Title: The Acute Leukaemias
1The Acute Leukaemias
- Moira Stephens
- Clinical Nurse Specialist
- Haemato-oncology
- Royal Marsden Hospital, UK
2Leukaemia
- 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
3(No Transcript)
4Leukaemia
- Acute - Immature cell lines affected
- Myeloid or Lymphoid cell lines
- Chronic - Mature cell lines affected
- Myeloid or Lymphoid cell lines
5Diagnostics 1 - Morphology
Normal Bone Marrow
6Diagnostics 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
7Diagnostics 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)
8Diagnostics 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
9Acute 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
10AML - Morphological Classification (FAB)
- M0 - Undifferentiated
- M1 - Early myeloblastic
- M2 - Late myeloblastic
- M3 - Promyelocytic
- M4 - Myelomonocytic
- M5 - Monoblastic
- M6 - Erythroleukaemic
- M7 - Megakaryoblastic
11Pluripotent 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
12WHO 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
13Acute 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
14Acute Myeloid Leukaemia with multilineage
dysplasia
- Following myelodysplastic syndrome or
myeloproliferative disorder - Without antecedent myelodysplastic syndrome
15Acute Myeloid Leukaemia and myelodisplastic
syndromes therapy related
- Alkylating agent related (and/or RT)
- Topoisomerase type 2 inhibitor related
(Etoposide/Tenoposide)
16Acute 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
17Acute Leukaemias of ambiguous lineage
- Undifferentiated acute leukaemia no expression
- Bilineal acute leukaemia 2 groups
- Biphenotypic acute leukaemia co-express
18AML - diagnosis
- Morphology -
- Immunophenotyping - (CD surface protein markers)
- useful in M0, 4,5,6,7
- Cytogenetics -
- important in detecting deletions translocations
19AML m1 blast
20AML m3 auer rods
21AML - Clinical features
- Acute presentation common often critically ill
- Fever, malaise, anaemic symptoms, infections
- Bleeding, purpura, spontaneous bruising
- Leucostatic signs
- Soft tissue infiltration
22AML m4 - Gum Hypertrophy
23AML - 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
24AML - Treatment
- Stabilise -
- Leucostasis , Haemorrhage, Sepsis
- Psychological support
- Hydration allopurinol / rasburicase
- RBC platelet support
25AML -Specific treatment (non m3)
- Age and co-morbidity , trials
- 4 5 courses
- Induction consolidation
- Anthracycline Cytosine
26AML 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
27FLAG-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
28ADE (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
29DA (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
30Consolidation 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
31Acute 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
32ALL 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)
33WHO ALL Classification
- Precurser B cell acute lymphoblastic leukaemia
- Precurser T cell acute lymphoblastic leukaemia
- L1 and L2
- Burkitt Leukaemia L3
34Pluripotent 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
35ALL Lymphoblasts
36ALL - 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)
37ALL - Clinical features
- Malaise, sweats, wt. loss, anorexia
- Infections, bleeding, anaemia
- Leucostatic signs
- Widespread lymphadanopathy, mild/mod
splenomegaly/hepatomegaly/orchidomegaly - CNS signs
- SVCO
38ALL - 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
39ALL - Treatment
- Stabilise -
- Leucostasis , Haemorrhage, Sepsis
- LP if meningism
- Psychological support
- Hydration allopurinol/rasburicase
- RBC platelet support
40ALL - 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
41ALL - 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