Acute Lymphoblastic Leukemia (ALL)

Prepared by Dr. Salma Elgazzar

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Table of Contents

• Learning Objectives
• Clinical Recognition of Malignant Disease
• Childhood Cancer Epidemiology
• Acute Lymphoblastic Leukemia (ALL): Deep Dive
• Diagnostic Workup
• Prognosis and Risk Stratification
• Differential Diagnosis
• Management of ALL
• Complications and Long-Term Effects
• Key Takeaways

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Learning Objectives

• Clinical Recognition: Describe the findings from the history and physical exam that suggest malignant disease.
• Epidemiology: Know the incidence rates of the major childhood neoplasms and their significance in childhood mortality.
• Diagnosis: Identify the presenting symptoms, physical findings, and diagnostic tests for acute lymphoblastic leukemia.
• Differential Diagnosis: Distinguish ALL from other conditions with similar presentations.
• Prognosis: Understand prognostic factors that influence treatment outcomes.
• Treatment: Recognize the major therapeutic modalities for childhood ALL.

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Clinical Recognition of Malignant Disease

Cancer diagnosis in children is often delayed because presenting symptoms tend to be nonspecific and resemble those of benign conditions. When children exhibit red flag symptoms for malignancy, a complete history (including personal and family history) is fundamental.

Pattern of Symptom Onset

• Abrupt onset (e.g., bone pain after minor trauma)
• Insidious development over weeks to months (e.g., intermittent headaches)

Symptom Categories

• Constitutional and nonspecific (fatigue, pallor, fever, anorexia)
• Localized symptoms (e.g., a palpable mass)

Constitutional Symptoms (Red Flags)

• Unexplained Fever: Prolonged fever with no identifiable cause that persists despite appropriate treatment.
• Fatigue & Pallor: Persistent fatigue, pallor, malaise, and reduced activity level not associated with an acute infection.
• Persistent Anorexia: Concerning when it persists without explanation, results in failure to thrive or weight loss, or occurs with other suspicious findings.
• “B Symptoms”: Combination of prolonged drenching night sweats, fever, and significant weight loss; with lymphadenitis, typical of Hodgkin lymphoma.
• Hemorrhagic Diathesis: Characterized by petechiae, ecchymoses, recurrent epistaxis, and bleeding gums.

Neurologic and Lymphatic Red Flags

Lymphadenopathy

• Persistent lymphadenopathy.
• Enlarged supraclavicular and epitrochlear lymph nodes have a higher risk of malignancy than other sites.

Neurologic Symptoms

Present in 88% of patients with CNS tumors at diagnosis.

• Age < 2 years:
  • Unexplained irritability or lethargy
  • Developmental delay or regression
  • Increasing head circumference
• All Ages:
  • New-onset headaches (morning/night)
  • Vomiting with headaches
  • Ataxia and coordination problems
  • Seizures
  • Neurologic deficits
  • Deteriorating school performance
  • Personality changes

Gastrointestinal & Musculoskeletal Warning Signs

Musculoskeletal Symptoms

• Bone pain that:
  • Occurs at night
  • Awakens the child
  • Is persistent or intermittent
• Generalized bone pain
• Joint pain/arthritis suggesting leukemia
• Pathologic fractures at osteolytic lesions
• Palpable soft tissue masses

Bone pain in children without trauma history requires prompt evaluation to rule out malignancy.

Gastrointestinal Symptoms

• Abdominal masses
• Hepatosplenomegaly
• Persistent morning vomiting
• Treatment-resistant constipation
• Intussusception in children >6 years
• Diarrhea in leukemia/lymphoma, or a vasoactive intestinal-peptide-secreting neuroblastoma

Additional Systemic Warning Signs

Category	Findings
Genitourinary	• Hematuria • Urine retention or new enuresis • Vaginal bleeding in prepubertal girls • Scrotal masses • Varicocele (right kidney tumor) • Priapism (leukemia)
Cardiorespiratory	• Persistent nonproductive cough • Unexplained dyspnea or orthopnea (may result from a mediastinal mass or pleural effusion, potentially causing Superior Vena Caval Obstruction) • Hypertension (rare, associated with Wilms’ tumor, pheochromocytoma, or neuroblastoma)
ENT	• Gingival swelling or bleeding • Chronic otorrhea • Nasal obstruction • Epistaxis • Dysphagia

Dermatologic, Ocular, and Endocrine Warning Signs

Dermatologic

• Pallor and bruising/petechiae
• Subcutaneous nodules with bluish appearance (“blueberry muffin”), potentially caused by neuroblastoma or histiocytosis.
• Pruritus (rare in Hodgkin lymphoma)

Ocular

• Squinting and diplopia
• Leukokoria (white pupillary reflex - retinoblastoma)
• Proptosis (orbital lesions)
• Periorbital ecchymoses (“raccoon eyes”), associated with neuroblastoma.
• Aniridia (Wilms tumor)

Endocrine

• Diabetes insipidus (polyuria, polydipsia)
• Growth arrest
• Precocious puberty or pubertal delay

Clinical Pearls: When to Suspect Malignancy

Rule	Description
1. Persistent Symptoms	Symptoms that persist beyond 2-3 weeks without clear cause or fail to respond to appropriate therapy.
2. Multiple System Involvement	Symptoms affecting multiple organ systems simultaneously (e.g., fatigue + bone pain + bruising).
3. Symptom Progression	Gradually worsening symptoms despite supportive care or appropriate treatment.
4. Abnormal Labs + Clinical Findings	Combination of abnormal blood counts with suspicious physical findings (hepatosplenomegaly, lymphadenopathy).

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Childhood Cancer Epidemiology

Cancer in children is relatively rare, affecting approximately 1 in 500 children by 15 years of age. However, its impact is significant as it is the leading cause of disease-related death in children beyond the neonatal period.

Age-Specific Distribution

Cancer in children is relatively rare, affecting approximately 1 in 500 children by 15 years of age. However, its impact is significant as it is the leading cause of disease- related death in children beyond the neonatal period.

• All Ages: Leukemia affects children of all ages with an early childhood peak (2-5 years).
• Early Childhood: Neuroblastoma and Wilms tumor are almost always seen in the first 6 years of life.
• Adolescence: Hodgkin lymphoma and bone tumors peak in adolescence and early adult life.

Survival and Outcomes

Overall, the 5-year survival for childhood cancer is about 75%. Improvements are attributed to:

• Introduction of multiagent chemotherapy
• Enhanced supportive care
• Specialist multidisciplinary management

Global and Regional Variations

The global distribution of childhood cancers shows both similarities and important differences across regions. While leukemia remains common worldwide, its subtypes and other malignancies show geographic variation influenced by genetic, environmental, and socioeconomic factors .

• Leukemia is the most common malignancy (31% of all cases), followed by brain tumors.
• Acute Lymphoblastic Leukemia (ALL): Accounts for >77% of childhood leukemias.
• Acute Myelogenous Leukemia (AML): Accounts for ~11% of cases.

Saudi Arabia Statistics

Malignancy	No. of Cases	Percentage
Leukemia	152	25.3%
NHL	112	18.7%
Brain tumors	91	15.2%
Hodgkin’s	54	9.0%
Retinoblastoma	46	7.6%
Wilms’	31	5.2%
Neuroblastoma	28	4.6%
Rhabdomyosarcoma	23	3.8%
Histiocytosis X	17	2.8%
Germ cell	13	2.2%
Ewing’s	13	2.2%
Osteogenic sarcoma	10	1.7%
Others	10	1.7%
Total	600	100%

Unique Regional Factors:

• Higher frequency of certain cancers.
• Impact of consanguinity on genetic cancer predisposition.
• Lower average age at diagnosis.

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Acute Lymphoblastic Leukemia (ALL): Deep Dive

Definition & Pathophysiology

ALL is a malignant disorder characterized by:

• Uncontrolled proliferation of immature lymphoid cells (lymphoblasts).
• Accumulation of these cells in the bone marrow.
• Suppression of normal hematopoiesis.
• Infiltration of extramedullary sites.

Epidemiology of ALL

• Most common childhood malignancy (31% of cases in children <15 years).
• Peak incidence at 2–5 years of age.
• Higher incidence in males.
• Higher risk in certain conditions:
  • Down syndrome (10–20× increased risk)
  • Bloom syndrome
  • Ataxia-telangiectasia
  • Neurofibromatosis type 1
  • Identical twins

Etiology and Pathogenesis

The precise etiology is unknown, but involves genetic and environmental factors.

Genetic Factors & Abnormalities

• Post-conception somatic mutations in lymphoid cells.
• Two-hit hypothesis: Requires a predisposing genetic mutation (often prenatal) and a second triggering event (possibly abnormal immune response to infection).
• Common Abnormalities:
  • Hyperdiploidy (>50 chromosomes) - Favorable
  • Hypodiploidy (<44 chromosomes) - Poor
  • Translocations:
    • t(12;21) ETV6-RUNX1 (TEL-AML1) - Favorable
    • t(1;19) TCF3-PBX1
    • t(9;22) BCR-ABL1 (Philadelphia chromosome) - Very Poor
    • MLL gene rearrangements (11q23) - Poor

Environmental Factors

Exposure to medical diagnostic radiation both in utero and in childhood is associated with increased ALL incidence

• Ionizing radiation (prenatal or therapeutic).
• environmental: Exposure to benzene or alkylating agents.
• Possible association with Epstein-Barr virus (EBV) in B-cell ALL.

Infectious Agents

Infectious Agents In certain developing countries, association between B-cell ALL and Epstein-Barr virus (EBV) infections

• Abnormal immune response to common infections
• “Population mixing” hypothesis
• Delayed exposure to common pathogens

In ALL, lymphoid cell development stops at the lymphoblast stage.

Z Z

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Clinical Presentation

Leukemia produces systemic effects through bone marrow infiltration and extramedullary spread.

Systemic Effects

• Bone Marrow Failure:

  • Anemia (fatigue, pallor)
  • Thrombocytopenia (petechiae, bruising)
  • Neutropenia (recurrent infections)

• Extramedullary Disease:

  • Lymphadenopathy
  • Hepatosplenomegaly
  • CNS involvement
  • Testicular infiltration
  • Bone/joint pain

Metabolic Complications

• Tumor lysis syndrome
• Hyperleukocytosis
• Hyperuricemia

Pathogenesis of Acute Lymphoblastic Leukemia – a multifactorial process in which genetic lesions derail normal lymphocyte development, producing uncontrolled proliferation, blocked differentiation, and resistance to apoptosis.

Key cellular mechanisms

• Clonal expansion of immature lymphoid cells
• Arrest at an early progenitor stage
• ↓ spontaneous apoptosis
• Disruption of normal bone‑marrow architecture → marrow failure and spread to extramedullary sites

Common genetic abnormalities

• Hyperdiploidy (> 50 chromosomes)
• Hypodiploidy (< 44 chromosomes)
• Translocations
  • t(12;21) → ETV6‑RUNX1 (TEL‑AML1)
  • t(1;19) → TCF3‑PBX1 (E2A‑PBX1)
  • t(9;22) → BCR‑ABL1 (Philadelphia chromosome)
  • MLL‑gene rearrangements

These alterations collectively drive the malignant clone that characterises ALL.

Case Scenario: 4-Year-Old Girl

• History: Unwell, lethargic, pale, febrile for 9 weeks. Antibiotics for sore throat ineffective.
• Physical Exam: Pallor, petechiae, generalized lymphadenopathy, mild hepatosplenomegaly.
• Labs:
  • Hb: 83 g/L (Anemia)
  • WBC: 15.6 × 10⁹/L
  • Platelets: 44 × 10⁹/L (Thrombocytopenia)
  • Blast cells on peripheral film.
• Diagnosis: Bone marrow confirmed ALL.

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Diagnostic Workup

Initial Investigations

• Complete Blood Count (CBC): The complete blood count CBC is the initial laboratory test that raises suspicion for ALL Abnormalities in multiple cell , .lines are characteristic with isolated cytopenias being less common
  • 95% have two or more cytopenias.
  • Thrombocytopenia (90%), Anemia (80%).
  • WBC: Elevated in 50%; blasts visible when WBC > 5000/μL.
• Peripheral Blood Smear: Check for lymphoblasts and smudge cells.

Cytopenias • — 90%Thrombocytopenia present in of cases • — 80%Anemia present in of cases • —Neutropenia common finding • 95% have two or more cytopenias • 4% have only one cytopenia • 1% have a normal CBC

White Blood Cell Findings • 50% with elevated WBC count • Evidence of circulating leukemic blast cells • > 5000/μBlasts typically visible when WBC L • Smudge cells often presen

Essential Diagnostic Procedures

• Bone Marrow Aspirate/Biopsy:
  • Defines diagnosis: ≥20% lymphoblasts (WHO criteria).
  • Hypercellular marrow with replacement of normal elements.
• Lumbar Puncture: Checks for CNS involvement.
• Additional Studies: LDH (elevated), Chest X-ray (check for mediastinal mass), Clotting screen.

Peripheral Blood Morphology in ALL

Peripheral blood showing leukocytosis with a population of large mononuclear cells with high nuclear-cytoplasmic ratio, scant blue cytoplasm, and fine chromatin with occasional nucleoli. These are features of lymphoblasts. Note scattered smudge cells, another feature often seen in peripheral smears with leu

Morphology and Smudge Cells

Smudge cells (basket cells) are artifacts from the rupture of fragile lymphoblasts during slide preparation. >30% proportion strongly suggests lymphoid neoplasm.

Diagnostic Value – Smudge cells in large numbers are a hallmark of lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).

Mechanism – Lymphoblasts possess fragile membranes; during smear preparation they succumb to mechanical stress, leading to rupture of the cytoplasm while the nucleus stays intact.

Quantification – When smudge cells exceed 30 % of nucleated cells, the finding strongly points toward a lymphoid neoplasm.

Morphology of a lymphoblast: nucleoli, pale staining nucleus, basophilic cytoplasm.

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Prognosis and Risk Stratification

Treatment intensity is adapted according to risk factors.

Prognostic Factors

• Age: 1–10 years (Favorable); <1 or >10 (Unfavorable).
• Gender: Girls do better than boys.
• Initial WBC: <50,000/μL (Favorable); >50,000/μL (Unfavorable).
• Response to Therapy: Rapid early response is favorable.
• Minimal Residual Disease (MRD): Detection by PCR/flow cytometry after induction is the most important indicator.

Risk Groups

Risk Level	Characteristics
Standard Risk	Age 1-9, WBC <50k, favorable cytogenetics, MRD negative.
High Risk	Age <1 or >10, WBC >50k, unfavorable cytogenetics, MRD positive.
Very High Risk	Philadelphia chromosome t(9;22), t(4;11), hypodiploidy, induction failure.

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Differential Diagnosis

Infectious Causes

• Infectious Mononucleosis (EBV): Lymphocytosis with atypical lymphocytes.
• Parvovirus B19: Transient aplastic crisis.
• Bordetella pertussis: Marked lymphocytosis.
• CMV, HIV, and Osteomyelitis.

Non-Infectious Causes

• Malignancies: Lymphoma, Neuroblastoma, Wilms tumor, Rhabdomyosarcoma.

• Langerhans Cell Histiocytosis (LCH): Characterized by seborrheic rash, soft tissue infiltration, bone pain/fractures, and diabetes insipidus.

• Malignant Conditions • Rhabdomyosarcoma • -Non Hodgkin’s lymphoma • CNS tumors • Neuroblastoma • Renal tumors • Bone tumors

• Autoimmune: SLE, Juvenile Idiopathic Arthritis.

• Hematological: Aplastic anemia, Fanconi anemia, Myelodysplasia, Myelofibrosis, Lymphoproliferative disorders, Megaloblastic anemia

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Treatment Overview for ALL

Induction – 4‑6 weeks
Initial intensive chemotherapy aimed at achieving remission.

Consolidation – 6‑9 months
High‑dose therapy to eradicate residual disease, including CNS‑directed treatment.

Maintenance – 2‑2.5 years
Lower‑intensity therapy to prevent relapse.

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Key Therapeutic Agents

• Corticosteroids – Prednisone or dexamethasone
• Antimetabolites – Methotrexate, mercaptopurine, cytarabine
• Other agents – Vincristine, asparaginase, anthracyclines (e.g., daunorubicin, doxorubicin), cyclophosphamide

These protocols combine multiple cytotoxic drugs to maximize disease control.

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The 5‑year survival rate for standard‑risk ALL now exceeds 80 %, marking one of the greatest success stories in pediatric oncology.

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Remission Induction Phase

Pre‑Treatment Considerations

• Correct anemia → give a blood transfusion.
• Platelet transfusion to lower bleeding risk.
• Treat any existing infections before starting therapy.
• Ensure adequate hydration and give allopurinol (or urate oxidase) to prevent tumor‑lysis syndrome.

Induction Therapy Components
Standard induction regimens typically include:

• Vincristine – administered weekly.
• Corticosteroids – either prednisone or dexamethasone.
• Asparaginase – pegylated or native form.
• Anthracycline – usually daunorubicin, reserved for higher‑risk patients.
• Intrathecal chemotherapy – methotrexate (used in ~95 % of protocols).

Remission Outcomes

• Current induction schedules achieve remission in ≈95 % of cases; <5 % of patients fail to respond.
• Remission is defined as absence of blasts in the bone marrow together with recovery of normal hematopoiesis.

Intensification Phase

A block of intensive chemotherapy is administered to consolidate remission and eliminate residual disease.

Typical agents include:

• High‑dose methotrexate
• Cytarabine
• Cyclophosphamide
• Asparaginase
• Anthracyclines

This regimen improves cure rates, though it is associated with increased toxicity.

CNS-Directed Therapy

Essential because cytotoxic drugs poorly cross the blood‑brain barrier.

• Intrathecal chemotherapy – administered directly into the cerebrospinal fluid; commonly uses methotrexate, cytarabine (often together with hydrocortisone).
• High‑dose systemic methotrexate – reserved for high‑risk patients who need aggressive treatment.
• Cranial or craniospinal radiotherapy – once a mainstay, now rarely employed given advances in chemotherapy.

These approaches are considered for patients who present with CNS disease at diagnosis.

Targeted Therapies in ALL

• Tyrosine Kinase Inhibitors (TKIs) – used in Philadelphia‑chromosome‑positive (Ph⁺) ALL.

  • Imatinib, dasatinib, nilotinib, and ponatinib block the BCR‑ABL fusion protein, dramatically improving outcomes for this historically poor‑prognosis subtype.

• Monoclonal Antibodies – directed against surface CD antigens on B‑cell blasts.

  • Rituximab targets CD20 (effective in CD20⁺ B‑ALL).
  • Inotuzumab ozogamicin binds CD22 and delivers the potent toxin calicheamicin.
  • Blinatumomab is a bispecific T‑cell engager (BiTE) that links CD19 on B cells with CD3 on T cells, fostering direct cytotoxicity.

• CAR T‑Cell Therapy – chimeric antigen receptor T cells engineered to recognize CD19 on leukemic cells.

  • Products such as tisagenlecleucel (and subsequent CAR‑T agents) have shown remarkable efficacy in patients with relapsed or refractory ALL.

These innovative approaches—TKIs, monoclonal antibodies, and CAR T cells—have collectively reshaped the therapeutic landscape of ALL, offering targeted, highly effective options beyond conventional chemotherapy.

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Complications and Long-Term Effects

Acute Complications

• Tumor Lysis Syndrome (TLS): Prevent with hydration and Allopurinol/Rasburicase.
• Myelosuppression (infections, bleeding).
• Mucositis, Nausea, Vomiting.
• Pancreatitis (Asparaginase).
• Neuropathy (Vincristine).
• Hyperglycemia steroid related

Long-Term Late Effects

• Neurocognitive deficits particularly with CNS radiation
• Cardiotoxicity anthracycline related)
• Growth abnormalities
• Endocrine dysfunction ( - )
• Osteonecrosis steroid related
• Secondary malignancies
• Infertility

Long term follow up is essential for ALL survivors Monitoring for late effects and implementing appropriate interventions improves quality of life and reduces morbidity

Chemotherapy Side Effects (Extended Reference) Z

Doxrubicin, carboplatin methortexate - hepatotoxicity - lft

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z Asparaginare = Pancreatitis

Key Takeaways

• Diagnosis: Requires CBC, Smear, and Bone Marrow Aspirate (≥20% blasts).
• Risk Stratification: Age, WBC, and MRD status are critical.
• Treatment: Long-term (2.5-3 years) multi-phase protocols; CNS prophylaxis is mandatory.
• Outcomes: High cure rate (>80%) but requires monitoring for late effects.