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B13 - Acute Leukaemia Flashcards

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1
Q

Acute Leukaemia

A
  • Malignant leucocyte precursors in bone marrow (blast cells)
    ○ Abnormality occurs in cells only just committed to either lymphoid or myeloid - will proliferate and stall at this stage of development
    • Replacement of BM by leukaemic cells (blast cells) outgrow the normal bone marrow resulting in bone marrow failure
    • Reduction in normal cells
    • Leukaemia (blast) cells proliferate but do not mature
    • Two main types:
      ○ lymphoid (lymphoblastic, ALL)
      ○ Myeloid (myeloblastic, AML)
    • Treatment chemotherapy +/- stem cell transplant
    • Genetic change resulting in a clonal abnormality of a primitive cell leading to leukaemia
      ○ Originates in the bone marrow and goes to blood
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2
Q

two main types of acute leukaemia

A

○ lymphoid (lymphoblastic, ALL)

○ Myeloid (myeloblastic, AML)

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3
Q

Haemopoiesis

- Acute leukaemia

A

○ Differentiation from pluripotent cell to myeloid and lymphoid
○ Acute leukaemia occurs early in cells only just committed to myeloid or lymphoid - stall at this stage and do not differentiate further

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4
Q

haemopoeisis - chronic leukaemia

A

○ Still differentiate leading to mature end stage cells that resemble normal cells but do not function
○ The abnormality is probably still in the very early stem cell but it’s able to differentiate

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5
Q

acute leukaemia - clinical features

A

○ Affects all ages (children: predominantly ALL), increasing incidence with aging
○ Symptoms: bone marrow failure because the leukaemic cells replace normal haemopoiesis in the bone marrow - unable to make red blood cells and become anaemic
§ Anaemia
§ Leukopenia - not able to make white blood cells - leukopoiesis, granulopoiesis
§ Thrombocytopenia - not enough megakaryocytes so they cant make platelets leading to thrombocytopaenia, bleeding, bruising
§ Lethargy
§ Infections
§ Fevers
§ Bleeding
§ bruising

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6
Q

○ Acute monocytic leukaemia (subtype of acute myeloid leukaemia)

A

§ Cells would have been monocytes if they had matured properly
§ Gum hypertrophy, gingival enlargement (enlarged gums with bleeding or swelling due to leukaemic infiltration of that tissue)
§ Red swollen gingiva (gums around teeth) due to leukaemia cells

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7
Q

○ Bone marrow replaced by immature blast cells (leukaemic cells)

A

§ Immature, fine chromatin (purple inside the nucleus is lighter in colour), nucleolus (pale staining region within the nucleus)
§ Variable amounts of cytoplasm - sometimes there are granules or other things giving an indication as to the type of cell
§ Don’t look like normal end stage cells

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8
Q

○ Blood count reduced with circulating blast cells

A

§ Type of leukemia determined by
□ Cell appearance (morphology)
□ Biomarkers (flow cytometry) or cellular antigens
□ Cell chromosomes of the leukaemic - to see if they differ from normal, or have chromosomes that are associated with a specific type of leukaemia and the likely prognosis

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9
Q

○ Cellular antigens expressed determines cell lineage - lymphoid or myeloid, B cell or T cell (if lymphoid)

A

§ B lineage: CD10, CD19, CD79a
§ T lineage: CD2, CD3, CD7
§ Myeloid: CD13, CD33, CD64, CD117

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10
Q

markers of B cell lineage

A

§ B lineage: CD10, CD19, CD79a

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11
Q

markers of T cell lineage

A

§ T lineage: CD2, CD3, CD7

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12
Q

markers of myeloid lineage

A

§ Myeloid: CD13, CD33, CD64, CD117

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13
Q

Stage of differentiation (maturity):

A

CD34, TdT - both markers that indicate immaturity, early in differentiation

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14
Q

Therapy

A

○ Depending on age and whether we are treating with curative intent
○ Aggressive cytotoxic chemotherapy (curative intent - kill or immortalise leukaemic cells in bone marrow, also kills normal haemopoietic cells causing prolonged pancytopenia - normal cells will have a low count (for two or three weeks) until bone marrow can recover
§ Generally needs more than 1 course because it can recur
§ Require multiple cycles
○ Bone marrow transplantation (allo from someone else - as opposed to auto)
§ Allogeneic - from another person
○ Monoclonal antibody therapy - more personalised and targeted
○ Specific targeted inhibitors
○ S/E prolonged pancytopenia
§ Blood transfusions, antibiotics - managing side effects
○ Antibiotics
○ Cytokines (e.g. G-CSF)
§ to encourage bone marrow to make more normal blood
§ be careful you are not encouraging growth of more leukaemia

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15
Q

Precursor Lymphoid Leukaemia

A
  • Also called: acute lymphoblastic leukaemia
    • Neoplastic (cancerous) proliferation of precursor cell committed to B or T lymphoid lineage (lymphoblastic leukaemia) 85% will be B cell lineage
    • Somatic mutation in early progenitor cell
    • Presentation
      ○ Symptoms of BM failure: anaemia, infection, bleeding
      ○ Organ infiltration: lymph nodes, spleen, liver, thymus
      § Organs that normally contain lots of lymphoid cells
      § Thymus only if it is T cell
    • Age: child or adult
    • Diagnosis: morphological blood and bone marrow examination
    • Classification: phenotype, genetics (chromosomes)
    • Prognosis: child=good (high cure rate 85-90%), adult=poor (we don’t fully know why adults have worse prognosis)
    • Most common leukaemia in children - if the child is 2-5 they have a good prognosis - 90% cure rate
    • 3.4/100 000
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16
Q

Precursor Lymphoid Leukaemia prognosis

A
  • Prognosis: child=good (high cure rate 85-90%), adult=poor (we don’t fully know why adults have worse prognosis)
    • Most common leukaemia in children - if the child is 2-5 they have a good prognosis - 90% cure rate
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17
Q

Precursor Lymphoid Leukaemia presentation

A

○ Symptoms of BM failure: anaemia, infection, bleeding
○ Organ infiltration: lymph nodes, spleen, liver, thymus
§ Organs that normally contain lots of lymphoid cells
§ Thymus only if it is T cell

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18
Q

Precursor Lymphoid Leukaemia - Children

A

○ ALL most common in children
○ B-lineage ALL
§ Accounts for 85% of ALL in children
○ T-lineage ALL
§ 15% of ALL in children
○ Childhood ALL: 90% cure (30-40% in adults)

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19
Q

precursor lymphoid leukaemia symptoms

A

○ Anaemia, lethargy, leukopenia, thrombocytopenia, blast cells, infections, fevers, bleeding, bruising, bone pain, weight loss, loss of appetite

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20
Q
  • B-lineage ALL
A

○ Commonest leukaemia in children
○ Small blast cell
○ Precursor B cell
§ Antigens: CD10 (immature B cell), CD19 (B cell associated antigen), TdT positive (marker of immaturity)

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21
Q
  • T-lineage ALL
Study These Flashcards
A

○ Antigens: cCD3, CD7 (both T cell associated, common), TdT (enzyme present in lymphoblasts, both B and T, marker of immaturity)

22
Q
  • Prognosis

of precursor lymphoid leukaemia

Study These Flashcards
A

Good in children, poor adults

23
Q

Lymphoblasts in precursor lymphoid leukaemia

Study These Flashcards
A
  • Resemble lymphocytes, larger, nuclear chromatin is not as dark, pale staining regions nucleolus - all the cells resemble each other, variable amounts of cytoplasm
    • Size: slightly larger that lymphocyte to size of neutrophil
    • Cytoplasm: scant, basophilic
    • Nucleus: round, may be convoluted
    • Chromatin: finely granular
    • Nucleolus: inconspicuous
    • Granules: usually nil
    • Vacuoles: precursor B and Burkitt
    • Other: “hand-mirror” morphology
    • Phenotypes
      ○ B: CD10, CD19, cCD79a, TdT
      ○ T: CD2, 3, 7, CD4/8, TdT
24
Q

cytogenetics of precursor lymphoid leukaemia

Study These Flashcards
A
  • To assess the chromosomes in the leukaemic cells - not the whole person
    • Indicates type of disease and likley prognosis
    • Karyogram - chromosomes laid out pictorially
    • Chromosomal makeup is associated with prognosis (outcome)
    • Hyperdiploidy - too many chromosomes, good prognosis disease, typical in children
    • Translocations - interchange of material between two chromosomes, occur at different ages of patients
      ○ T(9;22)
      ○ T(12;21)
      ○ T(1;19)
      ○ T(4;11)
    • By age
      ○ HeH and t(12;21) mostly in children - good prognosis
      ○ T(4;11) - almost entirely neonates - bad prognosis in all ages
      ○ T(9;22) - older population mostly, bad prognosis
25
hyperdiploidy in precusor lymphoid leukaemia
too many chromosomes, good prognosis disease, typical in children
26
translocations in precursor lymphoid leukaemia
``` nterchange of material between two chromosomes, occur at different ages of patients ○ T(9;22) ○ T(12;21) ○ T(1;19) ○ T(4;11) ```
27
cytogenetics by age in precursor lymphoid leukaemia
○ HeH and t(12;21) mostly in children - good prognosis ○ T(4;11) - almost entirely neonates - bad prognosis in all ages ○ T(9;22) - older population mostly, bad prognosis
28
Survival and Cytogenetics in precursor lymphoid leukaemia
``` - High hyperdiploidy ○ HeH ○ Frequent in children, good prognosis - T(12;21)(p13;q22)TEL-AML1 ○ 25% child ALL - T(1;19)(q23;p13) E2A-PBX1: ○ 5% child, 3% adult ALL - MLL (11q23) rearrangements: ○ 85% infant; <5% adult ALL ○ Poor prognosis - T(9;22)(q34;q11) BCR-ABL1: ○ 3% child; 25% adult (poor prognosis) ```
29
treatment based on prognosis
Bad prognosis disease: treat more intensively | Good prognosis: withdraw treatment early to prevent patient suffering consequences of the treatment
30
Acute Myeloid Leukaemia
- Clonal defect in primitive myeloblast - Paediatric (rare) and adults (more common) - increasing incidence with age - Many subtypes with different morphology ○ Looking at morphology gives guide to the type of disease - Immunophenotyping (antigen expression by flow cytometry) to characterise - Many genetic abnormalities ○ Chromosomal changes and point mutations (sequencing and PCR based methods ○ Karyotyping ○ Point mutations ○ T(8;21), t(15;17), inv(16); mutations NPM1 - Treatment: cytotoxic chemotherapy; transplantation (sometimes, depending on subtype, likely outcome and age) attempt to cure - Auer Rods: indicate acute myeloid leukaemia
31
- Myeloblasts in acute myeloid leukaemia
○ Size: variable: slightly larger that lymphocyte to size of monocyte ○ Cytoplasm: moderate amount; basophilic to blue-grey ○ Nucleus: round to ovoid; may be indented ○ Chromatin: granular ○ Nucleolus: present; one or several ○ Granules: few to many azurophilic; Auer rods ○ Vacuoles: common; esp. monocytoid (white hole)
32
- Flow cytometry in acute myeloid leukaemia
○ Look for the expression of myeloid associated antigens ○ CD13 and CD33 - pretty much myeloid specific ○ CD34 - marker of immaturity ○ CD14 - associated with monocytes ○ Positive for CD33 and CD34 would mean acute myeloid leukaemia ○ Positive for CD13 but negative for CD14 would indicate acute myeloblastic leukaemia
33
Acute Promyelocytic Leukaemia - Morphology
○ Blast cells with promyelocyte morphology, granules and Auer rods ○ Nucleus occupies only about half of the cells - cytoplasmic granules and Auer rods in the other half ○ Characteristic morphology
34
Acute Promyelocytic Leukaemia - Presentation - characteristic
○ Bleeding ○ Bleeding and clotting excessively, using up platelets and fibrinogen ○ May be having a stroke - Bleeding - leukaemic cells cause disseminated intravascular coagulation - utilizing all the fibrinogen and platelets - Presenting to emergency department with stroke - patients can die If not identified quickly
35
Acute Promyelocytic Leukaemia | - Coagulation
○ Disseminated intravascular coagulation ○ hypo-fibrinogenaemia ○ Bleeding and clotting excessively, consuming platelets and fibrinogen, cannot make a clot properly - bleeding ○ Presenting to emergency department - will die if not diagnosed quickly
36
Acute Promyelocytic Leukaemia | - Genetics
○ T(15;17) ○ PML (pro-myelocytic leukaemia gene)/RARA (retinoic acid receptor alpha gene) ○ Treat patients with retinoic acid - vit A - specific treatment
37
Acute Promyelocytic Leukaemia - Therapy
○ All-trans retinoic acid ○ Arsenic trioxide - small doses to kill leukaemic cell not fatal dose which will kill patient § Specific targeted treatment ○ Good prognosis disease with treatment
38
Acute Promyelocytic Leukaemia | Blast cells
○ Size: variable: may be large ○ Cytoplasm: densely packed granules; granules may obscure nuclear border ○ Auer dos: easily found, faggot cells 'bundle of sticks', larger than other AML ○ Nucleus: eccentric, reniform (buttock shaped)
39
Cytogenetics | of acute promyelocytic leukaemia
- Good prognosis t(15,17) (acute promyelocytic), t(8,21), t(16,16) - Intermediate prognosis: normal karyotype 46XX or 46XY - Poor prognosis: monosomy 3,5, or 7 - Acute myeloid leukaemia - worse prognosis than acute lymphoblastic - T(8;21) - loss of material from 8 goes to 21 making a long 21 - good prognosis disease in ages 20-40 - T(15;17) - loss of some material from 15 going to 17
40
good prognosis for acute promyelocytic leukaemia
- Good prognosis t(15,17) (acute promyelocytic), t(8,21), t(16,16)
41
intermediate prognosis for acute promyelocytic leukaemia
- Intermediate prognosis: normal karyotype 46XX or 46XY
42
poor prognosis for acute promyelocytic leukaemia
- Poor prognosis: monosomy 3,5, or 7
43
acute myeloid or acute lymphoblastic has a worse prognosis
Acute myeloid leukaemia
44
Molecular DNA studies
- Provide important prognostic information for further risk satisfaction, especially intermediate risk group - Many mutations - Good prognosis: NPM1 - Poor prognosis: FLT3 - Increasing use - because it gives information about outcome and there are targeting therapies for patients with particular mutations ○ eg. FLT3 inhibitors and IDH1 and IDH2 inhibitors - Next-generation sequencing
45
NPM1 good or poor prognosis
good
46
FLT3 good or poor prognosis
poor
47
Management approaches | - Cytotoxic therapy
- Cytotoxic therapy ○ Remission induction therapy ○ Consolidation therapy - maintaining remission to create durable long term remission ○ Children tend to be treated for 2-3 years ○ 2 for girls 3 for boys ○ Leukaemic cells hide in sanctuary sites especially the testes ○ More intense but not as long for acute myeloid
48
management approaches - Supportive care
○ Transmission: blood products red cells, platelets § Generally don’t need FFP unless they have a coagulation disturbance when presenting with acute promyelocytic leukaemia ○ Control of infection: antibiotics, anti-fungals (sometimes) ○ Cytokine therapy with GCSF - granulocyte colony stimulating factor
49
Management approaches | - Transplantation <60 years AML in remission
○ Age limit is increasing ○ Allogeneic (from someone else - usually done this way), autologous (risk of transfusing cancer cells - rarely done this way) or matched volunteer bone marrow - unrelated person who is an appropriate tissue type match ○ Peripheral blood stem cells or bone marrow stem cells if from another person ○ ALL - don’t transplant unless after relapse (2nd remission)
50
Cytotoxic chemotherapy
- Combination - not one drug alone ○ Destroy leukaemic ○ Damage normal bone marrow ○ Induce bone marrow failure causing side effects ○ Aim for remission § Absence of detectable leukaemia § Return of normal marrow function § Remission for five years generally means they wont relapse but they still can - one clonally abnormal cell may be hidden and cause patient to relapse - Supported with blood products and anti-microbials

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