Guidelines on the management of acute myeloid leukaemia inadults

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, transplanta-

tion, 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 est-

erase). 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 CBFB-

MYH11 in non-acute promyelocytic leukaemia (APL) and

promyelocytic leukaemia (PML) and retinoic acid recep-

tor-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)

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; evi-

dence level IV).

4 Patients opting for non-intensive chemotherapy who are

not entered into clinical trials should be offered treat-

ment 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 cryoprecip-

itate 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 induc-

tion, followed by anthracycline-based consolidation ther-

apy (grade A; evidence level 1b).

7 Patients should undergo molecular monitoring after

treatment to guide further therapy (grade B; evidence

level IIa).

Correspondence: BCSH Secretary, British Society for Haematology,

100 White Lion Street, London N1 9PF, UK.

E-mail: bcsh@b-s-h.org.uk

guideline

ª 2006 The Authorsdoi:10.1111/j.1365-2141.2006.06314.x Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

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).

Pregnancy

1 AML in pregnancy should be managed jointly between

the haematologist and the obstetrician with full involve-

ment 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; evi-

dence level III).

Transplantation

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 remis-

sion may be considered for a haplo-identical transplant

but this should be in the context of a clinical trial

(recommendation grade C; evidence level IV).

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).

Acute myeloid leukaemia has an overall incidence of 3Æ4per 100 000. The disease is more common in the elderly and

two-thirds of all cases occur in those aged over 60 years. The

management of AML represents a significant clinical chal-

lenge. These guidelines give an up-to-date overview of

evidence-based and expert opinion-based optimum manage-

ment of AML in the UK. These guidelines are abbreviated

from the full version that is available on http://www.bcsh-

guidelines.com.

1. Methods

The PubMed, Cochrane and Medline databases in the English

language were searched using the key words ‘acute myeloid

leukaemia/leukemia’, ‘acute promyelocytic leukaemia/leuke-

mia’, ‘stem cell transplantation’ with subheadings ‘anthracy-

cline’, ‘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 repre-

sentation from the Leukaemia Research Fund and the

Leukaemia Care Society. The recommendations were agreed

using the Agree instrument (http://www.agreecollabora-

tion.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)

2. Classification of AML

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.

• Reducing the marrow blast percentage separating myelo-

dysplastic syndrome (MDS) from AML from 30% to 20%.

• Taking account of preceding MDS or myeloproliferative

disorders.

• Creating categories defined by certain non-random cyto-

genetic 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.

Guideline

ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 451

• 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 four-

colour 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. Immunopheno-

typing 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. Com-

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. Multi-

colour flow cytometry correlates well with morphological

blast characterisation.

• All patients should have conventional cytogenetics per-

formed 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 RT-

PCR 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 micropar-

ticulate 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 thediagnosis 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 CBFB-

MYH11 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 diagno-

sis 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

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

Guideline

ª 2006 The Authors452 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

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 ‘stand-

ard-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;

Frohling et al, 2004; Dohner 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;

Dohner 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 im-

proved 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 overex-

pression 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 ofAML

The British Committee for Standards in Haematology (BCSH)

has produced guidelines for the minimum standards for the

treatment of patients with haematological malignancy (Whit-

taker 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 II. Use of risk stratification to determine consolidation therapy.

Good risk Any patient with favourable genetic abnormal-

ities – 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),

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).

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 Hospitals providing conventional chemotherapy and

other forms of outpatient treatment, using dose levels

that would not be expected to produce prolonged

neutropenia

Level 2 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

Level 3 Facilities for autologous transplantation, not requiring

total body irradiation

Level 4 Centres with expertise in both allogeneic and autolo-

gous 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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ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 453

4.1. Patient support

Patients with AML require considerable support. Excellent

written information concerning the disease and its manage-

ment should be readily available, e.g. information provided by

CancerBACUP (http://www.cancerbacup.org.uk), the Leukae-

mia 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.

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 break-

through, 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

life-threatening consequence of tumour lysis syndrome and

may require emergency therapy and dialysis.

There is evidence that recombinant urate oxidase (rasbur-

icase) 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).

5.1.3. 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).

Guideline

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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 haematolog-

ical 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

38�C 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. Meta-

analysis 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 colony-

stimulating 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 che-

motherapy.

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 (Lowen-

berg 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.

Guideline

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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/anthracy-

cline-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 mitoxant-

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 remis-

sion 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 treat-

ment 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

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for remission induction can be repeated but usually non-cross-

resistant 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 m-

amsacrine, 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 chemosensi-

tive 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 cytarabine-

based chemotherapy.

The ALSG have treated all patients with high-dose cytara-

bine 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 man-

agement 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 associ-

ated 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 chemo-

therapy 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 malfor-

mations 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 devel-

opment. 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 anthracy-

cline 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 informa-

tion 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 involve-

ment 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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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; evi-

dence 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 estab-

lished 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 accom-

panied 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 chemother-

apy. 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).

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 approxi-

mately 0Æ5% of patients. Risks are greater in patients with a

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 consol-

idation 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 chemother-

apy 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 immunofluo-

rescence 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).

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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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 symp-

toms, 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

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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).

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 com-

monly 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 chemo-

therapy 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 sensitiv-

ity 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 standard-

ised 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

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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 induc-

tion, followed by anthracycline-based consolidation ther-

apy 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 single-

agent 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 trans-

plantation 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 AML-

HR) found no benefit for fludarabine + cytarabine, with or

without G-CSF, in comparison with standard ADE (cytara-

bine, 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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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 demon-

strated 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 auto-

transplant 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 chemo-

therapy 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%; chemother-

apy 46%) but both transplant arms demonstrated an improve-

ment 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

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 (UD-

SCT) 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 inter-

pretation 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 chemother-

apy 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 myeloabla-

tive 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

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ª 2006 The Authors462 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

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 trans-

plants. 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 allo-

reactivity.

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 transplan-

tation 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 autol-

ogous 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-transplanta-

tion 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 remis-

sion may be considered for a haplo-identical transplant

but this should be in the context of a clinical trial

(recommendation grade C; evidence level IV).

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 cyto-

genetic abnormalities, higher incidence of secondary leukaemia

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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 ara-

binoside 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 under-

represented 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 cyto-

genetic abnormalities and lack of MDR gene expression (Leith

et al, 1997).

There have been few randomised studies comparing inten-

sive with non-intensive chemotherapy. An EORTC random-

ised 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 chemo-

therapy 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:

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 daunorubi-

cin 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-thio-

guanine) 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 hospital-

isation 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

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anthracycline) for 3 d plus cytarabine for 7–10 d is

recommended (grade A recommendation, level Ib evi-

dence). Where possible patients should be entered into

clinical trials.

2 There is no firm evidence to date to support the use of

MDR-blocking agents as an adjunct to induction chemo-

therapy (grade A recommendation, level Ib evidence).

3 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).

4 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).

5 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 recom-

mendation, 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, 6-

mercaptopurine 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 require-

ments 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 multidis-

ciplinary 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.

References

Ali, R., Ozkalemkas, F., Ozcelik, T., Ozkocaman, V., Ozan, U., Kimya,

Y. & Tunali, A. (2003) Maternal and fetal outcomes in pregnancy

complicated with acute leukemia: a single institutional experience

with 10 pregnancies at 16 years. Leukemia Research, 27, 381–385.

AML Collaborative Group (1998) A systematic collaborative overview

of randomized trials comparing idarubicin with daunorubicin (or

other anthracyclines) as induction therapy for acute myeloid leuk-

aemia. British Journal of Haematology, 103, 100–109.

Anderson, J.E., Kopecky, K.J., Willman, C.L., Head, D., O’Donnell,

M.R., Luthardt, F.W., Norwood, T.H., Chen, I.-M., Balcerzak, S.P.,

Johnson, D.B. & Appelbaum, F.R. (2002) Outcome after induction

chemotherapy for older patients with acute myeloid leukemia is not

improved with mitoxantrone and etoposide compared to cytarabine

and daunorubicin: a Southwest Oncology Group study. Blood, 100,

3869–3876.

Artlich, A., Moller, J., Tschakaloff, A., Schwinger, E., Kruse, K. &

Gortner, L. (1994) Teratogenic effects in a case of maternal treat-

ment for acute myelocytic leukaemia–neonatal and infantile course.

European Journal of Pediatrics, 153, 488–491.

Aversa, F., Tabilio, A., Velardi, A., Cunningham, I., Terenzi, A., Falz-

etti, F., Ruggeri, L., Barbabietola, G., Aristei, C., Latini, P., Reisner,

Y. & Martelli, M.F. (1998) Treatment of high-risk acute leukemia

with T-cell-depleted stem cells from related donors with one fully

mismatched HLA haplotype. New England Journal of Medicine, 339,

1186–1193.

Aversa, F., Terenzi, A., Felicini, R., Carotti, A., Falcinelli, F., Tabilio, A.,

Velardi, A. & Martelli, M.F. (2002) Haploidentical stem cell trans-

plantation for acute leukemia. International Journal of Hematology,

76(Suppl. 1), 165–168.

Avvisati, G., Lo Coco, F., Diverio, D., Falda, M., Ferrara, F.,

Lazzarino, M., Russo, D., Petti, M.C. & Mandelli, F. (1996) AIDA

(All trans retinoic acid + idarubicin) in newly diagnosed acute

promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche

Maligne dell’Adulto (GIMEMA) Pilot Study. Blood, 88, 1390–

1398.

Avvisati, G., Petti, M.C., Lo Coco, F., Testi, A.M., Fazi, P., Specchia, G.,

Malagola, M., Di Bona, E., Recchia, A., Marmont, F., Buelli, M.,

Guideline

ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 465

Lazzarino, M., Di Raimondo, F., Leoni, F., Kropp, M.G., Vineri, D.,

Miccolis, I., Rossi, G., Venditti, A. & Mandelli, F. (2003) AIDA: the

Italian way of treating acute promyelocytic leukemia (APL), final

act. Blood, 102(Suppl. 1): 142a (abstract).

Baer, M.R., George, S.L., Dodge, R.K., O’Loughlin, K.L., Minderman,

H., Caligiuri, M.A., Anastasi, J., Powell, B.L., Kolitz, J.E., Schiffer,

C.A., Bloomfield, C.D. & Larson, R.A. (2002) Phase III study of the

multidrug resistance modulator PSC-833 in previously untreated

patients 60 years of age and older with acute myeloid leukaemia:

Cancer and Leukemia Group B Study 9720. Blood, 100, 1224–1232.

Baldus, C.D., Thiede, C., Soucek, S., Bloomfield, C.D., Thiel, E. &

Ehninger, G. (2006) BAALC expression and FLT3 internal tandem

duplication mutations in acute myeloid leukemia patients with

normal cytogenetics: prognostic implications. Journal of Clinical

Oncology, 24, 790–797.

Barjesteh van Waalwijk van Doorn-Khosravani, S., Erpelinck, C., van

Putten, W.L., Valk, P.J., van der Poel-van de Luytgaarde, S., Hack,

R., Slater, R., Smit, E.M., Beverloo, H.B., Verhoef, G., Verdonck,

L.F., Ossenkoppele, G.J., Sonneveld, P., de Greef, G.E., Lowenberg,

B. & Delwel, R. (2003) High EVI1 expression predicts poor survival

in acute myeloid leukemia: a study of 319 de novo AML patients.

Blood, 101, 837–845.

Baudard, M., Marie, J.P., Cadiou, M., Viguie, F. & Zittoun, R. (1994)

Acute myelogenous leukaemia in the elderly: retrospective study of

235 consecutive patients. British Journal of Haematology, 86, 82–91.

Bennett, J.M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton,

D.A.G. & Sultan, C. (1985a) Proposed revised criteria for the clas-

sification of acute myeloid leukaemia. Annals of Internal Medicine,

103, 626–629.

Bennett, J.M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton,

D.A.G. & Sultan, C. (1985b) Criteria for the diagnosis of acute

leukaemia of megakaryocytic lineage (M7). A report of the French–

American–British Cooperative Group. Annals of Internal Medicine,

103, 460–462.

Bennett, J.M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton,

D.A.G. & Sultan, C. (1991) Proposals for the recognition of mini-

mally differentiated acute myeloid leukaemia (AML-M0). British

Journal of Haematology, 78, 325–329.

Bensinger, W.I., Martin, P.J., Storer, B., Clift, R., Forman, S.J., Negrin,

R., Kashyap, A., Flowers, M.E.D., Lilleby, K., Chauncey, T.R., Storb,

R. & Appelbaum, F.R. (2001) Transplantation of bone marrow as

compared with peripheral-blood cells from HLA-identical relatives

in patients with hematologic cancers. New England Journal of

Medicine, 344, 175–181.

Bergmann, L., Miething, C., Maurer, U., Brieger, J., Karakas, T.,

Weidmann, E. & Hoelzer, D. (1997) High levels of Wilms’ tumor

gene (wt1) mRNA in acute myeloid leukemias are associated with a

worse long-term outcome. Blood, 90, 1217–1225.

Beutler, E., McMillan, R. & Spruce, W. (1982) The role of bone

marrow transplantation in the treatment of acute leukemia in re-

mission. Blood, 59, 1115–1117

Bishop, J.F., Lowenthal, P.M., Joshua, D., Matthews, J.P., Todd, D.,

Cobcroft, R., Whiteside, M.G., Kronenberg, H., Ma, D. & Dodds, A.

(1990) Etoposide in acute non-lymphoblastic leukaemia. Blood, 75,

27–32.

Bishop, J.F., Matthews, J.P., Young, G.A., Szer, J., Gillett, A., Joshua,

D., Bradstock, K., Enno, A., Wolf, M.M., Fox, R., Cobalt, R.,

Herrmann, R., Van Der Weyden, M., Lowenthal, R.M., Page, F.,

Garson, M.O. & Juneja, S. (1996) Randomized study of high-dose

cytarabine in induction in acute myeloid leukaemia. Blood, 87,

1710–1717.

Breccia, M., Cimino, G., Alimena, G., De Carolis, S., Lo Coco, F. &

Mandelli, F. (2002) AIDA treatment for high-risk acute promyelo-

cytic leukemia in a pregnant woman at 21 weeks of gestation.

Haematologica, 87, ELT12.

Breems, D.A., Wim, L.J., Huijgens, P.G., Ossenkoppele, G.J., Verhoef,

L.F., Vellenga, E., De Greef, G.E., Jacky, E., Van der Lelie, J.,

Boogaerts, M. & Lowenberg, B. (2005) Prognostic index for adult

patients with acute myeloid leukemia in first relapse. Journal of

Clinical Oncology, 23, 1969–1978.

British Committee for Standards in Haematology, Blood Transfusion

Task Force (2003) Guidelines for the use of platelet transfusions.

British Journal of Haematology, 122, 10–23

Bross, P.F., Beitz, J., Chen, G., Chen, X.H., Duffy, E., Kieffer, L., Roy,

S., Sridhara, R., Rahman, A., Williams, G. & Pazdur, R. (2001)

Approval summary: gemtuzumab ozogamicin in relapsed acute

myeloid leukemia. Clinical Cancer Research, 7, 1490–1496.

Bunjes, D. (2001) The current status of T-cell depleted allogeneic stem-

cell transplants in adult patients with AML. Cytotherapy, 3, 175–188.

Burnett, A.K. (2002) Acute myeloid leukemia: treatment of adults

under 60 years. Reviews in Clinical and Experimental Hematology, 6,

26–45.

Burnett, A.K., Goldstone, A.H., Stevens, R.M.F., Hann, I.M., Rees,

J.K.H., Gray, R.G. & Wheatley, K. (1998) Randomised comparison

of addition of autologous bone-marrow transplantation to intensive

chemotherapy for acute myeloid-leukaemia in first remission – re-

sults of MRC AML-10 trial. Lancet, 351, 700–708.

Burnett, A.K., Grimwade, D., Solomon, E., Wheatley, K. & Goldstone,

A.H. (1999) Presenting white blood cell count and kinetics of mo-

lecular remission predict prognosis in acute promyelocytic leukemia

treated with all-trans retinoic acid: result of the randomized MRC

trial. Blood, 93, 4131–4143.

Burnett, A.K., Wheatley, K., Goldstone, A.H., Gibson, B., Webb, D.,

Prentice, A.G. & Milligan, D.W. (2002a) MRC AML12: a compar-

ison of ADE vs MAE and S-DAT vs H-DAT ± retinoic acid for

induction and four vs five total courses using chemotherapy or stem

cell transplant in consolidation, in 3459 patients under 60 years with

AML. Blood, 100, 582a.

Burnett, A.K., Wheatley, K., Goldstone, A.H., Stevens, R.F., Hann,

I.M., Rees, J.H. & Harrison, G. (2002b) The value of allogeneic bone

marrow transplant in patients with acute myeloid leukaemia at

differing risk of relapse: results of the UK MRC AML 12 trial. British

Journal of Haematology, 118, 385–400.

Burnett, A.K., Hills, R.K., Goldstone, A.H., Milligan, D., Prentice, A.G.,

Hann, I., Webb, D., Gibson, B. & Wheatley, K. (2004a) The impact

of transplant in AML in 2nd CR: a prospective study of 741 in the

MRC AML 10 and 12 trials. Blood, 104, 620a.

Burnett, A.K., Milligan, D., Prentice, A.G., Goldstone, A.H., McMullin,

M.F. & Wheatley, K. (2004b) Low dose Ara-C versus hydroxyurea

with or without retinoid in older patients not considered fit for

intensive chemotherapy: the UK NCRI AML14 trial. Blood, 104,

872a.

Byrd, J.C., Edenfield, W.J., Shields, D.J. & Dawson, N.A. (1995) Ex-

tramedullary myeloid cell tumours in acute nonlymphocytic leuke-

mia: a review. Journal of Clinical Oncology, 13, 1800–1816.

Byrd, J.C., Weiss, R.B., Arthur, D.C., Lawrence, D., Baer, M.R., Davey,

F., Trikha, E.S., Carroll, A.J., Tantravahi, R., Qumsiyeh, M., Patil,

S.R., Moore, J.O., Mayer, R.J., Schiffer, C.A. & Bloomfield, C.D.

Guideline

ª 2006 The Authors466 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

(1997) Extramedullary leukemia adversely affects hematologic

complete remission rate and overall survival in patients with

t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461.

Journal of Clinical Oncology, 15, 466–475.

Cardonick, E. & Iacobucci, A. (2004) Use of chemotherapy during

human pregnancy. Lancet Oncology, 5, 283–291.

Cartwright, R.A., Alexander, F.E., Mc Kinney, P.A. & Ricketts, T.J.

(1990) Leukaemia and Lymphoma: An Atlas of Distribution within

Areas of England and Wales 1984–88. Leukaemia Research Fund,

London.

Cassileth, P.A., Harrington, D.P., Appelbaum, F.R., Lazarus, H.M.,

Rowe, J.M., Paietta, E., Willman, C., Hurd, D.D., Bennett, J.M.,

Blume, K.G., Head, D.R. & Wiernik, P. (1998) Chemotherapy

compared with autologous or allogeneic transplantation in the

management of acute myeloid leukaemia in first remission. New

England Journal of Medicine, 339, 1649–1656.

Cheson, B.D. & Simon, R. (1987) Low-dose Ara-C in acute non-

lymphocytic leukemia and myelodysplastic syndromes: a review of

20 years’ experience. Seminars in Oncology, 14(Suppl. 1), 126–133.

Cheson, B.D., Bennett, J.M., Kopecky, K.J., Buchner, T., Willman, C.L.,

Estey, E.H., Schiffer, C.A., Doehner, H., Tallman, M.S., Lister, T.A.,

Lo Coco, F., Willemze, R., Biondi, A., Hiddemann, W., Larson, R.A.,

Lowenberg, B., Sanz, M.A., Head, D.R., Ohno, R. & Bloomfield,

C.D. (2003) Revised recommendations for the International

Working Group for diagnosis, standardization of response criteria,

treatment outcomes, and reporting standards for therapeutic trials

in acute myeloid leukaemia. Journal of Clinical Oncology, 21, 4642–

4649.

Chomienne, C., Ballerini, P., Balitrand, N., Daniel, M.T., Fenaux, P.,

Castaigne, S. & Degos, L. (1990) All-trans retinoic acid in acute

promyelocytic leukemias. II. In vitro studies: structure–function

relationship. Blood, 76, 1710–1717.

Clift, R.A., Buckner, C.D., Appelbaum, F.R., Schoch, G., Petersen, F.B.,

Bensinger, W.I., Sanders, J., Sullivan, K.M., Storb, R. & Singer, J.

(1992) Allogeneic marrow transplantation during untreated first

relapse of acute myeloid leukemia. Journal of Clinical Oncology, 10,

1723–1729.

De Botton, S., Fawaz, A., Chevret, S., Dombret, H., Thomas, X., Sanz,

M., Guerci, A., San Miguel, J., de la Serna, J., Stoppa, A.M., Reman,

O., Stamatoulas, A., Fey, M., Cahn, J.Y., Sotto, J.J., Bourhis, J.H.,

Parry, A., Chomienne, C., Degos, L. & Fenaux, P. (2005) Autologous

and allogeneic stem-cell transplantation as salvage treatment of

acute promyelocytic leukemia initially treated with all-trans-retinoic

acid: a retrospective analysis of the European Acute Promyelocytic

Leukemia Group. Journal of Clinical Oncology, 23, 120–126.

Detourmignies, L., Wattel, E., Lai, J.L., Bauters, F. & Fenaux, P. (1993)

Is there still a role for low-dose cytosine arabinoside in de novo

acute myeloid leukemia in the elderly? A report on 77 cases. Annals

of Hematology, 66, 235–240.

Diverio, D., Rossi, V., Avvisati, G., De Santis, S., Pistilli, A., Pane, F.,

Saglio, G., Martinelli, G., Petti, M.C., Santoro, A., Pelicci, P.G.,

Mandelli, F., Biondi, A. & Lo Coco, F. (1998) Early detection of

relapse by prospective reverse transcriptase-polymerase chain reac-

tion analysis of the PML/RARa fusion gene in patients with acute

promyelocytic leukemia enrolled in the GIMEMA-AIEOP multi-

center ‘‘AIDA’’ trial. Blood, 92, 784–789.

Dohner, K., Tobis, K., Ulrich, R., Frohling, S., Benner, A., Schlenk, R.F.

& Dohner, H. (2002) Prognostic significance of partial tandem

duplications of the MLL gene in adult patients 16 to 60 years old

with acute myeloid leukemia and normal cytogenetics: a study of the

Acute Myeloid Leukemia Study Group Ulm. Journal of Clinical

Oncology, 20, 3254–3261.

Dohner, K., Schlenk, R.F., Habdank, M., Scholl, C., Rucker, F.G.,

Corbacioglu, A., Bullinger, L., Frohling, S. & Dohner, H. (2005)

Mutant nucleophosmin (NPM1) predicts favorable prognosis in

younger adults with acute myeloid leukemia and normal cytoge-

netics: interaction with other gene mutations. Blood, 106, 3740–

3746.

Dombret, H., Chastang, C., Fenaux, P., Reiffers, J., Bordessoule, D.,

Bouabdallah, R., Mandelli, F., Ferrant, A., Auzanneau, G., Tilly, H.,

Yver, A. & Degos, L. (1995) A controlled study of recombinant

human granulocyte colony-stimulating factor in elderly patients

after treatment for acute myelogenous leukemia. AML Cooperative

Study Group. New England Journal of Medicine, 332, 1678–1683.

Douer, D. & Tallman, M.S. (2005) Arsenic trioxide: new clinical

experience with an old medication in hematologic malignancies.

Journal of Clinical Oncology, 23, 2396–2410.

Douer, D., Hu, W., Giralt, S., Lill, M. & DiPersio, J. (2003) Arsenic

trioxide (trisenox) therapy for acute promyelocytic leukemia in the

setting of hematopoietic stem cell transplantation. Oncologist, 8,

132–140.

Estey, E., Thall, P., Andreeff, M., Beran, M., Kantarjian, H., O’Brien, S.,

Escudier, S., Robertson, L.E., Koller, C. & Kornblau, S. (1994) Use of

granulocyte-stimulating factor before during and after fludarabine

plus cytarabine induction therapy of newly diagnosed acute mye-

logenous leukemia or myelodysplastic syndromes: comparisons with

fludarabine plus cytarabine without granulocyte colony-stimulating

factor. Journal of Clinical Oncology, 12, 671–678.

Estey, E., Kornblau, S., Pierce, S., Kantarjian, H., Beran, M. & Keating,

M. (1996) A stratification system for evaluating and selecting

therapies in patients with relapsed or primary refractory acute

myelogenous leukemia. Blood, 88, 756–801.

Evans, G.D. & Grimwade, D. (1999) Extramedullary disease in acute

promyelocytic leukemia. Leukemia & Lymphoma, 33, 219–229,

Falanga, A. & Rickles, F.R. (2003) Pathogenesis and management of the

bleeding diathesis in acute promyelocytic leukaemia. Best Practice &

Research. Clinical Haematology, 16, 463–482.

Falini, B., Flenghi, L., Fagioli, M., Lo Coco, F., Cordone, I., Diverio, D.,

Pasqualucci, L., Biondi, A., Riganelli, D., Orleth, A., Liso, A., Mar-

telli, M.F., Pelicci, P.G. & Pileri, S. (1997) Immunocytochemical

diagnosis of acute promyelocytic leukemia (M3) with the mono-

clonal-antibody PG-M3 (anti-PML). Blood, 90, 4046–4053.

Falini, B., Mecucci, C., Tiacci, E., Alcalay, M., Rosati, R., Pasqualucci,

L., La Starza, R., Diverio, D., Colombo, E., Santucci, A., Bigerna, B.,

Pacini, R., Pucciarini, A., Liso, A., Vignetti, M., Fazi, P., Meani, N.,

Pettirossi, V., Saglio, G., Mandelli, F., Lo-Coco, F., Pelicci, P.G.,

Martelli, M.F. & GIMEMA Acute Leukemia Working Party (2005)

Cytoplasmic nucleophosmin in acute myelogenous leukemia with a

normal karyotype. New England Journal of Medicine, 352, 254–266.

Feliu, J., Juarez, S., Ordonez, A., Garcia-Paredes, M.L., Gonzalez-Bar-

on, M. & Montero, J.M. (1988) Acute leukemia and pregnancy.

Cancer, 61, 580–584.

Fenaux, P., Le Deley, M.C., Castaigne, S., Archimbaud, E., Chomienne,

C., Link, H., Guerci, A., Duarte, M., Daniel, M.T., Bowen, D.,

Huebner, G., Bauters, F., Fegueux, N., Fey, M., Sanz, M., Lowenberg,

B., Maloisel, F., Auzanneau, G., Sadoun, A., Gardin, C., Bastion, Y.,

Ganser, A., Jacky, E., Dombret, H., Chastang, C. & Degos, L. (1993)

Effect of all-trans retinoic acid in newly diagnosed acute promye-

Guideline

ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 467

locytic leukemia. Results of a multicenter randomized trial. Eur-

opean APL 91 Group. Blood, 82, 3241–3249–1200.

Fenaux, P., Chastang, C., Chevret, S., Sanz, M., Dombret, H., Ar-

chimbaud, E., Fey, M., Rayon, C., Huguet, F., Sotto, J.J., Gardin, C.,

Makhoul, P.C., Travade, P., Solary, E., Fegueux, N., Bordessoule, D.,

Miguel, J.S., Link, H., Desablens, B., Stamatoullas, A., Deconinck, E.,

Maloisel, F., Castaigne, S., Preudhomme, C. & Degos, L. (1999) A

randomized comparison of all trans retinoic acid (ATRA) followed

by chemotherapy and ATRA plus chemotherapy and the role of

maintenance therapy in newly diagnosed acute promyelocytic leu-

kemia. Blood, 94, 1192–1200.

Ferrara, F. & Del Vecchio, L. (2002) Acute myeloid leukemia with

t(8;21)/AML1/ETO: a distinct biological and clinical entity. Hae-

matologica, 87, 306–319.

Firkin, F., Matthews, J., Bradstock, K. & Wiley, J.S. (1999) A phase II

study of all-trans retinoic acid (ATRA) with prednisone prophylaxis

in the treatment of acute promyelocytic leukemia (APL). Blood,

94(Suppl. 2), 228b (abstract).

Forman, S.J., Spruce, W.E., Farbstein, M.J., Wolf, J.L., Scott, E.P.,

Nademanee, A.P., Fahey, J.L., Hecht, T., Zaia, J.A., Krance, R.A.,

Findley, D.O. & Blume, K.G. (1983) Bone marrow ablation followed

by allogeneic marrow grafting during first complete remission of

acute nonlymphocytic leukemia. Blood, 61, 439–442.

Frassoni, F. (2000) Commentary and randomized studies in acute

myeloid leukaemia: the double truth. Bone Marrow Transplantation,

25, 471–473.

Frohling, S., Schlenk, R.F., Stolze, I., Bihlmayr, J., Benner, A.,

Kreitmeier, S., Tobis, K., Dohner, H. & Dohner, K. (2004) CEBPA

mutations in younger adults with acute myeloid leukemia and

normal cytogenetics: prognostic relevance and analysis of

cooperating mutations. Journal of Clinical Oncology, 22, 624–633.

Fung, H.C., Stein, A., Slovak, M., O’donnell, M.R., Snyder, D.S.,

Cohen, S., Smith, D., Krishnan, A., Spielberger, R., Bhatia, R.,

Bhatia, S., Falk, P., Molina, A., Nademanee, A., Parker, P.,

Rodriguez, R., Rosenthal, J., Sweetman, R., Kogut, N., Sahebi, F.,

Popplewell, L., Vora, N., Somlo, G., Margolin, K., Chow, W., Smith,

E. & Forman, S.J. (2003) A long-term follow-up report on allogeneic

stem cell transplantation for patients with primary refractory acute

myelogenous leukemia: impact of cytogenetic characteristics on

transplantation outcome. Biology of Blood and Marrow Transplan-

tation, 9, 766–771.

Gale, R.P., Kay, H.E., Rimm, A.A. & Bortin, M.M. (1982) Bone-mar-

row transplantation for acute leukaemia in first remission. Lancet, 2,

1006–1009.

Gale, R.P., Buchner, T., Zang, M.J., Heinocke, A., Champlin, R.E.,

Dicke, K.A., Gluckman, E., Good, R.A., Gratwohl, A., Herzig, R.H.,

Keating, A., Klein, J.P., Marmont, A.M., Prentice, H.G., Rowlings,

P.A., Sobocinski, K.A., Speck, B., Weiner, R.S. & Horowitz, M.M.

(1996) HLA-identical sibling bone marrow transplants vs che-

motherapy for acute myelogenous leukemia in first remission.

Leukemia, 10, 1687–1691.

Gandhi, V., Kemena, A., Keating, M.J. & Plunkett, W. (1993) Cellular

pharmacology of fludarabine triphosphate in chronic lymphocytic

leukemia cells during fludarabine therapy. Leukemia & Lymphoma,

10, 49–56.

Giles, F.J., Kantarjian, H.M., Kornblau, S.M., Thomas, D.A., Garcia-

Manero, G., Waddelow, T.A., David, C.L., Phan, A.T., Colburn,

D.E., Rashid, A., Estey, E.H. (2001) Mylotarg (gemtuzumab ozo-

gamicin) therapy is associated with hepatic venoocclusive disease in

patients who have not received stem cell transplantation. Cancer, 92,

406–413.

Godwin, J.E., Kopecky, K.J., Head, D.R., Willman, C.L., Leith, C.P.,

Hynes, H.E., Balcerzak, S.P. & Appelbaum, F.R. (1998) A double-

blind placebo-controlled trial of granulocyte colony-stimulating

factor in elderly patients with previously untreated acute myeloid

leukemia: a Southwest Oncology Group study (9031). Blood, 91,

3607–3615

Goldman, S.C., Holcenberg, J.S., Finklestein, J.Z., Hutchinson, R.,

Kreissman, S., Johnson, F.L., Tou, C., Harvey, E., Morris, E. & Cairo,

M.S. (2001) A randomized comparison between rasburicase and

allopurinol in children with lymphoma or leukemia at high risk for

tumor lysis. Blood, 97, 2998–3003.

Goldstone, A.H., Burnett, A.K., Wheatley, K., Smith, A.G., Hutchin-

son, R.M. & Clark, R.E. (2001) Attempts to improve treatment

outcomes in acute myeloid leukemia (AML) in older patients: the

results of the United Kingdom Medical Research Council AML 11

trial. Blood, 98, 1302–1311.

Goulden, N., Virgo, P. & Grimwade, D. (2006) Minimal residual

disease directed therapy for childhood acute myeloid leukaemia: the

time is now. British Journal of Haematology, 134, 273–282.

Grimwade, D. (1999) The pathogenesis of acute promyelocytic leuk-

aemia: evaluation of the role of molecular diagnosis and monitoring

in the management of the disease. British Journal of Haematology,

106, 591–613.

Grimwade, D. & Lo Coco, F. (2002) Acute promyelocytic leukemia: a

model for the role of molecular diagnosis and residual disease

monitoring in directing treatment approach in acute myeloid leu-

kemia. Leukemia, 16, 1959–1973.

Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Rees,

J., Hann, I., Stevens, R., Burnett, A. & Goldstone, A. (1998) The

importance of cytogenetics on outcome in AML: analysis of 1,612

patients entered into the MRC AML 10 trial. Blood, 92, 2322–2333.

Grimwade, D., Biondi, A., Mozziconacci, M.-J., Hagemeijer, A., Berger,

R., Neat, M., Howe, K., Dastugue, N., Jansen, J., Radford-Weiss, I.,

Lo Coco, F., Lessard, M., Hernandez, J.-M., Delabesse, E., Head, D.,

Liso, V., Sainty, D., Flandrin, G., Solomon, E., Birg, F. & Lafage-

Pochitaloff, M. (2000) Characterization of acute promyelocytic

leukemia cases lacking the classical t(15;17): results of the European

working party. Blood, 96, 1297–1308.

Grimwade, D., Walker, H., Harrison, G., Oliver, F., Chatters, S.,

Harrison, C.J., Wheatley, K., Burnett, A.K. & Goldstone, A.J. (2001)

The predictive value of hierarchical cytogenetic classification in

older adults with acute myeloid leukemia (AML): analysis of 1065

patients entered into the United Kingdom Medical Research Council

AML11 trial. Blood, 98, 1312–1320.

Hann, I.M., Stevens, R.F., Goldstone, A., Rees, J.K.H., Wheatley, K.,

Gray, R.G. & Burnett, A.K. (1997) Randomized comparison of DAT

versus ADE as induction chemotherapy in children and young

adults with acute myeloid leukaemia. Results of the medical research

council’s 10th AML Trial (MRC AML 10). Blood, 89, 2311–2318.

Harousseau, J.L., Witz, B., Lioure, B., Hunault-Berger, M., Desab-

lens, B., Delain, M., Guilhot, F., Le Prise, P.Y., Abgrall, J.F.,

Deconinck, E., Guyotat, D., Vilque, J.P., Casassus, P., Tournilhac,

O., Audhuy, B. & Solary, E. (2000) Granulocyte colony-stimu-

lating factor after intensive consolidation chemotherapy in acute

myeloid leukemia: results of a randomized trial of the Groupe

Ouest-Est Leucemies Aigues Myeloblastiques. Journal of Clinical

Oncology, 18, 780–787.

Guideline

ª 2006 The Authors468 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

Harrousseau, J.L., Cahn, J.Y., Pignon, B., Witz, F., Milpied, N., Delain,

M., Lioure, B., Lamy, T., Desablens, B., Guilhot, F., Caillot, D.,

Abgrall, J.-F., Francois, S., Briere, J., Guyotat, D., Casassus, P.,

Audhuy, B., Tellier, Z., Hurteloup, P. & Herve, P. (1997) Com-

parison of autologous bone marrow transplantation and intensive

chemotherapy as post-remission therapy in adult acute myeloid

leukemia. The Group Ouese Est Leucemies Aigues Myeloblastiques

(GOELAM). Blood, 90, 2978–2986.

Head, D., Kopecky, K.J., Weick, J., Files, J., Ryan, D., Foucar, K.,

Montiel, M., Bickers, J., Fishleder, A., Miller, M., Spier, C., Hanson,

C., Bitter, M., Braziel, R., Mills, G., Welborn, J., Williams, W.,

Hewlett, J., Willman, C. & Appelbaum, F. (1995) Effect of aggressive

daunomycin therapy on survival in acute promyelocytic leukemia.

Blood, 86, 1717–1728.

Heil, G., Hoelzer, D., Sanz, M.A., Lechner, K., Liu Yin, J.A., Papa, G.,

Noens, L., Szer, J., Ganser, A., O’Brien, C., Matcham, J. & Barge, A.

(1997) A randomized, double-blind, placebo-controlled, phase III

study of filgrastim in remission induction and consolidation therapy

for adults with de novo acute myeloid leukemia. The International

Acute Myeloid Leukemia Study Group. Blood, 90, 4710–4718.

Holmes, R., Keating, M.J., Cork, A., Broach, Y., Trujillo, J., Dalton, Jr,

W.T., McCredie, K.B., Freireich, E.J. (1985) A unique pattern of

central nervous system leukemia in acute myelomonocytic leukemia

associated with inv(16)(p13q22). Blood, 65, 1071–1078.

Huang, M.-E., Ye, Y.-C., Chen, S.-R., Chai, J.-R., Lu, J.-X., Zhoa, L.,

Gu, L.-J. & Wang, Z.-Y. (1988) Use of all-trans retinoic acid in the

treatment of acute promyelocytic leukemia. Blood, 72, 567–572.

Jackson, G., Taylor, P., Smith, G.M., Marcus, R., Smith, A., Chu, P.,

Littlewood, T.,J., Duncombe, A., Hutchinson, M., Mehta, A.B.,

Johnson, S.A., Carey, P., Mackie, M.J., Ganly, P.S., Turner, G.E.,

Deane, M., Schey, S., Brookes, J., Tollerfield, S. & Wilson, M.P.

(2001) A multicentre open non-comparative phase II study of a

combination of fludarabine phosphate, cytarabine, granulocyte

colony-stimulating factor in relapsed and refractory acute myeloid

leukaemia and de novo refractory anaemia with excess of blasts in

transformation. British Journal of Haematology, 112, 127–137.

Jaffe, E.S., Harris, N.L., Stein, H. & Vardiman, J. (2001) Tumours of

Haematopoietic and Lymphoid Tissues. World Health Organisation

Classification of Tumours. IARC Press, Lyon.

Kawamura, S., Yoshiike, M., Shimoyama, T., Suzuki, Y., Itoh, J.,

Yamagata, K., Fukushima, K., Ogasawara, H., Saitoh, S. & Tsushima,

K. (1994) Management of acute leukemia during pregnancy: from

the results of a nationwide questionnaire survey and literature sur-

vey. Tohoku Journal of Experimental Medicine, 174, 167–175.

Kell, W.J., Burnett, A.K., Chopra, R., Yin, J.A.L., Clark, R.E., Rohatiner,

A., Culligan, D., Hunter, A., Prentice, A.G. & Milligan, D.W. (2003)

A feasibility study of simultaneous administration of gemtuzumab

ozogamicin with intensive chemotherapy in induction and con-

solidation in younger patients with acute myeloid leukemia. Blood,

102, 4277–4283.

Kern, W., Schoch, C., Haferlach, T., Braess, J., Unterhalt, M., Wor-

mann, B., Buchner, T. & Hiddemann, W. (2000) Multivariate ana-

lysis of prognostic factors in patients with refractory and relapsed

acute myeloid leukemia undergoing sequential high-dose cytosine

arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance

of cytogenetic abnormalities. Leukemia, 14, 226–231.

Kerr, J.P., Liakopolou, E., Brown, J., Cornish, J.M., Fleming, D.,

Massey, E., Oakhill, A., Pamphilon, D.H., Robinson, S.P., Totem, A.,

Valencia, A.M. & Marks, D.I. (2003) The use of stimulated granu-

locyte transfusions to prevent recurrence of past severe infections

after allogeneic stem cell transplantation. British Journal of Haema-

tology, 123, 114–118.

Kersey, J.H., Ramsay, N.K., Kim, T., McGlave, P., Krivit, W., Levitt, S.,

Filipovich, A., Woods, W., O’Leary, M., Coccia, P. & Nesbit, M.E.

(1982) Allogeneic bone marrow transplantation in acute non-

lymphocytic leukemia: a pilot study. Blood, 60, 400–403.

Kottaridis, P.D., Gale, R.E., Frew, M.E., Harrison, G., Langabeer, S.E.,

Belton, A.A., Walker, H., Wheatley, K., Bowen, D.T., Burnett, A.K.,

Goldstone, A.H. & Linch, D.C. (2001) The presence of a FLT3 in-

ternal tandem duplication in patients with acute myeloid leukemia

(AML) adds important prognostic information to cytogenetic risk

group and response to the first cycle of chemotherapy: analysis of

854 patients from the United Kingdom Medical Research Council

AML 10 and 12 trials. Blood, 98, 1752–1759.

Kroger, N., Zabelina, T., Kruger, W., Renges, H., Stute, N., Rischewski,

J., Sonnenberg, S., Ayuk, F., Togel, F., Schade, U., Fiegel, H., Ertt-

mann, R., Loliger, C., Zander, A.R. (2002) in vivo T cell depletion

with pre-transplant anti-thymocyte globulin reduces graft versus

host disease without increasing relapse in good risk myeloid leuk-

aemia patients from matched related donors. Bone Marrow Trans-

plantation, 29, 683–689.

Langabeer, S.E., Walker, H., Gale, R.E., Wheatley, K., Burnett, A.K.,

Goldstone, A.H. & Linch, D.C. (1997a) Frequency of CBF beta/

MYH11 fusion transcripts in patients entered into the U.K. MRC

AML trials. The MRC adult leukaemia working party. British Journal

of Haematology, 96, 736–739.

Langabeer, S.E., Walker, H., Rogers, J.R., Burnett, A.K., Wheatley, K.,

Swirsky, D., Goldstone, A.H. & Linch, D.C. (1997b) Incidence of

AML1/ETO fusion transcripts in patients entered into the MRC

AML trials. MRC adult leukaemia working party. British Journal of

Haematology, 99, 925–928.

Larson, R.S. & Tallman, M.S. (2003) Retinoic acid syndrome: mani-

festations, pathogenesis and treatment. Best Practice & Research.

Clinical Haematology, 16, 453–461.

Leith, C.P., Kopecky, K.J., Godwin, J., McConnell, T., Slovak, M.L.,

Chen, I.-M., Head, D.R., Appelbaum, F.R. & Willman, C.L. (1997)

Acute myeloid leukemia in the elderly: assessment of

multidrug resistance (MDR1) and cytogenetics distinguishes bio-

logic subgroups with remarkably distinct responses to standard

chemotherapy. A Southwest Oncology Group study. Blood, 89,

3323–3329.

Leith, C.P., Kopecky, K.J., Chen, I.M., Eijdems, L., Slovak, M.L.,

McConnell, T.S., Head, D.R., Weick, J., Grever, M.R., Appelbaum,

F.R. & Willman, C.L. (1999) Frequency and clinical significance of

the expression of the multidrug resistance proteins MDR1/P-gly-

coprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest

Oncology Group Study. Blood, 94, 1086–1099.

Leoni, F., Gianfaldoni, G., Annunziata, M., Fanci, R., Ciolli, S.,

Nozzoli, C. & Ferrara, F. (2002) Arsenic trioxide therapy for relapsed

acute promyelocytic leukemia: a bridge to transplantation. Haema-

tologica, 87, 485–489.

Leopold, L.H. & Willemze, R. (2002) The treatment of acute myeloid

leukemia in first relapse: a comprehensive review of the literature.

Leukemia & Lymphoma, 43, 1715–1727.

Lo Coco, F., Diverio, D., Avvisati, G., Petti, M.C., Meloni, G., Pogliani,

E.M., Biondi, A., Rossi, G., Carlo-Stella, C., Selleri, C., Martino, B.,

Specchia, G. & Mandelli, F. (1999) Therapy of molecular relapse in

acute promyelocytic leukemia. Blood, 94, 2225–2229.

Guideline

ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 469

Lo Coco, F., Romano, A., Mengarelli, A., Diverio, D., Iori, A.P., Moleti,

M.L., De Santis, S., Cerretti, R., Mandelli, F. & Arcese, W. (2003)

Allogeneic stem cell transplantation for advanced acute promyelo-

cytic leukemia: results in patients treated in second molecular re-

mission or with molecularly persistent disease. Leukemia, 17, 1930–

1933.

Lo Coco, F., Cimino, G., Breccia, M., Noguera, N.I., Diverio, D.,

Finolezzi, E., Pogliani, E.M., Di Bona, E., Micalizzi, C., Kropp, M.,

Venditti, A., Tafuri, A. & Mandelli, F. (2004) Gemtuzumab ozoga-

micin (Mylotarg) as a single agent for molecularly relapsed acute

promyelocytic leukemia. Blood, 104, 1995–1999.

Lowenberg, B., Zittoun, R., Kerkhofs, H., Jehn, U., Abels, J., Debus-

scher, L., Cauchie, C., Peetermans, M., Solbu, G. & Suciu, S.,. (1989)

On the value of intensive remission-induction chemotherapy in

elderly patients of 65 + years with acute myeloid leukemia: a

randomized phase III study of the European Organization for

Research and Treatment of Cancer Leukemia Group. Journal of

Clinical Oncology, 7, 1268–1274.

Lowenberg, B., Boogaerts, M. & Daenen, S. (1997a) Value of different

modalities of granulocyte macrophage colony stimulating factor

applied during or after induction therapy of acute myeloid leukemia.

Journal of Clinical Oncology, 15, 3496–3506.

Lowenberg, B., Suciu, S., Archimbaud, E., Ossenkoppele, G., Verhoef,

G.E.G., Vellenga, E., Wijermans, P., Berneman, Z., Dekker, A.W.,

Stryckmans, P., Schouten, H., Jehn, U., Muus, P., Sonneveld, P.,

Dardenne, M. & Zittoun, R. (1997b) Use of recombinant granulo-

cyte-macrophage colony-stimulating factor during and after remis-

sion induction chemotherapy in patients aged 61 years and older

with acute myeloid leukaemia (AML): final report of AML-11, a

phase III randomised study of the Leukemia Cooperative Group of

the European Organization for the Research and Treatment of

Cancer and the Dutch Belgian Hemato-oncology Cooperative

Group (HOVON). Blood, 90, 2952–2961.

Lowenberg, B., Suciu, S., Archimbaud, E., Haak, H., Stryckmans, P., de

Cataldo, R., Dekker, A.W., Berneman, Z.N., Thyss, A., van der Lelie,

J., Sonneveld, P., Visani, G., Fillet, G., Hayat, M., Hagemeijer, A.,

Solbu, G. & Zittoun, R. (1998) Mitoxantrone versus daunorubicin in

induction-consolidation chemotherapy-the value of low-dose

cytarabine for maintenance of remission, and an assessment of

prognostic factors in acute myeloid leukemia in the elderly: final

report. European Organization for the Research and Treatment of

Cancer and the Dutch-Belgian Hemato-Oncology Cooperative

Hovon Group. Journal of Clinical Oncology, 16, 872–881.

Lowenberg, B., van Putten, W., Theobald, M., Gmur, J., Verdonck, L.,

Sonneveld, P., Fey, M., Schouten, H., de Greef, G., Ferrant, A.,

Kovacsovics, T., Gratwohl, A., Daenen, S., Huijgens, P. & Boogaerts,

M. (2003) Effect of priming with granulocyte colony-stimulating

factor on the outcome of chemotherapy for acute myeloid leukemia.

New England Journal of Medicine, 349, 743–752.

Marcucci, G., Baldus, C.D., Ruppert, A.S., Radmacher, M.D., Mrozek,

K., Whitman, S.P., Kolitz, J.E., Edwards, C.G., Vardiman, J.W.,

Powell, B.L., Baer, M.R., Moore, J.O., Perotti, D., Caligiuri, M.A.,

Carroll, A.J., Larson, R.A., de la Chapelle, A. & Bloomfield, C.D.

(2005) Overexpression of the ETS-related gene, ERG, predicts a

worse outcome in acute myeloid leukemia with normal karyotype: a

Cancer and Leukemia Group B study. Journal of Clinical Oncology,

23, 9234–9242.

Mayer, R.J., Davis, R.B., Schiffer, C.A., Berg, D., Powell, B.L., Schul-

man, P., Omura, G.A., Moore, J.O., McIntyre, O.R. & Frei, E. (1994)

Intensive post-remission chemotherapy in adults with acute myeloid

leukaemia. Cancer Leukaemia Group B. New England Journal of

Medicine, 331, 896–903.

Meloni, G., Vignetti, M., Avvisati, G., Capria, S., Micozzi, A., Giona, F.

& Mandelli, F. (1996) BAVC regimen and autograft for acute

myelogenous leukemia in second complete remission. Bone Marrow

Transplantation, 18, 693–698.

Meloni, G., Diverio, D., Vignetti, M., Avvisati, G., Capria, S., Petti,

M.C., Mandelli, F. & Lo Coco, F. (1997) Autologous bone-marrow

transplantation for acute promyelocytic leukemia in 2nd remission –

prognostic relevance of pretransplant minimal residual disease

assessment by reverse-transcription polymerase chain reaction of the

pml/rar-alpha fusion gene. Blood, 90, 1321–1325.

Milligan, D.W., Wheatley, K., Littlewood, T., Craig, J.I., Burnett, A.K.,

NCRI Haematological Oncology Clinical Studies Group (2006)

Fludarabine and cytosine are less effective than standard ADE che-

motherapy in high-risk acute myeloid leukemia, and addition of G-

CSF and ATRA are not beneficial: results of the MRC-HR rand-

omized trial. Blood, 107, 4614–4622.

Mistry, A.R., Wessel Pedersen, E., Solomon, E. & Grimwade, D. (2003)

The molecular pathogenesis of acute promyelocytic leukaemia: im-

plications for the clinical management of the disease. Blood Reviews,

17, 71–97.

Murphy, M., Brown, M., Carrington, P., Hall, G., Jeffrey, R., Machin,

S., Taylor, C. & Thomas, D. (2003) Guidelines for the use of platelet

transfusion. British Journal of Haematology, 122, 10–23.

Murray, N.A., Acolet, D., Deane, M., Price, J. & Roberts, I.A. (1994)

Fetal marrow suppression after maternal chemotherapy for leukae-

mia. Archives of Disease in Childhood. Fetal & Neonatal Edition, 71,

F209–F210.

O’Connor, S.J., Forsyth, P.D., Dalal, S., Evans, P.A., Short, M.A.,

Schiach, C., Jack, A.S. & Morgan, G.J. (1997) The rapid diagnosis of

acute promyelocytic leukaemia using PML (5E10) monoclonal an-

tibody. British Journal of Haematology, 99, 597–604.

Ohno, R., Naoe, T., Kanamaru, A., Yoshida, M., Hiraoka, A.,

Kobayashi, T., Ueda, T., Minami, S., Morishima, Y. & Saito, Y.

(1994) A double blind controlled study of granulocyte colony sti-

mulating factor started two days before induction chemotherapy in

refractory acute myeloid leukaemia. Blood, 83, 2086–2092.

Orfao, A., Chillon, M.C., Bortolucci, A.M., Lopes-Berges, M.A.,

Garcia-Sanz, R., Gonzalez, M., Tabernero, M.D., Garcia-Marcos,

M.A., Rasillo, A.I., Hernandez-Rivas, J. & San Miguel, J.F. (1999)

The flow cytometric pattern of CD34, CD15 and CD13 expression in

acute myeloblastic leukemia is highly characteristic of the presence

of PML-RARa gene rearrangements. Haematologica, 84, 405–412.

Ozer, H., Armitage, J.O., Bennett, C.L., Crawford, J., Demetri, G.D.,

Pizzo, P.A., Schiffer, C.A., Smith, T.J., Somlo, G., Wade, J.L., Winn,

R.J., Wozniak, A.J., Somerfield, M.R., for ASCO growth factors

expert panel. (2000) Update of recommendations for the use of

haematopoietic colony-stimulating factors: evidence based, clinical

practice guidelines. Journal of Clinical Oncology, 18, 3558–3585.

Pagliuca, A., Carrington, P., Pettengell, R., Rule, S., Keidan, J. & on

behalf of the Haemato-Oncology Task Force of the British Com-

mittee for Standards in Haematology (2003) Guidelines on the use

of colony-stimulating factors in haematological malignancies. British

Journal of Haematology, 123, 22–33.

Papadopoulos, E.B., Carabasi, M.H., Castro-Malaspina, H., Childs,

B.H., Mackinnon, S., Boulad, F., Gillio, A.P., Kernan, N.A., Small,

T.N., Szabolcs, P., Taylor, J., Yahalom, J., Collins, N.A., Bleau, S.A.,

Guideline

ª 2006 The Authors470 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

Black, P.M., Heller, G., O’Reilly, R.J. & Young, J.W. (1998) T cell

depleted allogeneic bone marrow transplantation as postremission

therapy for acute myelogenous leukemia: freedom from relapse in

the absence of graft versus host disease. Blood, 91, 1083–1090.

Paul, M., Soares-Weiser, K., Grozinsky, S. & Leibovici, L. (2005) Beta-

lactam Versus beta-Lactam–aminoglycoside Combination Therapy in

Cancer Patients with Neutropenia (Cochrane Review) The Cochrane

Library, Issue 1. John Wiley & Sons, Ltd, Chichester, UK.

Petti, M.C., Pinazzi, M.B., Diverio, D., Romano, A., Petrucci, M.T.,

De Santis, S., Meloni, G., Tafuri, A., Mandelli, F. & Lo Coco, F.

(2001) Prolonged molecular remission in advanced acute

promyelocytic leukaemia after treatment with gemtuzumab

ozogamicin (Mylotarg CMA-676). British Journal of Haematology,

115, 63–65.

Powell, B.L., Capizzi, R.L., Muss, H.B., Bearden, J.D., Lyerly, E.S.,

Rosenbaum, D.L., Morgan, T.M., Richards, F., Jackson, D.V. &

White, D.R. (1989) Low-dose ara-C therapy for acute myelogenous

leukemia in elderly patients. Leukemia, 3, 23–28.

Powles, R., Sirohi, B. & Kulkarni, S. (2003) Investigation and man-

agement of hyperleukocytosis in adults. In: The Effective Prevention

and Management of Common Complications of Induction Che-

motherapy in Haematological Malignancy (ed. by R. Pinketon, A.

Rohatiner & A. Miles), Ch. 3, pp. 33–50. Aesculapius Medical Press,

St Bartholomews Hospital, London.

Preisler, H., Davis, R.B., Kirshner, J., Dupre, E., Richards,F.3d., Hoa-

gland, H.C., Kopel, S., Levy, R.N., Carey, R. & Schulman, P. (1987)

Comparison of three remission induction regimens and two post-

induction strategies for the treatment of acute nonlymphocytic

leukemia: a cancer and leukemia group B study. Blood, 69, 1441–

1449.

Preudhomme, C., Sagot, C., Boissel, N., Cayuela, J.M., Tigaud, I., de

Botton, S., Thomas, X., Raffoux, E., Lamandin, C., Castaigne, S.,

Fenaux, P. & Dombret, H. (2002) Favorable prognostic significance

of CEBPA mutations in patients with de novo acute myeloid leu-

kemia: a study from the Acute Leukemia French Association

(ALFA). Blood, 100, 2717–2723.

Rebulla, P., Finazzi, G., Marangoni, F.,, Avvisati, G., Gugliotta, L.,

Tognoni, G., Barbui, T., Mandelli, F. & Sirchia, ?? (1997) The

threshold for prophylactic platelet transfusions in adults with acute

myeloid leukaemia. Gruppo Italiano Malattie Ematologiche Maligne

dell’Adulto. New England Journal of Medicine, 337, 1870–1875.

Rees, J.K., Gray, R.G., Swirsky, D. & Hayhoe, F.G. (1986) Principal

results of the Medical Research Council’s 8th acute myeloid leuk-

aemia trial. Lancet, 2, 1236–1241.

Rees, J.K.H., Gray, R.G. & Wheatley, K. (1996) Dose intensification in

acute myeloid leukaemia: greater effectiveness at lower cost. Prin-

cipal report of the Medical Research Council’s AML 9 study. MRC

Leukaemia in Adults Working Party. British Journal of Haematology,

94, 89–98.

Reisner, Y., Gur, H., Reich-Zeliger, S., Martelli, M.F. & Bachar-Lustig,

E. (2003) Hematopoietic stem cell transplantation across major

genetic barriers: tolerance induction by megadose CD34 cells and

other veto cells. Annals of the New York Academy of Sciences, 996,

72–79.

Reynoso, E.E., Shepherd, F.A., Messner, H.A., Farquharson, H.A.,

Garvey, M.B. & Baker, M.A. (1987) Acute leukemia during preg-

nancy: the Toronto Leukemia Study Group experience with long-

term follow-up of children exposed in utero to chemotherapeutic

agents. Journal of Clinical Oncology, 5, 1098–1106.

Rowe, J.M., Andersen, J.W., Mazza, J.J., Bennett, J.M., Paietta, E.,

Hayes, F.A., Oette, D., Cassileth, P.A., Stadtmauer, E.A. & Wiernik,

P.H. (1995) A randomized placebo-controlled phase III study of

granulocyte–macrophage colony-stimulating factor in adult patients

(>55 to 70 years of age) with acute myelogenous leukemia: a study

of the Eastern Cooperative Oncology Group (E1490). Blood, 86,

457–462.

Rowe, J.M., Neuberg, D., Friedenberg, W., Bennett, J.M., Paietta, E.,

Makary, A.Z., Liesveld, J.L., Abboud, C.N., Dewald, G., Hayes, F.A.,

Tallman, M.S., Wiernik, P.H. & Eastern Cooperative Oncology

(2004) A phase 3 study of three induction regimens and of priming

with GM-CSF in older adults with acute myeloid leukemia: a trial by

the Eastern Cooperative Oncology Group. Blood, 103, 479–485.

Sainty, D., Liso, V., Cantu-Rajnoldi, A., Head, D., Mozziconacci, M.-J.,

Arnoulet, C., Benattar, L., Fenu, S., Mancini, M., Delabesse, E.,

Duchayne, E., Mahon, F.-X., Gutierrez, N., Birg, F., Biondi, A.,

Grimwade, D., Lafage-Pochitaloff, M., Hagemeijer, A. & Flandrin, G.

(2000) A new morphological classification system for acute pro-

myelocytic leukemia distinguishes cases with underlying PLZF-

RARa rearrangements. Blood, 96, 1287–1296.

Sanz, M.A., Martın, G., Rayon, C., Esteve, J., Gonzalez, M., Dıaz-

Mediavilla, J., Bolufer, P., Barragan, E., Terol, M.J., Gonzalez, J.D.,

Colomer, D., Chillon, C., Rivas, C., Gomez, T., Ribera, J.M.,

Bornstein, R., Roman, J., Calasanz, M.J., Arias, J., Alvarez, C.,

Ramos, F. & Deben, G. (1999) A modified AIDA protocol with

anthracycline-based consolidation results in high antileukemic-

positive acute efficacy and reduced toxicity in newly diagnosed

PML/RAR promyelocytic leukemia. Blood, 94, 3015–3021.

Sanz, M.A., Martın, G., Gonzalez, M., Leon, A., Rayon, C., Rivas, C.,

Colomer, D., Amutio, E., Capote, F.J., Milone, G.A., de la Serna, J.,

Roman, J., Barragan, E., Bergua, J., Escoda, L., Parody, R., Negri, S.,

Calasanz, M.J. & Bolufer, P. (2004a) Risk-adapted treatment of acute

promyelocytic leukemia with all-trans-retinoic acid and anthracy-

cline monochemotherapy: a multicenter study by the PETHEMA

group. Blood, 103, 1237–1243.

Sanz, M.A., Vellenga, E., Rayon, C., Dıaz-Mediavilla, J., Rivas, C.,

Amutio, E., Arias, J., Deben, G., Novo, A., Bergua, J., de la Serna, J.,

Bueno, J., Negri, S., Beltran de Heredia, J.M. & Martın, G. (2004b)

All-trans-retinoic acid and anthracycline monochemotherapy for

the treatment of elderly patients with acute promyelocytic leukemia.

Blood, 104, 3490–3493.

Sanz, M.A., Tallman, M.S. & Lo-Coco, F. (2005) The tricks of the trade

for the appropriate management of newly diagnosed acute pro-

myelocytic leukemia. Blood, 105, 3019–3025.

Sayer, H.G., Kroger, M., Beyer, J., Kiehl, M., Klein, S.A., Schaefer-

Eckart, K., Schwerdtfeger, R., Siegert, W., Runde, V., Theuser, C.,

Martin, H., Schetelig, J., Beelen, D.W., Fauser, A., Kienast, J.,

Hoffken, K., Ehninger, G. & Bornhauser, M. (2003) Reduced in-

tensity conditioning for allogeneic hematopoietic stem cell trans-

plantation in patients with acute myeloid leukemia: disease status by

marrow blasts is the strongest prognostic factor. Bone Marrow

Transplantation, 31, 1089–1095.

Schnittger, S., Kinkelin, U., Schoch, C., Heinecke, A., Haase, D., Ha-

ferlach, T., Buchner, T., Wormann, B., Hiddemann, W. & Grie-

singer, F. (2000) Screening for MLL tandem duplication in 387

unselected patients with AML identify a prognostically unfavorable

subset of AML. Leukemia, 14, 796–804.

Schnittger, S., Schoch, C., Kern, W., Mecucci, C., Tschulik, C., Martelli,

M.F., Haferlach, T., Hiddemann, W. & Falini, B. (2005) Nucleo-

Guideline

ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474 471

phosmin gene mutations are predictors of favorable prognosis in

acute myelogenous leukemia with a normal karyotype. Blood, 106,

3733–3739.

Sierra, J., Storer, B., Hansen, J.A., Martin, P.J., Petersdorf, E.W.,

Woolfrey, A., Matthews, D., Sanders, J.E., Storb, R., Appelbaum,

F.R. & Anasetti, C. (2000) Unrelated donor marrow transplantation

for acute myeloid leukemia: an update of the Seattle experience.

Bone Marrow Transplantation, 26, 397–404.

Sievers, E.L., Larson, R.A., Stadtmauer, E.A., Estey, E., Lowenberg, B.,

Dombret, H., Karanes, C., Theobald, M., Bennett, J.M., Sherman,

M.L., Berger, M.S., Eten, C.B., Loken, M.R., Van Dongen, J.J.,

Bernstein, I.D., Appelbaum, F.R., Mylotarg Study Group. (2001)

Efficacy and safety of gemtuzumab ozogamicin in patients with

CD33-positive acute myeloid leukemia in first relapse. Journal of

Clinical Oncology, 19, 3244–3254.

Stone, R.M. & Mayer, R.J. (1990) The unique aspects of acute pro-

myelocytic leukemia. Journal of Clinical Oncology, 8, 1913–1921.

Stone, R.M., Berg, D.T., George, S.L., Dodge, R.K., Paciucci, P.A.,

Schulman, P., Lee, E.J., Moore, J.O., Powell, B.L. & Schiffer, C.A.

(1995) Granulocyte-macrophage colony-stimulating factor after in-

itial chemotherapy for elderly patients with primary acute myelo-

genous leukemia. Cancer and Leukemia Group B. New England

Journal of Medicine, 332, 1671–1677.

Stone, R.M., Berg, D.T., George, S.L., Dodge, R.K., Paciucci, P.A.,

Schulman, P.P., Lee, E.J., Moore, J.O., Powell, B.L., Baer, M.R.,

Bloomfield, C.D. & Schiffer, C.A. (2001) Post-remission therapy in

older patients with de novo acute myeloid leukaemia (AML): A

randomised trial comparing mitozantrone/intermediate dose cytar-

abine with standard dose cytarabine (CALGB Study 8923). Blood,

98, 548–553.

Suciu, S., Mandelli, F., de Witte, T., Zittoun, R., Gallo, E., Labar, B., De

Rosa, G., Belhabri, A., Giustolisi, R., Delarue, R., Liso, V., Mirto, S.,

Leone, G., Bourhis, J.H., Fioritoni, G., Jehn, U., Amadori, S., Fazi,

P., Hagemeijer, A. & Willemze, R. (2003) Allogeneic compared with

autologous stem cell transplantation in the treatment of patients

younger than 46 years with acute myeloid leukemia (AML) in first

complete remission (CR1): an intention-to-treat analysis of the

EORTC/GIMEMA AML-10 trial. Blood, 102, 1232–1240.

Swirsky, D.M. & Richards, S.J. (2001) Laboratory diagnosis of acute

myeloid leukaemia. Bailliere’s Best Practice & Research. Clinical

Haematology, 14, 1–17.

Swirsky, D.M., Li, Y.S., Mathews, J.G., Flemans, R.J., Rees, J.K. &

Hayhoe, F.G. (1984) 8;21 Chromosomal translocation in acute

granulocytic leukaemia: cytological, cytochemical and clinical fea-

tures. British Journal of Haematology, 56, 199–213.

Szydlo, R., Goldman, J.M., Klein, J.P., Gale, R.P., Ash, R.C., Bach, F.H.,

Bradley, B.A., Casper, J.T., Flomenberg, N., Gajewski, J.L., Gluck-

man, E., Henslee-Downey, P.J., Hows, J.M., Jacobsen, N., Kolb, H.J.,

Lowenberg, B., Masaoka, T., Rowlings, P.A., Sondel, P.M., van

Bekkum, D.W., van Rood, J.J., Vowels, M.R., Zhang, M.J. &

Horowitz, M.M. (1997) Results of allogeneic bone marrow trans-

plants for leukemia using donors other than HLA-identical siblings.

Journal of Clinical Oncology, 15, 1767.

Takeshita, A., Ohno, R., Hirashima, K., Toyama, K., Okuma, M., Saito,

H., Ikeda, Y., Tomonaga, M. & Asano, S. (1995) A randomized

double-blind controlled study of recombinant human granulocyte

colony-stimulating factor in patients with neutropenia induced by

consolidation chemotherapy for acute myeloid leukemia. Rinsho

Ketsueki. Japanese Journal of Clinical Hematology, 36, 606–614.

Tallman, M.S. & Kwaan, H.C. (1992) Reassessing the hemostatic dis-

order associated with acute promyelocytic leukemia. Blood, 79, 543–

553.

Tallman, M.S., Hakimian, D., Shaw, J.M., Lissner, G.S., Russell, E.J.,

Variakojis, D. (1993) Granulocytic sarcoma is associated with the

8;21 translocation in acute myeloid leukemia. Journal of Clinical

Oncology, 11, 690–697.

Tallman, M.S., Andersen, J.W., Schiffer, C.A., Appelbaum, F.R.,

Feusner, J.H., Ogden, A., Shepherd, L., Willman, C., Bloomfield,

C.D., Rowe, J.M. & Wiernik, P.H. (1997) All-trans-retinoic acid in

acute promyelocytic leukemia. New England Journal of Medicine,

337, 1021–1028.

Tallman, M.S., Rowlings, P.A., Milone, G., Zhang, M.-J., Perez, W.S.,

Weisdorf, D., Keating, A., Gale, R.P., Geller, R.B., Laughlin, M.J.,

Lazarus, H.M., Luger, S.M., McCarthy, P.L., Rowe, J.M., Saez, R.A.,

Vowles, M.R. & Horowitz, M.M. (2000) Effect of postremission

chemotherapy before human leukocyte antigen-identical sibling

transplantation for acute myelogenous leukemia in first complete

remission. Blood, 96, 1254–1258.

Tallman, M.S., Nabhan, C., Feusner, J.H. & Rowe, J.M. (2002) Acute

promyelocytic leukemia: evolving therapeutic strategies. Blood, 99,

759–767.

Tallman, M.S., Lefebvre, P., Baine, R.M., Shoji, M., Cohen, I., Green,

D., Kwaan, H.C., Paietta, E. & Rickles, F.R. (2004) Effects of all-

trans retinoic acid or chemotherapy on the molecular regulation of

systemic blood coagulation and fibrinolysis in patients with acute

promyelocytic leukemia. Journal of Thrombosis and Haemostasis, 2,

1341–1350.

Taussig, D.C., Davies, A.J., Cavenagh, J.D., Oakervee, H., Synderco-

mbe-Court, D., Kelsey, S., Amess, J.A., Rohatiner, A.Z., Lister, T.A.

& Barnett, M.J. (2003) Durable remissions of myelodysplastic syn-

drome and acute myeloid leukemia after reduced-intensity allo-

grafting. Journal of Clinical Oncology, 21, 3060–3065.

Tilly, H., Castaigne, S., Bordessoule, D., Casassus, P., Le Prise, P.Y.,

Tertian, G., Desablens, B., Henry-Amar, M. & Degos, L. (1990) Low-

dose cytarabine versus intensive chemotherapy in the treatment of

acute nonlymphocytic leukemia in the elderly. Journal of Clinical

Oncology, 8, 272–279.

Tomas, F., Gomez-Garcia de Soria, V., Lopez-Lorenzo, J.L., Arranz, R.,

Figuera, A., Camara, R., Alegre, A. & Fernandez-Ranada, J.M. (1996)

Autologous or allogeneic bone marrow transplantation for acute

myeloblastic leukemia in second complete remission. Importance of

duration of first complete remission in final outcome. Bone Marrow

Transplantation, 17, 979–984.

Usuki, K., Urabe, A., Masaoka, T., Ohno, R., Mizoguchi, H., Hamaj-

ima, N., Miyazaki, T., Niitsu, Y., Yoshida, Y., Miura, A., Shibata, A.,

Abe, T., Miura, Y., Ikeda, Y., Nomura, T., Nagao, T., Saitou, H.,

Shirakawa, S., Ohkuma, M., Matsuda, T., Nakamura, T., Horiuchi,

A., Kuramoto, A., Kimura, I., Irino, S., Niho, Y., Takatsuki, K.,

Tomonaga, M., Uchino, H. & Takaku, F. (2002) Efficacy of granu-

locyte colony-stimulating factor in the treatment of acute myelo-

genous leukaemia: a multicentre randomized study. British Journal

of Haematology, 116, 103–112.

Vahdat, L., Maslak, P., Miller, W.H., Eardley, A., Heller, G., Schein-

berg, D.A. & Warrell, R.P. (1994) Early mortality and the retinoic

acid syndrome in acute promyelocytic leukemia: impact of leuko-

cytosis, low-dose chemotherapy, PML-RARa isoform, and CD13

expression in patients treated with All-trans retinoic acid. Blood, 84,

3843–3849.

Guideline

ª 2006 The Authors472 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474

Verhaak, R.G., Goudswaard, C.S., van Putten, W., Bijl, M.A., Sanders,

M.A., Hugens, W., Uitterlinden, A.G., Erpelinck, C.A., Delwel, R.,

Lowenberg, B. & Valk, P.J. (2005) Mutations in nucleophosmin

(NPM1) in acute myeloid leukemia (AML): association with other

gene abnormalities and previously established gene expression sig-

natures and their favorable prognostic significance. Blood, 106,

3747–3754.

Voak, D., Chapman, J., Finney, K., Forman, K., Kelsey, P., Knowles,

S.M., Napier, J.F., Phillips, P., Mitchell, R., Murphy, M.F.,

Waters, A.H. & Wood, J.K. (1996) Guidelines for gamma

irradiation of blood components for the prevention of trans-

fusion-associated graft-versus-host disease. Transfusion Medicine,

6, 261–271.

Watson, M., Wheatley, K., Harrison, G.A., Zittoun, R., Gray, R.G.,

Goldstone, A.H. & Burnett, A.K. (1999) Severe adverse impact on

sexual functioning and fertility of bone marrow transplantation,

either allogeneic or autologous, compared with consolidation che-

motherapy alone: analysis of the MRC AML 10 trial. Cancer, 86,

1231–1239.

Watson, M., Buck, G., Wheatley, K., Homewood, J.R., Goldstone,

A.H., Rees, J.K. & Burnett, A.K. (2004) UK Medical Research

Council AML 10 trial. Adverse impact of bone marrow trans-

plantation on quality of life in acute myeloid leukaemia patients;

analysis of the UK Medical Research Council AML 10 Trial.

Randomized Controlled Trial. European Journal of Cancer, 40, 971–

978.

Weick, J.K., Kopecky, K.J., Appelbaum, F.R., Head, D.R., Kingsbury,

L.L., Balcerzak, S.P., Bickers, J.N., Hynes, H.E., Welborn, J.L., Si-

mon, S.R. & Grever, M. (1996) A randomized investigation of high-

dose versus standard-dose cytosine arabinoside with daunorubicin

in patients with previously untreated acute myeloid leukemia: a

Southwest Oncology Group study. Blood, 88, 2841–2851,

Weltermann, A., Fonatsch, C., Haas, O.A., Greinix, H.T., Kahls, P.,

Miterbauer, G., Jager, U., Geissler, K., Valent, P., Sperr, W., Knobl,

P., Schwarzinger, I., Gleiss, A. & Lechner, K. (2004) Impact of Cy-

togenetics on the prognosis of adults with de novo AML in first

relapse. Leukemia, 18, 293–302.

Wheatley, K. (2002) Which patients with acute myeloid leukaemia

should receive a bone marrow transplantation? – A statistician’s

view. British Journal of Haematology, 118, 353–356.

Wheatley, K., Burnett, A.K., Goldstone, A.H., Gray, R.G., Hann, I.M.,

Harrison, C.J., Rees, J.K., Stevens, R.F. & Walker, H. (1999) A

simple, robust, validated and highly predictive index for the de-

termination of risk-directed therapy in acute myeloid leukaemia

derived from the MRC AML 10 trial. United Kingdom Medical

Research Council’s Adult and Childhood Leukaemia Working Par-

ties. British Journal of Haematology, 107, 69–79.

Whittaker, J.A., Sommerfield, G.P., Clough, J.V., Franklin, I.M., Gib-

son, B.E.S., Gorst, D.W., Murphy, M.F., Smith, J.G., Thomas, J.S. &

Wood, J.K. (1995) British Committee for Standards in Haematology

guidelines on he provision of facilities for the care of adult patients

with haematological malignancies. Clinical and Laboratory Haema-

tology, 17, 3–10.

Wiley, J.S. & Firkin, F.C. (1995) Reduction of pulmonary toxicity by

prednisolone prophylaxis during all-trans retinoic acid treatment of

acute promyelocytic leukemia. Leukemia, 9, 774–778.

Witz, F., Sadoun, A., Perrin, M.C., Berthou, C., Briere, J., Cahn, J.Y.,

Lioure, B., Witz, B., Francois, S., Desablens, B., Pignon, B., Le Prise,

P.Y., Audhuy, B., Caillot, D., Casassus, P., Delain, M., Christian, B.,

Tellier, Z., Polin, V., Hurteloup, P. & Harousseau, J.L. (1998) A

placebo-controlled study of recombinant human granulocyte–

macrophage colony-stimulating factor administered during and

after induction treatment for de novo acute myelogenous leukemia

in elderly patients. Groupe Ouest Est Leucemies Aigues Myeloblas-

tiques (GOELAM). Blood, 91, 2722–2730.

Wong, R., Giralt, S.A., Martin, T., Couriel, D.R., Anagnostopoulos, A.,

Hosing, C., Andersson, B.S., Cano, P., Shahjahan, M., Ippoliti, C.,

Estey, E.H., McMannis, J., Gajewski, J.L., Champlin, R.E. & de Lima,

M. (2003) Reduced-intensity conditioning for unrelated donor he-

matopoietic stem cell transplantation as treatment for myeloid

malignancies in patients older than 55 years. Blood, 102, 3052–3059.

Yin, J. & Grimwade, D. (2002) Minimal residual disease evaluation in

acute myeloid leukaemia. Lancet, 360, 160–162.

Yin, J.A., Wheatley, K., Rees, J.K. & Burnett, A.K. (2001) Comparison

of ‘sequential’ versus ‘standard’ chemotherapy as re-induction

treatment, with or without cyclosporine, in refractory/relapsed acute

myeloid leukaemia (AML): results of the UK Medical research

Council AML-R trial. British Journal of Haematology, 122, 164–165.

Zittoun, R.A., Mandelli, F., Willemze, R., de Witte, T., Labar, B.,

Resegotti, L., Leoni, F., Damasio, E., Visani, G., Papa, G., Caronia,

F., Hayat, M., Stryckmans, P., Rotoli, B., Leoni, P., Peetermans,

M.E., Dardenne, M., Vegna, M.L., Petti, M.C., Solbu, G. & Suciu, S.

(1995) Autologous or allogeneic bone marrow transplantation

compared with intensive chemotherapy in acute myelogenous leu-

kemia. EORTC and GIMEMA groups. New England Journal of

Medicine, 332, 217–223.

Zittoun, R., Suciu, S., Mandelli, F., de Witte, T., Thaler, J., Stryckmans,

P., Hayat, M., Peetermans, M., Cadiou, M., Solbu, G., Petti, M.C. &

Willemze, R. (1996) Granulocyte-macrophage colony-stimulating

factor associated with induction treatment of acute myelogenous

leukemia: a randomized trial by the European Organization for

Research and Treatment of Cancer Leukemia Cooperative Group.

Journal of Clinical Oncology, 14, 2150–2159.

Zittoun, R., Suciu, S., Watson, M., Solbu, G., Muus, P., Mandelli, F.,

Stryckmans, P., Peetermans, M., Thaler, J., Resegotti, L., Dardenne,

M. & Willemze, R. (1997) Quality of life in patients with acute

myelogenous leukaemia in prolonged first complete remission after

bone marrow transplantation (allogeneic or autologous) or che-

motherapy: a cross-sectional study of the EORTC-GIMEMA AML

8A trial. Bone Marrow Transplantation, 20, 307–315.

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 con-

trolled study without randomisation.

IIb. Evidence obtained from at least one other type of well-

designed quasi-experimental study.

III. Evidence obtained from well-designed non-experimental

descriptive studies, such as comparative studies, correla-

tion studies and case studies.

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IV. Evidence obtained from expert committee reports or

opinions and/or clinical experiences of respected author-

ities.

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).

B. Requires the availability of well-conducted clinical studies

but no randomised clinical trials on the topic of recom-

mendation (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).

Guideline

ª 2006 The Authors474 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 135, 450–474