Acute Lymphoblastic Leukemia

1. Acute Lymphoblastic
Leukemia
By Dr Haja S Sovula
Registrar
10/29/2023 1

2. Outline
• Overview
• Epidemiology
• Etiology
• Clinical Presentation
• Classification and Staging
• Diagnosis
• Treatment
• Summary
• References
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3. Overview
• Acute lymphoblastic leukaemia (ALL) is a
heterogeneous hematologic disease characterized by
the proliferation of immature lymphoid cells in the bone
marrow, peripheral blood, and other organs.
• Most common childhood malignancy.
• Accounts 75%–80% of acute leukemias among children
• Was first clearly described by 2 pathologists in 1845
• High complete remission rates ( 97%)and Five-Year
survival rates (89%) in children (61%) AYA
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4. ACUTE LYMPHOBLASTIC LEUKEMIA
EPIDEMIOLOGY
• Most common leukemia in children.
• Accounts for (1/3rd) of childhood Malignancies
• 60% of ALL patients are diagnosed younger than 20
years of age.
• Peak age 2-5yrs
• Boys > girls
• 2500-3500 new cases in the US annually
• 3.4 cases per 100,000
• Greatest incidence in the US among Hispanics
• Higher incidence in whites vs blacks
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5. Epidemiology contd
•Incidence is generally low in Africa and a study in
Kenya incidence of 1.2/100,000 (<15yrs)
•1 case at our oncology unit (5 yr old M died)
•ALL is 5 times commoner in children than AML
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6. Epidemiology contd
•Identical twins, the risk to the
• second twin if one twin develops leukemia is greater than
that in the general population.
•The risk is >70% if ALL is diagnosed in the first twin
during the 1st yr of life and monochorionic
• If the first twin develops ALL by 5-7 yr of age, the risk to the
second twin is at least twice that of the general
population, regardless of zygosity.
•Other siblings
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7. ALL - ETIOLOGY
•A two-step process of genetic mutation and
exposure to infection play a prominent role.
• The first step occurs in utero, when fusion gene
formation or hyperdiploidy generates a covert,
pre-leukemic clone.
•The second step is the acquisition of secondary
genetic changes that drive conversion to overt
leukemia.
•Only 1% of children born with a pre-leukemic
clone progress to leukemia.
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8. ETIOLOGY
• Children with certain genetic and immunodeficiency
syndromes are at increased risk: Down syndrome, Klinefilter
syndrome, Neurofibromatosis type 1, Bloom syndrome,
Fanconi anemia and ataxia telangiectasia.
• Radiation exposure may be associated with increased risk :
Survivors of the 1945 atomic bombings of Hiroshima and
Nagasaki have an overall relative risk of 9.1 for developing
ALL compared with an age-matched controls.
• Chemical toxins : exposure to high levels of benzene.
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9. ETIOLOGY Contd
•Secondary ALL may occur after certain
chemotherapies ( eg, cyclophosphamide, etoposide
doxorubicin)
•Viruses : Some potential associations were
identified between EBV and Burkitt-ALL ( Mature B-
Cell ALL) HTLV-1
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10. Classification of ALL
• FAB ( French-American-British) classification
• Based largely on morphology
• Little prognostic or therapeutic information to help guide treatment
decisions.
• WHO ( World Health Organization) classification
• Revised in 2008,2016
• Discarded the FAB terms since morphological classification has no
clinical or prognostic relevance.
• Changed the classification to reflect increased understanding of the
biology and molecular pathogenesis of ALL.
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11. WHO Classification of B-lymphoblastic
leukemia/lymphoma(WHO-HAEM5R)
• B-lymphoblastic leukemia/lymphoma, NOS
• B-lymphoblastic leukemia/lymphoma with recurrent genetic
abnormalities
• B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-
ABL1(fusion)
• B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A
rearranged
• B-lymphoblastic leukemia/lymphoma with
t(12;21)(p13.2;q22.1);ETV6-RUNX1
• B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1-like
features
• B-lymphoblastic leukemia/lymphoma with hyperdiploidy
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12. WHO Classification of B-lymphoblastic
leukemia/lymphoma(5th Edition)
• B-lymphoblastic leukemia/lymphoma with hypodiploidy
• B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-
IGH
• B-lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion
• B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-
PBX1
• B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like*
• B-lymphoblastic leukemia/lymphoma with iAMP21*
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13. WHO Classification of T-lymphoblastic
leukemia/lymphoma
• T-lymphoblastic leukaemia / lymphoma, NOS
• Early T-precursor lymphoblastic leukaemia / lymphoma
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14. Clinical Presentation
• Fever
• Signs and symptoms of anemia, such as pallor, fatigue, dizziness,
palpitations, cardiac flow murmur, and dyspnea with even mild
exertion
• Bleeding
• Disseminated intravascular coagulation (DIC) at diagnosis (about 10%
of cases)
• Blood clots
• Palpable lymphadenopathy
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15. Clinical Presentation
• Bone pain (can be severe common in lower limbs)
• Left upper quadrant fullness and early satiety due to splenomegaly
(about 10% of cases)
• Symptoms of leukostasis (eg, respiratory distress, altered mental
status)
• Kidney failure in patients with a high tumor burden
• Infections, including pneumonia
• Petechiae (particularly on lower extremities) and ecchymoses
• Rashes from skin infiltration with leukemic cells
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16. Clinical Presentation (Less Common)
• Headache is uncommon (<5 percent of cases), but leukemia involving
the central nervous system can present with
• headache, vomiting, lethargy, nuchal rigidity, and, rarely, with cranial
nerve abnormalities
• Testicular enlargement is rare (<1 percent),
• but painless unilateral testicular enlargement can be a presenting
sign of ALL/LBL.
• However, testicular involvement is present in up to 10 percent of
boys with relapsed leukemia
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17. Clinical Presentation (Less Common)
• A mediastinal mass, which is most often associated with T-ALL/LBL,
can cause superior vena cava (SVC) syndrome, which may manifest as
pain, dysphagia, dyspnea, or swelling of the neck, face, and
upper limbs due to obstruction the SVC.
• Respiratory distress may result from a mass compressing the
trachea.
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18. Diagnosis (Pre-treatment)
• Complete blood count (CBC) with peripheral smear
• Coagulation Profile (prothrombin time [PT], activated partial
thromboplastin time [aPTT], fibrinogen)
• Chemistry profile, U/E/Crs, LFTs , Uric Acids, and,LDH
• Bone marrow aspiration and biopsy – Definitive diagnostic tests
• Cultures; in particular, blood cultures
• Chest radiography
• Chest computed tomography (CT) scan, as indicated by symptoms
• Multiple-gated acquisition (MUGA) scan or echocardiogram
• Lumbar puncture
• HIV,HBSAsg, CMV,EBV
• HLA -typing
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19. Confirmatory Diagnosis
• ALL is characterized by presence of immature cells – blast cells
• of >20% in the -blood picture -bone marrow examination
• A negative myeloperoxidase (MPO) stain and a positive and terminal
deoxynucleotidyl transferase (TdT) is the hallmark of the diagnosis of
most cases of ALL
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20. 10/29/2023 20

21. Acute lymphoblastic leukemia (ALL), peripheral
blood of a child, Pappenheim stain, magnification
x100
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22. Diagnosis contd
• The polymerase chain reaction (PCR)
• Fluorescence in situ hybridization(FISH)
(to pinpoint molecular genetic abnormalities & can be used to detect small
numbers of malignant cells at diagnosis as well as during follow-up.)
• DNA microarray
( helps analyze the expression of thousands of genes in the leukemic
cell. This technique promises to further enhance the understanding of
the fundamental biology and to provide clues to the therapeutic
approach of ALL.)
• Flow cytometry helps to distinguish B-ALL from T-ALL.
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23. 10/29/2023 23

24. Phenotypically
Based on surface markers ALL derived from
• B lineage (85 percent), B-lymphoblastic leukemia
• T lineage ( 15 percent), T-lymphoblastic leukemia
• Mature B cells(1 percent) Burkitt leukemia
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25. Treatment
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26. Key Terminology in treatment
• Complete Remission : Criteria for CR include:
• Evidence of eradication of detectable leukemia cells
• ≤ 5% blasts present in the bone marrow.
• Evidence of normal Bone marrow recovery ( at least > 25% bone
marrow cellularity)
• platelet count ≥ 100 x 109/L
• neutrophil count ≥ 1 x 109/L.
• Minimal Residual Disease (MRD): Refers to residual leukemic cells
that remain following the achievement of CR, but are below the
limits of detection using conventional morphologic assessment.
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27. RELAPSE
• Reappearance of blast at any site in the body after initial remission
during chemotherapy or after completing chemo.
• Marrow relapse-poor outcome (15-20%)
• Hyper CVAD regimen
• Allogenic BM transplant
• CNS relapse –(<5%)
• Triple IT –alternate days till CSF clears, then twice weekly 6 doses. then one
dose every week 6 doses.
• cranial irradiation
• Testicular relapse
-chemotherapy plus b/l testicular radiation
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28. Risk-directed therapy
• is the standard of current ALL treatment and accounts
• for age at diagnosis, initial WBC count, immunophenotypic and
cytogenetic characteristics of blast populations, rapidity of early
treatment response and assessment of Minimal Residual Disease
MRD at the end of induction therapy.
• Pt are categorised as having
• STANDARD RISK- age 1-10 yr and a leukocyte count<50,000/µL are
used by the National Cancer Institute (NCI)
• High RISK- Children who are younger than 1 yr or older than 10 yr or
who have an
• initial leukocyte count of >50,000/µL are considered to be high risk.
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30. Prognostic Factors contd
• Characteristics that adversely affect outcome include T-cell
immunophenotype or a slow response to initial therapy.
• Chromosomal abnormalities, including
hypodiploidy, the Philadelphia chromosome, and KMT2A (MLL) gene
rearrangements, mutation in IKZF1 portend a poorer outcome.
• More favourable characteristics include a rapid response to therapy,
hyperdiploidy, trisomy of
• specific chromosomes (4, 10, and 17), and rearrangements of the
ETV6-RUNX1.
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31. ALL: TYPICAL TREATMENT
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Induction Consolidation Maintenance
Over a period
of months
2-3 years
CNS Prophylaxis (IT-MTX)
• Primary objective : to achieve and maintain a
complete remission (CR)
• Induction, consolidation, maintenance phases
• CNS prophylaxis with IT-MTX during induction and
consolidation phases

32. Remission induction
• is designed to eradicate the leukemic cells from the bone marrow.
• BFM regimen : frequently used in Pediatric ALL. Can be used in young adults
with good PS. Induction therapy consists of vincristine, daunorubicin,
prednisone, asparaginase, intrathecal cytarabine, and intrathecal
methotrexate.
• CALGB ALL : used in high-risk pediatric ALL, mostly AYA. Uses five drugs –
cyclophosphamide, daunorubicin, Vincristine, prednisone and L-
asparaginase in induction for 4 weeks.
• HyperCVAD : combination of hyperfractionated cyclophosphamide,
vincristine, Adramycin (doxorubicin) and dexamethasone alternating with
high-dose methotrexate and high-dose cytarabine – Regimen also includes a
risk-stratified schedule of CNS prophylaxis with IT methotrexate and IT
cytarabine. The dose-intensive phase spans six to seven months and is
followed by two years of maintenance therapy.
• Kasili Protocol: Vincristine, doxorubicin,prednisone, IT MTX (induction)
Cytarabine, cyclophosphamide in Consolidation
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33. BFM Regimen
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34. Prognosis
• The outcome for patients at higher risk can be improved by
administration of more intensive therapy despite the greater toxicity
of such therapy.
• Infants with ALL, along with patients who present with specific
chromosomal abnormalities, such as t(4;11), have an even higher risk
of relapse despite intensive therapy.
• Higher levels of MRD present at the end of induction suggest a
poorer prognosis and higher risk of subsequent relapse. MRD of
>0.01% on the marrow on day 29 of induction is a significant risk
factor for shorter event-free survival for all risk categories, compared
with patients with negative MRD.
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35. Imatinib
• Imatinib is an agent specifically designed to inhibit the BCR-ABL
kinase resulting from the translocation
• The poor outcome of Philadelphia chromosome–positive ALL with
t(9;22) has been dramatically changed by the addition of imatinib to
an intensive chemotherapy backbone.
• With this approach, the event-free survival has improved from 30%
to 70%.
• For patients with CD20 positive B-lymphoblastic leukemia, rituximab
can be added
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36. Nelarabine
• Current therapies for T-cell acute lymphoblastic leukemia (ALL)
produce high responses, but approximately one half of patients will
relapse within 2 years.
• Nelarabine demonstrates antineoplastic activity in patients with
relapsed/refractory T-cell ALL. The Cancer and Leukemia Group B,
nelarabine treatment produced complete remission rates of 26%
with minimal toxicities in relapsed/refractory ALL patients.
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37. Supportive Therapy
• Cytopenias : All patients treated with traditional induction will
develop cytopenias which may require intervention.
Transfusion support : Platelets and Packed red cell transfusion when
necessary.
• Prevention of Tumor Lysis Syndrome ( Risk highest in Burkitt-ALL and
T-Cell ALL)
• Intravenous hydration
• Allopurinol
• Rasburicase
• Correction of electrolyte disturbances (Hypocalcemia,
Hyperphospahtemia)
• Antibiotic Prophylaxis while on aggressive chemotherapies :
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38. Complications following Treatment of ALL
• Late complications of therapy
• Brain tumors (cerebral irradiation)
• Secondary AML from topoisomerase inhibitors and alkylating agents
• Cardiomyopathy (anthracyclines)
• Osteoporosis/Osteonecrosis (corticosteroids)
• Growth disturbances
• Thyroid dysfunction (cranial irradiation)
• Obesity (uncertain etiology)
• Neuropsychiatric disturbances and seizures (IT MTX and cranial
irradiation)
• Emotional problems
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39. In Conclusion
• Acute lymphoblastic leukemia (ALL) is the most common cancer in
children but also occurs in adults.
• Can either B/T lymphoblastic leukemia
• WHO classification predominantly used.
• Treatment involves 3 phases can last 2-3yrs
• Central nervous system (CNS) involvement is common; most patients
receive intrathecal chemotherapy and corticosteroids and sometimes
CNS radiation therapy.
• Response to treatment is good in children, with cure possible in >
80% of children but in < 50% of adults.
• Repeat induction chemotherapy, immunotherapy, and stem cell
transplantation may be helpful for relapse.
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41. References
• Nelson’s paediatrics 21st edition
• Medscape
• Up to date
• https://www.nature.com/articles/s41375-022-01620-2
• https://www.msdmanuals.com/professional/hematology-and-
oncology/leukemias/acute-lymphoblastic-leukemia-all
• http://erepository.uonbi.ac.ke/bitstream/handle/11295/28663/Agwa
ta_
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