Haemato-oncology‎ > ‎




§   >20% blasts in the blood or bone marrow

§   If recognised genetic abnormality, diagnosis can be made with blasts <20%


Classification systems

A.   WHO classification

AML with recurrent genetic abnormalities

1.      AML with t(8;21)(q22;22) (AML1(CBFa)/ETO)

2.      AML with inv(16)(p13q22) or t(16;16)(p13;q22); (CBFc/MYH11) abnormal bone marrow eosinophils

3.      AML with t(15;17(q22q12) (PML/RARa) (M3)

4.      AML with 11q23 (MLL)


AML with multilineage dysplasia

1.      AML with prior MDS

2.      AML without prior MDS


AML and MDS related to previous therapy


AML not otherwise categorised

Acute leukaemia of ambiguous lineage

§   Undifferentiated acute leukaemia

§   Bilineal acute leukaemia

§   Biphenotypic acute leukaemia


B.   French-American-British - FAB classification

§  Based largely on morphological features and immunophenotyping 

§   Usually used in conjunction with the WHO classification (e.g. AML inv(16) is often also categorised as FAB M4 and AML not otherwise categorised is often subdivided by the FAB classification)

§   M0              Minimally differentiated

§   M1               Without maturation

§   M2               With maturation

§   (M3               Promyelocytic)

§   M4              Myelomonocytic

§   M5               Monocytic (5a - with differentiation / 5b - without differentiation)

§   M6              Erythroleukoblastic

§   M7              Megakaryocytic leukaemia

Other morphological subtypes include:

§   Acute basophilic leukaemia

§   Acute panmyelosis with myelofibrosis

§   Myeloid sarcoma


AML with recurrent genetic abnormalities


AML with t(8;21)(q22;22) (AML1(CBFa)/ETO)

§   5-12% of all cases of AML

§   Younger patients

§   Sarcomas may be present at presentation so should still be diagnosed as AML even when the blast count is <20%

§   Cell of origin – myeloid stem cell with predominant neutrophil maturation.


§   Myeloid markers (CD13, CD33, CD34, CD117, MPO)

§   Lymphoid marker CD19)

§   CD56 sometimes present – worse prognosis

§   Good Prognosis


AML with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22); (CBFc/MYH11)

§        Inv (16) or t(16;16) / CBFbeta/MYH11

§        Morphologically – AMML & abnormal eosinophil component in marrow at all stages of maturation

§        PB eosinophils not usually increased

§        10-12% of AML

§        Myeloid sarcomas

§        Immuno

§        Myeloid markers

§        Monocytic markers

§        Good prognosis


APL t(15;17(q22q12) (PML/RARa) (M3)

§        Morphologically = APML

§        5-8% of AML

§        High leucocyte count and associated with DIC

§        Nucleus = kidney-shaped or bilobed

§        Densely packed with granules and auer rods

§        Hypogranular variant (DD – acute monocytic leukaemia, but MPO strongly positive)

§        Immunophenotype

§        Myeloid

§        Co-expression of CD2 and CD9

§        Lack of HLA-DR expression

§        If PML can’t be confirmed by PCR/FISH then can be confirmed rapidly by an immunofluorescence test for the nuclear PML protein

§        Rapid confirmation by PML immunofluorescence of FISH

§        1% have PLZF-RARa fusion secondary to t(11;17)

§        Resistenat to ATRA and ATO


§        Low wcc, might be an advantage to giving ATRA for longer before starting chemo to alleviate the coagulopathy

§        ATRA should be continued at least until documentation of morphological remission

§        Leucophoreisis with wcc >10 may precipitate fatal coagulopathy

§        Check coag bd, aim plts > 50.

§        Generally avoid tranexamic acid due to thrombotic risk



Initial treatment

§        ATRA as soon as the diagnosis is suspected

§        Over-rides the t(15;17) protein induced blockade of the retinoic acid receptor

§        Avoid leukophoresis

§        Platelet / FFP / Cryo to keep plts > 50

§        ATRA and anthracycline based therapy for induction


Retinoic acid syndrome

§        Life threatening complication10days after starting ATRA

§        Fluid retention and capillary leak - cough, dyspnoea, fever, weight gain, oedema, effusions and pulmonary infiltrates

§        Assoc with rising wcc

§        Lower rates when chemo started at same time as ATRA – if WC >10, high risk of developing retinoic acid syndrome and chemo should be started on day 1 after first dose of ATRA

§        Treatment

§        Stop ATRA

§        Steroids – dex 10mg iv minimum 3 days

§        Cautious reintroduction



§        Anthracytine based consolidation therapy

§        Transplant in CR1 has no overall survival advantage

§        After induction and 2 cycles of consolidation, >90% CR

§        Molecular monitoring to guide further therapy

§        Goal is PCR negativity in the bone marrow with a sensitivity of 1 in 104.

§        3 monthly for 2 years after completion of treatment

§        If positive repeat within 2 weeks at a different lab to confirm

§        Relapse is inevitable if PCR positive in 2 consecutive samples

§        Evidence suggests that there is a better outcome if treated at molecular relapse



§        Aim is to induce a 2nd CR and harvest PCR negative cells for an auto.

§        If PCR negativity not achieved can consider allo

§        ATRA should not be used as single agent due to high rates of secondary resistance

§        Arsenic trioxide

§        Degrades the PML-RARa fusion protein and induces apoptosis

§        Cardiac toxicity, esp arrythmias

§        Retinoic acid-type sundrome

§        Used as a ‘bridge’ as remissions not generally sustained

§        Gemtuzamab

§        Transplant

§        Autos are an option in patients who are PCR negative


AML with 11q23 (MLL) (5%)

§        Morphology = acute monoblastic leuakaemia

§        2 groups with high frequency of 11q23

§        Infants

§        Therapy – topoisomerase II inhibitors

§        DIC

§        Extramedullary sarcomas or tissue infiltration (gums)

§        Immuno

§        Myeloid and monocytic markers

§        Intermediate survival


AML with multilineage dysplasia

§        Dysplasia in 2 or more myeloid cell lines in >50% of the cells

§        Mainly elderly

§        With or without preceeding MDS

§        Immuno

§        Myeloid

§        Aberrant expression of CD56 and/ or CD7

§        Increased expression of MDR glycoprotein

§        Bad prognosis


AML and MDS related to previous therapy

§        Alkylating agent/ radiation

§        5-6 years following exposure

§        Risk is related to total cumulative dose

§        Usually panmyelosis

§        May get increased ring sideroblasts and increased marrow basophils

§        Immuno

§        As for AML with multi-lineage dysplasia

§        Genetics

§        Unbalanced translocations, deletions of 5,7

§        Poor prognosis

§        Topoisomerase II inhibitor related

§        Eg. Etoposide, anthracyclines

§        3 years following exposure

§        Usually monocytic

§        Genetics

§        Usually 11q23 abnormalties

§        Prognosis – not determined




AML not otherwise categorised


French-American-British - FAB classification


M0              AML with minimal myeloid differentiation (5%)

§        No evidence of myeloid differentiation by light microscopy

§        Cytochemistry

§        MPO and SBB negative

§        Immuno

§        Myeloid markers

§        Hamopoietic markers

§        Some express CD7, CD2, CD19, but at lower levels than in ALL

§        Poor prognosis


M1               AML without maturation (20%)

§        Blasts (>90% of non-erythroid)  with no significant maturation – more mature neutrophils

§        Cytochemistry

§        MPO and SBB positive

§        Immuno

§        Myeloid markers +/- CD34

§        Poor prognosis


M2               AML with maturation (30%)

§        Evidence of maturation (>10% neutrophils, monocytes <20%)

§        Immuno

§        Myeloid

§        May express CD117, CD34 and HLA-DR

§        Good prognosis if t(8;21)


M4              Myelomonocytic (20%)

§        Neutrophils and their precursors >20%

§        Monocytes and their precursors >20%

§        PB monocytes may be high

§        May be preceeded by CMML

§        Butyrate esterase is monocytic

§        Immuno

§        Myeloid markers

§        Some expression of monocytic markers

§        Previously M4Eo assoc with inv(16) (5-30% eosinophils)

§        Better prognosis if inv (16)


M5               5a monoblastic / 5b monocytic (10%)

§        >80% of leukaemic cells = monocytic, neutrophils <20%

§        Monoblastic >80% monocytic cells are blasts

§        MPO neg, non-specific esterase positive


M6              Erythroleukoblastic (>50% monoblasts) (5% de novo / 10% secondary)

§        >50% erythroid in nucleated cell population

§        > 20% myeloblasts in non-erythroid

§        Morphology

§        Erythroid dysplasia with vacuoles

§        Immuno

§        Erythroblasts

§        lack myeloid markers and negative with MPO

§        Glycophorin A and HbA

§        Myeloblasts

§        Myeloid markers and MPO

§        Poor prognosis


§        Pure erythroid leukaemia – FAB M6b

§        >80% erythroid

§        Very rare

§        Immuno

§        Glycophorin A and HbA

§        Poor prognosis


M7              Megakaryocytic leukaemia (5%)

§        50% blasts megakaryocytic lineage

§        Children has been assoc with t(1;22) and abdominal masses

§        Also an association with mediastinal germ cell tumours

§        May be assoc with extensive fibrosis

§        Immuno

§        CD41 (GPIIb/IIIa) and/or CD61 (GPIIIa)

§        More mature platelets – CD42 (GPIb)

§        Myeloid markers may be present

§        CD36 characteristcally present

§        Abs to factor VIII

§        Prognosis is poor, esp in infants with t(1;22)


Variant: AML/ transient MPD in Down syndrome

Increased predisposition to acute leukaemia, esp. AML – 20% develop later in life

Majority = megakaryoblastic

In some, spontaneous resolution = transient leukaemia

Usually neonatal

May be prominent extramedullary involvement

Immuno = similar to above, blasts may also express CD7

Genetics, as well as trisomy 21, often trisomy 8

Prognosis – transient, usually remits in 1-3 months; persistent, respond well, but usually relapse



Acute basophilic leukaemia (very rare, <1%)

§        Cutaneous involvement, organomegaly, lytic lesions, hyperhistaminaemia

§        Immuno

§        Myeloid and early haematopoietic markers

§        Usually express CD9


Acute panmyelosis with myelofibrosis

§        Panmyeloid proliferation with fibrosis

§        Rephine diagnois

§        Don’t have splenomegaly

§        Immuno

§        Mixed, represnting the cell population

§        Cd34, MPO, glycophorin, CD61

§        Prognosis is poor



Myeloid sarcoma

§        Tumour mass of myeloid blasts or immature myeloid cells in bone or extramedullary sites

§        Skull – subperiosteally, paranasal sinus, sternum, ribs, vertebrae, pelvis, lymph nodes and skin

§        Blastic; immature; differentiated

§        Monoblastic sarcomas rarely

§        Association with AML with maturation t(8;21) and AMML Eo with inv(16) or t(16;16)


Acute leukaemia of ambiguous lineage

§   No differentiating features

§        Immuno

§        HLA-DR, CD34, CD38

§        Lack cCD79a, cCD22, CD3, MPO


Bilineal acute leukaemia

Biphenotypic acute leukaemia

§        Features of myeloid and lymphoid

§        Dual population of blasts, eg. Myeloid and lympohoid or T and B

§        Multiple antigens assoc with more than one lineage

§        ‘lineage switch’ – probably represents expansion of a pre-existing minor population of blasts of a different lineage following therapeutic suppression of the major population

§        Genetics

§        Philadelphia chromosome, t(4;11) or 11q23 abnormalities

§        Pognosis is poor esp with Philadelphia or t(4;11)

§        Scoring  system

§        Diagnose biphenotypic if score 2 or more for myeloid and 2 or more for lymphoid





































§        Bone marrow

§        Blast percentage >20% in AML (was previously 30%) – defined using CD45, CD34 or CD117

§        May be omitted if high blast count and patient only suitable for palliative treatment

§        Trephine needed to assess fibrosis, define blast percentage and multilineage involvement



§        Haematopoietic precursors

§        CD34, HLA-DR, TdT, CD45

§        B-lineage

§        CD10, CD19, CD20, cCD22, CD79a, SmIg (anti-kappa, anti-lambda),u, CD138

§        T-lineage

§        CD1a, CD2, cCD3, CD5, CD7, CD8

§        Myeloid

§        CD13, CD14, CD33, Anti-MPO, CD117, CDw65

§        Megakaryoblastic

§        CD41, CD61, CD42

§        Monoblastic

§        CD14, CD4, CD11b, CD11c, CD64, CD68,  CD36, lysozyme

§        Erythroid

§        Anti-glycophorin A

§        Basophilic leukaemia

§        Toluidine blue stain


§        Cytochemistry can be omitted if four colour flow cytometry is available




§        AML 1-ETO                             t(8:21)

§        CBFB-MYH11                         inv(16) or t(16:16)

§        PML-RARA                             t(15:17)

§        MLL                                        t(v:11q23)

§        RT PCR or FISH



§   Patients undergoing intensive chemo should be tested for FLT3

§   Associated with worse outcome regardless of karyotype, except APL

§   Tyrosine kinase receptor with a role in stem cell survival and proliferation

§   Mutated in about one third

§   Internal tandem duplications of the juxtamembrane domain or point mutations involving the kinase domain activate FLT 3

§   FLT3 inhibitors in clinical trials eg. CEP-701, PKC 412

§   Short lived response as a single agent

§   Genomic instability leading to multiple pathways of escape

§   Being trialed with chemotherapy



§        Age

§        Karyotype

§        FLT3

§        Response to induction chemotherapy


Good risk







Normal karyotype



>15% blasts in marrow after first course of chemotherapy

-5 / del 5q


abn (3q)


Complex (5 or more abnormalities)

35% relapse


76% relapse


Standard risk

§        Absence of the newly discovered mutations in FLT-ITD, NPM1 and CEBPA confers improved prognosis on standard risk AML



§        Multidisciplinary team (Consultant haematologist, haematohistopathologist, microbiologist, radiologist, pharmacist, ward sister, palliative care, social worker, psychologist, team coordinator, data manager).

§        Serve population >0.5m and more than 5 patients per year


1. Hyperleukocytosis >100

§        Poor prognostic factor (15 v 5% early mortality)

§        No trials supporting leukophoresis but should be considered if symptomatic apart from in APL where it can exacerbate coagulopathy


2. Tumour lysis syndrome

§        Hydration / allopurinol

§        Rasburicase if developing ATLS or renal impairment

§        Recombinant uric acid oxidase


3. Transfusion

§        Red cells

§        CMV –ve until status known

§        Irradiated blood products if being given fludaribine

§        No defined transfusion triggers


§        Platelets

§        >10 / >20 if sepsis, antibiotics or altered haemostasis

§        >50 in APL


§        Granulocytes

§        No firm evidence for apheresed granulocytes or pooled buffy coat


4. Antiinfective measures

§        Side room with of en suite

§        Hand washing / decontamination

§        Flowers / plants source fungal spores and pseudomonas


§        Regular examination (Mouth / Hickman line / perineum)

§        Avoid PR / PV

§        Regular CXR / HRCT if fungal infection suspected


AML other than APL


Age <60

§        AML 15 (the current NCRI trial)

§        Otherwise DA 3+10 or 3+7


Age > 60

§        AML 16 (the current NCRI trial) – if suitable for non-intensive chemotherapy

§        Non-intensive chemotherapy - low dose cytaribine

§        Otherwise transfusion / antibiotic support / hydroxycarbamide to control WC




§        Joint management with obstetrician

§        First trimester

§        Avoid chemotherapy if possible

§        Discuss possibility of termination with the mother

§        If refused and the mothers life is at risk should start chemotherapy anyway

§        Second and third trimester

§        Chemotherapy is associated with an increased risk of abortion, premature delivery and low birth weight babies

§        Should consider induction of labour between cycles of chemotherapy


Treatment principles

§        To induce CR

§        Blasts <5%

§        Plts >100

§        N >1

§        BM cellularity >20%

§        Disappearance of karyotype not required

§        CR in 60-90% of younger patients

§        Post remission and consolidation

§        If CR maintained > 3yrs, <10% relapse

§        Relapse

§        Allogeneic SCT

§        If early and few blasts proceed directly into transplant

§        Otherwise, treatment to

§        Induce 2nd CR

§        Reduce tumour burden

§        If 1st remission <12 months and no donor, consider investigational therapies




§        TRM for sibling allos = 25% with a 3-5year DFS 50%

§        MUD 10% lower DFS primarily due to increased TRM

§        Large study (MRC AML 10) comparing high dose chemo, auto and allo in CR1  showed no overall survival difference (reduced relapse but TRM countered benefit)

§        Subgroup <35 years with standard risk most likely to benefit

§        Allograft in first remission

§        Pts with intermediate (as part of a trial) or poor risk cytogenetics may benefit from allo in CR1.

§        Reduces risk of relapse from 50-20%, but TRM 15-25%

§        TRM higher for older patients and non-HLA identical matches

§        Unrelated donor SCT are inferior to those from matched siblings because of increased GvHD and graft failure

§        This may improve with high resolution HLA typing

§        Unrelated donor allografting should be restricted to those with high risk disease in first remission or patients in second remission



Allograft in second remission

§        HLA matched sibling allograft may be the treatment of choice in young patients in second remission.

§        Long-term DFS rates of 30-40% in AML 2nd remission who undergo SCT from an HLA identical sibling donor

§        Patients <45yrs can be considered for an unrelated donor SCT with long term DFS rates of > 30%

§        Patients who have failed to respond to 2 courses of induction therapy, SCT using a myeloablative regime is assoc with long term DFS 0f 20-30%


RIC allografts

§        Older patients with high risk disease or beyond first remission



§        Profoundly immunosuppressive


T-cell depletion

§        Helps control GvHD but with subsequent loss in GvL and potentially higher relapse rates



§        Role contentious – only as part of a clinical trial


CNS disease (0.5%)

§        Associated with higher WC and monocytic disease

§        Trial show no benefit of intrathecal prophylaxis

§        5% of relapses involve CNS

§        Extradural deposits may be more common in t(8;21)

§        Intracerebral deposits may be more common in inv(16)

§        Treatment is IT cytarabine


Relapsed AML

§        >50%

§        Predictors of response to reinduction

§        Age

§        Karyotype – up to 90% if good risk cf. <40%

§        Duration of first remission - >6months

§        Previous SCT

§        Regimes rend to contain high-dose cytarabine in peroration for SCT



AML in the elderly

§        Median age at diagnosis is 65

§        Poorer  prognosis

§        More adverse cytogenetics

§        Higher incidence of secondary leukaemia

§        Increased expression of multidrug reistant phenotypes

§        Standard chemo

§        CR rates of about 60%, but remissions are short

§        Consider if < 70, good performance status, wcc <100, normal organ function, de novo presentation, lack of unfavourable cytogenetics and lack of MDR expression (P-glycoprotein)

§        No evidence to support thr role of MDR blocking agents

§        Insufficient evidence to support routine use of growth factors

§        Myoltarg shows promise as a salvage agent

§        Alternative agents

§        MDR modulators

§        Still in the context of clinical trials

§        CsA – promising results in association with chemotherapy

§        PSC-833 – assoc with marked toxixicity

§        LY335979 – results pending

§        Antibody therapy

§        Gemtuzumab – CD33 + calicheamicin, significant toxicity, trials ongoing with lower doses with promising results

·        30% CR in older patients sustained for 7 months

§        Bc1-2 inhibitor

§        Anti-apototic protein overexpressed in AML blasts

§        Oblimersen

§        Farnesyl transferase inhibitor

§        Targets activation of the RAS pathway

§        Zarnestra

§        FLT3 inhibitors

§        CEP-701, PKC412

§        RIC allografts

§        Upfront or in CR1

§        Non-intensive

§        Low dose cytarabine or clinical trials


Minimal residual disease

§        = lowest level of disease detectable in patients in CCR by the methods available

§        Specific, sensitive, reproducible and quantitative

§        Used to detect ealy relapse and prevent over-treatment