B13 - Acute Leukaemia Flashcards
Acute Leukaemia
- 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
two main types of acute leukaemia
○ lymphoid (lymphoblastic, ALL)
○ Myeloid (myeloblastic, AML)
Haemopoiesis
- Acute leukaemia
○ 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
haemopoeisis - chronic leukaemia
○ 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
acute leukaemia - clinical features
○ 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
○ Acute monocytic leukaemia (subtype of acute myeloid leukaemia)
§ 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
○ Bone marrow replaced by immature blast cells (leukaemic cells)
§ 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
○ Blood count reduced with circulating blast cells
§ 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
○ Cellular antigens expressed determines cell lineage - lymphoid or myeloid, B cell or T cell (if lymphoid)
§ B lineage: CD10, CD19, CD79a
§ T lineage: CD2, CD3, CD7
§ Myeloid: CD13, CD33, CD64, CD117
markers of B cell lineage
§ B lineage: CD10, CD19, CD79a
markers of T cell lineage
§ T lineage: CD2, CD3, CD7
markers of myeloid lineage
§ Myeloid: CD13, CD33, CD64, CD117
Stage of differentiation (maturity):
CD34, TdT - both markers that indicate immaturity, early in differentiation
Therapy
○ 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
Precursor Lymphoid Leukaemia
- 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
Precursor Lymphoid Leukaemia prognosis
- 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
Precursor Lymphoid Leukaemia 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
Precursor Lymphoid Leukaemia - Children
○ 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)
precursor lymphoid leukaemia symptoms
○ Anaemia, lethargy, leukopenia, thrombocytopenia, blast cells, infections, fevers, bleeding, bruising, bone pain, weight loss, loss of appetite
- B-lineage ALL
○ 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)
- T-lineage ALL
○ Antigens: cCD3, CD7 (both T cell associated, common), TdT (enzyme present in lymphoblasts, both B and T, marker of immaturity)
- Prognosis
of precursor lymphoid leukaemia
Good in children, poor adults
Lymphoblasts in precursor lymphoid leukaemia
- 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
cytogenetics of precursor lymphoid leukaemia
- 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
hyperdiploidy in precusor lymphoid leukaemia
too many chromosomes, good prognosis disease, typical in children
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)
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
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)
treatment based on prognosis
Bad prognosis disease: treat more intensively
Good prognosis: withdraw treatment early to prevent patient suffering consequences of the treatment
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
- 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)
- 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
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
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
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
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
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
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)
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
good prognosis for acute promyelocytic leukaemia
- Good prognosis t(15,17) (acute promyelocytic), t(8,21), t(16,16)
intermediate prognosis for acute promyelocytic leukaemia
- Intermediate prognosis: normal karyotype 46XX or 46XY
poor prognosis for acute promyelocytic leukaemia
- Poor prognosis: monosomy 3,5, or 7
acute myeloid or acute lymphoblastic has a worse prognosis
Acute myeloid leukaemia
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
NPM1 good or poor prognosis
good
FLT3 good or poor prognosis
poor
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
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
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)
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
