk Calculator

https://mds-risk-model.com/
Remarkable clinical impact …

@sanamloghavi
 Molecular characterization of TP53 mut AML
and high-risk MDS

2200 AML/MDS-EB
TP53 mutations 10.5%, median VAF 47%
Bi-allelic 76% patients
VAF not associated with survival
Tim Grob, et al. Molecular characterization of mutant TP53 acute myeloid
leukemia and high-risk myelodysplastic syndrome, Blood, 2022,
 Acute Myeloid Leukemia-WHO
Acute myeloid leukemia with defining genetic abnormalities
Acute promyelocytic leukemia with PML::RARA
Acute myeloid leukemia with RUNX1::RUNX1T1
Acute myeloid leukemia with CBFB::MYH11
Acute myeloid leukemia with DEK::NUP214
Acute myeloid leukemia with RBM15::MRTFA
Acute myeloid leukemia with BCR::ABL1 require 20% blasts
Acute myeloid leukemia with KMT2A rearrangement Most common partner MLLT3

Acute myeloid leukemia with MECOM rearrangement Novel

Acute myeloid leukemia with NUP98 rearrangement Often cryptic; ~FLT3, WT1 ,CEBPA

Acute myeloid leukemia with NPM1 mutation

Acute myeloid leukemia with CEBPA mutation WHO includes bi and bzip require 20% blasts
Acute myeloid leukemia, myelodysplasia-related **
Acute myeloid leukemia with other defined genetic alterations
Acute myeloid leukemia, defined by differentiation
 Acute Myeloid Leukemia-ICC
Acute myeloid leukemia with defining genetic abnormalities
Acute promyelocytic leukemia with PML::RARA
APL with other RARA rearrangements
AML with RUNX1::RUNX1T1
AML with CBFB::MYH11 fusion
AML with MLLT3::KMT2A
Require ≥10% blasts
AML with other KMT2A rearrangement
AML with DEK::NUP214 fusion

AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1)

AML with other MECOM rearrangement

AML with other rare translocations
Acute myeloid leukemia with BCR::ABL1 require 20% blasts
Acute myeloid leukemia with NPM1 mutation Require ≥10% blasts
Acute myeloid leukemia with bZIP CEBPA mutation
ML and MDS/AML w/ mutated TP53: 10-19% (MDS/AML) /≥20% (AML)
AML, myelodysplasia-related ** 10-19% (MDS/AML) and ≥20% (AML)
AML NOS, 10-19% (MDS/AML) and ≥20% (AML)
What’s with the double colon?

:: replaces – and / for designating fusion genes

@sanamloghavi
NPM1 mutated myeloid neoplasms with <20%
blasts.

@sanamloghavi
Is NPM1 mut VAF important?

@sanamloghavi
What about low VAF NPM1 mutation and low blasts count

We are characterizing this group-

collaboration with Drs. Keyur Patel,
Courtney DiNardo
 p53 IHC informs mutation status
Negative for overexpression (wild-type pattern) P53 high-level overexpression (mutant pattern)

NPM1/FLT3 mut- TP53 wild type

p53 – Negative (truncated) pattern Low-level overexpression (Pitfall).

Tashakori et al. Blood. 2022 Apr7;blood.2021013983. Agnostic of allelic state/copy number (deletion or cnLOH)
@sanamloghavi
 AML, myelodysplasia-related
WHO 2016 WHO 2022, ICC 2022
AML with MR AML-MR AML-MR cytogenetic
changes abnormalities
AML-MR mutations

Antecedent MDS or Antecedent MDS or

MDS/MPN MDS/MPN

Morphologic
dysplasia
MR-defining MR-defining cytogenetic MR-defining cytogenetic
cytogenetic changes changes changes

MR-defining mutations MR-defining mutations

AML ontogeny is defined by distinct
somatic mutations

Lindsley RC. Blood. 2015 Feb 26; 125(9): 1367–1376.

 AML, Myelodysplasia-Related
ICC
WHO
Defining cytogenetic abnormalities
Defining cytogenetic abnormalities
Complex karyotype (≥3 abnormalities)
Complex karyotype (≥3 abnormalities) -5/del(5q)
-5/del(5q) -7/del(7q)
-7/del(7q) +8
del(11q) del(11q)
del(12p) del(12p)
-13/del(13q) -13/del(13q)
del(17p) -17/del(17p)
Isochromosome 17q Isochromosome 17q
idic(X)(q13) del(20q)
Defining somatic mutations idic(X)(q13)
ASXL1, BCOR, EZH2, SF3B1, SRSF2, Defining somatic mutations
STAG2, U2AF1, or ZRSR2** ASXL1, BCOR, EZH2, RUNX1, SF3B1,
SRSF2, STAG2, U2AF1, or ZRSR2**
Loss of chromosomal regions due to unbalanced translocations is equivalent to deletion
**Neither system determines VAF
 Pure Erythroid Leukemia- WHO 2016
WHO
Acute erythroid leukemia (AEL)
high prevalence of biallelic TP53 alterations.
≥80% erythroids, ≥30% proerythroblasts
AEL supersedes AML-MR

ICC
AML with mut TP53
p53
“erythroleukemia”
 Also published in 2022-
ELN Recommendations for AML

*ELN classification is largely based on ICC @sanamloghavi

 AML- 2022 ELN Risk classification by genetics at initial diagnosis

Favorable

• t(8;21)(q22;q22. 1)/RUNX1::RUNX1T1
• inv(16)(p13.1q22) or
t(16;16)(p13.1;q22)/CBFB::MYH11
• Mutated NPM1 without FLT3-ITD
• bZIP in-frame mutated CEBPA

Intermediate

• Mutated NPM1 with FLT3-ITD

• Wild-type NPM1 with FLT3-ITD
• t(9;11)(p21.3;q23.3)/MLLT3::KMT2A
• Cytogenetic and/or molecular abnormalities not classified as favorable or adverse
Adverse

• t(6;9)(p23;q34.1)/DEK::NUP214
• t(v;11q23.3)KMT2A-rearranged (excludes PTD)
• t(9:22)(q34.1;q11.2)/BCR::ABL1
• t(8:16)(p11;p13)/KAT6A::CREBBP
• inv(3)(q21 .3q26 2) or t(3;3)(q21.3;q26.2)/GATA2,MECOM(EVI1)
• t(3q26.2 ;v)/MECOM(EVI1)-rearranged
• -5 or del(5q): -7: -17/abn(17p)
• Complex karyotype, monosomal karyotype
• Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2
• Mutated TP53
 ELN Risk classification by genetics –
fine print
• Risk is assigned mainly based on results observed in intensively treated patients
• Initial risk assignment may change during the treatment course based on the MRD status
– CBF AML
– NPM1 mut AML
– MLLT3::KMT2A
• Concurrent KIT and/or FLT3 mutation does not alter risk categorization
– CBF AML
• Adverse-risk cytogenetics trump NPM1 mut
• MLLT3::KMT2A trumps concurrent adverse mutations
• Complex karyotype: ≥3 unrelated chromosome (other class-defining recurring genetic
abnormalities; hyperdiploid karyotypes (≥3 trisomies or polysomies) don’t count)
• Monosomal karyotype: ≥2 distinct monosomies (excluding X/Y) or one autosomal monosomy + ≥1
structural abnormality (excluding CBF)

• Adverse mutations don’t count as adverse “for the time being” if they co-occur with favorable-risk
AML (i.e. NPM1, CEBPA, CBF)

• TP53 mutation (at VAF ≥ 10%), irrespective of allelic status

@sanamloghavi
 Most significant changes to ELN 2022
• FLT3-ITD allelic ratio is no longer considered in the risk classification; all are intermediate-risk
– Methodological issues with standardization
– Modifying impact of midostaurin-based therapy on FLT3-ITD without NPM1 mutation
– Increasing role of MRD status in treatment decisions

• AML with myelodysplasia-related (MR) mutations: adverse-risk

– ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2

• Adverse-risk cytogenetics + NPM1-mutated AML now defines adverse risk

• Only in-frame bZIP mutations of CEBPA are favorable, irrespective of allelic state
– ~90% of biallelic CEBPA localize to the bZIP region

• Added disease-defining recurring cytogenetic abnormalities in adverse-risk group

– t(3q26.2;v) involving the MECOM
– t(8;16)(p11;p13): KAT6A::CREBBP

• Hyperdiploid karyotypes is no longer considered as complex karyotypes and as adverse-risk

@sanamloghavi
 bZIP CEBPA mutations

bzip 278-345 @sanamloghavi

 bZIP CEBPA mutations

Wakita et al. Blood Adv. 2022 Jan 11;6(1):238-247. @sanamloghavi

 bzip 278-345

Taube et al. Blood. 2022 Jan 6;139(1):87-103. @sanamloghavi

 Impact of co-mutations in CEBPA mut
AML • CSF3R and GATA2 mut
mutually exclusive in
CEBPA-mutant AML
• co-occurrence of
a CSF3R mut associated
with shorter EFS and
increased risk of relapse
• GATA2 status has no
impact on clinical
outcomes

Tarlock et al. Blood. 2021 Sep 30;138(13):1137-1147. @sanamloghavi

 Take home message
• Significant overlap between WHO and ICC, many entities
unchanged from WHO 2016
• However, there are several significant differences
– Variation in nomenclature for same entities
– Some differences in diagnostic criteria, particularly notable in
MDS and AML and the “grey zone” with 10-20% blasts
– New entities recognized in one classification but not the other
• Impact on pathology reports…
– Be prepared… you may see two interpretations….
• Important implications for treatment and clinical trial
enrollment
– Need to keep in mind variations in classification when designing
clinical trials and defining inclusion criteria

@sanamloghavi
 The silver lining..
• No classification system is perfect
• Fortunately, classification systems are evolving entities
• There is room for improvement in both

Scent of a Woman, 1992

Thank you for your attention!