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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+
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
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 New name for MLL
DNMT3A, TET2, ASXL1 Often present in preleukaemic stem cells —> may persist after Rx
WHO 2016 Classification
Addition new category of ‘Myeloid neoplasms with germ line predisposition’. Includes:
Biallelic CEBPA, ETV6, GATA2
When associated with Downs, Noonan, Neurofibromatosis (JMML)
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
HIV, Hep A/B/C
Urine dip, Pregnancy test
Oocyte / Sperm cryopreservation
Aspirate mandatory, trephine optional
May-Grunwald-Giemsa or Wright-Giemsa stain
>20% Blasts in marrow for AML diagnosis (Exceptions: t(15;17), t(8;21) and inv(16))
Myeloperoxidase (MPO), Sudan back B (SBB) and non-specific esterase (NSE) stains
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.
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
Research methods for identification of new genetic abnormalities
Single Nucleotide Polymorphism (SNP)-arrays
High-throughput DNA sequencing
Large scale RNA interference screens
Patient-Related Factors (predict TRM)
AML-Related Factors (predict response to treatment)
Prior Cytotoxic chemotherapy
Strongest AML-related prognostic factor predicting response to initial therapy
Favourable, Intermediate and Adverse
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
ELN Response Assessment
Performed between day 21-28 of induction chemotherapy (e.g. DA 3+7)
CR = marrow blasts <5%, Neut >1, Plt >100
CR with MRD negativity
CRi, PR, 1o Refactory (Also in clinical trials - Stable, Progressive Disease)
(N.B. NPM1 MRD positivity after 2 cycles of induction associated with very poor prognosis)
Adults 18-60 years old
Induction therapy achieves CR in 60-80% of adults <60 y.o.
Current trial – DA vs FLAG-Ida, each with 1 or 2 doses Myelotarg
Standard of care is 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
Remission induction chemotherapy provides better QOL and longer survival than supportive care alone so offering induction chemo should be considered
60-74 years old
Standard induction chemo à CR 50%, TRM 15%
RIC Allograft has been performed up to age of 74
>75 or not fit for intensive chemo
Azacitidine if Blasts 20-30% in marrow
Low dose cytarabine à 30-day mortality 25%
Supportive care alone
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
Often excluded from trials so data lacking. Allograft highest chance of long term survival
Majority of patients with a CR will relapse within 3 years
1-year survival 70% for favourable AML, 16% for adverse
Other NICE Approved Agents 2018
Gemtuzumab ozogamicin (Myelotarg)
Anti-CD33 combined with calicheamicin (DNA synthesis inhibitor)
Approved for previously untreated AML, where patient is known to have favourable, intermediate or unknown cytogenetics at the start of treatment.
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
Midostaurin (FLT3 Inhibitor)
Approved for FLT3-ITD positive patients, given in combination with DA
Other new agents - see bottom of page
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
Fungal, viral and bacterial prophylaxis
Platelet, red cell transfusions
AML 19 Trial – Adults with AML or High Risk MDS
1. Is the use of 2 doses of Myelotarg superior to 1 dose when combined with Da or FLAG-Ida?
2. Does FLAG-Ida+GO induction improve survival compared to DA(60)+GO?
3. Does the addition of 1 or 2 courses of high dose Ara-C consolidation to 2 courses of FLAG-Ida improve survival?
4. In high-risk patients, is CPX-351 superior to FLAG-Ida at induction?
Flow for patients not known to be high risk:
Flow for patients known to be high risk at diagnosis:
Further randomisation available for patients who become high risk at any point during treatment.
Indications for transplant:
All patients defined as high-risk at any point
At diagnosis: if patient has known adverse risk cytogenetics
Post course 1: high risk genotype (mutated FLT3-ITD + normal NPM1), or refractory
Post course 2: mutated NPM1 transcripts still detectable in PB, or refractory
AML in Pregnancy
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
Anti-emetics – Cyclizine preferred
Abx - Penicillin, cephalosporins, metronidazole, erythromycin safe in pregnancy
Anti-fungal – Ambisome preferred
Targeted Therapies (BJH 2018)
(drugs in italics are currently FDA approved in AML)
Only 3% of AML cases now have no detectable causative mutation
CD33-targeted therapy – Gemtuzumab ozogamicin (GO, Myelotarg), Vadastuximab talirine
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
Myelotarg is a combo of Anti-CD33 and calicheamicin, a cytoxic antibiotic.
Liposomal Preparations - CPX-351 (Liposomal Daunorubicin + Cytarabine)
Improves OS in phase 3 study, particularly in therapy-related / MDS-related AML
FLT3 Tyrosine Kinase Inhibitors – Midostaurin, Quizartinib, Crenolanib, Gilteritinib
FLT3 mutations present in a third of AML cases
- 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.
The other drugs listed are second generation FLT3 TKI’s with more potent, more specific action.
Quizartinib has been used in relapsed/refractory patients, allowing some to bridge to transplant.
IDH Inhibitors – Enasidenib (IDH2 inhib), ivosidenib (IDH1 inhib)
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.
Enasidenib trialled in R/R AML —> Median OS 9 months (19 months for patients in CR)
Pro-Apoptotic Agents – Venetoclax
Venetoclax – BCL2 inhibitor. Trialled in combo with low dose cyatabine / Aza / Decitabine.
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.
Bispecific Antibodies – Flotezumab (CD123+CD3) looks promising
Pracinostat (HDAC inhibitor)
CART Cells – CD123 (IL3 receptor) present on 90% of blast cells. Has been used to bridge to HSCT