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Clinical Management Guideline
for Acute Myeloid Leukaemia
Document Control
Prepared by:
Approved by:
Issue date:
Review date:
Version:
Mark Drummond, Anne Parker, John Murphy
RCAG Prescribing Advisory Subgroup
December 2009
December 2011
Version 1.0
Contents
1. Initial Presentation .................................................................................3
2. Initial Management ................................................................................. 4
If APL suspected....................................................................................... 4
All AML patients........................................................................................ 4
3. Patients < 60yrs (or selected fit pts > 60yrs)........................................ 4
Prognostic Information (<60yrs)................................................................ 6
a)
Cytogenetically / molecularly determined risk group:.......................6
b)
Conventional MRC approach (from MRC AML 10 & 12 trial data):.. 6
c)
AML 17 Risk Score:......................................................................... 7
Further Management during intensive therapy ......................................... 7
Choice of Intensive Therapy ..................................................................... 8
Assessment of Response ......................................................................... 8
Definitions of Response ............................................................................ 8
Indications for Consideration of Allogeneic SCT in 1st CR: ....................... 9
Management of Refractory / Relapsed Disease Outwith Study ................ 9
a)
Refractory Disease .......................................................................... 9
b)
Management of Relapse ................................................................. 9
4. Patients > 60yrs or Frail....................................................................... 10
a)
Intensive Therapy .......................................................................... 10
b)
Non-Intensive Therapy .................................................................. 10
5. Follow Up Following Completion of Therapy..................................... 11
6. Supportive Care.................................................................................... 11
7. References & Additional Reading (Hyperlinked) ............................... 11
8. Summary Flow Chart ........................................................................... 12
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1. Initial Presentation
1. History – to include symptoms of infection, bleeding +/- bruising, occupation,
previous chemotherapy/ radiotherapy exposure, neurological symptoms, comorbidities & siblings.
2. Examination – include fundi, skin & gums for infiltration
3. Assess performance status
4. Measure height & weight
5. If patient is aged < 26 years discuss at Regional MDT & consider transfer to
Teenage Cancer Unit at BOC and discussion with teenage cancer team
including Clic Sergeant SW and Clinical Nurse Specialist (contact via
switchboard 0141 211 2000 or direct 0141 301 7616).
6. Laboratory Tests
a. FBC – manual differential & film
b. Coagulation screen – Fibrinogen, D dimers
c. U+E
d. LFT
e. Urate
f. LDH
g. G+S
h. ECG
i. CMV serostatus if potential HSCT allograft candidate (generally
<60yrs or >60yrs in AML16 trial Intensive Pathway).
j. Tissue typing if potential HSCT allograft candidate.
k. Check HIV, Hep B, Hep C status.
l. Consent for Research Blood Sample (50mls if peripheral blasts) using
Generic Consent form. Tel 0141 301 7880 to inform research team
(Paul O’Gorman) and keep in 40C overnight if required.
m. Infection screen if clinically infected including
 blood cultures,
 MSU,
 stool sample
n. Bone marrow aspirate.
o. Bone marrow trephine- only if dry tap or no particles in aspirate. Carry
out trephine roll in this situation, put part of sample into cytogenetics
medium and agitate, plus part of sample into formalin.
p. Cytogenetics – preferably on bone marrow but PB can be used. If no
aspirate available and no/ low circulating blasts send trephine sample
in media.
q. Immunophenotyping (including sample to GGH for central markers to
establish baseline leukaemia-associated phenotype / MRD marker in
case of subsequent transplant).
r. Molecular biology sample (bone marrow). NB cytogenetics fails to
detect 15% of patients who would fall into the good risk group.
s. LP if neurological symptoms and imaging normal– flow cytometry,
cytospin, MC+S, glucose, protein. Needs to get to flow lab within 4
hours.
7. Imaging
a. CXR
b. CT/ MR scan if neurological symptoms
8. Discuss patient at MDT (Local or Regional)
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2. Initial Management
If APL suspected
1. Correct coagulation aggressively – maintain fibrinogen >1.0g/dl with
cryoprecipitate, and plts > 50 x109/l, normalise PT & PTT with FFP. This
should happen even if not clinically haemorrhagic.
2. Start ATRA 45mg/m2 immediately (including presentations out of hours) if
suspicious of diagnosis & monitor for ATRA syndrome.
3. If WCC >10 Idarubicin doses should be brought forward by one day in
patients presenting with WBC>10, with first dose given within a few hours of
starting ATRA. Consider giving prophylactic dexamethasone 10mg IV 12hourly, although evidence lacking for this prophylactic approach.
4. If ATRA syndrome suspected clinically (unexplained fever, weight gain,
respiratory distress, pulmonary infiltrates, pleural or pericardial effusion) start
dexamethasone 10mg i.v. 12 hourly (to continue for a minimum of 3 days and
until disappearance of symptoms & signs). ATRA should be temporarily
interrupted only in severe cases.
5. Arrange urgent cytogenetics: telephone 0141 201 6945 to alert lab to urgent
sample. If sample is received before 12pm FISH can be performed on the
same day.
All AML patients
1. Treat any infection according to local antibiotic policy for the
immunocompromised
2. Start – allopurinol, acyclovir 400mg bd, azole prophylaxis (withhold if
myelotarg being considered), ciprofloxacin 500mg bd if does not require iv
antibiotics
3. Correct coagulation abnormalities – MUST be done aggressively if APL
suspected (see above)
4. Monitor K+ levels
5. Rehydrate as required, maintain good diuresis with iv fluids if necessary
6. Assess re requirement for leucopheresis – confusion, retinal changes,
headache. Do NOT leucopherese if APL suspected
7. Correct Hb if clinically indicated UNLESS signs of leucostasis. If WCC high eg
>100 do not transfuse unless patient is symptomatic and then only slowly.
Use CMV neg products until CMV status known in HSCT potential candidates
8. Discuss any clinical trials available eg AML 17, AML 16 and conventional
chemotherapy. Allow patient time to read PIS.
9. Consent for agreed therapy
10. It is important to commence definitive chemotherapy promptly in young
patients (<60yrs) as outcomes are better if treatment is started within 5 days
of diagnosis 1.
3. Patients < 60yrs (or selected fit pts > 60yrs)
11. Assess re risk of tumour lysis syndrome – if LDH >2xULN, WCC >50, Urate
>0.5 consider rasburicase (particularly if monoblastic). Daily U+E, Ca2+, PO4,
urate until WCC <10. NB if already receiving rasburicase urate will be falsely
low.
12. Echo if previous history of cardiac problems or previous chemotherapy
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13. Fertility counselling re loss of fertility for premenopausal women and men,
counselling re risk of partners pregnancy for men whilst on chemotherapy.
Discuss sperm storage if deemed appropriate.
14. Tissue typing sample + VUD form if potential allograft candidate
a. This includes patients >60 entering AML16 intensive arm
a. Details of siblings to Clinical Apheresis Unit
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Prognostic Information (<60yrs)
This can be determined in 3 different ways:
a) Cytogenetically / molecularly determined risk group:
Risk Group
Karyotype marker*
Good risk
t(15;17)
t(8;21)
inv(16)
t(16;16)
Intermediate risk
Poor risk
Normal cytogenetics
Abnormalities
NOT
included in good or poor
risk groups
>2 abnormalities
t(9;22)
-5
-7
5q7q11q23 except for t(9;11)
t(6;9)
inv(3)
Molecular marker
PML/RARA
AML1/ETO
CBFB/MYH11
Normal cytogenetics with
NPM1 or CEBPA (& Flt-3
negative).
All these patients require
molecular analysis (Flt-3,
NPM1, CEBPA).
Normal cytogenetics with
Flt3 ITD
*In the event of a failed marrow aspirate it is vital that either a trephine or PB
sample (if adequate circulating blasts) is sent to cytogenetics lab. If
metaphase preps fail it is necessary to get as full a FISH & molecular profile
as possible. Suggest discuss directly with relevant lab in light of
morphological / clinical features to guide testing. NB molecular markers for
t(8;21) and inv(16) are NOT done as part of AML17
b) Conventional MRC approach (from MRC AML 10 & 12 trial
data):
Good risk: Any patient with favourable genetic abnormalities – t(8;21),
inv(16), t(15;17),irrespective of other genetic abnormalities or marrow status
after Course 1.
Standard: Any patient not in either good or poor risk groups.
Poor risk: Any patient with more than 15% blasts* in the bone marrow after
Course 1, or with adverse genetic abnormalities: -5, -7, del(5q), abn (3q) or
complex (5 or more abnormalities) – and without favourable genetic
abnormalities.
Risk Group
Good
Standard
Poor
5 Year Survival
76%
48%
21%
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5 Year Relapse rate
25%
52%
73%
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NB: *In AML12, patients with >15% blasts after cycle 1 have a poor outlook (5
year survival of 26%), while ‘partial remitters’ (5-15% blasts) do only slightly
worse than complete remitters (5 year survivals of 44% and 56% respectively).
c) AML 17 Risk Score:
See associated Excel file for calculation. Developed from AML12 data, tested
prospectively on AML 15 cohort as below:
Pending further clarification from trial data it is reasonable to manage patients as per
risk group determined by any or all of the above methods.
Further Management during intensive therapy
1. In APL or cases with propensity for fibrinolysis / DIC (eg monocytic lineage)
twice daily coagulation screen to include fibrinogen and D Dimers until
WCC<1.0 or coagulation returned to normal whichever is achieved last.
2. In patients with monocytic lineage leukaemia and high WCC ie. >50 consider
giving Dexamethasone 8mg daily to reduce risk of pneumonitis.
3. Regular FBC, U&E, LFT to assess requirement for blood products (see local
policies), renal function and drug toxicity
4. If the patient develops a pyrexia >380C they should be treated according to
local policies for neutropenic sepsis
5. Irradiated blood products are ONLY required for patients who have been
given CLOFARABINE or FLUDARABINE
6. CMV negative blood products are ONLY required if CMV neg AND candidate
for HSCT (note that all CMV negative blood products are now irradiated)
7. G-CSF should not be used routinely, but may be commenced in patients who
are slow to recover or have significant infections. NB this may make BM
interpretation at the time of count recovery more difficult
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Choice of Intensive Therapy
See flow chart for treatment summary. Ideally pts suitable for intensive therapy
should be entered into the age appropriate clinical trial (for those >60yrs see below).
The standard approach outwith study is DA 3+10 followed by DA 3+8 (i.e. 2 induction
cycles) followed by two cycles of HD ARA-C (1.5g/m2). The latter appears to be at
least as effective as the conventional MACE / MiDAC approach (AML 15 data,
unpublished) and is more straightforward (although the latter regimes are an
acceptable alternative).
Assessment of Response
1. This should be done once the patient has
 neutrophil count> 0.5 x 109/l
 21 days from the end of chemotherapy without count recovery. If a
hypoplastic BM this should be repeated every 7-10 days until recovers
 circulating blasts are identified in the peripheral blood
2. This should be done by
 Bone marrow aspirate morphology (trephine is NOT required unless
dry tap)
 Cytogenetics ONLY if previously abnormal
 Molecular studies ONLY if previously abnormal
 Immunophenotyping (FU sample to GGH if sent at diagnosis)
3. This only requires to be repeated after subsequent courses if
 they are more than 28 days from the end of chemotherapy without
count recovery
 circulating blasts are identified in the peripheral blood
 Cytogenetics ONLY if abnormal after previous course
 Molecular studies have MRD marker
 Immunophenotyping ONLY if MRD marker
4. After completion of cycle 1 assign risk group as detailed above.
Definitions of Response
1. Complete Remission (CR): The bone marrow is regenerating normal
haemopoietic cells and contains <5% blast cells by morphology in an aspirate
sample with at least 200 nucleated cells. Additionally there is an absolute
neutrophil count of more than 1.0 x 109/l and platelet count of at least 100 x
109/l.
2. Complete Remission with incomplete recovery (CRi): Fulfilling all criteria
for CR except for residual neutropenia (<1.0 x 109/l) or thrombocytopenia
(<100 x 109/l).
3. Partial Remission (PR): The bone marrow is regenerating normal
haemopoietic cells and blast count has reduced by at least half, to a value
between 5 and 25% leukaemic cells.
4. Resistant Disease (RD): The bone marrow shows persistent AML, and
patient survives at least 7 days beyond end of course.
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Indications for Consideration of Allogeneic SCT in 1st CR outwith
trial:

Age >35 yrs & preceding MDS or Poor Risk

Age < 35 yrs, either Standard or Poor Risk (not good risk patients) who are
NPM1 negative. This is an evolving indication: please discuss individual
patients with BMTU.
Management of Refractory / Relapsed Disease Outwith Study
a) Refractory Disease
Patients who do not respond to induction therapy i.e. fail to have a blast count <15%
should be considered for alloSCT. Prior remission induction should be attempted with
alternative regimen such as FLAG-Ida.
b) Management of Relapse
Such patients should be discussed at relevant MDT and clinical trial considered if
available. It is important to consider relevant prognostic factors before attempting
salvage therapy in this setting (see below). Early relapses (< 6 months) do
particularly poorly. 3 main factors are relevant:
1. Duration of first remission*
2. Patient age
3. Cytogenetics at the time of original presentation
The decision to treat the patient with relapsed disease should take into account
prognostic factors. The HOVON prognostic index2 (see table and subgroups below)
can be used to define outcome risk and should be used to aid decision making.
Three prognostic sub-groups can be defined. Patients with prognostic scores of 1014 may be considered for palliation or experimental therapy.
Group A: Overall survival 70% at 1 year and 46% at 5 years Score 1-6
Group B: Overall survival 49% at 1 year and 18% at 5 years Score 7-9
Group C Overall survival of 16% at 1 year and 4% at 5 years Score 10-14
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__________________________________________________________________
HOVON Prognostic Factor Points
__________________________________________________________________
Relapse-free interval from first complete remission, months
>18 months
0
7-18 months
3
6 months
5
Cytogenetics at diagnosis
t(16;16) or inv(16)*
0
t(8;21)*
3
Other‡
5
Age at first relapse
35 years
0
36-45 years
1
> 45 years
2
Stem-cell transplantation before first relapse
No SCT
0
Previous SCT (allogeneic or autologous)
2
__________________________________________________________________
Although the optimal salvage regimen for patients with relapsed disease is unknown,
most regimens rely upon high-dose cytarabine in combination with other
chemotherapeutic agents e.g. FLAG or FLAG-Ida, or as single agent.
Patients deemed suitable for intensive salvage therapy should be discussed
with the Transplantation team.
* In patients experiencing late relapse (> 2years from 1st CR) consolidation with an
autograft can be considered in place of allogeneic SCT.
4. Patients > 60yrs or Frail
a) Intensive Therapy
The decision to treat with intensive (curative) therapy or palliate is a key one and is
made on an individual basis. In general pts over the age of 60 may be considered for
intensive therapy if they have a good PS (ECOG 0-2): if a patient is clearly a
candidate for intensive therapy it is reasonable to start induction treatment in the
absence of cytogenetic data. Ideally treatment should be on a clinical trial (eg
intensive arm of AML 16 or AML17); the optimal induction therapy for these patients
remains unknown (DA 3+7 is standard). Local experience is that FLAG is well
tolerated in this setting but there is no evidence that it is superior. 2-3 cycles of
therapy are likely to be optimum. For poor risk pts consider RIC if remission is
achieved. Management of such patients should largely be as described for < 60 yrs
above.
b) Non-Intensive Therapy
This is appropriate for frail (ECOG > 2) or elderly patients. Where possible enter
patients into AML 16 non-intensive arm. Standard treatment is LD ARA C, 20mg bd
for 10 days. The CR rate is 18% with this therapy, although pts who have poor risk
cytogenetics are unlikely to respond and may be considered for supportive care (+/hydroxycarbamide) only (AML 14 results3). It is therefore appropriate to delay
definitive management while cytogenetics are awaited.
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5. Follow Up After Completion of Therapy
1. Stop prophylactic medication unless previous fludarabine/ clofarabine. In this
circumstance it seems reasonable to continue PCP prophylaxis for 6 months.
2. Regular FBC
3. Consider venesection programme after 4-6 months if Hb in normal range, and
if pt treated with curative intent
 If ferritin >1000 and &/or Transferrin Saturation > 50%.
 Ferritin >1000 and deranged LFTs
4. Review
 1 monthly for 6 months post therapy
 2 monthly until 1 year post therapy
 3 - 4 monthly until 3 years post therapy
 6 monthly to 4 years and then consider annually
 Consider referral to late effects clinic (if available) from 4 years post
therapy
6. Supportive Care
As a minimum the following policies should be available to the clinical care
team






Blood product transfusion
Antimicrobial prophylaxis and treatment
Care of Neutropenic sepsis
Tumour lysis
Mouth care
Long term indwelling catheter care
7. References & Additional Reading (Hyperlinked)








Guidelines on management of AML (BCSH)
Practical Guidelines for Oncology – Acute myeloid leukaemia (NCCN)
Management of acute promyelocytic leukemia: recommendations from an
expert panel on behalf of the European LeukemiaNet. Sanz, M.A. et al (2009)
Blood, 113, 1875-1891.
AML 17 website
AML 16 website
Guidelines on the management of invasive fungal infection during therapy for
haematological malignancy (BCSH)
Guidelines On The Insertion And Management Of Central Venous Access
Devices In Adults (BCSH)
Obtaining Consent for Chemotherapy (BCSH)
1.
Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis to treatment
initiation predicts survival in younger, but not older, acute myeloid leukemia patients.
Blood. 2009;113:28-36.
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2.
Breems DA, Van Putten WLJ, Huijgens PC, et al. Prognostic Index for Adult
Patients With Acute Myeloid Leukemia in First Relapse. J Clin Oncol. 2005;23:19691978.
3.
Alan KB, Donald M, Archie GP, et al. A comparison of low-dose cytarabine
and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and
high-risk myelodysplastic syndrome in patients not considered fit for intensive
treatment. Cancer. 2007;109:1114-1124.
8. Summary Flow Chart
See over:
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