AML + WHO 2016 + Pregnancy (BCSH 2010, 2015, 2016. ELN 2017, BJH 2018)

 

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 à 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) detects:

-       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

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

o   Favourable, Intermediate and Adverse

-       Molecular Genetics

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

o   E.g. FLT3-ITD poorer prognosis

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

-       Minimal Residual Disease (MRD) monitoring

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

 

 

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.

o   Current trial – DA vs FLAG-Ida, each with 1 or 2 doses Myelotarg

-       Postremission therapy

o   Standard of care is 2nd DA followed by 2 x HD Cytarabine

o   (current trial complicated)

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

o   Allograft TRM 15-50%

o   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 despite poor outcomes, offering induction chemo should be considered

-       60-74 years old

o   Standard induction chemo à CR 50%, TRM 15%

o   RIC Allograft has been performed up to age of 74

-       75 or older

o   Low dose cytarabine à 30-day mortality 25%!

o   Hydroxycarbamide

o   Supportive care alone

 

Therapy-Related AML

-       Many pathways, poorly understood but two groups stand out

o   5-7 years post alkylating agents or irradiation à 5q or 7q deletion AML

o   2-3 years post topoisomerase II drugs à 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 agents

-       Gemtuzumab ozogamicin (Myelotarg)

o   Anti-CD33 combined with calicheamicin (DNA synthesis inhibitor)

-       FLT3 Inhibitors

o   FLT3 –selective tyrosine kinase inhibitor – e.g. sunitinib

-       Demethylating aents

o   Azacitidine approved for older patients with AML where blasts are 20-30%

 

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

 

 

Acute Promyelocytic Leukaemia (APML) (Blood 2009, iHaematology)

 

Intro

 

10-15% of AML cases

Usually young, with leukopenia and life-threatening coagulopathy

A balanced translocation between PML (Promyelocyte) & RARA (Retinoic Acid Receptor-a) generates a fusion protein à leukaemic promyelocytes have the unique ability to differentiate when exposed to retionoic acid.

 

Diagnostic Investigations

 

Morphology

-       Kidney-shaped/bi-lobed nucleus, cytoplasm densely packed with granules/auer rods

-       Hypogranular variant exists, differential diagnosis of acute monocytic leukaemia

Immunophenotype

-       CD45+, MPO+, CD117+, CD33+, CD13+, CD64+/-, Aberrant CD9+

-       CD34-, HLADR-, CD11b-, CD11c-

Cytogenetics

-       t(15;17)

-       PCR as gold standard – able to detect PML-RARA in leukopenic patients. Takes 48 hours.

-       FISH – can give an answer in 6 hours

-       Karyotyping – expensive and time consuming

 

Risk Classification

 

WBC <10 – Low to intermediate risk disease

WBC >10 – High risk disease

 

Supportive Treatment

 

Coagulopathic bleeding responsible for 50-60% of early deaths (CNS, lung and GI)

Risk of bleeding may persist up to 20 days

-       Twice or thrice daily FBC, PT, APTT and FGN

-       Keep platelets >30-50

-       Keep PT/APTT normal

-       Keep FGN >1.5g/l

 

Definitive Treatment

 

Treatment should start based on morphological assessment, do not wait for FISH.

 

ATRA

-       Overrides the t(15;17) protein induced blockade of the retinoic acid receptor

-       45mg/m2 daily in two divided doses to start on day 1

-       Continued until haematological CR and for a maximum of 60 days

 

Idarubicin

-       12mg/m2 on days 2,4,6 and 8. Or start on day 1 if WBC >10

 

Arsenic + ATRA is a highly effective (97% CR) non-chemo regimen, not currently available in UK

-       Arsenic degrades the fusion protein and induces apoptosis

 

ATRA Toxicity

 

Pseudotumour Cerebri

-       Usually patients <20 y.o.

-       Severe headache, nausea, vomiting and visual disturbance

 

Hepatoxicity

-       Bili/ALT/AlkP >5x the ULN

 

ATRA/APL Differentiation Syndrome

-       10 days after starting ATRA

-       Fluid retention, capillary leak – cough, hypoxia, effusion, oedema, weight gain, fever

-       Associated with rising WBC count. Risk lower when ATRA given with chemo.

-       Rx: Stop ATRA, give IV Dexamethasone, Cautious re-introduction when Sx resolve

 

Other adverse effects

-       Rash (Sweet’s Syn)

-       Pancreatitis, hypercalcaemia, bone marrow necrosis

 

Consolidation & F/up

 

>90% CR after induction + 2 cycles of consolidation. No role for transplant in CR1

MRD monitoring 3-monthly for two years after completion of treatment

Relapse inevitable if PCR positive in two consecutive samples à treat at molecular relapse.

 

At relapse

-       Induce 2nd CR if aim to harvest PCR negative cells for autograft

-       Consider Allograft in patients in whom PCR negativity cannot be achieved.

 

 

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

o   At diagnosis: if patient has known adverse risk cytogenetics

o   Post course 1: high risk genotype (mutated FLT3-ITD + normal NPM1), or refractory

o   Post course 2: mutated NPM1 transcripts still detectable in PB, or refractory

 

AML 18 Trial – Older Patients with AML or high risk MDS

 

 

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 à 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, ivosidenib

 

IDH1 or IDH2 (Isocitrate DeHydrogenase) mutations present in 20% of AML cases

 

Enasidenib trialled in R/R AML à Median OS 9 months (19 months for patients in CR)

 

Pro-Apoptotic Agents – Venetoclax

 

Venetoclax – BCL2 inhibitor. Combined with LD cytarabine in elderly patients looks promising

 

Immune Checkpoint Inhibition – Nivolumab, Pembrolizumab

 

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

 

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