Critical Reviews in Oncology/Hematology 50 (2004) 197222

Adult acute myeloid leukaemia

Matthew Smith a, , Michael Barnett a , Renato Bassan b , Gemma Gatta c , Carlo Tondini d , Wolfgang Kern e
c

St. Bartholomews Hospital, London, UK b Ospedali Riuniti, Bergamo, Italy Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy d START Project and Ospedali Riuniti, Bergamo, Italy e University Hospital Grosshadern, Munich, Germany Accepted 18 November 2003

Contents
1. General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Referral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Selected reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Morphological classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Cytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Immunophenotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Molecular analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. Research investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Physical and laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Laboratory ndings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Pathological diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Appropriate diagnostic sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Appropriate handling of diagnostic specimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Staging procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Staging classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Clinical prognostic factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Response to therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.3. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Biological prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Other variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 199 199 199 199 199 200 200 200 201 201 201 202 202 202 203 203 203 203 203 203 203 203 203 204 204 204 204 204 204 204 204 204 205

2.

3.

4.

5.

Corresponding author.

1040-8428/$ see front matter 2003 Published by Elsevier Ireland Ltd. doi:10.1016/j.critrevonc.2003.11.002

198 5.4.

M. Smith et al. / Critical Reviews in Oncology/Hematology 50 (2004) 197222 Potential prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Multi-drug resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2. FLT3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3. Research prognostic markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3.1. Pharmacokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3.2. Genetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3.3. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 205 205 206 206 206 206 206 206 206 206 206 207 207 207 208 209 209 209 209 209 209 209 210 210 210 211 211 211 211 211 212 212 212 212 212 212 213 213 213 213 213 213 214 214 214 214 214 214 214 215 215 221

5.5. 6.

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Supportive care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. Metabolic complications and venous access. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. Coagulopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Principles of remission induction phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Remission induction chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Side effects and complications of remission induction chemotherapy . . . . . . . . . . . . . . . . . 6.2.3. Growth factors during remission induction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Principles of continuation (post-remission) therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Consolidation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. central nervous system (CNS) prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3. Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Myeloablative therapy with infusion of stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.1. Autologous stem cell rescue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.2. Allogeneic stem cell transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Frontline strategy for all patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Post-remission strategy in good risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7. Post-remission strategy in intermediate risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8. Post-remission strategy in poor risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9. Salvage therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.1. Relapsed AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.2. Refractory AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10. Acute promyelocytic leukaemia (APML) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.1. Induction therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.2. Consolidation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.3. Maintenance therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.4. Relapsed acute promyelocytic leukaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11. AML in the elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12. AML during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13. Re-staging and relapse criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.1. Denition of response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.2. Re-staging strategy and response evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14. Experimental therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14.1. New cytotoxic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14.2. Biological agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14.3. Future developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Late sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Treatment and late effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Secondary tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. General principles and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Suggested protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.

8.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract The curability of acute myeloid leukaemia (AML) in a fraction of adult patients was demonstrated a long time ago. Currently, the probability of cure is consistently above fty per cent in patients with de novo disease expressing favourable-risk associated cytogenetic features. Even better, the cure rate exceeds 75% in the acute promyelocytic subtype since the introduction of retinoic acid-containing regimens. In the meantime, continuing progress in supportive care systems and stem cell transplant procedures is making myeloablative therapies, when needed, somewhat less toxicand thereby more effectivethan in the recent past. Therefore, evidence is accumulating to indicate an improved therapeutic trend over the years, with the notable exception of older (>55 years) patients with adverse-risk chromosomal aberrations and/or leukemia secondary to myelodysplasia or prior cancer-related chemotherapy and/or radiotherapy. This review conveys the many facets

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of this progress, focusing on diagnostic subsets, risk classes, newer biological issues and conventional as well as innovative therapeutic interventions with or without autologous/allogeneic stem cell transplantation. 2003 Published by Elsevier Ireland Ltd.
Keywords: Acute myeloid leukaemia (AML); Diagnosis; Prognosis; Treatment; Recommendations

1. General information 1.1. Incidence Acute myeloid leukaemia (AML) accounts for about 30% of all leukaemias in adults, and about 18,300 new cases are diagnosed in Europe each year, about 0.6% of all cancers. Overall, AML is marginally less common than chronic lymphoid leukaemia, the most common leukaemia in adults, but is ve times more frequent under the age of 50 [1,2]. The annual incidence rates in Europe were from 2 and 4 per 100,000 [2]. The trend in overall incidence of AML have generally been stable or slowly increasing. However, incidence in England and Wales has risen by about 70% in both sexes since 1971. Mortality has also rose between 1971 and 1995, but to a lesser degree, by 40% for men and 26% for women [3,4]. 1.2. Survival In Europe, relative survival for adults diagnosed with AML during 19901994 was 34% at 1 year and 15% at 5 years, with no difference between men and women. Five year relative survival decreased markedly with age from 37 to 2% from the youngest (1545 years) to the oldest age group of patients (75 years and over). There are major between-country differences in survival for European patients with AML: some Eastern European countries like Poland and Estonia were characterised by low 5 years relative survival (less than 2%). In some Northern European countries (Sweden, Finland), and Austria, France and Switzerland survival was generally higher (more than 15%) [5]. In Europe as a whole, 5 year survival rose by 3% for men and 8% for women [6]. 1.3. Risk factors Ionizing radiation (nuclear bombs, medical procedures) and occupational exposure to benzene are associated with AML [7]. AML may occur in a small proportion of cancer patients treated with chlorambucil, cyclophosphamide, melphalan, thiotepa, treosulphan or etoposide, as well as certain combinations of chemotherapy [8]. Electricians, power line workers, and electronics and other workers thought to be exposed to non-ionising electrical and magnetic elds have been reported to have an elevated leukaemia (primarily AML) risk in some but non all stud-

ies in which assessment of occupational exposure was based on job titles [9]. A large study of Canadian and French utility workers demonstrated a small excess of AML [10]. Benzene-exposed shoe, leather, rubber and chemical manufacturing workers have been repeatedly shown to have excess leukaemia (primarily AML that is 210-fold increased) [11]. There are recognised autosomal dominant and recessive cases of familial AML [12,13] in addition to associations with a variety of genetic syndromes including trisomy 21 [14] and those characterised by defective DNA repair (eg Fanconis anaemia, ataxia telangiectasia and Blooms syndrome) [15]. 1.4. Referral The diagnosis of AML can be complex and there exists a need for accurate risk stratication. From the standpoint of therapy, an up to date knowledge of current treatment protocols and experimental therapies as well as an ability to deliver optimal supportive care are mandatory. Accurate data collection and appropriate follow-up are also important. It is therefore recommended on a type C basis that new patients be referred to centres with experience in the treatment of AML. 1.5. Selected reviews Acalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, et al. Common themes in the pathogenesis of acute myeloid leukaemia. Oncogene 2001;20:568094. Burnett AK. Treatment of acute myeloid leukaemia in younger patients. Best Pract Res Clin Haem 2001;14(1): 95118. Gilliland DG, Grifn JD. The roles of FLT3 in haematopoiesis and leukaemia. Blood 2002;100(5):153242. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization classication of tumours: pathology and genetics of tumours of haemopoietic and lymphoid tissues. Lyon: IARC Press; 2001. Kelly LM, Gilliland DG. Genetics of myeloid leukaemias. Annu Rev Hum Genet 2002;3:17998. Lowenberg B, Downing JR, Burnett AK. Acute myeloid leukaemia. New Eng J Med 1999;341(14) 105162. Piller GJ. Leukaemia: a brief historical review from ancient times to 1950. Br J Haem 2001;112:28292. Rohatiner AZ, Lister TA. Acute myelogenous leukaemia in adults. In: Henderson ES, Lister TA, Greaves MF, editors. Leukaemia. 7th ed. Philadelphia: Saunders; 2002. p. 485518.

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Lowenberg B, Burnett AK. Acute myeloid leukaemia in adults. In: Degos L, Linch D, Lowenberg B, editors. Textbook of malignant haematology. London: Martin Dunitz; 2003. Schoch C, Haferlach T. Cytogenetics in acute myeloid leukaemia. Curr Oncol Rep 2002;4:3907. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer 2002;2: 50213. Warrell RP, de The H, Wang ZY, Degos L. Acute promyelocytic leukaemia. New Engl J Med 1993;329(3):17787.

easily identiable. There are several excellent publications on this subject [18]. FAB classication system for AML Category M0 M1 M2 M3 M3 variant M4 M5a M5b M6 M7
a

Morphology AML with no differentiationa AML without maturation AML with granulocytic maturation Hypergranular APML Hypogranular variant APML Acute myelomonocytic leukaemia Acute monoblastic leukaemia Acute monocytic leukaemia Erythroleukaemia Megakaryoblastic leukaemiaa

Incidence (%) [18] 3 1520 2530 510 2530 210 35 312

2. Pathology and biology 2.1. Diagnostic studies 2.1.1. Morphological classication Light microscopy supplemented by cytochemistry is the principle method for the diagnosis of AML and its further subclassication. Examination of bone marrow and peripheral blood specimens stained with Wright Giemsa or MayGrunwaldGiemsa (MGG) stain provides a rapid initial and frequently conclusive diagnosis. Myeloblasts are characteristically large cells with a low nuclear-cytoplasmic ratio, a nely stippled nuclear chromatin pattern and often multiple prominent nucleoli. Cytoplasmic azurophilic granules are usually present with Auer rods visible in over one third of cases. Such blasts occur in a background of other lineages appearing in varying proportion and degree of maturation. In some cases, this can include mature eosinophils and basophils. Evidence of trilineage dysplasia is noted in 1015% of de novo cases. Acute promyelocytic leukaemia (APML) is morphologically distinct in over 90% of cases. These cells are typically hypergranular with Auer rods present, often collected into bundles or faggots. One quarter of cases of APML appear as a microgranular variant. This should be suspected in cases with minimal granulation, bi-lobed nuclei with a folded conguration, monocytoid features and strong myeloperoxidase (MPO) staining, CD2, CD9 and CD33 positivity and HLA-DR or CD34 negativity. The main classication system used for AML to date has been that of the FrenchAmericanBritish (FAB) group which was devised in 1976 [16] and revised in 1985 [17]. It is recommended that a 500 cell count be performed on diagnostic marrow samples as classication will depend on accurate morphological and cytochemical quantitation of the degree of differentiation and level of lineage commitment. The diagnosis of AML in this system rests on the presence of greater than 30% myeloid blasts in the bone marrow with more than 3% of blasts being positive on Sudan Black (SBB) or MPO staining. There are two exceptions to this: (1) AML M6 where there is erythroid predominance of 50% and at least 30% of the non-erythroid cells are blasts; (2) AML M3 where the morphology of the hypergranular promyelocyte is

Typically diagnosed on immunophenotyping.

The World Health Organisation (WHO) has recently modied the FAB classication [19,20] with the aim of identifying discrete clinical entities within AML as a whole. WHO classication of AML Category AML with recurrent cytogenetic translocations Morphology AML with features of t(8;21)(q22;q22) AML with features of t(15;17)(q22;q12) AML with features of inv(16)(p13;q22) AML with 11q23 abnormalities AML with multi-lineage dysplasia AML arising in previous MDS 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] Incidence (%) [21] 512 1015 5 35 1015

AML with MDS-related features Acute myeloid leukaemia, unspecied

4050

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201

Acute basophilic leukaemia Acute panmyelosis with myelobrosis AML, therapyrelated Alkylating agent-related Epipodophyllotoxinrelated Other types 510

The WHO classication has lowered the threshold between AML and MDS from 30 to 20% bone marrow blasts reecting evidence that suggests RAEB-t is biologically and prognostically related to de novo AML rather than to MDS. Additional changes are the diagnosis of AML at blasts counts under 20% in the presence of one of the main four chromosomal translocations and the addition of several new categories that reect the aetiology of the leukaemia either arising from a pre-existing dysplasia or as a consequence of exposure to chemotherapy. Acute basophilic leukaemia and acute panmyelosis with myelobrosis have also appeared as new categories within AMLunspecied. 2.1.2. Cytochemistry Cytochemistry is standard on a type C basis. All cases of AML, except M0, require MPO or SBB positivity. Positive reactions tend to be coarse and granular. MPO may be negative by light microscopy, or only showing up as a faint ne granularity. This is particularly the case in subtypes M0 or M5, M6 and M7 with minimal maturation or basophilic/mast cell leukaemias. These cases would require immunophenotyping in order to detect cytoplasmic MPO positivity. Other stains such as -naphthyl acetate esterase (ANAE) or non-specic esterase, (NSE) can be used to identify a monocytic component. A NSE stain is essential if AML-M2, M4 or M5 are suspected. Monoblasts are diffusely positive, although punctate positivity is seen in megakaryoblasts and erythroblasts. Chloroacetate esterase (CAE) staining is positive in the late myeloblast and early promyelocyte stage. CAE can be combined with ANAE in a combined esterase test to identify separate granulocytic and monocytic components. The CAE should not replace either the MPO or SBB staining, as it is less sensitive, often being negative in early myeloblasts, and hence is not essential. Acid phosphatase and PAS stains are also no longer necessary, however, a Perls iron stain may help in detecting dyserythropoietic ring sideroblasts and a toluidine blue stain may identify an abnormal basophil or mast cell component. Lysozyme although not routinely performed may be helpful in individual patients in identifying a monocytic component. 2.1.3. Immunophenotyping Immunophenotyping is essential if the blasts are not obviously myeloid or when cytochemistry is uninformative

or equivocal. Options for analysis include ow cytometry or immunocytochemistry [22]. The latter however, is less reliable for cytoplasmic markers and is more subjective. All haemopoietic cells will express the common leucocyte antigen (CD45) and 4060% of cases will express the stem cell marker CD34. Most cases express highly specic myeloid antigens such as CD117 (c-kit) and cytoplasmic myeloperoxidase (cMPO). Other myeloid antigens, such as CD33, CD15 and CD13, are less specic, and can occur in certain cases of acute lymphoblastic leukaemia (ALL). As well as conrming the myeloid origin of the blasts, immunophenotyping can identify evidence of monocytic, erythroid, or megakaryocytic differentiation. Markers associated with lineage differentiation include CD14 and CD11b in AML-M4 and M5, glycophorin A in AML-M6 and platelet glycoproteins CD41, CD42 and CD61 in AML-M7. Two consequences of the increased use of immunophenotyping have been the recognition of the category AML-M0 and of bi-phenotypic/bilineage leukaemias. In AML-M0 less than 3% of blasts are positive by MPO or SBB staining yet are conrmed to be myeloid by the demonstration of either MPO antigen positivity with immunophenotyping or by the ultrastructural expression of myeloperoxidase using electron microscopy [23]. Biphenotypic leukaemias express both lymphoid and myeloid antigens and there exist well-validated scoring systems for the recognition of these leukaemias. Distinction should be made between these entities and lymphoid antigen positive AML (Ly + AML), as expression of other less specic lymphoid antigens is a recognised feature in approximately 2030% of cases of AML. CD7 is most commonly expressed (approximately 20% of cases) although CD19, CD2, CD20 or CD10 may be present. Immunocytochemistry may sometimes be used to diagnose genetic translocations, for example, anti-PML monoclonal antibodies will show a microspeckled distribution in the presence of a PML-RAR fusion protein rather than obvious nuclear bodies seen with wild-type PML. 2.1.4. Cytogenetics Cytogenetic evaluation is recommended on a type C basis in all cases of acute leukaemia. Metaphase G banding can detect the majority of chromosomal abnormalities and karyotypic changes, both numerical and structural, that occur in 5070% of adults with AML [24]. Trisomy 8 is the most common numerical cytogenetic abnormality seen. Certain structural chromosomal translocations are recognised to have characteristic morphological features [25]. t(8;21) translocation: 90% of cases are classied as AML-M2 [26]. This entity is associated with characteristic prominent Auer rods, marrow eosinophilia, salmon-coloured cytoplasmic granules in early myeloid

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cells, large cytoplasmic vacuoles, CD19 positivity and strong MPO staining. Other associations are high CD34 positivity, CD56 expression, low CD33 expression and loss of the Y chromosome in men. t(15;17) which is seen in the majority of cases of AML-M3 and M3-variant. inv(16): 90% are classied as AML-M4Eo. Abnormalities of 11q23: typically have monocytic or myelomonocytic morphology and are often seen in infant and congenital leukaemias or podophyllotoxin-related leukaemias. t(9;11)(p21;q23) and t911;19)(q23;p13.3) are the most commonly seen translocations at this site. t(6;9): M1 or M4 morphology with marrow basophilia. inv(3): M1 morphology with trilineage dysplasia and peripheral thrombocytosis. t(8;16): myelomonocytic features and associated with erythrophagocytosis.

mechanisms for abrogation of function including activating tandem duplication mutations, activating point mutations, dominant negative mutations and inactivating mutations with resultant haploinsufciency. Screening for such mutations remains investigational, however, mutation of FLT3 is increasingly seen as an adverse prognostic factor (see Section 5.4). Analysis of FLT3 mutation status is now being incorporated into current trials and may soon be extended into standard practice for those patients with intermediate risk AML. Work is underway using a genomic approach to AML genetics including 24 colour FISH, spectral karyotyping and M-FISH or CGH arrays [41]. These studies have the potential to identify multiple small insertions and deletions throughout the genome. Gene expression analysis using either cDNA or oligonucleotide array technology has been shown to separate AML from acute lymphoblastic leukaemia and to separate the common translocations from each other [42,43]. Their use, however, remains investigational. 2.2. Differential diagnosis Alternative diagnoses for AML include MDS, ALL, biphenotypic acute leukaemia, myeloid blast phase of chronic myeloid leukaemia, transformed myelobrosis, secondary metastases, e.g. alveolar rhabdomyosarcoma or even gross megaloblastic anaemia (masquerading as AML-M6). Once a haematological malignancy has been conrmed, using CD45 expression if necessary, it is then essential to differentiate AML from ALL, rare bi-lineage and bi-phenotypic leukaemias [44] and MDS. Conventional morphology supplemented by cytochemistry is often sufcient for this purpose identifying the presence of granulation, Auer rods and myeloid maturation. Occasionally, myeloblasts can have typical agranular L2 lymphoblast morphology and may present some diagnostic confusion. These cases are typically M0, M1, M6 or M7 and their myeloid nature can be demonstrated either by immunological markers or, in cases of M7, by ultrastructural demonstration of platelet peroxidase. It is therefore recommended on a type C basis that all acute leukaemias with lymphoblast morphology should be examined immunologically using a standard primary panel of antibodies to conrm their myeloid nature and to exclude ALL by demonstrating negativity for lymphoid markers [45]. Bi-phenotypic leukaemias will be identied by the careful application of primary antibody panels, supplemented with secondary panels as necessary, according to established guidelines [46]. Scoring systems exist to differentiate bi-phenotypic leukaemias from AML expressing aberrant lymphoid antigens (Ly + AML) [47]. It is important to emphasise that diagnostic cut-offs between categories in existing classication systems are inevitably arbitrary. The need for therapy should therefore be decided in light of the patients condition as well as their marrow morphology.

2.1.5. Molecular analysis Reciprocal translocations can be detected by PCRbased techniques. Genetic targets for these include RUNX1 (CBF2)-ETO [t(8;21)], CBF-MYH11 [inv(16)] and PMLRAR [t(15;17)]. There are also exceptions where APML is seen with t(11;17)(q23;q21) [PLZF/RAR], t(11;17) (q13;q21) [NuMA/RAR] or t(5;17)(q32;q12) [NPM/RAR] [27]. Occasionally, molecular techniques highlight discordance between standard cytogenetic analysis, FISH and PCR-based methods. This may reect the presence of cryptic translocations [28,29] and suggests a need to screen samples by molecular analysis when morphology is suggestive of a translocation despite normal cytogenetics and FISH [30]. For example, PCR remains the gold standard for the diagnosis of APML. Only approximately 80% of patients with molecular evidence of the PML/RAR fusion have a detectable t(15;17) on G-banding. This may be due to either failure to obtain metaphase cells or cryptic translocations with insertion of RAR into PML. Inv(16) can often be a subtle rearrangement on G-banding and may be missed. Therefore, if it is suspected, e.g. M4Eo morphology, one should consider FISH or RT-PCR analysis for exclusion of a CBFMYH11 rearrangement. Unfortunately, not all translocations have easily recognisable morphology and some translocations, such as 11q23 abnormalities affecting the MLL gene, have many partner genes that would necessitate multiplex PCR [31]. 2.1.6. Research investigations There is an increasing body of work looking at the presence of mutations within genes involved in myelopoiesis in the context of AML. Such genes include N- and K-RAS [32], FLT3 [33], C-KIT [34], CEBPA, [35,36]. PU.1 [37] and RUNX1 [38,39] The Gilliland hypothesis of combinations of classes of mutations has been proposed [40] and remains to be conrmed. Of these genes there exist a variety of

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3. Diagnosis 3.1. Physical and laboratory 3.1.1. Clinical presentation Symptoms present at diagnosis typically result from the increasing burden of leukaemic cells, their effects on bone marrow function and their inltration of other tissues. Bone marrow failure may present with the symptoms of anaemia such as fatigue, exertional dyspnoea, palpitations, angina or claudication. Thrombocytopenia is usually manifest as epistaxis, gingival haemorrhage, menorrhagia, cutaneous petechiae or occasionally signicant gastrointestinal, urinary or intracranial haemorrhage. Neutropenia predisposes the patient to infection. These are typically bacterial or fungal in nature and common sites for sepsis include the teeth and oropharynx, sinuses, lung, skin, perineum and bowel. Fever is a presenting feature in 1520% of patients. In those patients who present with a blast count >50109 /l there may be features of hyperviscosity due to leucostasis, such as dyspnoea, hypoxia, respiratory failure, headache, seizures, confusion, coma visual disturbances or priapism. Organomegaly and adenopathy are present in up to onehalf of patients. Leukaemic inltration may also involve the central nervous system (CNS) in 15% of adults. This is usually manifest as leptomeningeal disease with headache and isolated cranial nerve palsies (especially V and VII), however intracranial masses can occurusually in the setting of M4Eo with inv(16). Leukaemic inltration of the skin (leukaemia cutis) occurs in about 10% of cases and gingival inltration can also be seentypically in the monocytic leukaemias, AML-M4 and M5. Other organs can be involved, such as the testes, but this is rare. In some patients, a focal extramedullary collection of myeloblasts (chloroma, granulocytic sarcoma) can be identied. These are characteristically found in the orbit, sinuses, skin or bone although may occur in other tissues, such as bowel. 3.1.2. Laboratory ndings At diagnosis most patients are anaemic and neutropenic. A peripheral blood leucocytosis is present in over 50% of cases, although a white count greater than 100109 /l is only seen in 20% and usually occurs in the context of AML-M4 or M5. Aleukaemic leukaemia, where blasts are absent in the peripheral blood, is rare. At diagnosis the bone marrow is inltrated with between 20 and 100% myeloblasts. Renal function may be impaired secondary to renal inltration or hyperuricaemia and abnormalities of liver function may also reect leukaemic inltration. Disseminated intravascular coagulation (DIC) is common in varying degrees of severity and is especially, although not exclusively, associated with APML. Serum lysozyme concentration may be raised in cases of AML M4 or M5, with hypokalaemia from resultant renal tubular dysfunction. LDH levels may also be elevated in some cases.

3.2. Pathological diagnosis 3.2.1. Appropriate diagnostic sampling A bone marrow aspirate is the standard method for obtaining diagnostic samples. It is important that the resultant smear or crush preparation is well spread and well stained. A trephine biopsy should be performed in the event of a dry tap or a haemodilute or aparticulate sample. These poor quality samples are especially common in cases of AML M7 due to heavy bone marrow brosis or APML when the marrow often clots before spreading. It should be noted that a trephine imprint (trephine roll) can provide useful information on marrow cellularity and can be treated as an aspirate smear for morphological and cytochemical examination. Immunohistochemistry is also possible on sections of the trephine biopsy after xation [48] Trephine biopsy is therefore recommended when the aspirate quality is poor and is essential in order to distinguish hypoplastic AML from either hypoplastic MDS or aplastic anaemia. Peripheral blood can be used as an alternative to marrow for immunophenotyping and cytogenetic studies providing that there are signicant numbers of circulating blasts. Early examination of the cerebrospinal uid (CSF) is mandatory for patients with clinical signs or symptoms of CNS disease and is suggested for those at increased risk of CNS involvement, i.e. those with a high presenting count or subtypes AML-M4 or M5. Lumbar puncture should be performed once any coagulopathy has been corrected and following platelet transfusion if the platelet count is below 50 109 /l. 3.2.2. Appropriate handling of diagnostic specimens Freshly obtained presentation samples of peripheral blood and marrow are suitable for MGG staining and cytochemical tests [49]. Slides for MPO staining will last for 4 weeks if kept in the dark at 4 C. Sudan Black staining is not light sensitive and will not fade over time. Heparinised samples for immunophenotyping, cytogenetics and molecular studies should be kept at room temperature and processed within 24 h. These specialised tests take time for completion, hence the initial diagnosis and treatment plan will be made on morphology and cytochemistry supplemented by immunological studies.

4. Staging 4.1. Staging procedure Standard practice will include: Medical history Other medical conditionspast and current Pre-existing MDS or other marrow disease Occupational risk factors Drug history (including allergy) Family history, including siblings

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Examination

Performance status Temperature Oro-pharynx Lymphadenopathy Abdomen, hepato-splenomegaly, testes Cardio-respiratory examination Fundal and neurological examination FBC + differential + lm, blood group Liver and kidney function, albumin, LDH Glucose, uric acid, calcium and phosphate Coagulation screen, immunoglobulins Class I and II HLA typing Baseline virology [HBsAg, CMV IgG, HCV IgG, VZV IgG] ECG and chest X-ray Bone marrow aspirate biopsy

CR. A further signicant proportion will relapse in the rst 12 years following therapy. Of those with refractory and relapsed disease, few will achieve remission and their overall survival is less than 10% with current salvage therapies. 5.2. Clinical prognostic factors 5.2.1. Age Biological age is a highly signicant prognostic variable adversely affecting both attainment of remission and relapse risk. It has been repeatedly demonstrated in many studies that prognosis worsens with increasing age, both in terms of response and overall survival. For those patients less than 60 years, CR rates of 75% and 5 year survival rates of 3540% can be expected. Once the patient age exceeds 60 years, CR rates fall to 4555% and 5 year survival rates fall to less than 10%. The reasons for this include a reduction in the capacity of the patient to tolerate intensive therapy as well as a change in the nature of the disease to one characterised by a higher frequency of adverse cytogenetics, CD34 positivity and MDR-1 expression. 5.2.2. Response to therapy The time taken to clear leukaemic blasts from the peripheral blood or the marrow after 12 courses of induction chemotherapy is an important guide to outcome. The UK MRC consider a blast count of greater than 15% after course 1, or greater than 5% after course 2, as indicative of poor prognosis. The German AMLCG group report that failure to achieve blast clearance by day 16 is a poor prognostic marker [50]. This concept is likely to be developed in investigational studies looking at the signicance of minimal residual disease (MRD). Persistent MRD-positivity by immunophenotyping, FISH or molecular analysis is recognised as an indicator of increased relapse risk (see Section 6.13.2). 5.2.3. Miscellaneous AML arising on a background of prior myelodysplasia or following chemotherapy is associated with reduced CR and overall survival rates. This is also true for those patients with extramedullary or CNS disease. Clinical markers of a high tumour burden such as hepatosplenomegaly, raised serum LDH and a high peripheral blood white count are associated with a worse prognosis. Male sex and poor performance status also are seen to affect prognosis adversely. 5.3. Biological prognostic factors 5.3.1. Cytogenetics An abnormal karyotype is observed in approximately 60% of patients and is highly predictive of response. This has been conrmed in several studies both in younger and older patients [51,52]. It is now recommended on a type C basis to identify risk subsets based on diagnostic cytogenetics.

Laboratory

Other tests Invasive procedures

Consider further investigations (e.g. lung function, ECHO, lumbar puncture) depending on individual clinical status and the presence of host or disease-related complications. 4.2. Staging classication AML is a disseminated disease at diagnosis hence staging systems similar to those used for solid tumours are unhelpful and have therefore not been proposed. It is recommended that patients be divided on the basis of a variety of clinical and non-clinical factors (in particular, the diagnostic karyotype) into three risk groupsgood, standard and poor. This should then be the basis for discussions regarding prognosis and treatment.

5. Prognosis 5.1. Natural history Untreated AML is typically fatal over a period of days to weeks depending largely on the level of the blast count in the peripheral blood and on the presence of complications of marrow failure, tissue inltration or hyperuricaemia. Most patients will die from overwhelming sepsis, signicant haemorrhage or as a result of pulmonary or cerebral leucostasis. The likelihood of achieving a complete remission (CR) will depend on many factors and as a result of this heterogeneity, CR rates can vary from between 40 to 80% depending on the particular patient population being studied. Approximately, 1020% of those treated will die during induction therapy before remission status is evaluable. This proportion of induction deaths rises with increasing age. A further 1020% of patients will have refractory disease and rst line therapies will fail to bring about

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Roughly 25% of patients will have favourable cytogenetics which include t(15;17), inv(16), t(16;16) and t(8;21). This is irrespective of whether they are detected by G-banding, FISH or molecular methods. These translocations are more common in younger patients and in de novo AML and are associated with CR rates of over 90% and a 5 year survival of around 65%. Often there are additional cytogenetic abnormalities such as 9q, X, Y and +8 in association with the favourable abnormality. However, these additional cytogenetic changes (even if adverse) appear to be of little importance if they are in association with good risk translocations [51]. Ten percent of patients will have adverse cytogenetics, which include 7, 5 5q, abnormalities of 3q or a complex karyotype. These patients tend to be older, often with prior history of myelodysplasia or exposure to chemotherapy and can expect CR rates of around 60% and a 5 year survival of 10%. The remaining 4560% of patients will have intermediate cytogenetics. The majority of these will have a normal karyotype with no identiable genetic abnormality on G-banding. The CR rates for this group are about 80% with 5 year survival of 3040%. There are differences in denition of cytogenetic risk groups between research groups. A complex karyotype is dened by the MRC as 5 unrelated karyotypic abnormalities [51] and by the SWOG as = 3 [53]. The SWOG also include t(6;9), and t(9;22) as poor risk cytogenetic abnormalities. This has not been replicated by the MRC. Debate continues over the signicance of translocations involving 11q23, which are dened as poor risk by several groups, particularly in the setting of paediatric AML. This has not been conrmed by the MRC in the UK for adults and is likely to reect the heterogeneity of MLL gene fusion partners. As a result of these varied denitions, patient distribution among the three risk groups may be different between study centres and should be considered when comparing the results of treatment. 5.3.2. Other variables Variables associated with an above average outcome: Presence of Auer rods; FAB type M3 and M4Eo; expression of a pan-myeloid phenotype [MPO+ , CD13+ , CD33+ , CDw65+ and CD117+ ]. Variables associated with a below average outcome: Tri-lineage dysplasia at diagnosis, although this is now believed not to be an independent factor beyond its role as a marker of poor risk cytogenetics [54]; FAB types M0, M5, M6 and M7; CD 34 positivity; marrow dysplasia evident at remission.

The favourable prognosis group can be further subdivided. Several adverse prognostic factors exist for t(8;21) AML including CD56+ positivity [55], the presence of extramedullary disease [56], elevated white cell count [57] and associated 9q- [58]. Higher white cell count has also been shown to be poor risk for t(15;17) [59]. 5.4. Potential prognostic factors 5.4.1. Multi-drug resistance P-gp is a 170 kd drug efux protein coded for by the multi-drug resistance gene 1 (MDR-1) that is selective for anthracyclines and podophyllotoxins [60]. High levels of p-gp expression result in low intracellular drug concentrations. This is seen in 40% of cases of AML at diagnosis, and expression increases following exposure to chemotherapy as well as with advancing patient age. The prognostic signicance of p-gp expression in AML was previously unclear, reecting variation in methods of analysis. However, the implementation of consensus recommendations [61,62] for ow cytometry, functional assays and molecular techniques have led to the conclusion that p-gp expression is a negative prognostic factor [6365]. Other drug resistance proteins have been identied including MDR-related protein (MRP) [66], lung resistance protein (LRP) [67,68] and breast cancer resistance protein (BRCP) [69,70] yet their roles and prognostic signicance remain unclear. The calcein assay that identies both MDR and MRP positive cells may become increasingly important [71,72]. 5.4.2. FLT3 Fms-like tyrosine kinase 3 (t-3) is the receptor for tligand, belonging to the same family as the c-kit and the PDGF receptor [33]. It is involved in normal haemopoiesis and is expressed by AML blasts in a signicant proportion of cases. In-frame internal tandem duplication (ITD) mutations of exons 1415 have been noted in 1530% of cases of AML. This elongates the juxtamembrane segment of t-3 resulting in its dimerization and constitutive activation [73]. Such ITD mutations occur across FAB types, with a bias towards M3. They primarily occur in intermediate risk patients and are more frequent in adults than in children [74]. ITD mutations of FLT3 have been shown to be an independent poor prognostic factor in several studies [7578] and mutation status can delineate a poor risk group from a previously homogeneous intermediate risk group. Bi-allelic mutations are noted in approximately 10% and are associated with an even poorer outcome.This adverse effect is less clear in older patients and there is debate whether intensication of therapy might overcome this negative impact [79]. The potential for FLT3 to be used as a MRD marker is uncertain as there is signicant movement between the ITD + and groups at relapse [80,81].

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Additionally, point mutation of codon 835 of FLT3 has been reported in 78% of cases of de novo AML [82]. This mutation results in up-regulation of the function of the kinase domain, the prognostic signicance of which is unknown. 5.4.3. Research prognostic markers 5.4.3.1. Pharmacokinetic Autonomous proliferation in short-term culture; Expression of pro and anti-apoptotic proteins such as bcl2 [83] and bax [84]; In vitro sensitivity to anthracyclines or cytarabine and AraCTP incorporation [85] and Km of 5nucleotidase [86]; Glutathionine-S-transferase enzyme activity [87]. 5.4.3.2. Genetic CEBPA: This transcription factor is important in early myeloid development. Acquired mutations at both the N- and C-termini are found in 57% of cases of AMLprimarily in M1 and M2 intermediate risk cases. The prognostic impact of such mutations remains unclear, however two groups have identied CEBPA mutation as a favourable prognostic variable [88,89]. EVI 1: High levels of expression have been found to be an independent poor prognostic variable in those with intermediate risk AML [90]. 5.4.3.3. Miscellaneous A variety of markers have been identied in the literature as potential prognostic markers. Their role in current practice remains investigational. Tryptase [91]; Angiogenin [92]; P-selectin [93]; Caspase [94]; nm23-H1 [95]; Survivin [96].

6. Treatment 6.1. Supportive care 6.1.1. Metabolic complications and venous access An awareness of the possibility of the metabolic complications of instituting therapy in a patient with AML is vital. Although acute tumour lysis syndrome (ATLS) occurs uncommonly in AML, it should be a concern in treating patients with high presenting counts and bulky extramedullary disease. ATLS is characterised by hyperuricaemia, hyperphosphataemia, hyperkalaemia, hypocalcaemia and oliguria [97]. Allopurinol should be commenced prior to therapy in addition to ensuring a high urine output with intravenous uids and diuretics as necessary. Regular monitoring of electrolytes and uid balance is standard. Alkalinisation of the urine by the administration of intravenous bicarbonate or oral acetazolamide remains controversial as it may exacerbate calcium phosphate deposition in organs including the heart and may reduce tubular solubility of xanthine. Urate oxidase (RasburicaseTM ) has been shown to be more effective than allopurinol and can be used as an alternative suitable for individual clinical use [98,99]. Hypokalaemia may also be a feature at presentation and during induction therapy, particularly in those patients with monocytic leukaemias and resultant high serum lysozyme. This requires vigorous intravenous or oral potassium replacement. Establishment of secure central venous access through a tunnelled Hickman line or a temporary jugular or subclavian central line is recommended prior to starting therapy. This is to enable safe administration of vesicant drugs, facilitate frequent blood sampling and provide access for intravenous medication and blood products. This practice must however be weighed against the nite risks of catheter associated thrombosis and infection. Patients presenting with a high peripheral white count are at high risk from the pulmonary, cardiac and cerebral complications of leucostasis. Leucapheresis brings about rapid cytoreduction and should be considered as suitable for individual clinical use. 6.1.2. Infection The risk of infection is related to the degree of neutropenia, which may be either a result of bone marrow inltration or cytotoxic-induced aplasia. Breaches in the integument, such as from intravenous access devices (IAD) or mucositis increase the likelihood of systemic bacterial translocation and alterations in bacterial ora can occur as a consequence of broad-spectrum antibiotic use, gastric acid suppression and prolonged periods of hospitalisation. Fever is often the cardinal sign of sepsis although may sometimes be masked or absent, for example in elderly patients or with the concurrent administration of antipyretics or corticosteroids. Sepsis should be suspected in the presence of any sudden nonspecic deterioration in clinical condition, hypotension or new cellulitic changes around an IAD or the oropharynx or perineum. The febrile patient should have central and periph-

5.5. Risk groups It is now standard practice, on a type C basis, to utilise clinical and laboratory features at diagnosis to categorise patients into one of three discrete risk groups: good, standard and poor. Age, karyotype and initial response to induction therapy are the prime prognostic variables, however, biological features of AML cells, for example FLT3 mutation status, may play an important role in the future. All patients, irrespective of their risk group should be considered for entry into clinical studies. It is hoped that in time the therapies for the different risk groups will diverge to produce a risk-adapted approach to therapy. This is already happening in terms of avoiding myeloablative therapy for those with good risk disease and advocating early allografting for those considered to be at high risk of relapse.

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eral blood cultures taken as well as appropriate microbiological cultures of urine and stool. A chest radiograph should complement careful clinical examination of the chest, perineum, oropharynx and IAD. The past decade has seen a shift away from Gram-negative aerobes such as Klebsiella, Pseudomonas, and Escherichia coli as causative agents of sepsis in neutropenic patients towards Gram-positive organisms, such as Streptococcus viridans and Staphylococcus spp, being more frequently isolated. This reects the widespread practice of quinolone prophylaxis, more frequent IAD use and the greater mucosal toxicity resultant from increases in the intensity of chemotherapeutic regimens. Antibiotic prophylaxis has not been shown to reduce mortality but may reduce the incidence and morbidity of Gram-negative infections. Their use encourages the selection of resistant organisms, therefore the use of ciprooxacin as prophylaxis is not recommended as standard. It should be considered as suitable for individual clinical use on a type 3 level of evidence, depending on the likely duration of severe neutropenia and following microbiological advice. Fungal prophylaxis with uconazole has been shown to reduce systemic or invasive fungal infections but with a reduction in mortality only for patients undergoing haemopoietic stem cell transplantation [100]. Fluconazole has little activity against Aspergillus spp. and there is evidence that it selects for resistant strains of Candida, especially C. kruseii and glabrata spp. It is therefore suitable for individual clinical use on a type R basis. Itraconazole has a broader spectrum of activity and has been shown to reduce fungal infections and associated mortality. However, patient compliance and pharmacokinetic considerations make itraconazole difcult to use effectively in clinical practice. Primary CMV infection can be prevented by the use of blood products from CMV IgG negative donors in CMV seronegative patients. Standard empirical therapy for febrile neutropenia based on a type C basis comprises either monotherapy with a third generation cephalosporin or carbapenem or combination therapy given for at least 1014 days. Combination therapy should consist of either a broad-spectrum penicillin or cephalosporin in addition to an aminoglycoside. Local microbiological advice, based on the resistance patterns of the most prevalent bacterial isolates, should guide the exact choice of antibiotic therapy. The addition of vancomycin or teicoplanin as a third drug to broaden Gram-positive cover is recommended on a type R basis if there are concerns over IAD infection or a high local frequency of MRSA infections, however their routine empirical use is not recommended on a type 1 level of evidence. Further modications to the initial antibiotic regimen should be based on culture results and clinical examination. If the patient remains febrile despite negative culture results, consideration should be given to occult fungal infections, viral infections or non-infectious causes of fever, such as drug reactions. It is standard practice on a type 2 level of evidence to start antifungal agents after 47 days of pyrexia in patients with severe neutropenia and inconclusive blood culture results. Use of granulo-

cyte transfusions is problematic, complicated by alloimmunisation, febrile reactions, pulmonary inltrates and primary CMV infection [101]. Their use should therefore be considered as suitable for individual clinical use on a type 3 level of evidence. 6.1.3. Coagulopathy Life-threatening bleeding has been noted to affect 1% of patients at presentation, 5.57% during induction and 1733% during induction in association with infection [102]. Such bleeding usually occurs in the context of disseminated intravascular coagulation (DIC) with hypobrinogenaemia or a platelet count under 20 109 /l and this risk may be further increased by pulmonary infection or hyperleucocytosis. Death from haemorrhage during consolidation is less common, occurring in approximately 2% of cases, although this rate increases with advancing age. The use of prophylactic transfusions of either single-donor apheresis or multipledonor pooled platelet concentrates is recommended on a type C basis to reduce the rates of signicant bleeding. The threshold for such platelet transfusion remains a subject of debate. It is currently standard to transfuse one adult dose of platelets if the platelet count is below 10 109 /l and the patient is otherwise well and not bleeding, 20 109 /l if the patient is septic, is on antibiotics or has abnormalities of haemostasis and 50 109 /l if the patient is actively bleeding [103105]. Patients who achieve poor 24 h increments to fresh ABO-compatible single-donor platelets should be screened for the presence of anti-HLA alloantibodies and the need for HLA-matched platelets discussed with the regional transfusion centre. Acute promyelocytic leukaemia, particularly the microgranular variant (M3v), is associated with a 10% incidence of signicant haemorrhage, although this has fallen with the introduction of all trans retinoic acid (ATRA) into remission induction therapy. Transfusion of platelets should be standard during induction with a view to maintaining a platelet count greater than 20 109 /l in the absence of bleeding and greater than 50109 /l if there is active bleeding. Cryoprecipitate should be infused to maintain the brinogen above 1 g/l with the addition of fresh frozen plasma if either the prothrombin time or the activated partial thromboplastin time is prolonged in association with active bleeding. Heparin has not been shown to be of any significant benet in APML in either reducing early deaths due to bleeding or improving remission rates or overall survival [106]. Its routine use cannot be recommended on a type 1 level of evidence. Fibrinolytic agents, such as tranexamic acid, should also be used as suitable for individual clinical use in cases of incipient life-threatening intracranial haemorrhage based on a type R basis. 6.2. Principles of remission induction phase 6.2.1. Remission induction chemotherapy The aim of induction therapy is to produce maximal tumour destruction in order to restore normal haemopoiesis.

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For the past three decades this has been achieved with an anthracycline plus cytarabine [107]. Most of such regimens result in complete remission rates of 6585% in those under 60 years and this remains the standard of care on a type C basis. There is uncertainty as to the best anthracycline to use. Daunorubicin appears better than doxorubicin with less gut toxicity. The CR rate for daunorubicin is higher at a dose of 45 mg/m2 compared to 30 mg/m2 , however there is no survival advantage [108]. Several randomised studies [109] have suggested that idarubicin is superior to daunorubicin in patients under 50 years. More patients achieve remission after the rst course and the duration of this remission is longer [110112]. Idarubicin has better CNS penetration, lacks p-gp modulation, has a longer half-life and is metabolised into active compounds. However, it is more myelosuppressive and hepatotoxic and any survival advantage lessens with increasing patient age. Standard therapy on a type C basis consists of either daunorubicin or idarubicin given for 3 days. Other anthracyclines such as mitoxantrone can be considered as suitable for individual clinical use on a type 3 level of evidence. Cytarabine is traditionally given 100200 mg/m2 per day as either a continuous infusion or intermittent iv injections. The same results are achieved for 100 and 200 mg/m2 per day as a continuous infusion given for 7 days or intermittent injections given for 10 days [113,114]. Gastro-intestinal toxicity is higher if the cytarabine is given as an infusion. High-dose cytarabine has been used for induction at doses of 13 g/m2 bd for 46 days and high CR rates have been observed in uncontrolled trials [115]. In randomised studies, there was no signicant improvement in CR rate but there was a benecial effect on disease-free survival [116118]. This remains a subject of debate. It is clearly advantageous to receive one or more course of cytarabine at gram/m2 doses, however there are many who would prefer to give such blocks of treatment as consolidation once remission has been achieved. Standard therapy on a type 1 level of evidence is either 100200 mg/m2 per day for 7 days as a continuous infusion or 100 mg/m2 bd for 710 days as bolus injections. Intermediate and high doses of cytarabine may be considered as suitable for individual clinical use or as part of a clinical trial based on a type 2 level of evidence. There has been interest in adding a third drug to an anthracycline and cytarabine combination. 6-Thioguanine (6TG) was initially used but has not been shown to offer any benet in terms of remission induction, remission duration or overall survival. The addition of etoposide improves remission duration but not CR rates or overall survival and any benets noted were only seen in those under 55 years [119]. Studies comparing a thioguanine-containing regimen (DAT) to an identical one containing etoposide (ADE) found no signicant difference between the two [120,121]. The addition of a third drug is therefore optional and should only be considered suitable for individual clinical use, on a type 1 level of evidence [122]. Fludarabine given prior to cytarabine blocks its metabolism and hence increases ara-CTP lev-

els [123]. Regimens utilising this approach may be suitable for individual clinical use on a type 3 level of evidence. Examples of induction regimens Regimen 3+7 Drugs and schedule Daunorubicin 50 mg/m2 iv Days 1, 3, 5 Cytarabine 100200 mg/m2 bd iv Days 17 [14 doses]

DAT Daunorubicin 45 mg/m2 iv Days 1, 3, 5 3 + 10 + 5 Cytarabine 100 200 mg/m2 bd iv Days 110 [20 doses] 6-Thioguanine 100 mg/m2 bd po Days 110 ADE Daunorubicin 50 mg/m2 iv Days 1, 3, 5 3 + 10 + 5 Cytarabine 100 mg/m2 bd iv Days 110 [20 doses] Etoposide 100 mg/m2 iv Days 15 MAE Mitoxantrone 12 mg/m2 iv Days 1, 3, 5 3 + 10 + 5 Cytarabine 100 mg/m2 bd iv Days 110 [20 doses] Etoposide 100 mg/m2 iv Days 15 ICE Idarubicin 10 mg/m2 iv Days 13 Cytarabine 100 mg/m2 bd iv Days 15 [10 doses] Etoposide 100 mg/m2 iv Days 15 Fludarabine 30 mg/m2 iv Days 15 Cytarabine 2 g/m2 bd iv Days 15 [10 doses] Idarubicin 10 mg/m2 iv Days 1 3 G-CSF 5 mcg/kg per day s/c from Day 1

FLAG Ida

6.2.2. Side effects and complications of remission induction chemotherapy The common side effects of cytotoxic chemotherapy include marrow suppression with requirement for red cell and platelet support and risks of neutropenic sepsis. This is more signicant with the use of idarubicin or the addition of a third drug. 10% of patients will die during induction therapy, typically as a result of sepsis or bleeding consequent on bone marrow suppression. Gastrointestinal toxicity with consequent mucositis, nausea, vomiting and diarrhoea is also common. This is more pronounced with doxorubicin as compared to daunorubicin and is more likely with infusional rather than bolus cytarabine administration. Alopoecia and fatigue occur frequently. Fertility may be lost as a result of AML therapy, therefore it is recommended that all males be offered the opportunity for semen cryopreservation prior to starting therapy, provided that treatment is not delayed or compromised. High doses of cytarabine (1 g/m2 and above) are associated with colitis, cerebellar toxicity, conjunctivitis and a blistering erythematous rash particularly affecting the hands and feet. Daily examination for cerebellar signs and

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prophylactic steroid eye drops are therefore recommended on a type C basis in this group of patients. Cerebellar toxicity is primarily seen in the elderly and those with renal impairment. Dose reductions should be considered in these groups. MiDAC 6.2.3. Growth factors during remission induction Both granulocyte colony stimulating factor (G-CSF) and granulocyte/macrophage colony stimulating factor (GM-CSF) has been used in association with induction chemotherapy. Both agents shorten the duration of severe neutropenia (<0.5 109 /l) by between 2 and 6 days; however, the majority of studies show no benecial effect on either CR rate or survival. The use of growth factors entails additional costs and they have side effects, such as fever, that may cause diagnostic confusion. Use of growth factors prior to chemotherapy as cell-cycle primers has not been shown to be of benet in terms of response rate, remission duration or overall survival. Concern over potential stimulation of myeloid blasts by growth factors has not been justied. Current recommendations for the use of CSFs advise weighing their potential benets against their cost. Their routine use cannot be advocated on a type 1 level of evidence however they may be suitable for individual clinical use, especially in older patients [124,125]. 6.3. Principles of continuation (post-remission) therapy 6.3.1. Consolidation therapy Without post-remission consolidation therapy, the median remission duration is 4 months. It is therefore standard practice on a type C basis to give consolidation chemotherapy. This typically tends to be at least two courses of therapy similar to that used for induction, as the use of non crossreactive drugs does not appear to be important in AML. Examples of consolidation regimens Regimen MACE Drugs and schedule Amsacrine 100 mg/m2 iv Days 15 Cytarabine 200 mg/m2 continuous infusion Days 15 [5 doses] Etoposide 100 mg/m2 iv Days 15 Cytarabine 3 g/m2 3 h infusion bd Days 13 [6 doses] Mitoxantrone 10 mg/m2 iv Days 35 Cytarabine 13 g/m2 bd Days 14 to 6 [812 doses] Cytarabine Continuous infusion Days 1 and 2 [2 doses] Bolus bd Days 38 [12 doses] Daunorubicin 60 mg/m2 iv Days 35 Idarubicin 10 mg/m2 iv Days 15 100 mg/m2

Cytarabine 100 mg/m2 bd iv Days 15 [10 doses] Etoposide 100 mg/m2 iv Days 15 Mitoxantrone 10 mg/m2 Days 15 Cytarabine 1 g/m2 iv bd Days 13 [6 doses]

It is important to balance the benets of further therapy against the potential risks of toxicity. For example, there is a type 1 level of evidence that four courses in total may be as effective as ve [126]. However, even despite consolidation therapy many patients will relapse. A CALGB study suggests that increasing the dose intensity does appear to be of benet in terms of remission duration and survival for those who received intensive cytarabine at a dose of 3 g/m2 compared to 400 mg/m2 or 100 mg/m2 [127]. Subgroup analysis suggested that patients with t(8;21) appeared to benet the most [128], although this approach was limited by the toxicity of high-dose cytarabine in older patients. 6.3.2. Central nervous system (CNS) prophylaxis CNS disease in AML is uncommon at presentation, therefore a diagnostic lumbar puncture is not standard in the absence of symptoms or signs to suggest CNS involvement. It is recommended on a type R basis that patients with FAB types M4 or M5 or high presenting counts, who are at increased risk of CNS disease, have a single CSF examination to exclude occult disease. This should ideally be once the blasts have cleared from the peripheral blood and involve the intrathecal instillation of methotrexate or cytarabine. The impact of treatment regimens containing high-dose cytarabine, which penetrates the blood-brain barrier well, may make this intervention less important. CNS relapse is rare in adult AML therefore routine prophylaxis is not recommended, however clinicians may wish to consider this approach as suitable for individual clinical use. 6.3.3. Maintenance Maintenance chemotherapy in AML is typically less intensive and myelosuppressive than standard consolidation cycles, usually involving short courses of subcutaneous cytarabine combined with oral agents such as a thiopurine or etoposide given for 23 years. Maintenance may prolong initial remissions but is of no benet in improving overall survival rates [129] and is not recommended if post-remission therapy is of adequate intensity. 6.4. Myeloablative therapy with infusion of stem cells 6.4.1. Autologous stem cell rescue Autologous stem cell rescue using bone marrow or peripheral blood taken in remission, allows the administration of myeloablative doses of chemotherapy or chemoradiotherapy [130,131]. This approach has been shown in nonrandomised studies to produce a 4555% disease-free sur-

HAM

Intermediate/high dose ARA C TAD

ICE

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vival. Autografting has been evaluated in multiple studies as consolidation therapy, both instead of and in addition to chemotherapy [132135]. It has been demonstrated to reduce the risk of relapse, although this may in part reect the reduced relapse risk of those patients who remain in remission whilst the procedure is organised. Also of note, many patients who were randomised to receive an autograft did do so and this low uptake may in fact underestimate the anti-leukaemic efcacy of autografting. Overall survival is not signicantly different between patients in CR1 treated with chemotherapy and those who were autografted. This is especially true for those patients who received high-dose cytarabine as consolidation. Given these results and the long-term effects on fertility, sexual health, quality of life and second malignancy, autografting is not standard therapy for CR1 on a type 1 level of evidence. It may be suitable for individual clinical use in CR2 on a type 3 level of evidence. These include children, those with a long CR1 or those with favourable cytogenetics. The use of blood rather than marrow-derived stem cells has not made the procedure safer. Similarly, purging with positive selection for CD34+ cells or negative selection using chemotherapy or monoclonal antibodies to reduce tumour contamination of the autograft has not been shown to improve the results and these approaches remain investigational on a type 3 level of evidence. 6.4.2. Allogeneic stem cell transplantation Conventional allografting allows intensication of therapy in addition to harnessing a graft-versus-leukaemia effect in order to reduce relapse risk. Unfortunately problems regarding conditioning regimen-related toxicity, graft-versus-host disease (GVHD) and infection result in a 2025% transplantrelated mortality and generally limit the procedure to those under 50 year-old. Despite this, allografting remains the most effective anti-leukaemic treatment with a relapse risk of 2025%. Unfortunately, excess toxicity results in a 5 year survival of 50% for allografts performed in CR1 . Outcome is related to patient age with a 60% 5 year survival for patients under 20 years and 40% for those over 20 years. Outcome is also related to transplant timing whereby those transplanted in rst relapse or CR2 have a 2030% 5 year survival and those transplanted with advanced disease have a 1015% 5 year survival. The disadvantage of allografting in CR1 is that it exposes patients who are potentially cured with chemotherapy alone to the one in four risk of death from a transplant procedure and the long-term morbidity of chronic GVHD. It has therefore been argued that it is better to allograft in early relapse or CR2 , if that can be achieved. There have been no direct randomised comparisons of chemotherapy and allografting although some studies using so-called biological randomisation between donor/no donor have shown a benet for allografting in CR1 in certain subgroups [136]. In general, the relapse risk is less for allografting, but there is no overall survival benet [137139].

There is considerable international variation in attitude towards the role of autografting or allografting in CR1 . An interesting series of recently published reviews outlines the differences in approach to this situation [136,140142]. Whilst there is a clear reduction in relapse risk associated with stem cell transplantation, this is offset by the signicant transplant-related mortality and increased long-term morbidity resulting in no clear survival advantage [143]. High-dose cytarabine containing regimens appear to offer curative therapy to an increasing proportion of patients with AML [144]. Good risk patients have a signicant chance of cure with standard chemotherapy and salvage rates are high at recurrence. It is appropriate that allografting should therefore be delayed until disease recurrence. For poor risk patients, allografting is unlikely to be of benet, although the Intergroup study [135] found otherwise. Realistically, there is little to offer this group except an allograft in CR1 . Standard risk patients appear to be the only group to gain benet from transplantation in terms of overall survival [136,145]. However, this is not the case in children or those over 35 years. The exact role of transplantation in CR1 must still therefore remain the subject of clinical trial. It may be possible to identify new prognostic factors, such as FLT3 or CEBPA, that yield important information on relapse risk or the chances of achieving CR2 . Such information will aid in selecting those patients to undergo allografting in CR1 . Unrelated and mismatched-related donor transplants are associated with a higher risk of transplant-related mortality and should therefore be reserved for individual patients at relapse or those at high risk of relapse. Unfortunately, high risk patients tend to do as badly with allografting as with chemotherapy [146]. Non-myeloablative allografts using reduced intensity conditioning regimens are less hazardous and allow the procedure to be carried out in patients over 50 years or those with comorbidities [147]. The risks of GVHD and immunosuppression remain, however, and therefore these approaches should be considered investigational. 6.5. Frontline strategy for all patients Optimal supportive care and remission induction chemotherapy is standard on type C basis. There remains uncertainty over the anthracycline, however either 45 mg/m2 daunorubicin or 1012.5 mg/m2 idarubicin for 3 days as intravenous bolus injections are standard. This should be combined with cytarabine given as either 100200 mg/m2 per day for 7 days as a continuous infusion or 100 mg/m2 bd for 710 days as intermittent injections. A third drug, such as etoposide or 6-thioguanine, can be considered as suitable for individual clinical use on a type 3 level of evidence. The addition of other agents remains investigational. 6.6. Post-remission strategy in good risk Between 2 and 4 cycles of post-remission consolidation therapy should be given as standard on a type C basis. In-

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termediate/high doses of cytarabine should be included in at least one of these cycles as standard on a type 2 level of evidence. The benets of multiple cycles of high-dose cytarabine for specic cytogentic translocations and the optimal cytarabine dose level remain to be elucidated. There is no role for allografting or autografting in CR1 in this group of patients and such treatment remains investigational. 6.7. Post-remission strategy in intermediate risk This group forms the majority of AML patients. Between 2 and 4 cycles of post-remission consolidation therapy should be given as standard based on type C basis. Intermediate/high doses of cytarabine should be included in at least one of these cycles as standard on a type 2 level of evidence. High dose therapy may be suitable for individual clinical use on a type 3 level of evidence. Routine HLA-matched related donor allografting using myeloablative conditioning in those under 4050 years and non-myeloablative conditioning in older patients remains a subject of considerable debate across the speciality and is therefore an approach to be evaluated in the context of clinical trials. 6.8. Post-remission strategy in poor risk Post-remission consolidation therapy should be given as standard based on type C basis although the relapse rate is disappointingly high and the benets of intermediate/high doses of cytarabine are less clear [148]. High-dose therapies, including allogeneic transplantation, typically do not significantly improve the overall survival of this group [146] although there is a suggestion that early allografting is better. The reality is that there is little else to offer these patients to prevent relapse and, for selected patients with high risk disease in CR1 , allografting is probably the best treatment available. Therefore, transplantation is considered as standard therapy on a type R basis. HLA-matched related donor allografts should be considered as suitable for individual clinical use on a type 2 level of evidence. Unrelated or mismatchedrelated donor transplants remain investigational. This group should also be considered suitable for individual clinical use for experimental therapies on a type C basis. 6.9. Salvage therapy 6.9.1. Relapsed AML Relapse is the main cause of treatment failure, occurring in about 5080% of those entering complete remission [149]. The majority of relapses are within the marrow rather than at extramedullary sites and in the main they occur during the rst year. Important variables to consider when counselling these patients are the duration of rst CR, age, performance status, other comorbidities and the availability of an HLA-compatible donor. The chances of achieving a second CR are related to the length of the rst CR with cytogenetic risk group becoming less important. If the du-

ration of CR1 was less than 1 year, the chances of achieving a second CR are under 1/3. Conversely, if the duration of CR1 was greater than 1 year, the chances of achieving a second CR approach 2/3. If a patient is t enough for intensive therapy, re-induction chemotherapy is recommended on a type R basis, although there is no consensus as to the protocol that should be used. A variety of regimens exist combining an anthracycline with cytarabine at standard or high doses, in addition to other agents such as etoposide, udarabine, 2-CdA or asparaginase [150152]. These are suitable for individual clinical use on a type 3 level of evidence. P-gp modulators have also been evaluated in this setting although with unimpressive results [153,154] and they remain investigational. The achievement of a second CR with salvage chemotherapy is possible in 4060%, however considerably more toxicity is experienced than during initial induction therapy and second remissions are shorter. Many patients will be unt for intensive chemotherapy, yet may be suitable for individual clinical use for experimental therapies. There remains a lack of consensus regarding optimal consolidation therapy. Most haemato-oncologists would advise two to three courses of chemotherapy, similar to that used for induction, with a nal course comprising high-dose therapy with an autograft or allogeneic transplantation (myeloablative or non-myeloablative). Allografting can result in long-term survival in 2535% of patients, therefore a search for an HLA-matched related donor is recommended without delay on a type R basis. Partially mismatched-related or unrelated donor transplantation may be suitable for individual clinical use on a type 3 level of evidence. Haploidentical transplantation remains investigational. Some individual patients with early relapse may be considered for allografting without initial re-induction therapy on a type 3 level of evidence. For some patients lacking an HLA-matched related donor consolidation of CR2 by high-dose therapy with an autograft can produce durable remissions. This approach may be suitable for individual clinical use in low risk patients i.e. those younger patients with favourable or intermediate risk cytogenetics whose CR1 lasted greater than 1 year. Relapse following allogeneic marrow transplantation poses a major problem. Re-induction chemotherapy followed by donor leucocyte infusions should be considered as suitable for individual clinical use on a type 3 level of evidence. 6.9.2. Refractory AML Approximately 10% of patients will not enter remission with standard induction therapies. The prognosis for these refractory patients is dismal with few long-term survivors. No consensus exists over the optimal salvage regimen although most contain intermediate or high-dose cytarabine. Allogeneic marrow transplantation offers a 10% chance of long-term survival. Therefore, identication of an HLAmatched related donor is recommended on type R basis for

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individual patients who are likely to tolerate the transplant and who are aware of the risks and benets of such a procedure. Mismatched-related or unrelated donor transplantation may be suitable for individual clinical use on a type 3 level of evidence. 6.10. Acute promyelocytic leukaemia (APML) 6.10.1. Induction therapy APML is highly sensitive to anthracyclines and induction therapy containing daunorubicin or idarubicin will produce a CR in 5590% [155,156]. Either anthracycline may be given as per protocols used for the other subtypes of AML. Alternatively, they may be given as a single agent as the efcacy of an anthracycline given alone or in combination with cytarabine is equivalent [157,158]. Indeed dropping the cytarabine may allow more anthracycline to be given. Monotherapy results in CR rates of between 75 and 95%. Standard therapy on a type 2 level of evidence therefore consists of either daunorubicin at 5060 mg/m2 per day for 3 days or idarubicin 12 mg/m2 per day every other day for 4 days. ATRA is a Vitamin A derivative that as a single agent can induce CR in APML, but these are of short duration. It is therefore standard practice, based on a type 1 level of evidence to give ATRA concurrently with induction chemotherapy [159]. ATRA at 45 mg/m2 per day, in two divided oral doses, should be started 24 days prior to cytotoxic chemotherapy in order to reduce the complications of the associated coagulopathy, whilst closely observing the white cell count [160,161]. ATRA should then be continued until CR is achieved. The side effects of ATRA therapy include bone pain, dry skin and mucosa, headache and raised blood lipids. It is also teratogenic. Two other complications following ATRA therapy include hyperleucocytosis in 40% and the retinoic acid syndrome (RAS) in 25%. RAS is characterised by weight gain, respiratory distress, pleural and pericardial effusions, fever and hypotension [162,163]. RAS can occur from days 2 to 28 with a median at day 11. Standard treatment for RAS on a type C basis is intravenous dexamethasone (10 mg bd for at least 3 days). If the RAS is mild, the ATRA can be continued, however it should be stopped if the RAS is moderate or severe. Rechallenging should be considered once the RAS has resolved. Chemotherapy may need to be instituted due to a rapidly rising white cell count. 6.10.2. Consolidation therapy Standard care is to give at least 12 cycles of anthracyclinecontaining therapy post-remission on a type 3 level of evidence, however the optimal dose and number remain unknown. There is a type 3 level of evidence that a solely anthracycline-based consolidation protocol is as effective as one with the addition of other cytotoxics. If molecular remission is not achieved, high-dose cytarabine containing regimens can be considered as suitable for individual clinical use on a type 3 level of evidence.

6.10.3. Maintenance therapy It is standard practice on a type 2 level of evidence to give maintenance therapy for 2 years in APML. The recommendation is for ATRA (45 mg/m2 daily for 15 days every 3 months) in conjunction with low-dose chemotherapy (6-mercaptopurine 100 mg/m2 per day and methotrexate 10 mg/m2 per week). There is a suggestion of extra benet in those at greatest risk of relapse such as older patients and those with high presenting white cell counts. MRD detection is possible by RT-PCR assessment [164166]. PML/RAR positivity after therapy predicts subsequent relapse and negativity predicts long-term survival [166]. An example of a schedule for MRD follow-up is that two marrow samples should be studied at the end of therapy, one every 3 months for the rst 2 years and then every 6 months for the next 23 years. It is recommended on type R basis that molecular relapse should be an indication for chemotherapy as the results appear superior to delaying therapy until the onset of frank haematological relapse. 6.10.4. Relapsed acute promyelocytic leukaemia Arsenic trioxide at a dose of 0.15 mg/kg per day can induce CR in greater than 80% of cases of relapsed and refractory disease [167,168]. Molecular remissions are also observed. Side effects include QT interval prolongation and a differentiation syndrome similar to RAS. Its use should be considered as suitable for individual clinical use on a type 3 level of evidence. High-dose therapy with autografting and allogeneic transplantation are suitable therapy for individual clinical use on a type 3 level of evidence once a second remission has been achieved. To date a high treatment-related mortality has been observed from registry data for allografting in this setting. Autografting may therefore be preferable. Molecular monitoring allows screening of the stem cell harvest prior to autografting to ensure a RT-PCR negative graft. Late relapses in individual patients can often be re-induced with ATRA. An algorithmn for this situation is presented in Douer [169]. 6.11. AML in the elderly Age is consistently a major unfavourable prognostic factor, reecting co-morbidity and poor drug handling mechanisms in addition to different disease biology with a higher frequency of adverse cytogenetics, MDR-1 positivity, prior myelodysplasia and the stem cell phenotype [170,171]. For selected good risk patients over 60, with de novo disease and MDR-1 negativity, CR rates approach 75%. However, for the bulk of patients, remission rates are only 3050% with a median survival of 612 months [172,173]. It is standard practice on a type C basis, therefore, to tailor treatment to the individual following extensive discussion regarding the risks and likely benets. An evaluation should be made of prognostic factors such as performance status, co-morbidities, cytogenetics, MDR-1 status and any antecedent haematological disorder [174]. Intensive therapy will be appropriate for

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relatively few patients and supportive care is recommended on a type C basis for those with smouldering AML, severe co-morbidities or other adverse risk factors. This group of patients tolerate the complications of chemotherapy poorly with a signicant risk of death during induction, mainly related to sepsis. Supportive care should comprise close monitoring of peripheral blood counts, regular clinical review and frequent platelet and red cell transfusion. Routine use of G-CSF in this population is not recommended but may be appropriate for individual patients. Options for palliation include oral hydoxyurea or 6-mercaptopurine to control the blast count. Low dose subcutaneous cytarabine can also be used. If possible, all patients should be considered for new experimental agents as part of a clinical trial. Other individual patients may benet from intensive chemotherapy on a type 2 level of evidence, although the best regimen is unclear. All include an anthracycline in association with standard dose cytarabine, however there is no clearly superior anthracycline. Theoretical benets of mitoxantrone and idarubicin over daunorubicin have not been borne out in randomised studies [175]. No consensus exists regarding the optimal type and duration of consolidation therapy although most centres would not use high-dose cytarabine containing regimens in this age group due to the signicant risk of cerebellar toxicity. Two courses of post-remission therapy similar to that used for induction are recommended on a type R basis. 6.12. AML during pregnancy Cytotoxic agents are potentially teratogenic, therefore it is recommended on a type C basis that they be avoided during the rst trimester where their use is associated with a 20% chance of fetal malformation. As the time of commencing chemotherapy for AML moves from the rst to the third trimester, the number of spontaneous abortions and stillbirths decreases, with most neonates being normal regardless of premature or term births. Anthracyclines and cytarabine have not been associated with an increased incidence of birth defects, however other complications of their use, namely bleeding and infection, may be of signicance before delivery [176]. Prompt institution of standard induction chemotherapy is recommended so as not to compromise maternal survival. Remission rates are the same between pregnant and non-pregnant women. Chemotherapy does not appear to have a signicant impact on the future growth and development of the child [177]. 6.13. Re-staging and relapse criteria 6.13.1. Denition of response Complete remission is dened as the patient being in good health with recovery of peripheral counts, i.e. a platelet count greater than 100 109 /l, a neutrophil count greater than 1.0 109 /l (1.5 109 /l by NCI criteria although this has recently been reassessed [178]), haemoglobin >10 g/dl and no blasts in the peripheral blood. Marrow blast cells

should be less than 5% and there should be resolution of any extramedullary disease. The cellularity of the marrow should be greater than 20% with evidence of trilineage haematopoiesis [179]. It is important to recognise that no visible leukaemia in a hypocellular marrow is not CR. Partial remission (PR) tends to be referred to only in the context of phases I and II trials of novel agents and then requires all the criteria of CR to be met except for the percentage of blasts in the marrow. The UK MRC dene PR as 615% blasts, however some centres set a more generous range of 625% blasts. Marrow blast percentages above these thresholds are termed refractory disease. Induction failure is dened as death occurring before response is assessable and relapse is when the marrow blast count rises above 5% or extramedullary disease is noted in any site, including the CNS. Overall survival is calculated as the time from the date of diagnosis to the date of death by any cause or last follow-up. Disease-free survival or leukaemia-free survival is the time from the date of CR to the date of relapse in any site, death or last follow-up. 6.13.2. Re-staging strategy and response evaluation It is standard to repeat a bone marrow aspirate for morphological examination at 2128 days from the start of induction therapy. The purpose is to allow the early detection of refractory disease enabling further chemotherapy to be given without delay. However, if the counts are recovering well the marrow can be done later. A bone marrow biopsy may be helpful in certain cases, especially if the aspirate is haemodilute as immunohistochemistry allows the detection of islands of blasts in an otherwise hypocellular marrow. Flow cytometry, FISH or molecular techniques may conrm remission at a more sensitive level (1 in 104 105 ) or identify the presence of minimal residual disease [180182]. However, these tests are expensive as well as time-consuming and it is unclear what methodology should be used, when they should be performed or their frequency. Until current trials are completed, their place in the routine management of patients with AML remains investigational. There is, however, evidence of the importance of MRD analysis in the setting of APML [165,183] and increasingly in other types of AML that have a molecular marker, e.g. those with a CBF-MYH or CBFA2-ETO rearrangement [184,185]. The potential for increases in the expression of WT1 to predict relapse is being investigated [186]. Flow cytometry is able to detect small populations of malignant cells that are predictive of recurrence [187]. Although this allows MRD detection for the majority of cases of AML that have no molecular marker, it is limited by technical considerations and alterations in the malignant phenotype over time. 6.14. Experimental therapies 6.14.1. New cytotoxic agents A variety of novel chemotherapeutic agents have been evaluated in AML [188,189]. These include topoiso-

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merase I inhibitors such as topotecan and campothecin [190], platinum containing agents (carboplatin) and new anti-metabolites including gemcitabine [191], troxcitabine and clofarabine [192]. All of these agents have activity against leukaemic blasts but their use remains investigational. MDR-1 blockade using cyclosporine A or PSC 833 is not of proven benet [153,154] and may either increase toxicity or necessitate dose reduction and hence reduce overall chemotherapy exposure [193,194]. BCL-2 downregulation is being evaluated using oral or liposomal ATRA in non-APML AML or bcl-2 antisense oligonucleotides in several studies [195]. Arsenic trioxide is also being evaluated in non-M3 AML. Alternatives to conventional cytotoxics include t-3 antagonists [196200], histone deacetylase inhibitors, e.g. trichostatin and valproate [201], angiogenesis inhibitors, e.g. thalidomide, hypomethylating agents, e.g. decitabine, farnesyl transferase inhibitors [202] and cyclin-dependent kinase modulators such as avopiridol. All of these approaches remain investigational. 6.14.2. Biological agents Monoclonal antibodies offer the possibility of increasing response with minimal additional toxicity [203,204]. CD33 is found on 90% of AML blast cells but not on stem cells. Naked antibodies to CD33, such as HuM195 humanised mouse IgG1, rely on effective antibody-dependent cell cytotoxic (ADCC) pathways. HuM195 has been used in induction, at relapse [205], in the setting of minimal residual disease in APML and also with IL-2 to enhance ADCC. Immunoconjugates [206] have been developed between anti-CD33 and radioisotopes including 131 I, 90 Y and 213 Bi [207,208]. Drug-antibody conjugates have also been developed, e.g. calicheamicin conjugated humanised IgG4 anti-CD33 (Gemtuzumab Ozogamicin [GO], Myelotarg). This has shown promising efcacy with acceptable toxicity, although long lasting cytopenias have been noted as has hepatotoxicity [25,209,210]. This can range from minor alterations in liver function test results to a clinical picture of weight gain, jaundice, ascites, and tender hepatomegaly, resembling veno-occlusive disease, termed sinusoidal obstruction syndrome. GO is currently being evaluated with cytotoxics in a variety of protocols [211] but may be suitable as a single agent for individual clinical use on a type 3 level of evidence. 6.14.3. Future developments Immunotherapy is likely to become more important as the strategy of non-myeloablative conditioning exploits the graft-versus-leukaemia effect with signicantly reduced transplant-related mortality thereby increasing the applicability of allografting [212214]. Dendritic cell vaccination using tumour specic vaccines is another interesting although investigational approach.

7. Late sequelae 7.1. Treatment and late effects A concern for long-term survivors is the cardiomyopathy consequent upon high doses of anthracyclines. It is know that 1020% of patients who have received above a cumulative dose of 450500 mg/m2 doxorubicin will develop cardiac dysfunction and similar results are seen for daunorubicin [215]. Idarubicin is thought to be less cardiotoxic and evidence suggests that cumulative doses up to 150 mg/m2 are safe and that further increases up to 290 mg/m2 are associated with a low risk of cardiac dysfunction [216]. Additionally endocrine and gonadal dysfunction is occasionally seen as a consequence of AML chemotherapy. Myeloablative therapy, especially with TBI-containing regimens, is associated with a variety of long-term effects including pulmonary brosis, premature arteriosclerosis, hypothyroidism, growth failure, delayed or absent puberty, cataracts, avascular necrosis, osteoporosis and functional hyposplenism [217,218]. Sexual dysfunction, fertility and quality of life issues are important considerations in assessing the impact of more intensive therapeutic options. 7.2. Secondary tumours It is well recognised that curative chemotherapy or radiotherapy for other disorders is associated with an increased incidence of second malignancy. The frequency of these secondary malignancies in AML is small. An increased risk of invasive cancer was not noted in a cohort of potentially cured AML patients at the MD Anderson [219]. One of these patients developed an invasive cancer for every 107.8 years of follow-up. Transplant survivors, however, are at an increased risk of a variety of neoplasms [220,221]. These include lymphoproliferative disorders that are often EBV driven, MDS/leukaemia and solid tumours. These solid tumours occur after a delay of 510 years and preferentially affect the skin, oropharynx, brain and liver. Topoisomerase II inhibitor use is associated with the development of secondary leukaemias. These leukaemias typically occur 23 years following exposure, are usually of a FAB type M4 or M5 and are associated with 11q23 abnormalities. Alkylating agents also predispose to secondary leukaemias but these typically present 510 years after exposure with a preceding myelodysplastic phase and associated abnormalities of chromosomes 5 or 7.

8. Follow-up 8.1. General principles and objectives Regular follow-up is essential in order to detect early relapse and to identify the potential complications of therapy. Many patients who enter remission and complete therapy

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will quickly return to their previous life-style, including employment and this should be strongly supported by their medical team. 8.2. Suggested protocols Following completion of therapy, patients should be checked every 23 months for the rst year, then at progressively longer intervals until reaching annual follow-up at 5 years and beyond, providing everything remains satisfactory. Outpatient checks should focus on clinical examination and assessment of the full blood count as well as the evaluation of any new problem the patient may report. Additional tests, such as marrow examination, will depend on symptoms, signs, blood results and participation in any current MRD investigational studies.

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Biographies Matthew Smith is a haematologist, currently employed as a clinical research fellow by Cancer Research UK Medical Oncology Unit, St. Bartholomews Hospital in London. Michael Barnett was professor of transplantation oncology at St. Bartholomews Hospital in London when this review was written. He is now head of haematology at the University of British Columbia in Vancouver. Renato Bassan is associate editor of the START Project, consultant haematologist at Bergamo Hospital, Italy, and responsible coordinator of the Northern Italy Leukemia Group (NILG) Gemma Gatta is research assistant at the Epidemiology Unit, Istituto Nazionale dei Tumori, Milan, Italy. Carlo Tondini is clinical editor of the START Programme. He is the Clinical Coordinator of the Breast Cancer Service at the Ospedali Riuniti of Bergamo, Italy, and Director of the Cancer Genetic Prevention Program. Wolfgang Kern is assistant researcher in the eld of acute myeloid leukemia at the University of Munich, Germany. His scientic focus is immunologic monitoring of AML.

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