The Acute Leukaemias

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The Acute Leukaemias

• Moira Stephens
• Clinical Nurse Specialist
• Haemato-oncology
• Royal Marsden Hospital, UK

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Leukaemia

• Is the proliferation and accumulation of abnormal
  white cells within the bone marrow
• The white cells may cause a crowding out
  phenomena causing -
• Bone marrow failure
• Cells spilling into the peripheral blood and may
  infiltrate other organs

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Leukaemia

• Acute - Immature cell lines affected
• Myeloid or Lymphoid cell lines
• Chronic - Mature cell lines affected
• Myeloid or Lymphoid cell lines

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Diagnostics 1 - Morphology
Normal Bone Marrow
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Diagnostics 2-Immunophenotyping

• Identification of cell surface proteins by
  reactivity with monoclonal antibodies of known
  specificity
• Common Diagnostic profiles -
• AML - CD 13, CD33, CD34, CD14 ve
• cALL - CD10 ve, TdTve
• T-ALL - CD3, CD7, TdT ve
• B-ALL - CD10, CD19, surface Ig ve
• CLL - CD5, CD19, CD23, weak surface Ig ve

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Diagnostics 3 -Cytogenetics

• Acquired chromosomal abnormalities are common in
  haematological malignancies (determination of
  patterns - karyotyping)
• normal cell- (46 chromosomes, 22 pairs xx or
  xy. 2 arms meet at centromere - short arm p, long
  arm q, usually only visible during condensation
  at metaphase, Fluorescence In Situ Hybridisation,
  cell cultures stimulants)

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Diagnostics 3aCommon Karyotype Abnormalities

• AML - t(821) m2, better prognosis
• t(1517) m3, better prognosis
• inv 16 m4, better prognosis
• -5, -7 Complex abnormalities have poor
  prognosis
• ALL t(922) Philadelphia chromosome creates
  bcr-abl gene
• t(922) poor prognosis
• t(411) poor prognosis
• hyperdiploidy- increase in total
  chromosome no. - good prognosis
• Hypodiploidy - decrease in total chromosomes
  - bad prognosis
• B-ALL - (t814) bad prognosis

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Acute Myeloid Leukaemia

• Malignant tumour of haemopoietic precursor cells
  of non-lymphoid lineage.
• Incidence - 1/10,000 annually
• Increasing frequency with age
• (median 60yrs)
• Cause unclear - assoc. radiation exposure,
  benzene, alkylating agents, hereditary
  predisposition in Downs, Fanconis and Blooms
  Klinfelters syndromes

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AML - Morphological Classification (FAB)

• M0 - Undifferentiated
• M1 - Early myeloblastic
• M2 - Late myeloblastic
• M3 - Promyelocytic
• M4 - Myelomonocytic
• M5 - Monoblastic
• M6 - Erythroleukaemic
• M7 - Megakaryoblastic

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Pluripotent stem cell
Multipoint Myeloid stem cell
Lymphoid stem cell common NULL
Pre-T cell
Pre-B cell
CFU-Gemm
T.Lymphoblast T ALL
B.Lymphoblast B ALL
CFU-E
CFU-MEG
CFU-GM
CFU-G
CFU-M
Erythroblast M6
Megakaryoblast M7
Myeloblast M1, M2
Prolymphocyte B PLL
Prolymphocyte T PLL
Monoblast M5
Promegakayocyte
Promyelocyte M3
Promonocyte
T Cell T CLL, Sezary
Reticulocyte
B Cell B CLL. HCL
Megakaryocyte
Neutrophilic Monocyte M4
Plasma Cell Myeloma, PCL
Erythrocyte
Thrombocyte
Monocyte
Macrophage
Polymorph
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WHO AML Classification

• Acute Myeloid Leukaemia with recurrent genetic
  abnormalities
• Acute Myeloid Leukaemia with multilineage
  dysplasia
• Acute Myeloid Leukaemia and myelodisplastic
  syndromes therapy related
• Acute Myeloid Leukaemia not otherwise categorised
• Acute Leukaemias of ambiguous lineage

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Acute Myeloid Leukaemia with recurrent genetic
abnormalities

• AML with t(821) (q22q22) (AML1/ETO)
• AML with abnormal bone marrow eosinophils inv
  (16)(p13q22) or t(1616)(p13q22)
• PML with t(1517)(q22q12) and variants
• AML with 11q23 abnormalities

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Acute Myeloid Leukaemia with multilineage
dysplasia

• Following myelodysplastic syndrome or
  myeloproliferative disorder
• Without antecedent myelodysplastic syndrome

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Acute Myeloid Leukaemia and myelodisplastic
syndromes therapy related

• Alkylating agent related (and/or RT)
• Topoisomerase type 2 inhibitor related
  (Etoposide/Tenoposide)

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Acute Myeloid Leukaemia not otherwise
categorised

• AML minimally differentiated M0
• AML without maturation M1
• AML with maturation M2
• Acute myelomonocytic leukaemia M4
• Acute monoblastic (M5a) and
• myelomonocytic leukaemia (M5b)
• Acute erythroid leukaemia M6
• Acute megakaryoblastic leukaemia M7
• Acute basophilic leukaemia
• Acute panmyelosis with myelofibrosis acute
  myelofibrosis/sclerosis
• Myeloid Sarcoma chloroma/granulocytic
  sarcoma/extramedullary myeloid tumour

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Acute Leukaemias of ambiguous lineage

• Undifferentiated acute leukaemia no expression
• Bilineal acute leukaemia 2 groups
• Biphenotypic acute leukaemia co-express

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AML - diagnosis

• Morphology -
• Immunophenotyping - (CD surface protein markers)
• useful in M0, 4,5,6,7
• Cytogenetics -
• important in detecting deletions translocations

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AML m1 blast
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AML m3 auer rods
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AML - Clinical features

• Acute presentation common often critically ill
• Fever, malaise, anaemic symptoms, infections
• Bleeding, purpura, spontaneous bruising
• Leucostatic signs
• Soft tissue infiltration

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AML m4 - Gum Hypertrophy
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AML - investigations

• FBC and blood film
• WBC, diff, plats RBC
• Bone marrow -asp biopsy -
• hypercellular with proliferation of blasts (gt
  30)
• Other- ? LP, ? CxR, ? CT/MRI

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AML - Treatment

• Stabilise -
• Leucostasis , Haemorrhage, Sepsis
• Psychological support
• Hydration allopurinol / rasburicase
• RBC platelet support

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AML -Specific treatment (non m3)

• Age and co-morbidity , trials
• 4 5 courses
• Induction consolidation
• Anthracycline Cytosine

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AML M3

• MRC approach 4 courses
• ADE (310) ATRA to CR
• ADE (38)
• MACE or MACE Mylotarg
• MiDAC
• Spanish approach -
• Idarubicin 12mg/m2 ATRA to CR
• Idarubicin 7mg/m2 ATRA
• Mitoxantrone ATRA /- Myelotarg
• Idarubicin 12mg/m2
• Maintenance MTX weekly,6MP ATRA 15 days for 3
  monthly for 2 years

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FLAG-Ida

• Fludarabine 30mg/m2 od IV (1/2 hr inf)
• Days 2 6 ( T 0)
• Cytosine 2gm/m2 od infusion
• days 2 6 (T4)
• Idarubicin 10mg/m2 od IV days 4,5,6
• G-CSF (lenograstin 263ug) s.c. od
• days 1 7
• Bone marrow between days 18 - 21

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ADE (1035) (835)

• Cytosine 100mg/m2 12 hourly IV push days 1 10
  (8)
• Daunorubicin 50mg/m2 IV push od
• days 1,3,5
• Etoposide 100mg/m2 od IV infusion
• days 1 5
• Bone marrow day 18 - 21

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DA (310) (38)

• Daunorubicin 50mg/m2 IV push
• days 1,3,5
• Cytosine 100mg/m2 12 hourly by IV push on days 1
  -10
• Bone marrow day 18 - 21

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Consolidation treatment

• Course 3
• MACE /- myelotarg
• Ara C (1.5 OR 3 gm/M2) /- myelotarg
• Standard allograft
• MACE
• Course 4
• MiDAC
• Ara C 1.5 or 3gm/m2
• Mini allograft
• Course 5
• Ara C 1.5gm/m2
• No further treatment

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Acute Lymphoblastic Leukaemia

• Malignant tumour of haemopoetic precursor cells
  of lymphoid lineage
• Incidence - commonest malignancy in childhood,
  majority of cases 2 - 10yrs, rare in adults
  170,000 annually
• slight peak in old age
• Cause unclear, as AML proximity to Radon and
  Power lines postulated

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ALL Classification

• Morphology (FAB)
• L1 - Commonest, small homogenous blasts, single
  nucleolus
• L2 - Blasts larger, more pleomorphic and
  multinucleolate
• L3 - Blasts larger, basophilic and vacuoles
  (assoc with B cell phenotype)

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WHO ALL Classification

• Precurser B cell acute lymphoblastic leukaemia
• Precurser T cell acute lymphoblastic leukaemia
• L1 and L2
• Burkitt Leukaemia L3

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Pluripotent stem cell
Multipoint Myeloid stem cell
Lymphoid stem cell common NULL
Pre-T cell
Pre-B cell
CFU-Gemm
T.Lymphoblast T ALL
B.Lymphoblast B ALL
CFU-E
CFU-MEG
CFU-GM
CFU-G
CFU-M
Erythroblast M6
Megakaryoblast M7
Myeloblast M1, M2
Prolymphocyte B PLL
Prolymphocyte T PLL
Monoblast M5
Promegakayocyte
Promyelocyte M3
Promonocyte
T Cell T CLL, Sezary
Reticulocyte
B Cell B CLL. HCL
Neutrophilic Monocyte M4
Megakaryocyte
Plasma Cell Myeloma, PCL
Erythrocyte
Thrombocyte
Polymorph
Monocyte
Macrophage
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ALL Lymphoblasts
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ALL - Classification

• Immunophenotyping - lymphocyte maturation markers
  distinguish early or null from pre-Bcell or
  common ALL
• lt 10 T cell lineage
• lt 5 B cell lineage
• Cytogenetics - 10 -20 Ph ve (922)

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ALL - Clinical features

• Malaise, sweats, wt. loss, anorexia
• Infections, bleeding, anaemia
• Leucostatic signs
• Widespread lymphadanopathy, mild/mod
  splenomegaly/hepatomegaly/orchidomegaly
• CNS signs
• SVCO

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ALL - Investigations

• FBC and blood film -
• wbc (may be low), blasts on film
• Hb platelets often low
• Bone marrow -asp biopsy
• heavy infiltration of blasts
• FISH (BCR-ABL)
• Other- LP, CxR, CT

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ALL - Treatment

• Stabilise -
• Leucostasis , Haemorrhage, Sepsis
• LP if meningism
• Psychological support
• Hydration allopurinol/rasburicase
• RBC platelet support

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ALL - Specific treatment

• UKALL XII (PH negative)
• Induction
• Phase 1 days 1 28
• Daunorubicin vincristine days 1,8,15
• Prednisone days 1-28
• Asparaginase days17-28
• mtx IT Bone marrow d24)
• Phase 2 starts on day 29 (or wbc gt3.0)
• Cyclophosphamide days 1,15 29
• Cytosine days 1-4, 8-11,15-18, 22-25
• 6mp od days 1-28
• Intrathecal MTX days -1,7,14,21
• Special considerations thrombophilia, PCP,
  fungal infection

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ALL - Specific treatment

• UKALL XII (PH negative)
• Intensification
• Methotrexate 3gm/m2 days 1,8 22 FA rescue
• then Allograft or autograft or cycles 1 -4
  consolidation maintenance for 1 year
• CNS prophylaxis
• Intrathecal MTX
• Cranial RT (2,400 gray 12 )
• Intrathecal cytosine x 4 weekly with RT then 1
  dose 3 monthly during maintenance (1 year)
• If for BMT no RT, 1 extra MTX