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AML (BSH 2015, ELN 2022, BSH 2022, BSH 2022(2))

 

Precursors – CD34+, CD38+, CD117+, CD133+, HLA-DR+

Granulocytes – CD13+, CD15+, CD16+, CD33+, CD65+, cMPO+

Monocytes – NSE+, CD11c+, CD14+, CD64+, lysozyme, CD4+, CD11b+, CD36+

Megakaryocytes – CD41+, CD61+, CD42+

Erythroid – CD235a+

 

AML(2).jpg

Intro

 

Median Age: 70 years

Age <65: 3-8 cases per 100,000 adults per year. 40% 5-year OS

Age >65: 9-17 cases per 100,000 per year. 10% 5-year OS

 

WHO-HAEM5 Classification

(Note: ICC classification also published the same year, see below)

Notes

  • >20% blasts no longer required for AML with defining genetic abnormalities (except CEBPA, BCR-ABL1)

  • ‘post cytotoxic therapy’ (pCT) can be added as suffix to myeloid diagnoses where indicated by medical history, e.g. CMML-pCT.

  • See WHO-HAEM5 for detailed sub-sections:

    • AML, myelodysplasia-related: list of defining abnormalities.

    • AML, definitions by differentiation

    • Myeloid neoplasms associated with germline predispositions

    • Mixed lineage phenotypes

ICC 2022 Classification

Unfortunately two classification systems were published in WHO and ICC

They are the same in principle, e.g. genetics > morphology, and the change to blast % cutoffs

The ELN have opted to use the ICC. You can see the ICC 2022 Classification here.

Clonal Haemtopoeisis of Indeterminate Potential (CHIP)

  • Found from large, population-level cohorts of elderly, seemingly healthy subjects

  • May behave like MGUS / MBL in terms of risk to progression of AML

  • Commonly DNMT3A, ASXL1, TET2, SF3B1, SRSF2

 

Diagnosis

 

Basics

  • FBC, film

  • Biochemistry, Coag,

  • HIV, Hep A/B/C

  • HLA-typing

  • Urine dip, Pregnancy test

  • CXR

  • Oocyte / Sperm cryopreservation

 

Morphology

  • Aspirate mandatory, trephine optional

  • May-Grunwald-Giemsa or Wright-Giemsa stain

  • >20% Blasts in marrow for morphological AML diagnosis (Exceptions: t(15;17), t(8;21) and inv(16))

 

Immunophenotyping

  • Used to determine lineage

  • >20% of leukaemic cells expressing a marker counted as positive, as a general rule

  • Flow blast count is not a substitute for morphological count.

  • Examples of specific phenotypes:

    • Acute megakaryoblastic - CD41+, CD61+ (CD42 usually lost on megakaryoblasts)

    • t(8;21) RUNX1:RUNX1T1 - CD19+, CD56+/-, Strong CD34+, Weak CD33+, MPO+

    • t(15;17) APML - High SSC, CD33+, CD13+, CD117+, MPO+, CD34-, HLA-DR-, CD11b-

    • BPDCN - CD123+, CD4+, CD56+, HLA-DR+, CD34-, CD13-

Cytogenetics

  • 55% of AML cases have detectable chromosome abnormalities

  • Minimum of 20 metaphases must be examined for a normal karyotype

 

Molecular Cytogenetics (FISH)

  • PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11

  • KMT2A fusion gene, 5q deletion, 7q deletion

 

Molecular Genetics (RT-PCR)

  • Detects fusion genes, such as those listed under FISH

  • Detects somatic mutations – NPM1, FLT3, CEBPA, KMT2A, RUNX1, KIT, TET2, IDH1

  • NPM1, FLT3 and CEBPA should be tested as a minimum in pts with normal cytogenetics

  • Can be use for MRD monitoring of AML cases with NPM1, PML::RARA or CBF / KMT2A fusions

 

Genome-wide studies

  • Research methods for identification of new genetic abnormalities

  • Single Nucleotide Polymorphism (SNP)-arrays

  • High-throughput DNA sequencing

  • Large scale RNA interference screens

  • Testing paired tumour + germline (e.g. skin) samples to investigate for germline predisposition, consider in AML cases with RUNX1, CEBPA, DDX41, ANKRD26, ETV6 or GATA2 mutations present.

Minimum genetic tests for all new AML patients in 2022 (BSH 2022)

  • FISH/PCR/Karyotype for Inv16 (CBFB::MYH11), t(8;21) (RUNX1::RUNX1T1) & KMT2A (MLL)

  • Karyotype

  • Molecular for FLT3-ITD, FLT3-TKD, NPM1

  • NGS Panel to include ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2, TP53, FLT3, IDH1, IDH2, DNMT3a and WT1

Some Significant Genetic Mutations

PML-RARA translocation

  • t(15;17) – APML

NPM1 mutation

  • 1o genetic lesions (“Class II”) impairing haemopoietic differentiation

CEBPA mutation

  • 1o genetic lesions (“Class II”) impairing haemopoietic differentiation

FLT3-ITD

  • “Class I” mutation found in approx. 1/3 of AML cases.

RUNX1    

  • Alters transcription activity

IDH1&2  

  • Mutations lead to arrest of haematopoietic differentiation

KMT2A (prev. MLL)

  • Lysine Methyl Transferase 2A.

  • 5% of AML cases. 5yr OS 38% in AML17+19.

  • MRD testing becoming available (as of 2025)

DNMT3A, TET2, ASXL1

  • Often present in preleukaemic stem cells —> may persist after Rx

Germline predisposition (UKCGG 2023, ELN 2022)

Increasing number of gene mutations associated with heritable risk of leukaemia

Somatic gene varaints w/ variant allele frequency (VAF) approaching 50% suggest possible germline involvement

  • Potential cases will usually be reviewed at a specialist haematopathology MDT

  • These patients may warrant germline testing, e.g. skin biopsy

  • UKCGG: Offer germline testing for pathogenic or likely pathogenic variants with VAF >20-30%

Consenting for germline testing

  • Ideally start conversation prior to somatic testing, mandatory prior to germline testing itself

Source of germline samples

  • Skin biopsy or remission bone marrow aspirate are preferred

  • Blood and saliva unsuitable for testing in setting of haematological malignancies

  • Other samples currently have various limitations to testing in UK. Examples discussed in link above.

Examples

  • DDX41 variants, first reported 2015, are now the most strongly associated with germline predispositions

    • Present in >5% of adult AML. Median age of onset in later life.

    • Modest disease penetrance (40% by age of 90 and <30% patients report a FHx of haem malig)

  • Other potential genes are RUNX1, CEBPA, ETV6, GATA2, TP53, TERT, TERC, ANKRD26, CHEK2

Prognostic Factors

 

Patient-Related Factors (predict TRM)

  • Age

  • Co-morbidities

 

AML-Related Factors (predict response to treatment)

  • WBC

  • Prior MDS

  • Prior Cytotoxic chemotherapy

  • Cytogenetics

    • Strongest AML-related prognostic factor predicting response to initial therapy

    • Favourable, Intermediate and Adverse

  • Molecular Genetics

    • Becomes relevant when patient is cytogenetically normal (CN-AML)

    • E.g. FLT3-ITD poorer prognosis

    • E.g. NPM1 and CEBPA mutations have favourable prognosis

  • Minimal Residual Disease (MRD) monitoring

    • Flow 1 log less sensitive but more available than RT-PCR

    • MRD status prior to allograft significantly affects survival post-transplant

 

Personalised risk calculator available from the Sanger Institute (currently a reserach tool only)

 

ELN Risk Stratification by Genetics 2022

ELN 2022. Note allelic ratios removed from the FLT3 mutations (compared to 2017)

 

ELN Response Assessment

  • Performed between day 21-28 of induction chemotherapy (e.g. DA 3+7)

  • CR = marrow blasts <5%, Neut >1, Plt >100, No circulating blasts

  • CR with MRD negativity

  • CRh, CRi, PR, No Response (see ELN for details, pg 1361)

 

(N.B. NPM1 MRD positivity after 2 cycles of induction associated with very poor prognosis)

 

Management

 

Adults 18-60 years old

  • Induction therapy achieves CR in 60-80% of adults <60 y.o. (TRM 5-10%)

    • Common UK regimens include FLAG-Ida-GO and DA-GO

    • Addition of small molecule drugs for pts with relevant mutations (see note below)

  • Postremission therapy

    • Up to 3 further cycles treatment, e.g. 2nd DA followed by 2 x HD Cytarabine

    • Allograft in 1st CR offers significant OS benefit if intermediate or adverse AML

    • Allograft TRM 15-50%

    • Allograft LT survival for adverse AML in 1st CR is 30% (but chemo alone dismal)

 

Adults >60 years old (BSH 2022)

  • Remission induction chemotherapy provides better QOL and longer survival than supportive care alone so offering induction chemo should be considered

  • All patients

    • Assess presence of frailty

    • Comprehensive geriatic assessment (GA) can aid decision making / sometimes prognosis

    • GA includes comorbidity, cognition, mental health, functional status, frailty, nutrition, polypharmacy, social support, quality of life. BSH good practice paper includes several of these scores in appendices.

    • Prophylactics: Quinolones, Aciclovir, Azole anti-fungals, Flu/Covid vaccination

  • 60-74 years old

    • Standard induction chemo —> CR 50%, TRM 10-20%, 2-yr OS 50%

    • RIC Allograft has been performed up to age of 74

    • Venetoclax + Azacitidine. NICE approved 2022 for patients not fit for intensive induction. Based on VIALE-A trial 2020 - 400 pts, median age 76, CR rate 36%, CR+CRi 66%. Long-term outcomes awaited. Venetoclax most effective in NPM1 mutated, FLT3-ITD negative AML but approved for all cytogentic groups.

    • Ivosidenib + Azacitidine. NICE approved 2024 for IDH1 R132 mutated AML in patients who cannot have standard intensive chemotherapy. Based on AGILE 2022 - 140 pts, Ivo+Aza vs placebo+Aza, median OS 24 months for Ivo+Aza. No head-to-head trials vs Ven+Aza as of 2024.

  • >75 or not fit for intensive chemo

    • Venetoclax + Azacitidine. NICE approved 2022 for patients not fit for intensive induction. Based on VIALE-A trial 2020 - 400 pts, median age 76 (oldest 91), CR rate 36%, CR+CRi 66%.

    • Ivosidenib + Azacitidine. NICE approved 2024 for IDH1 R132 mutated AML in patients who cannot have standard intensive chemotherapy. Based on AGILE 2022 - 140 pts, Ivo+Aza vs placebo+Aza, median OS 24 months for Ivo+Aza. No head-to-head trials vs Ven+Aza as of 2024.

    • Azacitidine monotherapy if blasts 20-30% in marrow - CR 10-30%, median OS 6-12 months

    • Hydroxycarbamide

    • Supportive care alone

  •  Relapse

    • Re-assess molecular status —> to aid consideration of small molecules, clinical trial

Therapy-Related AML

  • Many pathways, poorly understood but two groups stand out

    • 5-7 years post alkylating agents or irradiation —> 5q or 7q deletion AML

    • 2-3 years post topoisomerase II drugs —> MLL or RUNX1 AML

  • Poor prognosis

  • Often excluded from trials so data lacking. Allograft highest chance of long term survival

 

Relapsed AML

  • Majority of patients with a CR will relapse within 3 years

  • 1-year survival 70% for favourable AML, 16% for adverse

 

Special situations

  • Hyperleukocytosis (WBC >100) – hydroxycarbamide until WBC <10-20

  • CNS involvement - <5% of patients. 3 x per week IT cytarabine until no blasts

  • Myeloid sarcoma – normal AML induction +/- radiotherapy

 

Supportive Care

  • Fungal, viral and bacterial prophylaxis

  • Platelet, red cell transfusions

Notes on NICE Approved Agents

Antibody-Drug Conjugates - e.g. Gemtuzumab ozogamicin (GO, Myelotarg)

  • Mechanism of Action

    • Combination of Anti-CD33 + Calicheamicin, a cytoxic antibiotic.

    • CD33 highly expressed on AML blasts, and increasingly less so as myeloid cells differentiate

    • It is not expressed on CD34+ pluripotent stem cells

    • On non-haemopoitic cells, CD33 is found on hepatocytes —> risk of VOD

  • GO - Approved for prev. untreated CD33+ AML, where patient is known to have favourable, intermediate or unknown cytogenetics at the start of treatment, or the results are not yet available. NICE 2018

Lipsomal Drug Preparations - e.g.CPX-351

  • Liposomal daunorubicin + cytarabine combination.

  • Thought better marrow take up and longer half-life (longer cytopenias as a result)

  • Approved for Therapy-related AML and AML with MDS-related change. NICE 2018

FLT3 Tyrosine Kinase Inhibitors – e.g. Midostaurin, Quizartinib, Gilteritinib

  • FLT3 mutations present in a third of AML cases

  • Midostaurin combinations

    • Midostaurin + DA approved for FLT3-ITD postive patients. RATIFY 2017. NICE 2018.

    • OPTIMISE-FLT3 opening in 2025: M-DA vs M-DA-GO vs M-FLAGida-GO

    • (Negative trial for midostaurin + Ven-LD Cytarabine. FLT3 subgroup may benefit. ALLG AMLM25)

  • Gilteritinib monotherapy

  • Quizartinib + DA

    • Approved for newly diagnosed FLT3-ITD positive patients, followed by quizartinib monotherapy for maintenance. NICE 2024

  • Other FLT3 inhibitors not currently approved include Crenolanib, Sorafenib

IDH1 Inhibitors - e.g. Ivosidenib

  • Ivosidenib (IDH1 inhibitor)

  • IDH1 or IDH2 (Isocitrate DeHydrogenase) mutations present in 20% of AML cases. IDH is an enzyme in the kreb cycle. Mutant IDH1 and IDH2 produces an abnormal metabolite which blocks normal cell differentiation.

  • Ivosidenib + Azacitidine - Approved for patients not fit for standard induction regimens. NICE 2024

AML in Pregnancy

 

General Points

  • MDT approach

  • Diagnose as per the WHO classification

  • Treat without delay, DA(60) 3+10

  • Use actual body weight

  • Avoid quinolones, tetracyclines, sulphonamides

  • CMV negative products

 

Diagnosis in first trimester

  • Successful pregnancy outcome is unlikely and spontaneous pregnancy loss dangerous for patient (bleeding in thrombocytopenia / coagulopathy / infection)

  • Counsel patient on termination of pregnancy

 

Diagnosis at 12-24 weeks

  • Balance risks of foetal chemotherapy exposure against premature delivery

  • Chemotherapy in 2-3rd trimester rarely causes congenital malformation but does increase risk of late miscarriage, prematurity, fetal growth restriction and neonatal sepsis.

  • Where possible, deliver baby at least 3 weeks post-chemotherapy to reduce neonatal myelosuppression

 

Diagnosis beyond 32 weeks

  • Consider delivering baby first

  • NVD preferred over C-section

  • Active management of third stage of labour is recommended

 

Supportive therapies

  • Anti-emetics – Cyclizine preferred

  • Abx - Penicillin, cephalosporins, metronidazole, erythromycin safe in pregnancy

  • Anti-fungal – Ambisome preferred

 

emerging therapies / non-nice approved

(Notes from BJH 2018 and more recent ASH updates)

Key Principle

Only 3% of AML cases now have no detectable causative mutation —> Wide range of targeted therapies in development

Menin Inhibitors - eg Revumenib, Ziftomenib

Target KMT2A re-arrangements and NPM1 mutations

Disrupt the menin-KMT2A complex —> differentiation and apoptosis of AML cells (Hematol Rep 2024)

IDH2 Inhibitors

Enasidenib (IDH2 inhib) trialled in R/R AML —> Median OS 9 months (19 months for patients in CR)

Immune Checkpoint Inhibition – Nivolumab, Pembrolizumab

Nivolumab combined with azacitidine in older patients appears tolerable and some benefit.

CDK9 Inhibitors - Alvocidib

CDK9 regulates MCL1 expression. MCL1 is an anti-apoptotic protein.

E-selectin inhibitors - Uproleselan, others in development

Uproleselan - Ph3 trial, 380 R/R patients in combo with intensive chemo. No OS benefit. Possible benefit in primary refractory patients? ASH 2024

Hypomethylating Agents (other than azacitidine) - e.g. Decitabine

Ventoclax-Decitabine vs SOC for 1st line AML <60yo. Adverse risk group has higher 1st CR rate (ASH 2024)

Others

Monoclonals - e.g. Cusatuzumab (Anti-CD70) - outcomes awaited

Bispecific Antibodies – Flotezumab (CD123+CD3) - outcomes awaited

Smoothened inhibitors - Glasdegib - negative phase 3 trial (BRIGHT AML 1019, 2023)

HDAC inhibitors - Pracinostat - negative phase 3 trial (PRIMULA 2024)

CAR-T therapy – CD123 (IL3 receptor) present on 90% of blast cells - outcomes awaited

 

 trial notes

MyeChild Trial (ASH 2024)

Paediatric AML. Phase 3. Added Gemtuzumab ozogamcin (GO) to mitoxantrone-cytarabine induction

CR 94% and 2-yr OS 88%

AML-19 (multiple publications, see below)

Phase 3. Patients <60yo or ‘fit’. First Line AML therapy. FLAG-Ida-GO vs DA-GO.

4 Questions:

  • Is the use of 2 doses of Myelotarg superior to 1 dose when combined with DA or FLAG-Ida?

  • Does FLAG-Ida+GO induction improve survival compared to DA(60)+GO?

    • FLAG-Ida+GO reduced relapse rate but no difference in OS. Subgroup with NPM1 or FLT3 mutation had better 3-yr OS with FLAG-Ida+GO (JCO 2024)

  • Does the addition of 1 or 2 courses of high dose Ara-C consolidation to 2 courses of FLAG-Ida improve survival?

  • In high-risk patients, is CPX-351 superior to FLAG-Ida at induction?

    • No difference in OS or EFS. RFS was longer with CPX-351. Exploratory subgroup showed longer OS in patients with MDS-related mutations. (Blood Advances 2023)

RATIFY 2017

  • Midostaurin + DA(3+7) induction for FLT3-ITD AML. Placebo controlled.

  • Greatest impact when as close to diagnosis as possible. Maintenance therapy not effective.

  • Median OS in younger adults 74 months with midostaurin, 25 months with placebo

  • Only additional side effect was an increased rate of grade 3 rash/desquamation.