Acute Lymphoblastic Leukaemia Flashcards
(27 cards)
What is Acute lymphoblastic leukemia (ALL)?
Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by the accumulation of lymphoblast in peripheral blood, bone marrow and extramedullary sites like the Central nervous system, thymus, lymph nodes.
What is the Aetiology/ Risk factors of ALL?
Genetic :
Hereditary - <5%
Down syndrome
Ataxia telangiectasia
Bloom syndrome
Schwachman-diamond
Congenital immunodeficiency e.g x-linked agammaglobulinaemia
Germline Mutations in Tp53 present in 40% of patients with low hypodiploid ALL.
Fraternal twins or siblings have 2×-4× risk in 1st decade of life
20% probability in identical twins
Environmental :
Ionizing radiation
Chemical mutagenesis
Chronic infections e.g viral or bacterial
In-utero exposure to X-rays
Parental use of drugs and Medications
Discuss the pathogenesis of ALL?
- ALL is due to single genetic mutation that acts as initiating and driving stimulus
- This mutation acts as the trigger that causes the cell to become cancerous and start multiplying abnormally
- Other subtypes of ALL result from series of genetic events in A cell that has Acquired initiating mutation often in-utero.
- recurring leukaemia-associated chromosomal abnormalities are detected via karyotyping, fish (fluorescent in situ hybridization) and molecular techniques
- Even after treatment, additional mutations result in minor clones having resistance to treatment
- These minor clones become the dominant population at relapse, hence salvage therapy is less effective than 1st line therapy.
- Evidence suggests that very late relapse COULD ARISE from primary leukaemic cells with additional mutations.
Clinical Features
- GENERALIZED WEAKNESS
- Fever and infections
BLEEDING FROM THROMBCYTOPENIA - LYMPHADENOPATHY
- Bone pain and arthralgia due to marrow expansion
- Or cortical infiltration (spread of lymphoblasts into the cerebral cortex)
- Bulky extramedullary disease esp. overt CNS disease
- Mediastinal mass
- Renal Infiltrates in t-cell ALL
- Meningism and cranial nerve palsy
- Ocular involvement (esp. At relapse) e.g retina, cornea, orbit, ocular nerve, or ant. Chamber with hypopyon (pus-like leukemic cells)
- Painless scrotal enlargement due to testicular infiltrates or hydrocoele (lymphatic obstruction).
Laboratory Features
Pancytopaenia on FBC
WBC may be increased , normal or decreased
Circulating blasts on pbf-difficult in aleukaemic leukaemia
Blast count greater than or equal to 20% is needed for diagnosis
Investigations –
- FBC
- Bone marrow aspiration
- CYTOCHEMISTRY
- IMMUNOPHENOTYPING AND CYTOGENETICS
- CLOTTING PROFILE, SEU CR, CXR, LFT, VIRAL MARKERS
- LUMBAR PUNCTURE
List the FAB Classification
This classification is based entirely on morphology of the bone marrow and peripheral blood film
1. ALL-L1: small uniform lymphoblasts
2. ALL-L2: large heterogeneous lymphoblasts
3. ALL-L3: large heterogeneous with vacuoles also called Burkits type ALL
Difference between ALL, ALL2 and ALL3
ALL
ALL 2
ALL 3
Cytochemistry: All is pas +ve, sudan black and mpo negative and t all has localized positivity for acid phosphatase
Lab features
Immunologic Classification: The WHO classification is based on immunophenotyping
Because lymphoblasts lack specific morphologic and cytochemical features, immunophenotyping is an essential part of the diagnostic evaluation.
These analysis methods enable a firm diagnosis in 99% of cases.
Discuss the Immunophenotypic classification
B -linage:
Pro B ALL
Pre B
Common B
Mature B
T- linage:
Pro T ALL
cortical T ALL
Mature T ALL
Surface and specific markers for B-lineage
Surface markers
HLA-DR+, TdT+, CD19+ and/or CD79a+
Specific markers
1. CD 10-
2. CD 10+
3. CD10+/–, cytoplasmic Immunoglobulin (cyIgM+)
4. CD10+/–, surface immunoglobulin (sIgM+)
Surface Markers for T-lineage
- Early T-ALL:
TdT+, cytoplasmic CD3 (cyCD3) or surface CD3+ - Cortical T-ALL (Thy ALL):
cyCD3+, CD7+, CD5 +/−, CD2 +/−
cyCD3+, CD7+, CD1a+, sCD3+/– - Mature T-ALL : sCD3+, CD1a–
Discuss Pro B ALL
Pro-B ALL, also termed pre-pre-B ALL or early pre-B is CD10 negative and lacks specific B- or T-cell differentiation markers but expresses human leukocyte antigen (HLA)-DR, TdT (terminal deoxynucleotidyl transferase) and CD19, and has rearranged immunoglobulin genes
It occurs in approximately 9–11% of adult ALL.
Discuss Pre-B ALL
Pre-B ALL is characterized by the expression of cytoplasmic immunoglobulin, which is absent in common ALL, but is identical to common ALL with respect to the expression of all other cell markers
Discuss Mature B-cell ALL
Mature B-cell ALL is found in approximately 5% of adult ALL patients.
The blast cells express surface antigens of mature B cells, including surface membrane immunoglobulin.
CD10 may be present, as well as, occasionally, cytoplasmic immunoglobulin
Discuss Common ALL
Common ALL (c-ALL) is the major immunological subtype in adult ALL.
It constitutes > 50% of cases of adult ALL.
C-ALL is characterized by the presence of CD10 blast cells
do not express markers that characterize relatively mature B cells such as cytoplasmic or surface membrane immunoglobulins.
The blast cells are positive for CD19 and TdT
Discuss ADULT ALL Classification
PRO B ALL: 10% OF adult ALL, CD 10 is Negative, cyt IG is negative, tdt positive
COMMON ALL (c-ALL): Most common form of adult all, CD 10 +ve, cyt IG IS NEGATIVE, tdt positive
PRE B ALL: IDENTICAL TO C-ALL BUT CYT immunoglobulin is +ve, tdt positive
MATURE B ALL: 4% OF ADULT ALL, NOW BURKITTS LYMPHOMA, TDT is negative, surface ig positive as well as mature b cell surface antigens
T-cell ALL: Incidence increases with age
Expresses cd7 and cd3(mostly cytoplasmic)
Also expresses cd2, cd5 and tdt.
Cd1a, surface cd3, Cd4, cd8 in <45% of cases
Hla-dr is uncommon. Cd10 &/or cd21 in 40-45%. Cd79a weakly expressed.
Membrane cd3 and tcr are absent in 2/3rds of cases; 50% have cytoplasmic tcr proteins (tcra or tcrb or both).
Early t-cell lineage: cd7+, ccd3+, surface cd3-, cd8-, cd4-
CoRTICAL/mid t-cell all: cCd3+, surface cd3-, cd4+, cd8+, cd1a+
Late / MATURE t-cell all: Surface cd3+, Cd1a- and cd4+ or cd8+.
Cytogenetics
Cytogenetic or Molecular:
1. Hyperdiploid and hypodiploid ALL
High hyperploidy(51-65 xsomes)- is the most common genetic abnormality and has a favourable outcome due to sensitivity to methotrexate
Hyperdiploidy with trisomies 4, 10 & 17 have favourable outcome while others with trisomy 18 has low relapse risk.
Near triploidy (69-81) and non-hyperploidy have poor prognosis
Near tetraploidy (82-94) has high frequency of t-cell immunophenotype
- All with tel-AML1 (etv6-runx1) rearrangements:
Most prevalent translocation in paediatrics but rare in adults
T (12;21)(p13;q22).
Cytogenetically cryptic and determined by fish
Has excellent overall survival with very low rate of relapse
favourable outcome is due to optimal asparaginase therapy. - All with E2a-pbx1(Tcf3-pbx1) rearrangements:
Occurs in 20-25% of pre-b all
T(1;19)(Q23;p13)
Excellent response to initial therapy and favourable overall outcome
Patients present with hypercalcaemia and coagulopathy and this has a poor prognosis. - All with mll gene rearrangement:
Involves band 11q23 of chromosome 11
Most frequent abnormality in infants and 1-2% of older children
Most common 11q23 defect is t(4;11)(Q21;q23)
Mll is crucial for embryonic development and haemopoiesis, hence fusion genes can turn hemopoietic cells to leukaemia-initiating cells.
Treatment outcome differs with age with infants having the worst outcome. - All With bcr-abl1 rearrangements:
The t(9;22)(q34;Q11) abnormality results in formation of a 190kda fusion gene.
Active abl tyrosine kinase Activates multiple cellular pathways
Bcr-abl1 all is refractory to standard therapy
improved outcome in combination treatment with tkis such as imatinib
Patients unresponsive to 1st genration TKIs may respond to 2nd and 3rd generation TKIs such as nilotinib, dasatinib and bosutinib. - All with iamp21:
Presence of intracytoplasmic amplification of chromosome 21
Has significantly lower event-free and overall survival at 5 years
Threefold risk of relapse hence treated as cytogenetic high risk
Discuss Risk stratification
Standard risk: Patients <10 years old with Wcc of <50×109/l at diagnosis
Intermediate risk: patients >10 years with wcc Of >50×109/l at diagnosis
High risk: mll rearrangement, Hypoploidy (<40 chromosomes), Iamp21, E2a abnormality and failure to remit at day 29 or induction.
Discuss Management: SUPPORTIVE MANAGEMENT
- Generous hydration with 1.5-2x maintenance fluid and tabs allopurinol
- Blood support as necessary
- Subcut filgastim (a granulocyte colony-stimulating factor (G-CSF) — a medication that stimulates the bone marrow to produce neutrophils) for neutropenia
- Broad spectrum antibiotics then pathogen-sensitive antibiotics depending on results of MCS.
- Adequate analgesia and antipyretics as needed
- Psychological support for both patient and relatives and consent form
- Barrier nursing
- Antifungals and bacterial prophylactic medication such as cotrimoxazole use.
Discuss Management: Definitve therapy
- Pre induction – steroids (prednisolone and vincristine
- Induction – prednisolone, vincristine, daunorubicin, arac , cyclophosphamide
- COAP (Cyclophosphamide, Oncovin (vincristine), Ara-C, Prednisolone) regimen or DAP (Daunorubicin, Ara-C, Prednisolone) v + l asparaginase (1 -2 cycles)
- Intensification – with high dose iv methotrexate
- Consolidation – 4 cycles of same drugs as induction
- Maintenance – mercaptopurine, IV methotrexate, prednisonlone, vincristine (2 years outpatient therapy)
What is Induction Chemotherapy?
Standard induction therapy for acute lymphoblastic leukaemia is prednisone, vincristine, anthracyclines (mostly daunorubicin) and L asparaginase.
All approaches for induction therapy cure rate of approximately 80% in adults and 97.5% in children.
Failure of induction therapy occurs in 20% of adult and about 3% of children
What is Maintenance therapy?
The aim of maintenance or continuation therapy is to eliminate minimal residual disease (MRD) especially from sanctuary sites.
It lasts for 2 years in girls and 3 years in boys
It consists of daily Oral Mercaptopurine and weekly IV Methotrexate.
What is Consolidation chemotherapy?
Consolidation therapy refers to high-dose chemotherapy with multiple new agents, or re-administration of the induction regimen.
These measures are aimed at eliminating residual leukemia after induction chemotherapy and thereby preventing relapse as well as emergence of drug-resistant cells
Discuss the use of CNS prophylaxis
Treatment and prophylaxis of CNS leukemia may consist of
1. intrathecal methotrexate alone or in combination with Hydrocortisone and cytosine arabinoside
2. Intraventricular therapy with above agents
3. Systemic treatment with High dose Cytosine Arabinoside or high dose methetrexate
Or cranial irradiation
