Acute Myeloid Leukaemia (AML)
Haematological Pathway
for
South Wales Cancer Network
Document Control Sheet
Organisation
Specialty/Project
Document Title
Document Number
Version
2.0
Approved by
South Wales Haematology
Cancer Network Group
South Wales Cancer Network
Haematological Site Specific Group
Acute Myeloid Leukaemia Haematological Pathway
05/006
Author/s
Dr S Knapper
Dr J Kell
Dr C Alvares
Dr U Mohite
Approval date
Ratified by
19/03/15
19/03/16
Dr C Fegan
Dr W Ingram
Date of next review
Acute Myeloid Leukaemia
NSAG Patient Care Pathway
Demographics
- Approximately 100 new cases in Wales per year (2,500 in UK). Median
age is 68. Incidence rises from ~1-2 per 100,000 <45yrs to 10-15 per
100,000 >70yrs
- This pathway covers patients with a diagnosis of AML aged 16 years
upwards
Diagnosis
- Confirmed by the presence of ≥20% myeloid blast cells in the bone
marrow
- May alternatively be made by demonstrating a recurrent cytogenetic
abnormality: t(8;21), inv(16), t(16;16), t(15;17) irrespective of blast
count
Required tests:
- Full blood count with differential white blood count
- Blood film examination
- Bone marrow aspirate: (trephine optional – but essential if ‘dry tap’)
Morphology
Immunophenotypic characterisation of blast population
Cytogenetics (or, if fails, FISH for recurrent abnormalities)
- Coagulation screen (including fibrinogen level)
- Renal and liver chemistry
Additional investigations:
- Molecular genetics: PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11
consider FLT3, NPM1 mutation screening
- HLA-typing and CMV serology should be performed at the earliest
available opportunity (potential allogeneic stem cell transplant candidates
only)
- If CNS involvement is suspected: lumbar puncture and CSF cytospin
- Echocardiogram (prior to intensive therapy if ≥60yrs / cardiac comorbidity)
Staging and Prognostication
- There is no formal ‘staging’ system in AML
- Patient-related factors include age, performance status, co-morbidities
- AML-related factors:
presenting WBC
primary/secondary disease
cytogenetic risk group
FLT3/NPM1 mutation status
Information Required at MDT
At the time of initial MDT discussion:
- Blood and bone marrow morphology, immunophenotyping
- Initial treatment plan, including clinical trial eligibility / entry
Acute Myeloid Leukaemia (AML)
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Patients aged between 16-24yrs should be referred to the appropriate Teenage /
Young Adult (TYA) team and discussed at the TYA MDT.
The specialist diagnostic information required for precise disease characterisation
(including cytogenetics and molecular studies) will generally be unavailable at
the initial MDT discussion. This information should be added at a follow-up MDT
discussion 2-4 weeks later in order to accurately document:
- Diagnosis according to Revised WHO classification (2008)
- ICD10 v4 and morphology codes
- Suitable minimal residual disease (MRD) marker, if identified
- Appropriateness of allogeneic stem cell transplant in first complete
remission (for patients considered likely to be candidates for allograft, the
Cardiff BMT team should be informed as soon as possible following this
discussion)
Indications to Treat
- AML is frequently an emergency presentation and the overwhelming
majority of cases require a prompt treatment decision and initiation of
active therapy.
- In older patients AML may evolve more slowly, often from antecedent
MDS allowing a brief period of initial observation, during which fitness for
therapy can be assessed and prognostic results (including cytogenetics)
obtained.
Treatment
General
The management of all new AML cases should be discussed by the MDT. Given
the emergency presentation of many patients, initial treatment will often
necessarily need to be instituted before the first formal MDT review.
Patients should be offered clinical trial entry where possible. Typically a range of
studies will be available including intensive and non-intensive therapies, and
trials for those with newly-diagnosed or relapsed / refractory disease.
Supportive treatment:
- Patients with excessive leucocytosis and accompanying clinical evidence of
leucostasis may require emergency leukapheresis before commencing
chemotherapy. This will only apply to a small percentage of cases.
Additionally, oral hydroxycarbamide (2-3g/day) should be used for initial
cytoreduction prior to the commencement of formal chemotherapy.
- Recombinant uric oxidase (rasburicase) should be used prior to initiation
of chemotherapy in patients with WBC>100x109/l or in those with
metabolic disturbances which increase the risk of acute tumour lysis
syndrome.
- Blood and platelet transfusions should be used according to the FBC and
clinical situation (also see specific guidance for APL). Irradiated cellular
blood products should follow purine analogue-containing chemotherapy
regimens.
- Antimicrobial prophylaxis should be given according to local guidelines.
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Intensive therapy:
- Intensive chemotherapy is considered ‘standard of care’ for patients
<60yrs, as well as those >60yrs with good performance status.
- Where possible, patients should be treated within the age-appropriate
NCRI clinical trial schedule (no current trial for under 60 years although
AML19 will open during 2015; AML18 open for patients aged over 60
years suitable for intensive treatment).
- Patients who are ineligible or unwilling to participate in clinical studies
should be offered standard induction therapy including an anthracycline
and cytarabine (typically DA3+10). There is no consensus on a single best
post-remission schedule: generally patients will receive a further cycle of
DA (3+8) followed, in younger adults in whom allogeneic SCT is first
remission is considered inappropriate, by 2 cycles of consolidation with a
high dose cytarabine-containing regimen.
- Allogeneic stem cell transplant in first complete remission should be
considered in patients with adverse and intermediate-risk disease and a
suitable HLA-matched donor. It is not justified in favourable-risk patients.
- Patients identified as potential allogeneic transplant recipients should be
discussed with the BMT team in Cardiff at the earliest available
opportunity
Relapsed / Refractory AML:
- Patients failing to respond to 1-2 cycles of induction treatment are
considered ‘refractory’ and have a poor prognosis. For relapsing patients,
a longer first remission is associated with a greater chance of subsequent
treatment success.
- Carefully selected patients with relapsed / refractory disease may be
offered further intensive chemotherapy, usually with a view to allogeneic
stem cell transplantation if a second remission is attained. If available,
patients should be treated within a suitable clinical trial protocol for
relapsed patients.
- Patients unsuited to further intensive chemotherapy should be offered
less-toxic non-intensive (palliative) treatment, again within a suitable
clinical trial protocol where possible.
Non-intensive therapy:
- The majority of patients >70yrs and younger patients with significant comorbidity will receive non-intensive (palliative) chemotherapy.
- Where possible, patients should be treated within an appropriate clinical
trial. Current local trial options include the NCRI LI-1 study (randomised
comparison of low dose cytarabine with a ‘rolling programme’ of novel
non-intensive chemotherapy approaches) and RAVVA (randomised
comparison of azacitidine with or without the histone deacetylase inhibitor
vorinostat).
- Low dose cytarabine remains standard of care for patients not entering
clinical trials.
- The hypomethylating agent azacitidine may be considered in patients with
20-30% bone marrow blasts at presentation, and is NICE-approved for
this indication.
Acute Myeloid Leukaemia (AML)
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-
Patients who are not felt able to tolerate non-intensive chemotherapy
should be given best supportive care: transfusion support and
hydroxycarbamide as required to control the white cell count.
Acute Promyelocytic Leukaemia (APL):
- The presentation of APL is a haematological emergency due to the high
early mortality rate as a consequence of associated coagulopathy
- All trans-retinoic acid (ATRA) should be started as soon as the diagnosis is
suspected (45mg/m2/day in divided doses). For patients presenting to
outlying DGHs, ATRA should be commenced before patient transfer.
- FBC and coagulation screen should be checked at least twice daily during
the initial phase of treatment. The platelet count should be maintained at
>50x109/l and FFP (and/or cryoprecipitate/ fibrinogen concentrates) used
to normalise coagulation times and maintain fibrinogen level close to 2g/l.
- Diagnosis should be confirmed promptly by demonstration of the
PML/RARα fusion (initially by FISH, then confirmed by molecular studies.)
- There is no currently-open clinical trial available for patients with APL, but
the AML19 is likely to include a research question for APL patients and will
open during 2015
- Patients deemed suitable for intensive therapy should be treated with
ATRA and anthracycline-based induction and consolidation therapy (AIDA
schedule)
- Arsenic trioxide (ATO), also used with ATRA, should be considered in
patients deemed unsuitable for anthracycline-based therapy.
- Minimal residual disease assessment (see below) should be used to guide
the need for further therapy. In the event of relapse (full relapse, or
confirmed molecular relapse with rising PML/RARα transcript levels) ATO
should be used, and consolidation with autologous transplant considered.
Monitoring
- Patients receiving active therapy require close monitoring with serial blood
counts and further bone marrow aspirates to assess and monitor
remission status.
- Following conclusion of active treatment patients should be followed up
clinically and with repeated blood count evaluation.
- In APL, the value of molecular monitoring (Q-PCR to measure PML/RARα
transcript level) in order to detect relapse at an early stage and intervene
pre-emptively is established. APL patients should be offered 3-monthly
bone marrow monitoring for 2-3 years following completion of active
treatment.
- For non-APL patients, serial bone marrow examinations in remission are of
uncertain value: the use of MRD monitoring in this context is currently
being evaluated within clinical studies (AML17, and to continue within
AML19).
- AML patients receiving supportive treatment only will require
individualised monitoring depending on their transfusion and other
requirements
Discharge
- Discharge may be offered to patients who have achieved stable
longstanding complete remission (usually >5 years from completion of
active therapy).
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References
Diagnosis and management of AML in adults: recommendation from an
international expert panel, on behalf of the European LeukemiaNet. (Dohner et
al. Blood 2010; 115: 453-473)
BCSH Guidelines on the management of AML in adults. (Milligan et al. BJH 2006;
135:350-474)
WHO classification of tumours of hematopoietic and lymphoid tissues. (edited by
Swerdlow et al. 2008)
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