Guidelines on the management of acute myeloid leukaemia in adults guideline

Transcription

guideline
Guidelines on the management of acute myeloid leukaemia in
adults
British Committee for Standards in Haematology: D. W. Milligan, D. Grimwade, J. O. Cullis, L. Bond, D. Swirsky, C. Craddock,
J. Kell, J. Homewood, K. Campbell, S. McGinley, K. Wheatley and G. Jackson
British Society for Haematology, London, UK
Keywords: acute myeloid leukaemia, guidelines, transplantation, pregnancy, acute promyelocytic leukaemia.
Key recommendations
Diagnosis
1 Bone marrow aspirate and trephine biopsy unless the
peripheral blast count is high.
2 Immunophenotyping [CD3, CD7, CD13, CD14, CD33,
CD34, CD64, CD117 and cytoplasmic myeloperoxidase
(MPO)].
3 Cytochemistry (MPO or Sudan Black, combined esterase). Can be omitted if four-colour flow cytometry is
available.
4 Cytogenetics [with reverse-transcription polymerase
chain reaction (RT-PCR) for AML 1-ETO and CBFBMYH11 in non-acute promyelocytic leukaemia (APL) and
promyelocytic leukaemia (PML) and retinoic acid receptor-alpha (RARA) in suspected APL; fluorescent in situ
hybridisation (FISH) in selected cases].
Treatment
1 Patients should be treated by a multidisciplinary team
that is experienced in the management of acute myeloid
leukaemia (AML), serving a population base of 0Æ5 m and
intensively treating five or more patients per annum
(recommendation grade C; evidence level IV).
2 All eligible patients up to age 60 years (or older than
60 years but able to receive intensive treatment) with de
novo or secondary AML should be asked to participate in
the current National Cancer Research Institute (NCRI)
Correspondence: BCSH Secretary, British Society for Haematology,
100 White Lion Street, London N1 9PF, UK.
study, at present AML 15 (http://www.aml15.bham.ac.uk/
trial/index.htm) (recommendation grade C; evidence level
IV).
3 Patients over 60 years old who are unable to tolerate
remission induction chemotherapy, but are suitable for
non-intensive therapy, should be asked to participate in
the current NCRI study, at present AML 16 (http://
www.aml16.bham.ac.uk) (recommendation grade C; evidence level IV).
4 Patients opting for non-intensive chemotherapy who are
not entered into clinical trials should be offered treatment with low-dose cytarabine (grade A; evidence level
Ib). Patients not able to tolerate chemotherapy should be
given best supportive care: transfusion support and
hydroxycarbamide to control the white cell count
(recommendation grade A; evidence level Ib).
Acute promyelocytic leukaemia
1 All trans-retinoic acid (ATRA) should be started as soon
as the diagnosis is suspected (grade A; evidence level Ib).
2 Leucopheresis should be avoided in patients a high white
cell count (grade B; evidence level III).
3 The platelet count should be maintained at >50 · 109/l,
together with fresh frozen plasma (FFP) and cryoprecipitate to normalise the activated partial thromboplastin
time and fibrinogen levels (grade B; evidence level IIb).
4 Differentiation syndrome should be treated promptly
with dexamethasone 10 mg twice daily iv, and ATRA
stopped temporarily until the symptoms resolve (grade C;
evidence level IV).
5 Diagnostic work-up should include documentation of
underlying PML–RARA fusion (grade B; evidence level IIa).
6 Patients with PML–RARA-positive APL, deemed suitable
for intensive therapy, should be treated with concurrent
ATRA and anthracycline-based chemotherapy for induction, followed by anthracycline-based consolidation therapy (grade A; evidence level 1b).
7 Patients should undergo molecular monitoring after
treatment to guide further therapy (grade B; evidence
level IIa).
E-mail: bcsh@b-s-h.org.uk
ª 2006 The Authors
doi:10.1111/j.1365-2141.2006.06314.x Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474
Guideline
8 For relapsed disease, ATRA should not be used as single
agent therapy due to the significant possibility of
acquired secondary resistance and arsenic trioxide
(ATO) should only be used in patients with confirmed
PML–RARA-positive APL. Treatment of relapse, with
respect to use of autologous or allogeneic transplantation
as consolidation should be guided by minimal residual
disease (MRD) assessment (grade B; evidence level IIa).
two-thirds of all cases occur in those aged over 60 years. The
management of AML represents a significant clinical challenge. These guidelines give an up-to-date overview of
evidence-based and expert opinion-based optimum management of AML in the UK. These guidelines are abbreviated
from the full version that is available on http://www.bcshguidelines.com.
1. Methods
Pregnancy
1 AML in pregnancy should be managed jointly between
the haematologist and the obstetrician with full involvement of the mother (grade B; evidence level III).
2 Chemotherapy in the first trimester is associated with a
high risk of fetal malformation and should be avoided if
possible. The opportunity to terminate the pregnancy
should be discussed with the mother. If termination is
refused and the mother’s life is at risk, chemotherapy
should be started (grade B; evidence level III).
3 Chemotherapy in the second and third trimesters is
associated with an increased risk of abortion and
premature delivery as well as low birth weight babies.
Consideration should be given to early induction of
labour between cycles of chemotherapy (grade B; evidence level III).
The PubMed, Cochrane and Medline databases in the English
language were searched using the key words ‘acute myeloid
leukaemia/leukemia’, ‘acute promyelocytic leukaemia/leukemia’, ‘stem cell transplantation’ with subheadings ‘anthracycline’, ‘pregnancy’, ‘disseminated intravascular coagulation’
(DIC), ‘growth factors’ and ‘quinolones’ from 1983 to 2005.
The authors have substantial experience in their field.
Stakeholder involvement was secured through patient representation from the Leukaemia Research Fund and the
Leukaemia Care Society. The recommendations were agreed
using the Agree instrument (http://www.agreecollaboration.org) and were further reviewed by a Sounding Board of
100 haematologists representing adult practice in both
teaching and district hospitals. The levels of evidence used
were those of the US Agency for Health Care Policy and
Research (Appendix 1)
Transplantation
2. Classification of AML
1 Allogeneic transplantation should be offered to patients
with high-risk AML in first remission who have a human
leucocyte antigen (HLA) identical donor, although it is
accepted that only a minority of patients will benefit
(recommendation grade B; evidence level III). Standard
risk patients may be offered allo-transplantation as part
of a clinical trial (recommendation grade B; evidence
level III).
2 HLA-matched sibling allogeneic transplantation may be
the treatment of choice for younger patients who are in
second remission (recommendation grade B; evidence
level III).
3 Older patients with high-risk disease or beyond first
remission may be offered a reduced-intensity conditioned
transplant but this should be in the context of a clinical
trial (recommendation grade C; evidence level IV).
4 Younger high-risk patients or those beyond first remission may be considered for a haplo-identical transplant
but this should be in the context of a clinical trial
5 The role of autografting in the management of AML is
contentious. Autografting should only be carried out in a
clinical trial (recommendation grade A; evidence level Ia).
The World Health Organisation (WHO) system for the
diagnosis and classification of AML (Jaffe et al, 2001) (Table I)
supersedes the modified French–American–British (FAB)
classification (Bennett et al, 1985a,b, 1991). This guideline
proposes that the WHO system is adopted for the diagnosis
and classification of AML. It differs significantly from the FAB
system as follows.
Acute myeloid leukaemia has an overall incidence of 3Æ4
per 100 000. The disease is more common in the elderly and
• Reducing the marrow blast percentage separating myelodysplastic syndrome (MDS) from AML from 30% to 20%.
• Taking account of preceding MDS or myeloproliferative
disorders.
• Creating categories defined by certain non-random cytogenetic abnormalities or the equivalent molecular genetic
abnormality (t(8;21), t(15;17), inv(16)/t(16;16) and
t(v;11q23).
• Taking account of multilineage dysplasia with or without a
preceding marrow disorder.
• Recognising previous cytotoxic therapy as part of the
classification.
• Introducing new morphological subtypes.
The laboratory diagnosis of AML has been recently reviewed
(Swirsky & Richards, 2001).
Practical issues regarding the diagnosis of AML include the
following.
ª 2006 The Authors
Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474
451
Guideline
Table I. World Health Organisation classification of acute myeloid
leukaemia (AML).
1.
AML with recurrent translocations
AML with t(8;21)(q22;q22)
AML with t(15;17)(q22;q21) (M3, M3V)
AML with inv(16)(p13q22) or t(16;16)(p13;q22) (M4Eo)
AML with t(v:11q23)
2.
AML with multilineage dysplasia
AML with prior myelodysplastic syndrome
AML without prior myelodysplastic syndrome
3.
AML therapy-related
Alkylating agent-related
Epipodophyllotoxin-related
4. Other
AML not otherwise categorised (FAB equivalent in parentheses)
AML minimally differentiated (M0)
AML without maturation (M1)
AML with maturation (M2)
Acute myelomonocytic leukaemia (M4)
Acute monocytic leukaemia (M5)
Acute erythroid leukaemia (M6)
Acute megakaryocytic leukaemia (M7)
Acute basophilic leukaemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
• All patients should have a marrow aspirate and trephine
biopsy. This may be omitted where the peripheral blast
count is high and the patient is for palliative treatment only,
or when APL is suspected. The trephine is required to
identify fibrosis and may reveal multilineage dysplasia
where the aspirate is inadequate. Acute panmyelosis with
marrow fibrosis is a trephine biopsy diagnosis, requiring
immunohistochemistry with antibodies identifying CD34,
MPO, glycophorin and megakaryocyte antigens (CD61 or
factor VIII) to identify and quantify the blast percentage
and multilineage involvement.
• Morphological categorisation requires a Romanowsky stain,
MPO or Sudan black B stain, and a combined esterase stain.
Multilineage dysplasia is defined as ‡50% dysplastic cells in
two of the erythroid, megakaryocytic and granulocytic/
monocytic lineages. Cytochemistry is not essential if fourcolour flow cytometry and estimation of cytoplasmic MPO
is available.
• Immunophenotyping is essential to identify AML cases that
are negative for cytochemical MPO, e.g. AML minimally
differentiated (FAB M0) and megakaryocytic leukaemia
(FAB M7). Both surface and intracellular antigens should be
studied. The absence of the lymphoid-specific antigens
cCD3 and cCD79a should be confirmed. Immunophenotyping of whole lysed marrow samples gives an objective
quantification of the blast percentage based on CD45/side
scatter (ssc), CD34/ssc or CD117/ssc characteristics. Com452
•
•
•
•
plex multicolour phenotyping patterns also correlate with
the common balanced translocations (Orfao et al, 1999;
Ferrara & Del Vecchio, 2002). Immunophenotyping should
utilise a minimum of two-colour flow cytometry. Multicolour flow cytometry correlates well with morphological
blast characterisation.
All patients should have conventional cytogenetics performed to identify favourable and unfavourable prognostic
abnormalities (Grimwade et al, 1998).
All patients who are suitable for intensive chemotherapy
should be tested for the favourable translocations by RTPCR as a few of these patients have normal cytogenetics
(Langabeer et al, 1997a,b). Cases testing positive in the
absence of the associated cytogenetic lesion should be
subject to confirmation by FISH or RT-PCR performed
independently. Patients suitable for intensive chemotherapy
should be tested for FLT3 internal tandem duplication
(ITD), predictive for poor outcome (Kottaridis et al, 2001),
although it remains uncertain whether alteration of the
treatment strategy in the light of this knowledge would
improve the outlook.
If FISH is not immediately available, patients with suspected
APL should have the diagnosis rapidly confirmed by a slide
immunofluorescence test for the characteristic microparticulate nuclear promyelocytic leukaemia (PML) protein
pattern of an underlying PML–RARA fusion (Falini et al,
1997; O’Connor et al, 1997). In doubtful cases, ATRA
should be commenced until a definitive result is available.
Patients with suspected acute basophilic leukaemia should
have this lineage confirmed by a toluidine blue stain.
Minimum laboratory requirements for the
diagnosis of AML
• Bone marrow aspirate and trephine biopsy unless the
peripheral blast count is high.
• Immunophenotyping (CD3, CD7, CD13, CD14, CD33,
CD34, CD64, CD117 and cytoplasmic MPO) and HLA-DR.
• Cytochemistry (MPO or Sudan Black, combined esterase).
Can be omitted if four-colour flow cytometry is available.
• Cytogenetics (with RT-PCR for AML 1-ETO and CBFBMYH11 in non-APL and PML–RARA in suspected APL;
FISH in selected cases).
3. Prognostic factors
Significant progress has been made in predicting the outcome
of patients with AML. A number of factors readily identifiable
after presentation can be used to predict the risk of disease
recurrence. The most important are age, karyotype, FMS-like
receptor tyrosine kinase (FLT3) status and response to
induction chemotherapy. Cytogenetic examination at diagnosis allows patients to be stratified into three groups with relapse
risks varying from 35% to 76% (Table II). Recent data
demonstrate that length mutations leading to constitutive
ª 2006 The Authors
Guideline
Table II. Use of risk stratification to determine consolidation therapy.
Good risk
Standard
Poor 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
Any patient not in either good or poor risk
groups
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),
t(9;22) or complex (five or more abnormalities)
– and without favourable genetic abnormalities
From the results of the MRC AML 10 and 12 trials, the MRC have
defined the following risk groups (Grimwade et al, 1998, 2001).
activation of FLT3, present in 25–30% of all patients with
AML, predict an increased risk of relapse across all cytogenetic
subgroups (Kottaridis et al, 2001). Over the last few years, a
number of other molecular markers have emerged that
distinguish subgroups of patients with cytogenetically ‘standard-risk’ AML with differing risk of relapse. In particular,
mutations in the gene encoding nucleophosmin (NPM1) occur
in approximately a third of AML cases, including over half of
those with normal karyotype (Falini et al, 2005); while
mutations in the gene encoding the transcription factor
CCAAT/enhancer-binding protein-a (CEBPA) are found in
approximately 10% of cases (Preudhomme et al, 2002). Recent
studies have shown that in the absence of co-existing FLT-ITD,
NPM1 and CEBPA mutations predict a relatively favourable
outcome in standard risk AML (Preudhomme et al, 2002;
Fro¨hling et al, 2004; Do¨hner et al, 2005; Schnittger et al, 2005;
Verhaak et al, 2005). Whereas, presence of partial tandem
duplications of MLL, identified in approximately 3% of AML,
is associated with a poorer prognosis (Schnittger et al, 2000;
Do¨hner et al, 2002). Adverse outcome has also been associated
with overexpression of a number of genes including WT1,
BAALC, EVI1 and ERG (Bergmann et al, 1997; Barjesteh van
Waalwijk van Doorn-Khosravani et al, 2003; Marcucci et al,
2005; Baldus et al, 2006). Work is currently in progress to
establish which markers are primary and secondary lesions in
AML and to determine which provide the most powerful
independent prognostic factors, forming the basis for improved risk stratification in the context of clinical trials.
Moreover, there is increasing evidence that monitoring for
MRD provides an independent prognostic factor in AML;
indeed in APL, quantification of PML–RARA transcript
numbers by real-time PCR has been shown to reliably identify
the subgroup of patients who would relapse in the absence of
additional therapy (reviewed in Grimwade & Lo Coco, 2002;
Goulden et al, 2006). Age remains one of the strongest adverse
prognostic factors in AML, partly reflecting the higher
proportion of cases with adverse cytogenetics and/or overexpression of the MDR1 gene encoding the drug efflux pump
p-glycoprotein (Leith et al, 1999), presenting white blood cell
count, and a history of antecedent myelodysplasia (Wheatley
et al, 1999).
4. Appropriate setting for the management of
AML
The British Committee for Standards in Haematology (BCSH)
has produced guidelines for the minimum standards for the
treatment of patients with haematological malignancy (Whittaker et al, 1995; Table III). Recent guidance from the National
Institute for Clinical Excellence has made recommendations
for the clinical facilities that should be available for the
management of patients with haematological malignancy
(http://www.nice.org). The recommendations are that patients
should be managed by a multidisciplinary team (Table IV)
serving a population of 500 000 and induction therapy should
only be carried out in centres treating at least five patients per
annum with induction chemotherapy with curative intent.
Table III. The British Committee for Standards in Haematology
Guidance on the provision of facilities for the care of adult patients
with haematological malignancies (Whittaker et al, 1995).
Level 1
Level 2
Level 3
Level 4
Hospitals providing conventional chemotherapy and
other forms of outpatient treatment, using dose levels
that would not be expected to produce prolonged
neutropenia
Facilities for remission induction in patients with acute
leukaemia, using standard intensive chemotherapy
regimens. This level of facility is also required to treat
patients with aggressive lymphoma
Facilities for autologous transplantation, not requiring
total body irradiation
Centres with expertise in both allogeneic and autologous transplantation
Table IV. Haemato-Oncology Multidisciplinary Team recommended
by the National Institute for Clinical Excellence improving outcomes
guidance.
Core team members
Consultant haematologist(s)
Central nervous system in haematology
Ward sister
Consultant haematopathologist
Palliative care specialist (consultant or nurse)
Consultant microbiologist
Oncology pharmacist
Multidisciplinary team coordinator
Extended team members
Social worker
Clinical psychologist
Consultant radiologist
Data manager
Clinical oncologist (if a level 4 transplant centre)
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453
Guideline
4.1. Patient support
Patients with AML require considerable support. Excellent
written information concerning the disease and its management should be readily available, e.g. information provided by
CancerBACUP (http://www.cancerbacup.org.uk), the Leukaemia Research Fund (http://www.lrf.org.uk) and the Leukaemia
Care Society (http://www.leukaemiacare.org). Translators
should be provided when required. Employment/financial
issues may be a problem and social worker support should be
available. Palliative care input should be provided as part of the
multidisciplinary team.
life-threatening consequence of tumour lysis syndrome and
may require emergency therapy and dialysis.
There is evidence that recombinant urate oxidase (rasburicase) can rapidly reverse hyperuricaemia and it may benefit
some patients with hyperleucocytosis at presentation, patients
with renal impairment or patients who are developing ATLS
(Goldman et al, 2001).
Recommendation
Rasburicase should be used with chemotherapy in patients
with hyperleucocytosis at risk of ATLS (recommendation
grade B; evidence level IIb).
5. Treatment of AML
5.1. General measures and supportive care
There has been a steady improvement in survival for patients
entering the UK Medical Research Council (MRC) trials over
the last 30 years without a major chemotherapeutic breakthrough, suggesting that these improvements have occurred
because of better supportive care and increased treatment
intensity (Burnett, 2002). Current studies show that nearly half
of all patients aged between 15 and 60 years will survive to
5 years of which many will be cured (Mayer et al, 1994; Hann
et al, 1997).
The most important threats to the patient come from
complications of the disease at presentation, myelosuppression
as a consequence of both the disease process and remission
induction chemotherapy and from resistant/relapsing disease.
5.1.1. Hyperleucocytosis. A high white cell count at
presentation is a poor prognostic factor (Powles et al, 2003).
Hyperleucocytosis is generally defined as an initial white cell
count/blast count of more than 100 · 109/l. Around 14% of
patients present with hyperleucocytosis and are at a greater risk
of early death (15% vs. 5Æ4%) when compared with patients
presenting with a white cell count of <100 (Powles et al, 2003).
There are no trials that prove leucopheresis is of benefit in
these patients but this procedure is generally safe and should
be considered in patients with AML presenting with
symptomatic hyperleucocytosis (Powles et al, 2003).
However, this procedure is contraindicated in patients with
suspected APL, as it can exacerbate the coagulopathy with fatal
consequences (Vahdat et al, 1994).
5.1.2. Prevention of tumour lysis syndrome. Acute tumour lysis
syndrome (ATLS) may be a consequence of initial therapy and
is more likely in patients presenting with hyperleucocytosis.
ATLS describes a collection of metabolic abnormalities that
include hyperuricaemia, hyperphosphataemia, hyperkalaemia,
hypocalcaemia and renal failure.
Preventative measures include hydration and allopurinol.
The urea and electrolytes should be monitored together with
the urine output. A rising potassium level is the most serious
454
5.1.3. Red cell transfusion support. There is no good evidence to
support a particular red cell transfusion policy in AML. All
patients in whom allogeneic transplantation may be considered
should receive cytomegalovirus (CMV)-negative products
until their CMV status is known. Patients treated with
fludarabine-based chemotherapeutic regimens should be
supported with irradiated blood products (Voak et al, 1996).
Iron overload may occur and it is important to assess iron
load in patients who have completed therapy. Some patients
with iron overload may benefit from venesection. Where
possible, chlorpheniramine should be used to control allergic
reactions and treatment with hydrocortisone should be avoided.
5.1.4. Platelet support. Platelet transfusions are given to
support thrombocytopenia with a transfusion threshold of
10 · 109/l unless there are additional risk factors. Risk factors
include sepsis, concurrent use of antibiotics or other
abnormalities of haemostasis (Rebulla et al, 1997; Murphy
et al, 2003). The presence of a coagulopathy increases the
likelihood of haemorrhage at any platelet count. The platelet
count should be kept at >20 · 109/l in patients who are
haemorrhagic (British Committee for Standards in
Haematology, Blood Transfusion Task Force, 2003) or
>50 · 109/l in patients with APL who are bleeding (Falanga
& Rickles, 2003). In the UK practice platelet (and blood)
tranfusions are routinely leucodepleted and this may reduce
the risk of alloimmunisation and a poor response to platelet
transfusion. Patients who are alloimmunised maybe befit from
HLA-matched platelet support. Tranexamic acid may be useful
for local bleeding, e.g. oral haemorrhage, but is contraindicated
in the presence of haematuria because of the possibility of
ureteric clot formation.
5.1.5. Granulocyte transfusions. There is no randomised
controlled trial evidence to support the routine use of
granulocyte transfusions following AML chemotherapy and
they are not recommended. There is anecdotal evidence that
pooled buffy coat or apheresed granulocytes may be used to
treat localised unresolving infection in neutropenic patients
(Kerr et al, 2003).
ª 2006 The Authors
Guideline
5.1.6. Antibiotic and anti-infective therapy. Patients with acute
leukaemia are prone to bacterial and fungal infections as a
result of prolonged neutropenia secondary to marrow
infiltration and/or the effects of chemotherapy.
Careful attention to personal hygiene and dental care are
important. The BCSH guidelines on facilities for haematological patients recommend that patients with AML are looked
after in units with at least level-2 facilities with dedicated
haematological beds and with single cubicles with en suite
facilities available (Whittaker et al, 1995).
Careful attention to hand washing and decontamination
before contact with the patient is mandatory for all healthcare
workers and visitors.
Flowers and plants are a potential source of fungal spores
and Pseudomonas and should be removed from the unit.
The development of infection may be accompanied by
marked clinical signs or by none at all. A temperature of over
38C may indicate a systemic infection but infection may be
associated with hypothermia, declining mental status, myalgia
or increasing lethargy.
The patient should be examined regularly, including the
mouth/throat for perioral/periodontal infection and to exclude
thrush, the skin for focal infections or for septic emboli and
intravenous catheter sites including the Hickman catheter.
Particular attention should be paid to the perineum for signs
of occult infection. Vaginal and rectal examination should only
be performed after careful consideration. Chest X-rays should
be performed regularly and high-resolution computerised
tomography (CT) scans of the chest should be considered to
exclude pulmonary aspergillosis and other infections. X-rays or
CT scans of the sinuses may help to exclude occult fungal
infections.
5.1.7. Bacterial infection. Severe sepsis may occur during
therapy and the prompt treatment of severe life-threatening
bacterial, fungal and viral infections is critical in patients
with AML. Patients should be aware of their susceptibility to
infection and the importance of presenting early to hospital.
All patients should have emergency contact details. Patients
with a central venous catheter are at risk of catheter-related
infections. These may be serious and require prompt
attention; persistent infection, infection with Gram-negative
organisms and infection with Candida should lead to
catheter removal.
The use of prophylactic antibiotics remains contentious and
there is no evidence that their use improves survival.
Empiric broad-spectrum antibacterial therapy is an absolute
necessity for febrile neutropenic patients. The choice of
therapy should be decided with local microbiologists. Metaanalysis suggests an advantage for beta-lactam antibiotic
monotherapy rather than the combination of a beta-lactam
with an aminoglycoside (Paul et al, 2005). There should be
clear guidelines agreed for the management of patients
admitted as an emergency with neutropenic sepsis and patients
should be admitted to a haematology unit.
Recommendation
There is no firm evidence of a survival advantage to support
the routine use of prophylactic antibiotics in patients with
AML and they are not recommended (recommendation
grade B; evidence level IIb).
5.1.8. Fungal infection. The risk of developing fungal infection
increases with the severity and duration of neutropenia so
patients should be observed for the symptoms and signs of
fungal infections. Symptoms are often non-specific. As
established fungal infections carry a high mortality, empiric
antifungal therapy is indicated in patients with persistent
pyrexia despite appropriate empirical antibacterial therapy.
Early detection of respiratory fungal infections may be aided by
the use of spiral CT scans of the chest.
5.1.9. Growth factors. Several large controlled trials have
examined whether growth factors influence the outcome of
remission induction therapy in AML. They show a modest
reduction in the duration but not the depth of the
neutropenia and provide no evidence that growth
factors induce the growth of myeloid leukaemia cells
(Dombret et al, 1995; Rowe et al, 1995; Stone et al, 1995;
Takeshita et al, 1995; Zittoun et al, 1996; Heil et al, 1997;
Lowenberg et al, 1997a,b; Godwin et al, 1998; Witz et al,
1998; Usuki et al, 2002). The effects of growth factors on
outcome, incidence of severe infection, antibiotic usage,
duration of hospitalisation and complete remission (CR)
rate are variable and the American Society of Clinical
Oncology (ASCO) and BCSH guidelines conclude that there
is no evidence to support the routine use of growth factors
after remission induction chemotherapy for AML (Ozer
et al, 2000; Pagliuca et al, 2003). Granulocyte colonystimulating factor (G-CSF) is recommended after induction
if it is appropriate to reduce hospital stay or antibiotic
usage. Two trials, in which G-CSF was given after
consolidation chemotherapy in AML showed a marked
decrease in the duration of neutropenia compared with
placebo, as well as a reduction in the use of antibiotic
therapy (Heil et al, 1997; Harousseau et al, 2000).
The BSCH and the ASCO guidelines conclude that
G-CSF can be recommended following consolidation chemotherapy.
There is experimental evidence to suggest that G-CSF given
prior to or with chemotherapy may enhance the cytotoxicity
of chemotherapy. It is not possible to separate a possible
priming effect from the impact on granulocyte recovery
(Ohno et al, 1994; Zittoun et al, 1996; Lowenberg et al,
1997a). A recent European trial of G-CSF in AML (Lowenberg et al, 2003) demonstrated a survival gain for patients
with standard-risk AML which appears to be due to a
reduction in relapse risk, but this is based on a subgroup
analysis within the trial, and has not been supported by other
studies.
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Guideline
Recommendations
There is no survival benefit from the use of growth factors
following AML chemotherapy but growth factor use does
reduce the duration of neutropenia, of antibiotic use and of
hospital stay. The cost–benefit advantages of routine growth
factor use are uncertain. The routine use of growth factor
therapy in AML is not recommended (recommendation
grade A; evidence level IIa).
5.2. Treatment of younger adult patients
The benefits of chemotherapy are greater in younger patients
because they withstand chemotherapy better and because of
the biological nature of their disease. The therapy of AML is
divided into two phases: induction therapy to achieve CR and
consolidation therapy once a CR has been achieved. It is
important to assess the response to initial treatment as patients
who fail to achieve CR have a poor prognosis. Patients who
have resistant disease after course 1 or who have an adverse
risk cytogenetic or molecular marker, should be considered for
an alternative treatment for high-risk leukaemia within the
context of a controlled study.
5.2.1. Induction therapy. The goal of remission induction
chemotherapy is the restoration of normal bone marrow
function. In MRC studies CR is defined as the recovery of
normal bone marrow cellularity with fewer than 5% blast cells
and without a detectable cytogenetic abnormality. Elsewhere,
the term morphologic remission is reserved for patients who
also have recovery of peripheral blood counts with a
neutrophil count >1Æ0 · 109/l and platelet count exceeding
100 · 109/l (Cheson et al, 2003).
The effectiveness of induction therapy can be measured by the
percentage of patients who achieve CR and also by relapse-free or
disease-free survival (RFS or DFS) and overall survival (OS).
Initial therapy should comprise an anthracycline/anthracycline-like drug given for 3 d combined with cytarabine given
over 7–10 d as a continuous infusion or as a twice daily bolus.
The most commonly used regimen is daunorubicin, given for
3 d at a dose of 45–60 mg/m2, and cytarabine 200 mg/m2
either given as a bolus in divided doses twice daily or as an
infusion over 12 h for 10 d (3 + 10) regimen (Hann et al,
1997). Although 10 d of cytosine has been widely used there is
no evidence that this schedule is superior to 7-d treatment and
may be associated with greater toxicity (Preisler et al, 1987).
Daunorubicin was the first anthracycline of value against
AML. It is less toxic than doxorubicin. An Eastern Cooperative
Oncology Group (ECOG) study randomised 363 adults with
AML over the age of 55 years to receive daunorubicin (45 mg/
m2), idarubicin (12 mg/m2) or mitoxantrone (12 mg/m2) each
for 3 d together with cytarabine Ara-C. The CR rates were
40%, 43% and 43%, and the median DFS was 5Æ7, 9Æ7 and
6Æ9 months respectively (Rowe et al, 1995). A further trial
from ECOG demonstrated no evidence that either mitoxant456
rone or idarubicin was superior to daunorubicin if given in
equitoxic doses (Rowe et al, 2004).
The inclusion of high-dose cytarabine (2–3 g/m2) in remission induction regimens has been investigated by the South
West Oncology group (SWOG; Weick et al, 1996) and the
Australian Leukemia Study Group (ALSG; Bishop et al, 1996).
There was no increase in the CR rate in patients <60 years of
age although there was an improvement in DFS in the ALSG
study but with increased toxicity.
5.2.2. Addition of other drugs. A study by the ALSG in which
etoposide (75 mg/m2) per day for 7 d was added to a ‘3 + 7’
regimen demonstrated that in younger patients (<55 years)
there was no difference in the CR rate, but the addition of
etoposide (ADE) resulted in a longer duration of remission but
not OS (Bishop et al, 1990). The MRC AML 10 trial found no
difference in DFS with the ADE or thioguanine (DAT) to a
standard MRC 3 + 10 regimen in a randomised trial of 1857
patients (Hann et al, 1997).
Patients who have not achieved at least a partial remission
(<15% blasts) after remission induction treatment may be
considered for treatment on experimental protocols as their
outlook is poor.
Recommendations
1 All eligible patients up to the age of 60 years (or
>60 years but able to receive intensive treatment) with
de novo or secondary AML should be asked to participate
in the current NCRI study, at present AML 15 (http://
www.aml15.bham.ac.uk/trial/index.htm).
2 Patients over 60 years who are able to tolerate remission
induction chemotherapy should be asked to participate in
the current NCRI study, at present LRF AML 14 (http://
www.aml14.bham.ac.uk) or HOVON/SAKK AML 43.
3 Patients not eligible or unwilling to participate in the
NCRI studies should be offered standard daunorubicin
and cytarabine 3 + 10 or 3 + 7 induction chemotherapy
(level 1b).
4 Patients opting for non-intensive chemotherapy who are
not entered into clinical trials should be offered treatment with low-dose cytarabine (grade A; evidence level
Ib). Patients not able to tolerate chemotherapy should be
given best supportive care: transfusion support and
hydroxycarbamide to control the white cell count
(recommendation grade A; evidence level Ib).
5.2.3. Postremission therapy. Following remission induction
therapy it is important that additional treatment is given, as
the median DFS for patients who receive no additional therapy
is only 4–8 months (Cassileth et al, 1998). The aim of
postinduction therapy is to prevent relapse with maximal
efficiency and minimal toxicity. Options include consolidation
chemotherapy and autologous, allogeneic-related or -unrelated
donor transplantation. The same chemotherapy regimen used
ª 2006 The Authors
Guideline
for remission induction can be repeated but usually non-crossresistant drugs are used. When several courses of consolidation
chemotherapy are given, survival rates at 2–3 years are 35–50%
for young to middle-aged adults who have achieved CR.
The UK MRC approach has been to give two courses of
induction chemotherapy followed by a third course of mamsacrine, cytarabine and etoposide, and a fourth course of
mitoxantrone and intermediate-dose cytarabine (Hann et al,
1997). Other groups have studied responses of patients to
variable and higher doses of cytarabine. The most important
study was the Cancer and Leukaemia Group B (CALGB) trial
(Mayer et al, 1994), which compared high-dose cytarabine
(3 g/m2) with 400 and 100 mg/m2 doses. For patients
<60 years old, the 4-year DFS was 44% in the high-dose
cytarabine arm compared with 29% and 24% in the
intermediate- and low-dose groups respectively (P ¼ 0Æ002).
There were very few late relapses in the high-dose group but
this therapy was toxic, with 5% treatment-related mortality
and significant neurotoxicity in patients older than 40 years.
Only 56% of patients received all four courses at the 3 g dose.
In a subgroup analysis there was a benefit from the higher dose
in younger patients, particularly those with a favourable
cytogenetic abnormality and especially those with core-binding
factor leukaemias. However, these patients have chemosensitive disease and there is no evidence that high-dose cytarabine
is superior to other intensive regimens and good-risk patients
in the MRC AML 10 trial fared just as well (Grimwade et al,
1998). There was no evidence that patients with a normal or an
unfavourable karyotype benefited from high-dose cytarabinebased chemotherapy.
The ALSG have treated all patients with high-dose cytarabine and idarubicin induction and then randomised patients to
a single similar course of consolidation or two courses of
idarubicin with conventional dose of cytarabine. With short
follow up there was no difference between these groups with an
OS of 60% at 3 years (Bishop et al, 1996). The UK MRC
approach does not use high-dose cytarabine and results are
very similar to the CALGB and ALSG results (Hann et al, 1997;
Burnett et al, 2002a).
Despite the use of more intensive consolidation therapy, it is
uncertain which drugs, in what combination and how many
courses are needed. As around 50% of patients still relapse, all
eligible patients with AML should be offered entry into clinical
trials so that important questions about remission induction
and consolidation therapy are answered.
5.2.4. Maintenance therapy. There is no evidence that
maintenance therapy is of benefit in patients with AML who
have undergone intensive consolidation therapy with the
possible exception of APL.
5.3. Management of AML in patients who are pregnant
Acute myeloid leukaemia may be diagnosed during pregnancy.
Chemotherapy during the first trimester is teratogenic (Artlich
et al, 1994) and associated with an increased risk of abortion
and should be avoided if possible. The risks of continuing the
pregnancy should be carefully discussed and, if appropriate,
the pregnancy should be terminated. If termination of
pregnancy is unacceptable, this presents a considerable management dilemma as delay in treatment is associated with an
adverse outcome (Kawamura et al, 1994) and the risks of delay
must be explained. Chemotherapy can proceed but is associated with increased risks of early fetal loss, congenital
malformation and low birth weight (Feliu et al, 1988; Artlich
et al, 1994; Ali et al, 2003). Patients presenting in the second
and third trimesters can more confidently be offered chemotherapy without a risk of causing congenital malformation
(reviewed in Cardonick & Iacobucci, 2004). A report of 58
cases of acute leukaemia in pregnancy (Reynoso et al, 1987)
showed that 49 resulted in the birth of 50 live infants. Half
were born prematurely and four had low birth weights for their
gestational age. One of the 50 infants had congenital malformations and subsequently developed tumours of the adrenal
and thyroid glands. Long-term follow up of a cohort of eight
children in this series has shown normal growth and development. Chemotherapy given close to delivery may result in
significant fetal pancytopenia requiring intensive support
(Reynoso et al, 1987; Murray et al, 1994).
For patients presenting with PML–RARA-positive APL in
the second or third trimesters of pregnancy, single-agent
ATRA may be the safest treatment approach and has been
associated with good outcome. Successful outcomes have also
been obtained with ATRA in combination with an anthracycline for patients presenting with APL in second or third
trimesters (reviewed in Breccia et al, 2002). However, this
approach may confer increased risk to the fetus and therefore
might be best employed in patients with a white blood cell
count >10 · 109/l who have poorer risk disease, including
higher rate of induction death. ATRA should be avoided in the
first trimester as it is a teratogen. ATO is teratogenic and there
have been no reports of its use for APL in pregnancy. Patients
with other forms of AML and with stable disease may defer
chemotherapy and be supported with growth factors and
blood products until delivery can be safely induced at about
30 weeks. It is critical that the patient is fully informed of her
choices and is able to exercise these. Finally, further information is required about the outcome of pregnant patients with
cancer and new cases should, with the consent of the patient,
be reported to the International Registry of Cancer in
Pregnancy (http://www.motherisk.org/cancer/index).
Recommendations
1 AML in pregnancy should be managed jointly between
the haematologist and the obstetrician with full involvement of the mother (grade B; evidence level III).
2 Chemotherapy in the first trimester is associated with a
high risk of fetal malformation and should be avoided if
possible. The opportunity to terminate the pregnancy
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457
Guideline
should be discussed with the mother. If termination is
refused and the mother’s life is at risk, chemotherapy
should be started (grade B; evidence level III).
3 Chemotherapy in the second and third trimesters is
associated with an increased risk of abortion and
premature delivery as well as low birth weight babies.
Consideration should be given to the early induction of
labour between cycles of chemotherapy (grade B; evidence level III).
4 ATRA can be used in pregnancy in the second and third
trimesters (grade B; evidence level III).
5.4. Management of extramedullary disease
Extramedullary disease in AML includes skin and gum
infiltrates, often seen in monocytic/monoblastic AML, and
the rare granulocytic sarcomas that may be seen in any organ.
Extramedullary tumours can arise:
• de novo as a primary manifestation of AML in patients with
no medullary evidence of leukaemia;
• simultaneously with marrow disease at presentation;
• as an isolated focus of relapse;
• simultaneously with marrow disease at relapse.
The incidence of extramedullary disease is not well established but predisposing factors are thought to include the
t(8;21) translocation (Swirsky et al, 1984; Tallman et al, 1993),
inv(16) (Holmes et al, 1985), high presenting white cell count,
lack of Auer rods and poor nutrition.
Extramedullary myeloid tumours may present in any site
(reviewed in Byrd et al, 1995). Histology reveals a diffuse
infiltrative population of mononuclear cells, usually accompanied by granulocytic cells at various stages of maturation.
The tumours are frequently misdiagnosed, usually as large cell
lymphoma, and immunohistochemistry is essential to make
the correct diagnosis.
Patients presenting de novo or in relapse with extramedullary
leukaemia should receive systemic antileukaemic chemotherapy. Surgical or radiotherapeutic approaches are reserved for
patients whose extramedullary tumours do not completely
resolve with initial treatment.
The prognostic impact of extramedullary disease is unclear
but may be an adverse prognostic factor in patients with
t(8;21) AML (Byrd et al, 1997).
high white cell count or monocytic lineage involvement. A
large randomised trial of intrathecal prophylaxis in AML has
shown no benefit (Rees et al, 1986). In patients achieving
remission approximately 5% of primary relapses involve the
central nervous system (CNS), with or without concurrent
marrow relapse (Rees et al, 1986).
Extradural deposits can present with neurological symptoms
depending on the site of disease, and may be more common in
AML with t(8;21). Extremely rarely intracerebral deposits of
AML occur, most commonly in patients with inv/t(16)
(Holmes et al, 1985).
In suspected CNS disease 50 mg of cytarabine should be
given intrathecally at the time of the diagnostic lumbar
puncture. If infiltration is confirmed, intrathecal cytarabine
50 mg should be given three times per week until the
cerebrospinal fluid is clear, and then fortnightly until consolidation treatment is completed. Platelet support may be
required (British Committee for Standards in Haematology,
Blood Transfusion Task Force, 2003).
Central nervous system relapse is generally followed by
marrow relapse if not already present. Reinduction chemotherapy should be given in addition to intrathecal treatment.
Extradural deposits generally respond to systemic chemotherapy.
6. Acute promyelocytic leukaemia
6.1. Diagnosis of APL
For patients with APL, it is important to establish the
underlying molecular abnormality. Presence of the PML–
RARA fusion gene, even in the absence of the t(15;17), predicts
a favourable response to molecularly targeted therapies in the
form of ATRA and ATO (Grimwade et al, 2000; reviewed
Mistry et al, 2003). Rapid confirmation of the presence of the
PML–RARA fusion can be undertaken by PML immunofluorescence test or FISH analysis; but marrow and peripheral
blood should also be routinely sent for molecular analysis as a
baseline for subsequent MRD monitoring. Approximately 1%
of APL cases have an underlying PLZF–RARA fusion, typically
as a result of t(11;17)(q23;q21). This subset of APL, which has
characteristic features (Sainty et al, 2000) is important to
recognise as it is resistant to both ATRA and ATO. This section
focuses on the management of PML–RARA-associated APL;
the treatment approach for rarer molecular variants has been
considered elsewhere (Mistry et al, 2003).
Recommendation
Patients presenting with extramedullary leukaemia should
receive systemic antileukaemic chemotherapy (grade C;
evidence level IV).
5.5. Management of central nervous system disease
Leptomeningeal disease at presentation occurs in approximately 0Æ5% of patients. Risks are greater in patients with a
458
6.2. Clinical management
The presentation of APL is a haematological emergency due to
the high risk of death as a result of the associated coagulopathy.
Rapid diagnosis and prompt initiation of therapy is essential.
6.2.1. Induction. Anti-leukaemic therapy: a number of studies
have reported that ATRA improves the coagulopathy
associated with APL (Huang et al, 1988; Chomienne et al,
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Guideline
1990; Fenaux et al, 1993; Tallman et al, 2004; reviewed in
Falanga & Rickles, 2003). Hence ATRA should be commenced
‘as soon as’ the diagnosis of APL is suspected. Treatment
should not be delayed until the diagnosis has been confirmed.
The optimal timing of starting chemotherapy relative to the
first dose of ATRA has not been established. For patients with a
lower presenting white cell count (<10 · 109/l), there may be
an advantage in giving ATRA for a longer period (i.e. 2–3 d)
before commencing chemotherapy to ameliorate the
coagulopathy; but chemotherapy should be started before the
onset of any ATRA-induced leucocytosis that accompanies
the retinoic acid (RA) syndrome (Tallman et al, 2002).
For patients with a higher presenting white cell count
(>10 · 109/l), risk of developing RA syndrome is higher and
chemotherapy should ideally be given on day 1 after the first
dose of ATRA. Induction with ATRA in combination with
chemotherapy has been shown in randomised clinical trials to
reduce relapse rates significantly and to improve OS when
compared with chemotherapy alone (Fenaux et al, 1993;
Tallman et al, 1997). Best results have been obtained when
ATRA is given as a prolonged course (21–60 d) commenced at
the same time as induction chemotherapy, when compared
with sequential therapy involving short (5 d) or more
prolonged courses of ATRA prior to starting chemotherapy
(Burnett et al, 1999; Fenaux et al, 1999). APL is very sensitive
to anthracyclines (Head et al, 1995), and excellent results have
been obtained with protocols based upon ATRA and
anthracyclines (Avvisati et al, 1996; Sanz et al, 1999, 2004a),
including older patients (Sanz et al, 2004b). However, these
protocols are only suitable for patients with PML–RARA APL,
not patients with the PLZF–RARA fusion or other forms of
AML, which should be treated with more intensive
anthracycline and cytarabine protocols.
Patients with PML–RARA associated APL should receive
concurrent ATRA and chemotherapy for induction, with
ATRA being continued at least until documentation of
morphological CR (level 1b, grade A).
6.2.2. Supportive care. Coagulopathy: a major cause of
treatment failure is induction death due to haemorrhage
(reviewed in Falanga & Rickles, 2003). Patients with a higher
presenting white cell count (i.e. >10 · 109/l) are at highest risk
of haemorrhagic death. They should not undergo
leucopheresis as it can precipitate fatal exacerbation of the
coagulopathy (Vahdat et al, 1994). Evidence suggests that
patients with high presenting white cell counts are best
commenced on ATRA and anthracycline-based induction
therapy. Haemorrhage may be reduced by monitoring of the
coagulation profile and administration of appropriate
replacement therapy until CR has been attained. Activated
partial thromboplastin time (APTT), prothrombin time,
thrombin time, fibrinogen level and platelet count should be
checked at least twice daily during the early stages of treatment.
Coagulation times should be kept within the normal range
using FFP as replacement. Fibrinogen levels may be low due to
DIC and cryoprecipitate should be given as replacement
aiming for a level of approximately 2 g/l. Elevated levels of
fibrinogen should be avoided due to an increased risk of
thrombosis, which may be further exacerbated by ATRA. The
platelet count should be maintained above 50 · 109/l (Falanga
& Rickles, 2003; Sanz et al, 2005) until remission. There is no
proven benefit for use of heparin/anti-fibrinolytics to reduce
induction death rates and their use is not recommended
(reviewed in Tallman & Kwaan, 1992; Falanga & Rickles, 2003;
Sanz et al, 2004a). Indeed, anti-fibrinolytic agents when
combined with ATRA may increase the risk of thrombosis.
Nevertheless, anti-fibrinolytic agents could be contemplated in
situations of life-threatening haemorrhage in the presence of
normal coagulation assays.
RA syndrome: this life-threatening complication of ATRA
therapy is characterised by fluid retention and capillary leak
and is most likely related to surface adhesion molecule
modulation and cytokine release following differentiation of
APL cells. Symptoms and signs include cough, dyspnoea, fever,
weight gain, oedema, pleural and pericardial effusions and
pulmonary infiltrates (reviewed in Larson & Tallman, 2003).
RA syndrome occurs in up to a third of patients receiving
ATRA as single-agent induction therapy and was fatal in
approximately 30% in early studies (Larson & Tallman, 2003).
The syndrome typically develops 10 d after initiation of ATRA,
but can occur earlier and is usually associated with a rising
white cell count. Lower rates of ATRA syndrome (<10%) have
been reported when chemotherapy is commenced with ATRA.
Patients on ATRA should be observed carefully for symptoms, signs or falling oxygen saturation levels. If early RA
syndrome develops, ATRA should be discontinued and
steroids administered promptly (dexamethasone 10 mg i.v.
b.d. until disappearance of symptoms and signs, and for a
minimum of 3 d). This may prevent progression to fulminant
respiratory failure. ATRA can then be cautiously reintroduced.
As RA syndrome is linked to the differentiation of APL blasts,
its occurrence during induction is not a contraindication to
use of ATRA later in the patient’s treatment. Patients with a
high presenting white cell count (>10 · 109/l) are at higher
risk of RA syndrome and some use prophylactic steroids with
induction therapy. Whether this approach confers any benefit
is uncertain (Wiley & Firkin, 1995; Firkin et al, 1999).
6.2.3. Consolidation. Primary resistance of APL to
simultaneous ATRA and anthracycline-based chemotherapy
is exceptionally rare. However, bone marrow appearances
following induction can be difficult to interpret and
misconstrued as primary resistance (Stone & Mayer, 1990;
Sanz et al, 2005); therefore, marrow assessment at this time has
been abandoned in some protocols. The majority of such
patients will achieve morphological CR following a further
course of chemotherapy in combination with continued ATRA
therapy and should not be considered to have an adverse
prognosis (Burnett et al, 1999). Induction therapy is followed
by two to three further anthracycline-based consolidation
ª 2006 The Authors
459
Guideline
courses. The number of consolidation courses or intensity of
consolidation may be reduced in patients experiencing
excessive toxicity in earlier courses and in the elderly. In
such instances, maintenance therapy provides a therapeutic
option and MRD monitoring may guide the need for
additional therapy (see below). A number of groups have
reported that maintenance therapy, given for 2 years, reduces
relapse risk, with the best results being obtained with ATRA in
combination with 6-mercaptopurine and methotrexate
(Tallman et al, 1997; Fenaux et al, 1999). It is unclear
whether maintenance is of any value in patients who have
received more intensive first-line therapy or who are in
molecular remission at the end of consolidation (Avvisati et al,
2003). Transplantation using autologous or allogeneic stem
cells performed in first CR (CR1) confers no OS advantage in
patients with PML–RARA-positive APL (Burnett et al, 1998,
2002b) and patients should not routinely undergo transplant
in CR1 (grade A; evidence level 1b).
6.3. Management of APL patients at high risk of relapse
For patients with PML–RARA-positive APL, a key goal is
achievement of PCR negativity in the bone marrow using
assays that detect one leukaemic cell in 104 cells. Patients with
persistent disease or molecular relapse, confirmed in two
consecutive assays after completion of consolidation, will
invariably relapse unless additional therapy is given (Diverio
et al, 1998). The optimal management for such patients is
uncertain although a matched donor stem cell transplantation
(SCT) can be curative (Lo Coco et al, 2003). Achievement of
PCR negativity is critical to achieving cure; for patients lacking
a donor, ATO or gemtuzumab ozogamicin (GO) used as single
agents or in conjunction with chemotherapy are potential
options (Petti et al, 2001; Douer et al, 2003; Lo Coco et al,
2004; Douer & Tallman, 2005). Once PCR negativity has been
achieved, stem cells may be harvested and if PCR negative,
autologous SCT (auto-SCT) can be undertaken. Poor results
are seen in patients with evidence of residual disease prior to
auto-SCT who receive a PCR-positive graft (Meloni et al,
1997) and this treatment is not recommended in this setting.
Outcome in patients in whom PCR status prior to transplant
and PCR status of the graft differ are uncertain (reviewed in
Grimwade, 1999).
6.4. Management of relapse
Approximately 10% of relapses involve an extramedullary site
(most commonly CNS, particularly in patients initially
presenting with elevated white cell count) and this should be
considered in the assessment and management of relapsed
disease (reviewed in Evans & Grimwade, 1999).
One treatment option for patients with confirmed PML–
RARA-positive relapse is ATO, which achieves high CR rates,
accompanied by PCR negativity in a significant proportion of
cases (reviewed in Douer et al, 2003; Douer & Tallman, 2005).
460
ATO has a number of adverse effects including cardiac toxicity
and fatal arrhythmias associated with lengthening of the QT
interval. It is critical to maintain serum magnesium and
potassium levels within the high normal range and monitor the
electrocardiogram regularly (drug data sheet and Sanz et al,
2005). ATO can induce a differentiation syndrome akin to RA
syndrome, which should be managed in the same way with
steroids (see above). ATO-induced hyperleucocytosis commonly accompanies clinical response but is not an indication
for treatment modification (Douer et al, 2003; Sanz et al,
2005). ATO-induced remissions are generally not sustained
and hence this agent is typically used as a ‘bridge to
transplantation’ (Leoni et al, 2002).
As an alternative to ATO, ATRA combined with chemotherapy or GO may induce a second CR, but ATRA alone
should not be used for treatment of relapse due to high rates of
secondary resistance (reviewed in Mistry et al, 2003).
The optimum management of relapsed APL remains to be
established; however, the key aim is to induce molecular
remission, as this is essential to achieve cure (grade B; evidence
level IIb). It is standard practice (if feasible) to proceed to
transplant as the final consolidation course. For patients failing
to achieve PCR negativity who have a donor, allogeneic bone
marrow transplantation (allo-BMT) is a potential option. The
role of reduced-intensity conditioned transplants has not been
established in APL; however, a recent study has provided some
evidence supporting a graft-versus-APL effect (Lo Coco et al,
2003). For patients who fail to achieve molecular remission
with ATO or ATRA/chemotherapy, GO provides a treatment
option that has been reported to achieve molecular CR in
advanced APL (Petti et al, 2001; Lo Coco et al, 2004). For
patients in molecular CR, transplantation using autologous
stem cells can be used as consolidation. This may be the
preferred treatment approach, even in patients with a potential
donor, in view of the reduced toxicity and favourable results
obtained with autologous transplantation in this subset of
AML (Meloni et al, 1997; De Botton et al, 2005).
6.5. Role of molecular monitoring
Molecular monitoring using an RT-PCR assay with a sensitivity threshold of 1 in 104 should be undertaken for 2 years
following completion of therapy. Patients with molecularly
persistent disease require additional treatment to prevent
relapse. Serial monitoring of bone marrow on a 3-monthly
basis following consolidation using conventional end-point
RT-PCR has been shown to permit early detection of disease in
approximately 70% of patients who ultimately relapse (Diverio
et al, 1998). It is likely that improvements in MRD monitoring
will be achieved with ‘real-time’ quantitative approaches that
afford comparable sensitivity, but are more readily standardised and allow identification of poor quality RNA samples that
can give false-negative results with conventional assays
(reviewed in Yin & Grimwade, 2002). For patients found to
test positive, the bone marrow should be repeated within
ª 2006 The Authors
Guideline
2 weeks and positivity confirmed in a second laboratory before
further treatment is given (although it is prudent to commence
the patient on ATRA whilst the result of the second assay is
pending). There is evidence to suggest that pre-emptive
treatment at molecular relapse affords superior outcome when
compared with treatment at frank relapse (Lo Coco et al, 1999;
reviewed in Grimwade & Lo Coco, 2002). Use of peripheral
blood for MRD assessment has not been validated as a reliable
means of predicting relapse (Sanz et al, 2005).
Recommendations
1 ATRA should be started as soon as the diagnosis is
suspected (grade A; evidence level Ib).
2 Leucopheresis should be avoided in high count patients
(grade B; evidence level III).
3 The coagulopathy should be treated to keep the platelets
>50 · 109/l, together with FFP and cryoprecipitate to
normalise the APTT and fibrinogen levels (grade B;
evidence level IIb).
4 Differentiation syndrome should be treated promptly
with dexamethasone 10 mg twice daily i.v., and ATRA
stopped temporarily until the symptoms resolve (grade C;
evidence level IV).
5 Diagnostic workup should include documentation of
underlying PML–RARA fusion (grade B; evidence level
IIa).
6 Patients with PML–RARA-positive APL, deemed suitable
for intensive therapy, should be treated with concurrent
ATRA and anthracycline-based chemotherapy for induction, followed by anthracycline-based consolidation therapy and should be offered entry into the NCRI AML trial
(currently AML 15) (grade A; evidence level Ib)
7 Patients should undergo molecular monitoring after
treatment to guide further therapy (grade B; evidence
level IIa)
8 For relapsed disease, ATRA should not be used as singleagent therapy due to the significant possibility of
acquired secondary resistance and ATO should only be
used in patients with confirmed PML–RARA-positive
APL (grade B; evidence level IIa). Treatment of relapse,
with respect to use of autologous or allogeneic transplantation as consolidation should be guided by MRD
assessment.
7. Management of relapsed AML
Relapse occurs in over 50% of patients and treatment options
for these patients remain limited. Median survival figures vary
from 3 to 12 months (reviewed by Leopold & Willemze, 2002).
The most important predictors of response to reinduction
chemotherapy are age, karyotype, duration of first remission
and history of previous SCT (Breems et al, 2005). Up to 90%
of patients with favourable karyotypic features who relapse can
be successfully reinduced, in contrast to patients with adverse
cytogenetics where response rates are <40% (Wheatley et al,
1999; Weltermann et al, 2004). Significantly higher rates of
response are also observed if the duration of CR1 is >6 months
(Rees et al, 1986; Kern et al, 2000). Patients with relapsed
disease should therefore be stratified according to cytogenetics,
age and length of CR1 to identify the best salvage approach
(Estey et al, 1996). In older patients with adverse cytogenetics
who relapse within 6 months of chemotherapy the likelihood
of durable response to salvage therapy is extremely low. In
those younger, fitter patients who achieve a second remission it
is reasonable to aim for SCT as part of the salvage therapy.
There is a suggestion from the Netherlands group (Breems
et al, 2005) that SCT conferred an improved outcome,
however, this data are descriptive and subject to considerable
selection bias.
Although there are very few randomised trials comparing
salvage treatments, the mainstay of salvage treatment in
relapsed AML is cytarabine, which has been used in low
(100–200 mg/m2), intermediate (1 g/m2) and high doses
(2–3 g/m2) and in combination with other drugs. Laboratory
data demonstrates that concurrent use of fludarabine enhances
the cytotoxicity of cytarabine (Gandhi et al, 1993) and this
combination (combined with G-CSF as the FLAG regimen)
has been reported to improve salvage rates in non-randomised
studies (Estey et al, 1994; Jackson et al, 2001). However, the
recent randomised MRC trial for high risk AML (MRC AMLHR) found no benefit for fludarabine + cytarabine, with or
without G-CSF, in comparison with standard ADE (cytarabine, daunorubicin and etoposide) (Milligan et al, 2006).
Neither is there evidence that timed sequential therapy is of
benefit (Yin et al, 2001). However, regimens incorporating
high-dose cytarabine are still widely used in young patients in
whom allogeneic SCT (allo-SCT) is planned. Clearly, improved
strategies are required and recent data show encouraging
results with both clofarabine and GO (Mylotarg) (Bross et al,
2001; Sievers et al, 2001; Kell et al, 2003).
8. Transplantation in AML
High relapse rates in patients with AML have led to enthusiasm
for the intensification of treatment by the use of high-dose
chemoradiotherapy followed by ‘rescue’ using allogeneic stem
cells (Beutler et al, 1982; Gale et al, 1982; Kersey et al, 1982;
Forman et al, 1983). The early results were encouraging.
Allo-SCT reduces the risk of relapse with a relapse risk
post-transplant of about 20% compared with 50% after
conventional chemotherapy. However, the transplant-related
mortality (TRM) remains high at about 15–25%, eroding the
anti-leukaemic advantage. Mortality rates are higher for older
patients and those transplanted from non-HLA-identical
family members or unrelated donors.
Although large registry studies have suggested that allo-SCT
in first remission is better than standard chemotherapy (Gale
et al, 1996), caution must be exercised in interpreting results
from non-randomised studies (Wheatley, 2002). There are a
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461
Guideline
number of prospective trials available to inform us. In the US
Intergroup Trial (Cassileth et al, 1998) a comparison was made
between consolidation with high-dose cytarabine (36 g/m2
total dose), allo-SCT from a matched-related donor and
autografting using purged bone marrow. The results demonstrated a small overall survivial advantage for high-dose
cytarabine compared with either auto- or allo-SCT. Allo-SCT
was associated with a lower relapse risk in comparison with
chemotherapy or auto-transplant (29% vs. 61% and 48%,
respectively) but these gains were offset by non-relapse
mortality (allo-transplant 25%, chemotherapy 3% and autotransplant 14%). In the MRC AML 10 trial (Burnett et al,
1998, 2002b), patients with no allogeneic donor received four
cycles of chemotherapy and were randomised to no further
treatment or a bone marrow autograft. Those with a matched
sibling donor were recommended an allograft. Comparing the
outcome of patients with and without a donor has shown a
significant reduction in the relapse risk and improvement in
DFS for the ‘with donor’ group (relative risk: 36% vs. 52%,
P ¼ 0Æ001; DFS: 50% vs. 42%, P ¼ 0Æ001). However, the OS
was not different between the groups (56% vs. 50% at 7 years,
P ¼ 0Æ1) because of the higher TRM in the donor group (19%
vs. 9%, P ¼ 0Æ001). Some subgroups might benefit from an
allo-SCT in CR1 and this study suggested an advantage for
patients aged below 35 years with standard risk AML. The
MRC AML 12 trial explored whether five cycles of chemotherapy was better than four and whether the final cycle should
be a transplant (Burnett et al, 2002a). This trial again found no
gain for patients undergoing a transplant on a donor versus no
donor analysis.
In the European Organization for Research (EORTC) and
Treatment of Cancer-Gruppo Italiano Malattie Ematologiche
dell’ Adulto AML 8 trial (Zittoun et al, 1995) patients with
AML in CR1 were treated with a consolidation cycle of
treatment and underwent allo-SCT if they had a matched
family donor or were randomised to either an autograft or
additional chemotherapy. The results for OS were similar in all
groups at 4 years (allo-SCT 59%; auto-SCT 56%; chemotherapy 46%) but both transplant arms demonstrated an improvement in relapse risk and DFS. A subsequent trial from the same
group (Suciu et al, 2003) has confirmed that, on a donor/no
donor analysis, allogeneic transplantation is associated with an
improved 4-year DFS (52% vs. 42%, P ¼ 0Æ05) but no OS gain
(58% vs. 51%, P ¼ not significant). The only group to derive
survival benefit in this small study were patients with an
abnormal karyotype without favourable cytogenetic changes.
In the Group Ouese Est Leucemies Aigues Myeloblastiques
trial (Harrousseau et al, 1997), no survival advantage could be
discerned for allografting patients aged 40 years or less with
AML in CR1 from matched family donors.
In most intention-to-treat studies of allo-SCT there is a
significant attrition of patients in the donor arm who fail to
receive a SCT and this makes the analysis of the impact of a
transplant difficult (Frassoni, 2000). There is little evidence
that patients who receive an allogeneic transplant benefit from
462
intensive pretransplant consolidation treatment (Tallman et al,
2000) and transplant-related toxicity might be reduced by
earlier transplantation.
If a matched sibling donor is not available closely matched
donors can be established through the donor registries (http://
www.bmdw.org). The results of unrelated donor SCT (UDSCT) are inferior to those from matched siblings because of
increased graft-versus-host disease and graft failure (Szydlo
et al, 1997) although it is hoped that, with high-resolution
HLA typing, the results may improve. Unrelated donor
allografting should be restricted to those with high-risk disease
in first remission and patients in second remission.
Transplantation in relapsed and refractory disease
Stem cell transplantation represents a potentially curative
strategy in relapsed disease although patients, particularly with
‘good risk’ cytogenetics and a CR1 duration longer than
24 months, can achieve durable second remissions using
chemotherapy alone (Gale et al, 1996).
While auto-SCT may produce long-term DFS the majority
of autografted patients relapse and allo-SCT using a sibling
donor remains the most effective transplant option in eligible
patients. There are fewer data to suggest outcome is improved
with an UD-SCT as there are no randomised trials and
potential biases in non-randomised studies hinder the interpretation of the results (Burnett et al, 2004a).
Long-term DFS rates of 30–40% have been reported in
patients with AML in second CR who undergo an allo-SCT
from an HLA-identical sibling donor (Gale et al, 1996). While
most centres restrict allo-SCT to patients who are in second
CR, data from Seattle suggest that equivalent results may be
obtained if patients are allografted in early first relapse (Clift
et al, 1992). However, arranging a transplant at such short
notice in all but indolent relapses limits the usefulness of this
approach. Patients who achieve a second CR with chemotherapy should proceed to SCT. There is no evidence that
additional cycles of chemotherapy improve outcome. The
majority of sibling allografts are performed using mobilised
peripheral blood stem cells, which appear to improve outcome
and lower TRM in patients with advanced acute leukaemia
(Bensinger et al, 2001). Patients under the age of 45 years who
lack an HLA-identical sibling are candidates for allografting
using an UD-SCT and long-term DFS rates in excess of 30%
have been reported (Sierra et al, 2000).
In patients who have failed to respond to two courses of
induction chemotherapy, transplantation using a myeloablative conditioning regimen is associated with long-term DFS
rates in the region of 20–30% (Fung et al, 2003).
Auto-SCT has the capacity to produce durable second
remissions in 25–30% of patients with relapsed AML who
achieve a second CR but its low TRM is offset by a high relapse
rate (Meloni et al, 1996; Tomas et al, 1996). Autografting is
currently restricted to older patients (in whom a myeloablative
allograft is precluded), patients with APL in second molecular
ª 2006 The Authors
Guideline
remission and younger AML patients lacking a sibling or
matched unrelated donor.
8.1. Reduced-intensity conditioning allografts
There are limited data on reduced-intensity conditioning
(RIC) schedules in AML. In general, the follow up has been
short and the patients heterogeneous. This procedure has
frequently been reserved for older patients (Sayer et al, 2003;
Taussig et al, 2003; Wong et al, 2003). In these patients TRM
varied from 6% to 53% with 1 year actuarial survival and
event-free survival being about 70% and 50% respectively. The
role of RIC regimens in the management of AML remains to be
established.
8.2. Haplo-identical transplants
The reports (reviewed by Reisner et al, 2003) that massive
doses of donor CD34 cells and T-cell depletion could
overcome host-versus-graft immunity and generate full-donor
chimaerism have generated interest in haplo-identical transplants. The conditioning schedules employed are profoundly
immunosuppressive and patients require detailed surveillance
post-transplant. The best results have been reported from
Perugia (Aversa et al, 1998, 2002). In a very high-risk group of
patients there was 98% engraftment. For patients with AML in
CR at the time of transplant, the probability of event-free
survival was 60% and was much better (70% vs. 7%) for those
demonstrating donor versus recipient natural killer cell alloreactivity.
8.3. T-cell depletion
T-cell depletion can control graft-versus-host disease and
reduce the TRM but the loss of a graft-versus-leukaemia (GVL)
effect considerably increases the risk of disease relapse. In AML
there is less evidence of a prominent GVL effect and good
results with improved quality of life (QoL) have been
demonstrated in a number of studies employing T-cell
depletion (Papadopoulos et al, 1998; Bunjes, 2001; Kroger
et al, 2002).
8.4. Quality of life issues
For most patients in first remission the gains from transplantation are likely to be small. BMT is associated with increased
treatment-related mortality and co-morbidity and a high cost
for remedial treatments for side effects.
Two cross-sectional QoL studies (Zittoun et al, 1997;
Watson et al, 1999, 2004), undertaken within randomised
controlled trials, have confirmed that there is higher risk of
long-lasting impairment of QoL after BMT. In these studies
there was a consistent ranking of the treatment effect on
QoL. Both BMT groups had greater impairment than
patients treated with chemotherapy alone, and those
receiving allo-BMT had worse QoL than those with autologous BMT.
Areas of QoL affected were physical, social functioning,
global health, fatigue and infection. There was a severe adverse
impact on sexual functioning and fertility in the BMT group.
Recommendations
1 Patients should be fully informed of both the advantages
and disadvantages of the available treatments, and of the
strategies that can be used to treat long-term side effects,
particularly in the area of sexual function and infertility.
2 Intensive consolidation chemotherapy treatment during
CR1 should be offered as the preferred treatment to
patients with favourable cytogenetics and to those
unwilling to accept the risk of permanent damage to
their sexual health and fertility, with BMT remaining as
the choice for salvage treatment in the event of relapse.
3 All patients of childbearing years undergoing BMT
should be offered the opportunity of preserving their
fertility (where possible) prior to treatment.
4 Allogeneic transplantation should be offered to patients
with high-risk AML (risk groups are defined in Table II)
in first remission who have an HLA-identical donor,
although it is accepted that only a minority of patients
will benefit (recommendation grade B; evidence level III).
Standard-risk patients may be offered allo-transplantation as part of a clinical trial (recommendation grade B;
evidence level III).
5 Allogeneic transplantation may be the treatment of
choice for younger patients who are in second remission
(recommendation grade B; evidence level III).
6 Older patients with high-risk disease or beyond first
remission may be offered a reduced-intensity conditioned
transplant but this should be in the context of a clinical
trial (recommendation grade C; evidence level IV).
7 Younger high-risk patients or those beyond first remission may be considered for a haplo-identical transplant
but this should be in the context of a clinical trial
8 The role of autografting in the management of AML is
contentious. Autografting should only be carried out in a
clinical trial (recommendation grade A; evidence level
Ib).
9. Acute myeloid leukaemia in the elderly
The median age at diagnosis of patients with AML is
approximately 65 years; in the UK around 70% of patients
presenting with AML are over the age of 60 years (Cartwright
et al, 1990). The reclassification by the WHO of refractory
anaemia with excess blasts in transformation as AML means
that the incidence of AML will be even higher. These older
patients have a poorer prognosis, more unfavourable cytogenetic abnormalities, higher incidence of secondary leukaemia
ª 2006 The Authors
463
Guideline
and increased frequency of overexpression of multidrug
resistance (MDR) phenotypes (Leith et al, 1997; Grimwade
et al, 2001). There is an increased resistance to chemotherapy,
increased treatment-related complications and an inferior
outcome. As a result, older patients require different treatment
approaches that take into account the features of the disease,
the performance status and co-morbidities of the patient, as
well as patient preference.
For the purposes of this guideline, we will define elderly as
over the age of 60–65 years. However, it is important to
consider the physiological age of the patient and the existence
of co-morbidities that permit some flexibility over the age
cutoffs. Options for management of these patients are:
• standard chemotherapy (e.g. daunorubicin + cytosine arabinoside 3 + 7);
• non-intensive (palliative) treatment;
• investigational treatments.
9.1. Standard chemotherapy
Overall, the results of standard chemotherapy in elderly
patients are poor and such patients are progressively underrepresented in clinical trials. CR rates are about 60%, but
remissions are short with median survival being 5–10 months,
and the probability of remaining in remission 3 years after
diagnosis is <10% (Baudard et al, 1994; Stone et al, 1995;
Goldstone et al, 2001).
Standard remission induction therapy should be considered
for those with the following features: relatively young age (60–
70 years), good performance status (WHO grade 0–2), white
cell count <100 · 109/l (Goldstone et al, 2001), normal organ
function, de novo presentation, lack of unfavourable cytogenetic abnormalities and lack of MDR gene expression (Leith
et al, 1997).
There have been few randomised studies comparing intensive with non-intensive chemotherapy. An EORTC randomised trial (Lowenberg et al, 1989) showed that elderly patients
with good performance status and preserved organ function
had improved survival following intensive therapy and also
required less hospitalisation than those receiving supportive
care. A trend towards improved survival was also seen in
another study (Tilly et al, 1990) in which patients aged
65 years and over were randomised to receive intensive therapy
or low-dose cytarabine.
Attempts have been made to improve induction chemotherapy by either reducing its intensity or substituting
mitoxantrone or idarubicin for daunorubicin. In the UK
MRC AML 9 study, patients were randomised to receive DAT
in a 1 + 5 or a standard 3 + 10 regimen: patients receiving
DAT 1 + 5 were less likely to achieve CR, and required more
time in hospital and more blood product support (Rees et al,
1996). An EORTC study (Lowenberg et al, 1998) randomised
patients over 60 years of age to mitoxantrone and cytarabine
or daunorubicin and cytarabine induction chemotherapy:
464
although CR rates were improved in patients receiving
mitoxantrone, there was no difference in RFS or OS. A
meta-analysis of trials comparing idarubicin with daunorubicin has similarly failed to demonstrate a survival advantage
with this agent (AML Collaborative Group, 1998). The MRC
AML 11 study (Goldstone et al, 2001) randomised 1314
patients to receive DAT (daunomycin, cytarabine and 6-thioguanine) 3 + 10, ADE or mitoxantrone and cytarabine (MAC)
as induction chemotherapy: the remission rate in the DAT arm
was significantly better than for either ADE or MAC, although
there were no differences with respect to OS at 5 years. A
SWOG randomised study demonstrated no improvement in
outcome when mitoxantrone and etoposide were compared
with daunorubicin and cytosine arabinoside in AML arising in
this age group (Anderson et al, 2002).
The role of MDR modulators is unclear although MDR
expression is more prevalent. A study examining the role of
PSC-833, a ciclosporin analogue with MDR-blocking activity,
was stopped prematurely due to an unexpectedly high death
rate in the PSC-833 arm (Baer et al, 2002).
Haemopoietic growth factors, G-CSF and granulocyte–
macrophage CSF (GM-CSF) reduce the duration of hospitalisation and febrile episodes after induction therapy but have no
effects on CR rate, CR duration or OS (Rowe et al, 1995;
Lowenberg et al, 1997a,b; Goldstone et al, 2001).
The optimal postremission therapy remains unclear as there
is no benefit from high-dose cytosine arabinoside-containing
consolidation regimens (Stone et al, 2001). In the EORTC/
HOVON study (Lowenberg et al, 1998) patients attaining CR
received one further course of the drugs used for induction
and were then randomised to receive low-dose cytosine
arabinoside or no further treatment: there was a marginal
improvement in DFS for those given low-dose cytarabine, but
no difference in OS.
There does not seem to be a role for extended consolidation
treatment (Goldstone et al, 2001) or for maintenance with
either low-intensity chemotherapy (Rees et al, 1996) or
interferon (Goldstone et al, 2001).
Aggressive salvage chemotherapy is seldom appropriate for
elderly patients unless the patient has good performance status
and has had a prolonged first remission. In a recent phase II
study (Sievers et al, 2001) of 142 patients with relapsed AML,
GO was infused at a dose of 9 mg/m2 on days 1 and 14: the
overall response rate was 30%, with half of these patients
achieving standard CR. However, caution must be exercised
following reports of cases of veno-occlusive disease in treated
patients (Giles et al, 2001).
Recommendations
1 For patients in whom intensive chemotherapy is deemed
justified (e.g. age < 70 years, good performance status,
white cell count <100 · 109/l, no adverse cytogenetic
abnormalities or MDR expression), standard induction
chemotherapy with daunorubicin (or an equivalent
ª 2006 The Authors
Guideline
2
3
4
5
anthracycline) for 3 d plus cytarabine for 7–10 d is
recommended (grade A recommendation, level Ib evidence). Where possible patients should be entered into
clinical trials.
There is no firm evidence to date to support the use of
MDR-blocking agents as an adjunct to induction chemotherapy (grade A recommendation, level Ib evidence).
Similarly there is insufficient evidence to support routine
use of G-CSF or GM-CSF with induction chemotherapy in
patients over 60 years of age, although this may be
appropriate if it is desirable to reduce hospitalisation or
antibiotic usage (grade A recommendation, level Ib
evidence).
The optimal postremission chemotherapy for older adult
patients with AML remains unclear. There does not seem
to be a role for extended consolidation chemotherapy or
maintenance treatment (grade A recommendation, level
Ib evidence).
GO shows promise as a salvage agent in patients with
relapsed disease, and may be preferable to further
intensive chemotherapy in this setting (grade B recommendation, level IIb evidence).
9.2. Non-intensive (palliative) chemotherapy
The aim of treatment is to control the white blood cell count
whilst minimising hospitalisation and providing the best QoL.
Low-dose cytarabine has been widely used (Cheson & Simon,
1987; Powell et al, 1989; Detourmignies et al, 1993), but
potentially useful oral agents include hydroxycarbamide, 6mercaptopurine and etoposide. The LRF AML 14 trial has
shown a highly significant survival benefit for low-dose
cytarabine, with no excess toxicity or supportive care requirements compared with hydroxycarbamide (Burnett et al,
2004b). While not curative, this treatment should now be
considered the standard against which to evaluate new
treatments.
Recommendations
1 Unless patients opting for palliative chemotherapy are
entered into clinical trials, treatment should be offered
with low-dose cytarabine (grade A; level Ib evidence).
10. Conclusions
Acute myeloid leukaemia is a complex group of disorders with
an expanding range of potential therapies. It requires specialist
care provided within the context of an experienced multidisciplinary team. Patients should be treated, wherever possible,
within an appropriate clinical trial. Outcomes have been
steadily improving over the last two or three decades. There
has been an increasing understanding of the risk factors that
influence outcome. New therapeutic options will become
available in the next few years including both new cytotoxic
agents, e.g. clofarabine, and targeted agents, e.g. FLT-3
antagonists; with the introduction of an expanding range of
molecular markers to enhance risk stratification and increasing
use of MRD monitoring, they are likely to herald a new era
involving a more tailored approach to the treatment of AML.
Disclaimer
While the advice and information in these guidelines is
believed to be true and accurate at the time of going to press,
neither the authors, nor the British Society for Haematology
nor the publishers accept any legal responsibility for the
content of these guidelines.
Acknowledgements
DG is supported by Leukaemia Research Fund of Great Britain
and the European LeukemiaNet.
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Appendix 1
Classification of evidence levels
Ia. Evidence obtained from meta-analysis of randomised
controlled trials.
Ib. Evidence obtained from at least one randomised controlled
trial.
IIa. Evidence obtained from at least one well-designed controlled study without randomisation.
IIb. Evidence obtained from at least one other type of welldesigned quasi-experimental study.
III. Evidence obtained from well-designed non-experimental
descriptive studies, such as comparative studies, correlation studies and case studies.
ª 2006 The Authors
473
Guideline
IV. Evidence obtained from expert committee reports or
opinions and/or clinical experiences of respected authorities.
Classification of grades of recommendations
A. Requires at least one randomised controlled trial as part of
a body of literature of overall good quality and consistency
addressing specific recommendation (evidence levels Ia and
Ib).
474
B. Requires the availability of well-conducted clinical studies
but no randomised clinical trials on the topic of recommendation (evidence levels IIa, IIb and III).
C. Requires evidence obtained from expert committee reports
or opinions and/or clinical experiences of respected
authorities. Indicates an absence of directly applicable
clinical studies of good quality (evidence level IV).
ª 2006 The Authors

Guidelines on the management of acute myeloid leukaemia in adults guideline

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