Leukemia Flashcards
Leukemia overview
Blood cancer originating in bone marrow - infiltrates crowd bone marrow leading to suppression
Accounts for 30% of total childhood malignancies
- ALL most common 23%, AML 5%
- Acute (high blasts, rapid progression) or chronic (mature WBCs, slowly progressive), myeloid or lymphoid progenitor cell lines
Myeloid: red blood cells, white bloods cells (neutrophils, eosinophils, basophils, monocytes), platelets
Lymphoid: B lymphocytes, T lymphocytes, NK cells
AML, CML, APML
ALL, CLL,
hairy cell leukemia, biphenotypic leukemia
History:
Systemic: weight loss, lethargy, bone pain/joint swelling, night sweats
Signs of BM failure: anaemia (fatigue & pallor), thrombocytopenia (petechiae/bleeding), neutropenia (recurrent fevers) - if >3 cell lines down think leukemia
- Bone pain, worse at night
- Lymphadenopathy, hepatosplenomegaly
Examination:
- pallor
- lymphadenopathy, hepatosplenomegaly (ALL > AML)
- swelling of gums (monocytic AML)
- SVC obstruction due to mediastinal mass (T cell ALL)
Risk factors:
- T21- ALL & AML
- Exposure to ionising radiation
- Myelodysplastic syndrome (pre-cancerous), blasts >20% - increases and leads to AML
- Alkylating chemotherapy
Pathogenesis
Mutation causes blood cells:
1. Lose ability to differentiate (ineffective blasts)
2. Divide uncontrollably (other cells crowded out = cytopenias)
- Then spread systemically lymph nodes, liver, spleen
- Also thymus & lymph nodes (T-cell ALL)
- Clotting cascade activation (APML) = DIC
Investigations:
- FBE & film (myeloblasts = AML, lymphoblasts = ALL)
- Blasts >20% on bone marrow biopsy
- Myeloblasts = large cell, fine chromatin, nucleoli, Auer rods (crystallised myeloperoxidase)
- Lymphoblasts (minimal cytoplasm, glycogen granules)
- Immunophenotyping (TDT- lymphoblasts, CD10- preB cells)
Treatment:
- Chemo
- Biologicals
- Stem cell transplant, bone marrow transplant
Acute lymphoblastic leukemia (ALL)
ALL
Most common malignancy of childhood
Peak age 2-5yrs, M>F
Associations: T21, NF1, Bloom syndrome, ataxia telengectasia
85% B cell- Pre-B = CD10-, mature (Burkitt)
15% T cell- CD2,3,4,5,7,8, 10% of T-cell ALL early/progenitor- worse prognosis, high remission failure/poor survival
Pathophysiology
Unknown cause
Translocation of 12-21 or 9-22 (philadelphia)
Abnormal intracellular proteins which lead to dysregulated proliferation/clonal expansion of lymphocytes
Blasts arise in BM → systemic spread
- *Clinical features**
- Systemic/B-symptoms
- BM supression/cytopenias
- SVC obstruction due to mediastinal adenopathy- more common in T cell disease
- CNS involvement (rare): headache, N&V, irritability, papilloedema, CN palsies (facial, trigeminal, abducens, accessory)- may rarely involve intracranial/spinal mass- symptoms of compression
- Testicular enlargement- painless/unilateral, more common with T-cell ALL
Risk stratification
- Age
- Cell counts (WCC)
- Cytogenetic/molecular results
- Response to chemotherapy induction biggest prognostic factor
Low risk
- Favourable cytogenetic features:
- Hyperdiploidy (multiple chromosomal duplications >50)
- Trisomies 4,10
- ETV-RUNX protein - t12:21/TEL-AML protein
Standard risk
- Not high risk but no favourable cytogenetic features
High risk
- <1yr, >10yrs
- High WCC at diagnosis >50
- CSF or testicular involvement
- Unfavourable cytogenetics
- *→ hypodiploidy (<44)**
- *→ KMT2A/MLL - translocation 11q23, t4:11**
- *→ iAMP21 amplication**
- *→ Philadelphia chromosome t(9:22), BCR-ABL fusion protein**
- *→ Abnormal 17p, l**oss 13q
- Failure to achieve remission by D29 of induction
Investigations
- FBE, CMP, UEC, LDH, uric acid, coags
- CXR ?mediastinal mass
- BMA- morphology, flow cytometry (immunophenotyping, ploidy), cytogenetics, molecular studies
- Typically >85% blasts- monomorphic, high nucleus:cytoplasm ratio, scanty/agranular cytoplasm, nuclear chromatin, nucleoli and vacuoles
- CSF for cytospin
Treatment
- Risk stratified
- Standard = chemotherapy 2-3 years
- Correct anemia/thrombocytopenia
- Prophylaxis/treatment of infection (i.e PJP- bactrim)
- Monitor/manage tumor lysis
High risk
- >10yrs, >50WCC, Pre-B /Pre-T
1. Induction (to achieve remission)
- ACV= asparaginase, vincristine, steroid
- Intrathecal 1-2x
- Day 8, 9 bloods to assess response
2. CNS protection
- Intrathecal CTx + radiotherapy
3. Post induction
- Rest block to allow marrow recovery, less intensive treatment
4. Maintainence
- Home oral medication
- MCP/MTx weekly, intermittent steroids/vincristine
- Imatinib BC-ABL kinase inhibitor if Philadelphia +ve
- TPMT gene testing- if decreased gene, will lead to increase of AZA → mercaptopurine
Prognosis
5 year survival 85%, 75%
- 90% overall cure rates, 995 ETV RUNX1
- T-ALL higher risk, WCC not prognostic in this group
- Improved outcomes for Philadelphia +ve ALL with imatinib
-70% have 7 year relapse free
- *Relapse**
- Measure with MRD negative status- minimal residual disease assays
- Timing, site, T cell relapse more difficult, response to therapy, donor
- Poorer prognosis if earlier relapse
- 20-30% if very early with transplantm 50% if early,
- T-Cell relapse. <30%
AML
AML
11% of childhood leukemias (2nd most common)
Increased incidence in adolescence
- *Classification**
1. AML with genetic abnormalities
2. AML myelodysplastic changes
3. Myeloid sarcoma
4. Myeloid proliferation related to T21
5. Blastic plasmacytoid dendritic cell neoplasm - *Presenting features:**
- BM failure
- Blastic infiltration/cytopenia
- Subcutaneous nodules (blueberry muffin lesions → infancy, due to extramedullary hematopoesis)
- Infiltration of gingiva
- DIC (APML)- purpura, thrombocytopenia, prolonged APTT/PT
- solid tumors: chloroma/granulocytic sarcoma - eye, oropharynx- contains primitive precursors of myeloblasts/promelocytes, myelocytes (more prevalent in t8:21)
- *Diagnosis**
- >20% myeloblasts on bone marrow aspirate
- Auer rods, abundant cytoplasm, granules
- Characterised by immature → mature immunophenotypes
- Cytogenetic abnormalities in 75% of cases
(t8: 21, inv16, t15:17, 11q23 translocation)
Risk assessment
Favourable
- Cytogenetics: t8:21, t15:17 translocation, RUNX1 gene, inv 16, NPM1 without FLT-ITD/CEBPA (normal karyotype) - 8-10% AML
Standard
- No favourable or high risk mutations
High risk
- Cytogenetics: FLT3/ITD (high ratio mutated : wild type), 10-15% AML- target for novel agents, t6:9, 3q abnormalities, monosomy 5,9,
- Residual disease following induction
- *Treatment**
- Remission in 85-90% of patients with aggressive chemotherapy
- Chemotherapy alone curative in 50%
- Matched sibling SCT or BMT achieves long term survival in ⅔rds
- Matched unrelated SCT if poor prognosis/high risk subtype due to risk of GVHD
Supportive: prophylactic antifungal, antibiotics- due to prolonged BM supression
- *Prognosis**
- Curable in 60-70% of children (lower than ALL)
APML
Translocation of 15-17 - PML-RARA
Disrupts retinoic acid pathway
Treatment: altransretinoic acid- allows maturation of blasts to neutrophils (clears from blood stream) + anthracyclines & cytarabine
Good prognosis if survives induction
Myelodysplastic syndrome
Pre-cancerous
Blasts >20% in blood
Diagnostic criteria for MDS include cytopoenia in 1 or more lineage (most commonly erythrocytes), dysplastic cells on film and <20% blasts in blood and bone marrow.
Associated- dyskeratosis congenita (abnormal nails, reticular skin pigmentation, leukoplakia- risk of MDS, aplastic anemia, leukemia/solid tumors)
Relationship between Down’s syndrome and leukemia
Leukemia
15-20x more frequent in T21
AML more common in first 3 yrs of life
- Poorer outcomes in ALL (lack good prognostic genotypes), very sensitive to MTX/metabolites- toxicity at standard doses = difficult to treat
- Improved outcomes with AML
- *Myeloproliferative disorder**
- High WCC, peripheral blasts, anemia/thrombocytopenia/HSM
- Resolving in first 3mo of life
- May require temporising transfusion
- 20-30% develop leukemia (megakaryocytic, usually by first 3yrs of life, GATA1 mutation associated)
Chronic myelogenous leukaemia
2-3% of childhood leukemias
Most due to Philadelphia chromosome- t9:22 (BCR-ABL protein)
Features/natural history
Fever, LOW, anorexia, splenomegaly
High WCC with myeloid cells at different stages seen on BMA/film
Initial chronic phase 3-4yrs, elevated mature leukocytes
Then accelerated blast crisis - rising blood counts
CNS complications
- *Treatment**
- Imatinib, dasantinib (inihibits BCR-ABL tyrosine kinase), >70%
- Second gen (dasantanib) = improved remission rate
- Hydroxyurea in chronic phase
- HSCT (sibling matched) 80% cure
Leukemia of infancy- Infant leukemia & Juvenile Myelomonocytic Leukaemia
Juvenile Myelomonocytic Leukaemia
Rare <1% , presents in infancy (<2yrs)
RAS/MAP kinase pathway, NF1 or KRAS/NRAS
Associated with NF1, Noonan
⅓rd URTI, hepatosplenomegaly, rash
FBE: monocytosis, anemia, thrombocytopenia, elevated foetal Hb
BM: hypercellular myeloid cells, <20% myeloblasts
Karyotype/FISH/molecular analysis: RAS/MAP, PTPN11, KRAS/NRAS
Minimal treatment options
Infant leukemia
2% of leukemia in <1yrs
ALL 2x incidence of AML
Malignant clone formation can occur in utero during foetal haematopoesis
>80% due to MLL gene 11q23 translocation- t14:11
High relapse rate with this genotype, if not similar prognosis to older kids with ALL
If AML + CNS involvement/skin =myelomonocytic leukemia
Features:
Hyperleucocytosis
Tissue infiltration- hepatosplenomegaly, CNS disease, nodules (leukemia cutis/blueberry muffin spots), pulmonary infiltrates
Treatment
Intensive chemotherapy + SCT if MLL gene
Myelomonocytic leukemia- treatment same as older kids with AML
