Evidence based
treatment and
recent guidelines of
ALL
Dr Faten Abdelaziz
Consultant:Dr Abeer Mokhles
Incidence
ALL is the most common cancer diagnosed in children, represents
approximately 25% of cancer among children younger than 15 years
peak incidence among children 1 - 4 years old
Childhood ALL originates in the T and B lymphoblasts in tissues with
hematopoietic progenitor cells in bone marrow and thymus
Clinical Manifestations of Extramedullary Disease
CNS Leukemia
• Most often asymptomatic
• symptoms reflect increased intracranial pressure ,cranial nerve palsy
• headache, vomiting, lethargy, irritability, neck pain, seizures
• Exam findings: papilledema, cranial nerve palsies
Testicular Leukemia
• Present at diagnosis in <1-2% of boys
• Painless, rock hard, lumpy, enlarged testicle
Diagnostic Workup
• Complete history and physical examination
• CBC with differential count
• Bone marrow aspirate (>25% blasts)
• Immunophenotyping
• Cytogenetics (Karyotyping and FISH)
• Molecular methods (RT-PCR)
• CSF by lumbar puncture
• Chest x-ray, abdominal US , Echo , fundus examination
• Serum Chemistry to evaluate tumor lysis and renal insufficiencies.
• LFT to evaluate the ability of liver to metabolize drugs
• Prognostic factors :
• Patient
Age
Initial count
CNS disease at diagnosis
• Leukemic cells
Immionophenotyping
Cytogenetic
• Therapy response
Treatment of childhood acute lymphoblastic
Evidence-based medicine (EBM) is a dynamic healthcare
approach that integrates the best available research
evidence with clinical expertise and patient values.
Evidence-based treatment for childhood ALL involves a
multi-phase approach utilizing chemotherapy, often
combined with targeted therapies, immunotherapy,
stem cell transplantation.
The treatment strategy is tailored to the specific
characteristics of the leukemia and the individual
patient, aiming to achieve remission, prevent relapse,
and minimize long-term side effects.
Evidence-Based Considerations:
Risk Stratification:
Treatment intensity is tailored based on the risk of relapse, determined by factors like age, initial
response to treatment, and genetic characteristics of the leukemia cells.
Minimal Residual Disease (MRD) Monitoring:
MRD monitoring plays a crucial role in guiding treatment decisions. It helps identify patients who
may be candidates for treatment de-escalation or intensification.
CNS Prophylaxis:
Strategies to prevent leukemia spread to the central nervous system (CNS) are essential. This
often involves intrathecal chemotherapy (directly into the spinal fluid) and may include cranial
irradiation in specific cases.
Long-Term Follow-up: to monitor for potential late effects of treatment, such as cognitive
impairment or secondary malignancies.
Treatment phases
Induction Phase
Goal: Achieve complete remission (CR)
drugs: vincristine, corticosteroid, asparaginase ± anthracycline
2. Consolidation Phase /intensification
Goal: Eradicate residual disease, prevent relapse
Uses high-dose methotrexate, MERCAPTOPURINE
3. Maintenance Phase
Goal: Suppress residual leukemic clones
Daily oral 6-mercaptopurine, weekly methotrexate, monthly pulses of vincristine &
steroid.
CNS Prophylaxis
Intrathecal chemo (methotrexate ± cytarabine ± hydrocortisone)
Cranial irradiation reserved for high-risk CNS disease only
Indications od additional ITH D8, D22
CNS Status Refinement
T cell
CNS ii, CNS iii , csf traumatic CNS- 1 No leukemic blasts
IAMP21
CNS- 2 < 5 WBC /mm3 with leukemic blasts
t(17:19)
CNS- 3 5 WBC/mm3 with leukemia blasts or
t (1:19)
t (9:22) cranial nerve palsy
MLL r
WBCS >100.000
HYPODEPLOIDY
D4 , D8
T cell
CNS ii, cNS iii , csf traumatic
REINTENSIFICATION post consolidation course one
Indications:
1-T-cell patients with MRD >= 0.1% after Early intensification.
2-B-precursor Patients with MRD >=1% at End of induction.
3-Any ALL patients with positive MRD at End of consolidation.
4-ALL with IAMP21 regardless MRD level.
5-Hypodiploidy B-precursor Patients regardless MRD level.
6-Philadelphia ALL patients with MRD >= 0.01 by flow at End of induction.
7-patients with t (17;19)
Reintensification course 2 if +ve MRD post course one
Indications of RTH
Typically includes all CNS3 :
• Current treatment dose (CNS3) usually 1800 cGycXRT, includes posterior halves
of globes of eyes
• Spinal irradiation rarely used any more
• CNS2 >>Most groups treat with extra IT during inductio
Testicular Involvement
Local testicular irradiation may be considered in testicular relapse if there is
incomplete response to chemotherapy.
Indications of BMT
● T-cell ALL patients with induction failure (BM or MRD ≥5%)
● T-cell ALL patient with MRD ≥ 0.1% after early intensification
● B-Precursor ALL patients with end of induction MRD ≥ 1%
● Any ALL patient with positive MRD at end of consolidation
● iAMP21 with MRD ≥ 0.01% at end of induction
● Hypodiploidy B-Precursor ALL patients with end of induction MRD ≥ 0.01%
● Philadelphia ALL patients with MRD end of induction ≥ 0.01% by flow or
molecular MRD at W7 < 4 log reduction
● Patients having t(17,19)
● Rising MRD after remission induction
TARGET THERAPY IN ALL
Ph+ve leukemia
Philadelphia Chromosome arises from a reciprocal translocation
involving the ABL1 oncogene on the long arm of ch9 and a
breakpoint cluster region (BCR) on the long arm of ch22, t(9;22)
(q34;q112)
The prognosis of Ph+ ALL patients has dramatically improved
with tyrosine kinase inhibitor (TKI)
Types of TKI
• 1ST generation : Imatinib
• 2ND generation : Dasatinib , Nilotinib
• 3RD generation : Ponatinib
Immunotherapy
Immunotherapy is a treatment that uses the patient's immune
system to fight cancer.
Substances made by the body or made in a laboratory are used to
boost, direct, or restore the body's natural defenses against cancer.
Examples of immunotherapy used to treat childhood ALL include
blinatumomab and CAR T-cell therapy.
Blinatumomab
works by bringing healthy T cells and leukemia cells close together so
the T cells can more effectively kill the leukemia.
It does this by binding to a protein called CD3 on healthy T cells and a
protein called CD19 on B cells.
Blinatumomab is a type of targeted therapy drug called a bispecific T-
cell engager (BiTE).
Used in relapsed/refractory B-cell ALL.
Inotuzumab ozogamicin (CD22-directed therapy)
The antibody component of inotuzumab ozogamicin binds to CD22
receptors, which are expressed mostly on B cells. The whole
conjugate is then drawn into the cell, where the ozogamicin is
cleaved from the antibody by the acidic environment of the
lysosome. The ozogamicin eventually travels to the nucleus where it
breaks up DNA, causing the cell to die.
Used in relapsed/refractory B-cell ALL.
CAR-T Cell Therapy
(Kymriah) – FDA approved for
children and young adults with
relapsed/refractory B-cell ALL
.Mechanism: Patient’s T-cells
are engineered to express a
chimeric antigen receptor
(CAR) that targets CD19.
Can induce long-term
remissions .
Nelarabine in Childhood ALL.
a purine nucleoside analogue (prodrug of ara-G).
Nelarabine metabolized by adenosine deaminase and
incorporated into the DNA of T-cells.
This incorporation leads to inhibition of DNA synthesis,
causing cell cycle arrest in the S-phase.
Selectively toxic to T-cells → used in T-cell ALL / T-cell
lymphoblastic lymphoma.
