2. DEFINITION
Leukaemia is a malignant disorders of heamatopoietic stem cells
characteristically associated with increase number of white cells in
bone marrow or/and peripheral blood.
3. Types of leukemia
Acute Chronic
⢠Proliferation of primitive
stem cells leading to an
accumulation of blasts,
predominantly in the bone
marrow which will lead to
bone marrow failure.
⢠Acute lymphoblastic
leukaemia and acute
myeloid leukaemia
⢠The malignant clone is
able to differentiate,
resulting in accumulation
of more mature cells.
⢠Chronic lymphoblastic
leukaemia and chronic
myeloid leukaemia.
4. Epidemiology
⢠Acute lymphoblastic leukaemia shows a peak
incidence in children age 1-5 years old
⢠Acute myeloid leukaemia has the lowest incidence in
young adult life and there is striking rise over the age
of 50
⢠Chronic lymphoblastic leukaemia and chronic myeloid
leukaemia mainly in middle and old age.
5. Risk factors
Environmental factors Genetic factors
1. family income
2. father with higher social contact
3. number of elder siblings
4. father who smokes
5. the distance of the house from a
power line
6. Alkylating Agents
7. Benzene Exposure
8. Advanced Maternal Age
1. Genetic diseases such as Down
syndrome.
2. People who have an identical twin
who develops leukemia are more
likely to develop it themselves.
3. Li-fraumeni syndrome
4. Blooms syndrome
5. Ataxia telangiectasia
6. NF Type1
6. BLAST CELLS
ALL is characterized by presence of immature cells â blast cells of >20%
in the
a. blood picture
b. bone marrow examination
Features of blast cells
- very high N:C ratio
- large cells with large nuclei
- absence of cytoplasmic granules
- presence of round or convoluted nuclei
7.
8.
9.
10. PATIENT PRESENTATION:
Ineffective hematopoiesis due to the excessive
proliferation of lymphoid precursor cells in bone
marrow:
â˘Neutropenia â fever, chills, infection
â˘Thrombocytopenia â bleeding, bruising
â˘Anemia â weakness, fatigue, dizziness,
palpitation, SOBOE
13. Investigations
⢠Full blood count- Anemia, thrombocytopenia, leucopenia or leukocytosis.
⢠Peripheral smear study- Total leucocyte count raised , normal or low,
Normocytic normochromic anemia, Thrombocytopenia
⢠Coagulation studies (prothrombin time [PT], activated partial
thromboplastin time [aPTT], fibrinogen)
⢠Renal profile and liver function test- due to tumour lysis syndrome, need to
monitor hyperkalemia, hyperuricaemia, hyperphosphotemia and
hypocalcemia
⢠Bone marrow aspiration and biopsy- hypercellular replacement of normal
cells by blast cells which more than 20%.
⢠Blood cultures- obtained in patients with fever and other signs of infection.
15. ⢠Lumbar puncture- used to evaluate CNS involvement. In pediatric
patients, LP is typically included in the diagnostic workup. CNS status
is classified as follows, on the basis of cerebrospinal fluid (CSF)
findings:
1. CNS-1: No lymphoblasts in CSF, regardless of white blood cell (WBC)
count
2. CNS-2: WBC < 5/mcL in CSF with presence of lymphoblasts
3. CNS-3: WBC âĽ5/mcL in CSF with presence of lymphoblasts
⢠Chest x ray- Nodular masses. Central lymphadenopathy, such as
mediastinal lymph node enlargement.
⢠Computed tomography scans- can further define the degree of
lymphadenopathy in some patients, including those with mediastinal
masses.
27. Induction phase
The primary goal of induction is achievement of an initial complete
remission (CR), defined as the eradication of ALL detectable leukemia
cells (less than 5 percent blasts) from the bone marrow and blood and
the restoration of normal hematopoiesis (>25 percent cellularity and
normal peripheral blood counts).
involves either a four-drug regimen of vincristine, prednisone, an
anthracycline, and cyclophosphamide or L-asparaginase or a five-drug
regimen of vincristine, prednisone, an anthracycline, cyclophosphamide,
and L -asparaginase given over the course of 4-6 weeks.
28. Consolidation therapy
The goal of post-induction chemotherapy is to prevent leukemic
regrowth, reduce residual tumor burden, and prevent the emergence
of drug-resistance in the remaining leukemic cells.
âCytarabine
âMethotrexate
âAnthracyclines (daunorubicin, doxorubicin)
âAlkylating agents (cyclophosphamide, ifosfamide)
âEpipodophyllotoxins (etoposide, etopophosphamide)
29. Maintenance therapy
After completion of the consolidation or intensification phase of
therapy, patients often receive a less intensive continuation regimen
(eg, maintenance chemotherapy) using daily oral 6-mercaptopurine (6-
MP), weekly methotrexate with periodic vincristine, prednisone, and
intrathecal therapy.
30. CNS PREVENTIVE THERAPY
CNS treatment usually begins during the induction phase and continues
throughout the remainder of the treatment regimen. Craniospinal
radiotherapy has been replaced by intrathecal chemotherapy in several
CNS preventive therapy protocols. As was associated with significant
toxicity, such as cognitive impairment and decreases in white matter
volume. In order to achieve effective CNS prophylaxis while minimizing
neurotoxicity, experts now recommend a lower dose of cranial
irradiation with intrathecal methotrexate.
31. Supportive therapy
⢠Packed red blood cells are given to patients with a hemoglobin level
of less than 7-8 g/dL or at a higher level if the patient has significant
cardiovascular or respiratory compromise.
⢠Platelets are transfused if the count is less than 10,000-20,000/¾L.
Patients with pulmonary or gastrointestinal hemorrhage receive
platelet transfusions to maintain a value greater than 50,000/ÂľL.
Patients with central nervous system CNS hemorrhage are transfused
to achieve a platelet count of 100,000/ÂľL.
⢠Fresh frozen plasma is given to patients with a significantly prolonged
prothrombin time (PT). Cryoprecipitate is given if the fibrinogen level
is less than 100-125 g/dL.
32.
33. Medications
DRUG ACTION
Vincristine vinca alkaloid agent that acts by arresting cells in metaphase.
asparaginase Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing
circulating levels of asparagine. Lack of asparagine synthetase activity results in
cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino
acid asparagine.
Pegaspargase Modified version of L-asparaginase. Selective killing of leukemic cells it thought to be
due to depletion of plasma asparagine, the amino acid required for protein synthesis. It
is indicated as a component of a multi-agent chemotherapeutic regimen for the first line
treatment of ALL. It is also indicated for use in patients with hypersensitivity to native
forms of L-asparaginase.
Methotrexate antimetabolite of the folic acid analogue type. This agent inhibits dihydrofolate
reductase, resulting in inhibition of DNA synthesis, repair, and cellular replication.
Mercaptopurine antimetabolite of the purine analogue type. Its primary effect is inhibition of DNA
synthesis.
Cyclophosphamide alkylating agent of the nitrogen mustard type that acts by inhibiting cell growth and
proliferation.
Cytosine
arabinoside
antimetabolite that induces activity as a result of activation to cytarabine triphosphate
and includes inhibition of DNA polymerase and incorporation into DNA and RNA.
34. DRUG ACTION
Daunorubicin anthracycline that inhibits topoisomerase II. This agent also inhibits DNA and RNA synthesis by
intercalating between DNA base pairs.
Idarubicin topoisomerase II inhibitor that inhibits cell proliferation by inhibiting DNA and RNA polymerase
Mitoxantrone topoisomerase II inhibitor. This agent inhibits cell proliferation by intercalating DNA and inhibiting
topoisomerase II.
Nelarabine prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G) that is
converted to the active 5'-triphosphate, ara-GTP, a T-cellâselective nucleoside analogue. Leukemic
blast cells accumulate ara-GTP, which allows for incorporation into DNA, leading to inhibition of
DNA synthesis and cell death.
Clofarabine purine nucleoside antimetabolite that inhibits DNA synthesis and is indicated for relapsed or
refractory acute lymphoblastic leukemia in pediatric patients. Pools of cellular deoxynucleotide
triphosphate are decreased by inhibiting ribonucleotide reductase and terminating DNA chain
elongation and repair. This agent also disrupts mitochondrial membrane integrity.
Inotuzumab CD22-directed antibody-drug conjugate (ADC) indicated for relapsed or refractory B-cell precursor
acute lymphoblastic leukemia. Recognizes human CD22. The small molecule, N-acetyl-gamma-
calicheamicin, is a cytotoxic agent which covalently attaches to antibody via a linker. Data suggest
anticancer activity of inotuzumab ozogamicin is due to binding of ADC to CD22-expressing tumor
cells, followed by internalization of ADC-CD22 complex, and ultimately activating N-acetyl-gamma-
calicheamicin 19 dimethylhydrazide, which induces double-strand DNA breaks, subsequently
inducing cell cycle arrest and apoptotic cell death.
