AML (BSH 2015, ELN 2017)

 

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+

 

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

 

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

 

who 2016 aml.png

Addition new category of ‘Myeloid neoplasms with germ line predisposition’. Includes:

  • RUNX1

  • 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

 

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 AML diagnosis (Exceptions: t(15;17), t(8;21) and inv(16))

 

Cytochemistry

  • Myeloperoxidase (MPO), Sudan back B (SBB) and non-specific esterase (NSE) stains

 

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.

 

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

 

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

 

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

 

 

ELN Risk Stratification by Genetics

aml risk.png

 

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)

 

Management

 

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

  • Postremission therapy

    • 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%

    • Hydroxycarbamide

    • Supportive care alone

 

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

 

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.

  • 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

  • Midostaurin (FLT3 Inhibitor)

    • Approved for FLT3-ITD positive patients, given in combination with DA

  • Other new agents - see bottom of page

 

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

 

 

AML 19 Trial – Adults with AML or High Risk MDS

 

4 Questions:

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:

aml 19 1.png

 

 

Flow for patients known to be high risk at diagnosis:

aml 19 2.png

 

 

Further randomisation available for patients who become high risk at any point during treatment.

aml 19 3.png

 

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

 

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

 

 

 

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 therapyGemtuzumab 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 InhibitorsMidostaurin, Quizartinib, Crenolanib, Gilteritinib

 

FLT3 mutations present in a third of AML cases

 

RATIFY trial

-       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 InhibitorsEnasidenib (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.

Others

 

Bispecific Antibodies – Flotezumab (CD123+CD3) looks promising

Smoothened inhibitors

E-selectin inhibitor

Pracinostat (HDAC inhibitor)

CART Cells – CD123 (IL3 receptor) present on 90% of blast cells. Has been used to bridge to HSCT