Acute Myeloid Neoplasms

Question 1

Which myeloid malignancies need add-on KIT analysis?

Answer 1

t(8;21) RUNX1::RUNX1T1

inv(16) / t(16;16) CBFB::MYH11

Question 2

“Core Binding Factor” AML

Answer 2

Umbrella term for AML with t(8;21) RUNX1::RUNX1T1 and AML with inv(16) / t(16;16) CBFB::MYH11.

RUNX1 encodes core binding factor alpha. CBFB encodes core binding factor beta.

Together, these represent 12-15% of AMLs in adults.

Have a generally favorable prognosis, and fall into the category of “it doesn’t matter how many blasts you have, if you have the molecular you have the leukemia.” However, concurrent KIT mutations (which may occur in both) portend a poorer prognosis.

Question 3

Poor prognostic factors in AML with inv(16) / t(16;16) CBFB::MYH11

Answer 3

KIT mutations
FLT3 mutations
Trisomy 8

Question 4

Good prognostic factors in AML with inv(16) / t(16;16) CBFB::MYH1

Answer 4

Trisomy 22

Question 5

Significance of exon 8 or 17 KIT mutations in Core Binding Factor AML

Answer 5

Since they portend a significantly worse prognosis, this finding is an indication for hematopoietic stem cell transplant at first remission.

Question 6

Acute promyelocytic leukemia

Answer 6

AML with t(15;17) PML::RARA, or rarely with other variant RARA translocations.

Has a favorable long-term prognosis if it is recognized early on - the potential for complications is with DIC when initiating the wrong chemotherapy.

FLT3 mutations are found in 30-40% of cases, and are of uncertain prognostic significance.

Question 7

Variant RARA translocations that are resistant to ATRA therapy

Answer 7

ZBTB16::RARA

STAT5B::RARA

Question 8

PML breakpoint isoforms in PML::RARA AML

Answer 8

Breakpoint1 and 2 / Long isoform PML: 70% of cases, produces the “hypergranular” APML

Breakpoint 3 / Short isoform PML: 30% of cases, produces the “hypogranular” or “microgranular” APML

Question 9

What to call AML with ZBTB16::RARA, STAT5B::RARA, NUMA1::RARA, or NPM1::RARA

Answer 9

“Acute promyelocytic leukemia with variant RARA translocation”

Always specify in a note whether the variant is ATRA sensitive or resistant.

Question 10

AML with t(9;11) KMT2A::MLLT3

Answer 10

2% of adult AML, 10% of pediatric AML

Blasts display monocytic or myelomonocytic differentiation. Risk of DIC or progression to myeloid sarcoma.

Numerous KMT2A translocation partners have been reported – MLLT3 is just the most common, at about 30% of KMT2A rearranged cases. Non-MLLT3 cases are just called “AML, NOS” at current.

NRAS or KRAS mutations are also identified in 30-40% of cases.

Incidence of FLT3 mutations is low compared to other AMLs.

ALWAYS comment on MECOM expressor status

Question 11

MECOM expression in AML with t(9;11) KMT2A::MLLT3

Answer 11

This is a key factor for this diagnosis.

There is evidence that MECOM expressing cases have significantly different biology compared to MECOM negative cases, and in fact MECOM expression is a very poor prognostic factor in these patients.

You should never diagnose KMT2A::MLLT3 AML without commenting on MECOM status

Question 12

AML with t(6;9) DEK::NUP214

Answer 12

Uncommon, representing only about 1-2% of AMLs

Often present with basophilia, cytopenias, and multilineage dysplasia.

Fusion of DEK with the nucleoporin results in constitutive DEK localization to the nucleus, enabling constitutive transcription of downstream effector genes.

This diagnosis carries a poor prognosis, and most of these patients will recieve early hematopoietic stem cell transplants.

Currently, the WHO system requires at least 20% blasts for AML diagnosis with this translocation, however this is controvertial, and most agree that you should report that these patients are likely to have a poor prognosis and may develop definitive DEK::NUP214 AML.

FLT3 mutations are seen in 70-80% of cases, but their prognostic significance is unclear – the diagnosis already has such a poor prognosis at baseline that it is hard to get much worse.

Question 13

AML with inv(3) / t(3;3) GATA2::MECOM

Answer 13

Rare diagnosis, accounting for 1-2% of AML

Often present with multilineage dysplasia and dwarf megakaryocytes.

This rearrangement pairs MECOM with the GATA2 enhancer.

Poor prognosis, resistant to most chemotherapy. Prognosis gets even worse if paired with a myelodysplastic karyotype alteration.

Almost ALWAYS paired with mutations in the RTK/RAS pathway, including NRAS, PTPN11, FLT3, KRAS, NF1, CBL, and KIT. (98% of cases)

Frequently also paired with secondary alterations that contribute to myelodysplasia – monosomy 7, del(5q), and complex karyotype.

Question 14

Megakaryoblastic acute myeloid leukemia with t(1;22) RBM15::MRTFA

Answer 14

Rare, representing less than 1% of AML, and 14% of non-Down syndrome related acute megakaryoblastic leukemias.

Characterized by megakaryoblastic differentiation, and almost exclusively seen in infants (80% of cases diagnosed before 1 year of age). Osteolytic lesions are seen on imaging. May present as a mass mimicking a small round blue cell tumor like Ewing.

In most cases, t(1;22) is the only cytogenetic aberrancy.

Intermediate prognostic category for AML.

Question 15

AML with mutated NPM1

Answer 15

Occurs in 5% of childhood AML, 30% of adult AML

Blasts typically have a monocytic or myelomonocytic phenotype.

Mutually exclusive of other leukemia-defining genetic signatures, and typically occurs with a normal karyotype or a very minimally altered karyotype, which is not of prognostic significance. Generally NPM1-mutated AML has a relatively faborable prognosis.

NPM1 encodes nucleophosmin, a chaperone which localizes to the nucleus, has a role in ribosomal synthesis, and regulates the ARF-TP53 pathway. NPM1 loss is considered a late event in leukemogenesis, and typically occurs following mutation in epigenetic regulators. Co-mutation of FLT3, IDH1/2, or NRAS/KRAS is common.

Mutations involve exon 12 and lead to frameshift in the C-terminal region, resulting in truncation and loss of nuclear localization (shift from nuclear to cytoplasmic).

Note: AML with myelodysplastia-related cytogenetics takes precedence over NPM1 mutation

Question 16

AML with biallelic CEBPA mutations

Answer 16

Seen in 5-10% of pediatric AML, and less than 5% in adult AML.

Has a good prognosis, similar to that of Core Binding Factor AML. No distinctive morphologic features.

CEBPA encodes CCAAT enhancer binding protein alpha, which has a role as a hematopoietic transcription factor as well as a tumor suppressor.

Biallelic mutation is required for diagnosis, and only sequence mutations count – other forms of CEBPA inactivation are not counted towards diagnosis.

More than 70% have a normal karyotype. Co-mutation of WT1 and GATA1 is common.

Abnormal karyotype and FLT3-ITD are poor prognostic factors.

Note: AML with myelodysplastia-related cytogenetics takes precedence over NPM1 mutation

Also, germline pathogenic CEBPA mutations have been reported, so if your patient is a child or young adult, consider testing for germline disease

Question 17

AML with BCR::ABL1

Answer 17

Only diagnosed in the absence of preceding CML (only de novo AML)

Rare, less than 1% of AMLs.

Often has additional cytogenetic abnormalities: Loss of 7, gain of 8, or complex karyotype.

This represents an aggressive disease with poor response to conventional AML therapy or TKIs alone.

Question 18

AML with mutated RUNX1

Answer 18

RUNX1 is fairly commonly seen mutated in AML, so this diagnosis is low priority, and is reserved for whenever there is no alternative diagnostic category which supercedes it.

The reason for separating this out is because these patients due worse overall compared to patients with AML, NOS.

It is also worth noting that RUNX1 pathogenic mutations may be germline – so ensure you are not dealing with a germline RUNX1 leukemia syndrome.

Question 19

AML with myelodysplasia-related changes

Answer 19

Diagnostic criteria:
1. >20% peripheral blood or bone marrow blasts
2. One of the following:
* Dysplasia in >50% of at least two lineages
* Preceding diagnosis of MDS or MDS/MPN
* Underlying MDS-associated cytogenetic abnormalities

Caveat: This diagnosis is superceded by therapy-related AML

Worse prognosis than most other AML types

Question 20

The presence of mutation in __ in AML is almost always associated with a complex karyotype and poor prognosis.

Answer 20

TP53

Question 21

“Therapy-related myeloid neoplasm”

Answer 21

May have the morphology of MDS or AML – but it does not really matter

If you have had cytotoxic chemotherapy, then the prognosis will be uniformly poor irrespective of the blast count. So, we use the term “therapy-related myeloid neoplasm” rather than saying “therapy-related MDS” or “therapy-related AML”

Question 22

Latency period between therapy and therapy-related myeloid neoplasia

Answer 22

Alkylating agents or radiation: 5-10 years

Topoisomerase II inhibitors: 1-3 years

Question 23

Molecular findings of AML status-post alkylating agent chemotherapy/radiation

Answer 23

-5 (or just -5q)
-7
Complex karyotype
TP53 mutation

Question 24

For patients who develop a therapy-related myeloid neoplasm after alkylating agent therapy/radiation, there is usually . . .

Answer 24

. . . a latency period in which the neoplasm behaves like MDS (MDS-phase)

Usually, the neoplasm will then take off as a clinical leukemia.

This is not true for patients post-topoisomerase II inhibitor chemotherapy, who tend to present in leukemia without an MDS phase.

Question 25

Germline mutations with predisposition to myeloid neoplasms

Answer 25

RUNX1
DDX41
CEBPA
ETV6
ANKRD26
GATA2
Noonan/Noonan-like/NF type 1
Telomere biology disorder-associated
“Bone marrow failure-associated”

Question 26

Germline/somatic karyotype abnormalities with predisposition to myeloid neoplasms

Answer 26

Down syndrome
(Mosaic) trisomy 8

Question 27

Down syndrome-assocaited transient abnormal myelopoiesis

Answer 27

Clonal myeloid neoplasms which can mimic (even meeting diagnostic criteria) for AML are frequently seen in Down syndrome patients, but are known to resolve in the vast majority of cases.

Almost all of these will acquire GATA1 mutations, usually in exon 2, resulting in N-terminal truncation. This finding is also present in the marrow of 25-30% of all neonates with Down syndrome, though the significance is unclear.

About 90% of cases spontaneously regress within the first 3 months of life.

If progression to clinical AML ever occurs, it is likely to occur between 3 months and 5 years of life, and in these cases the gain of additional oncogenic mutations is regularly identified.

Question 28

What MDS karyotype is associated with particularly poor prognosis?

Answer 28

del7
OR
complex karyotype

Question 29

del20q as the sole abnormality in MDS

Answer 29

MDS with isolated del20q has a good prognosis relative to other MDS

Question 30

t(11;14)

Answer 30

IGH::CCND1

Question 31

t(14;18)

Answer 31

IGH::BCL2

Question 32

t(8;14)

Answer 32

IGH::MYC