Acute Leukaemias

Acute leukemias represent a clonal expansion and arrest at a specific stage of normal myeloid or lymphoid hematopoiesis.

The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to a clonal proliferation of cells.

They account for 97% of childhood leukemias and consist of the following subtypes:

1. Acute Lymphoblastic Leukemia (ALL) – 75%
2. Acute Myeloblastic Leukemia (AML) – 20%
3. Acute Undifferentiated Leukemias – Less than 0.5%
4. Acute Mixed Lineage Leukemia (AMLL)

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, representing nearly one third of all pediatric cancers.

The annual incidence of ALL is about 30 cases per million people, with a peak incidence in patients aged 2 – 5 years.

Race: ALL occurs more frequently in whites than in blacks.

White and black children have approximately the same incidence of AML.

Sex: ALL occurs slightly more frequently in males than in females. This difference is most pronounced for T-cell ALL.

Age: The peak incidence of ALL is in children aged 2 – 5 years.

Aetiology (the cause of a disease) is unknown, but the following factors are important in the pathogenesis:

1. Exposure to Ionizing Radiation & Electromagnetic Fields
2. Chemicals (e.g., Benzene)
3. Drugs (e.g., Alkylating Agents)
4. Genetic Considerations: Some genetic syndromes are associated with an increased risk of leukemia, including:
• Down Syndrome
• Bloom Syndrome
• Blackfan-Diamond Syndrome

GENETIC CONDITIONS:

• Down syndrome
• Fanconi syndrome
• Bloom syndrome
• Diamond-Blackfan anemia
• Schwachman syndrome
• Klinefelter syndrome
• Turner syndrome
• Neurofibromatosis
• Ataxia-telangiectasia
• Severe combined immune deficiency
• Paroxysmal nocturnal hemoglobinuria
• Li Fraumeni syndrome

ENVIRONMENTAL FACTORS:

• Ionizing radiation
• Drugs
• Alkylating agents
• Nitrosourea
• Epipodophyllotoxin
• Benzene exposure
• Advanced maternal age

French-American-British (FAB) Classification of ALL:

• L1: Lymphoblasts are small with little cytoplasm.
• L2: Cells are larger with pleomorphism, increased cytoplasm, irregular nuclear shape, and prominent nucleoli.
• L3: Features finely stippled, homogeneous nuclear chromatin, prominent nucleoli, and deep blue cytoplasm with prominent vacuolization.

French American British (FAB) Classification of AML:

• M1: Acute myeloblastic leukemia without maturation.
• M2: Acute myeloblastic leukemia with maturation.
• M3: Acute promyeloblastic leukemia.
• M4: Acute myelomonocytic leukemia.
• M5: Acute monocytic leukemia.
• M6: Erythroleukemia.
• M7: Acute megakaryocytic leukemia.

Additional Information:

• The M1, M2, M4, and M5 subtypes account for 80% of childhood AMLs.
• M3 occurs in 10% of cases and is associated with a high risk of DIC (Disseminated Intravascular Coagulation).
• The M3 subtype is associated with t(15:17) chromosomal translocation.
• M7 is less common, and M6 is rare.

• Presenting Signs and Symptoms: Patients often present with signs and symptoms that reflect bone marrow infiltration and extramedullary disease.
• Bone Marrow Failure: Inquire about symptoms related to bone marrow failure, such as anemia, thrombocytopenia, and neutropenia.
• Clinical Manifestations: Explore the clinical manifestations, which may include fatigue, pallor, petechiae, bleeding episodes, and fever.
• Leukemic Spread: Assess for signs of leukemic spread, including lymphadenopathy (enlarged lymph nodes) and hepatosplenomegaly (enlarged liver and spleen).
• Other Symptoms: Ask about other symptoms such as unexplained weight loss, bone pain, and dyspnea (difficulty breathing).

A comprehensive leukemia history should also include the following:

• Duration of Symptoms: Determine how long the patient has been experiencing symptoms, as this can provide insights into the disease progression.
• Family History: Investigate if there is a family history of leukemia or other hematological disorders, as genetic predisposition can play a role.
• Past Medical History: Document any prior medical conditions, especially those related to immune function and exposure to potential risk factors.
• Medications and Treatments: Inquire about any medications, chemotherapy, or radiation therapy the patient may have received in the past, as these can impact the development of leukemia.
• Lifestyle and Environmental Exposures: Ask about exposure to ionizing radiation, chemicals, or other environmental factors that could contribute to leukemia.

• General Symptoms: Patients commonly report general symptoms, including fever (60% of cases), lassitude (50%), and pallor (40%).
• Bone Marrow Invasion: Leukemia often leads to bone marrow invasion, resulting in various clinical signs:
• Anemia: Manifesting as pallor and tachycardia due to reduced red blood cell production.
• Neutropenia: Associated with fever, increased susceptibility to infections.
• Thrombocytopenia: Low platelet counts, contributing to bleeding tendencies.
• Lymphoid System Invasion: Leukemic cells can infiltrate the lymphoid system, leading to:
• Lymphadenopathy: Enlargement of lymph nodes.
• Hepatosplenomegaly: Enlargement of the liver and spleen.
• Extramedullary Invasion: Leukemia can also involve extramedullary sites, leading to diverse clinical presentations:
• CNS (Central Nervous System) Invasion: May result in raised intracranial pressure (ICP), cranial nerve palsies, and chloromas (retro-orbital deposits) or affect the spinal cord.
• Other Extramedullary Sites: Leukemic cells can infiltrate organs such as the testes, kidneys, bones, joints, and lungs.

Clinical Features of Acute Lymphoblastic Leukemia (ALL)

Features	Percentage of Patients
Fever	61%
Bleeding	48%
Bone Pain	23%
Lymphadenopathy	50%
Splenomegaly	63%
Hepatosplenomegaly	68%

Laboratory Features

WBC count/cmm	Percentage of Patients
<10,000	53%
10,000 – 49,000	30%
>50,000	17%
Haemoglobin g/dL	Percentage of Patients
<7.0	43%
7.0 – 11.0	45%
>11.0	12%
Platelet count/cmm	Percentage of Patients
<20,000	28%
20,000 – 99,000	47%
>100,000	25%
Lymphoblast morphology	Percentage of Patients
L1	84%
L2	15%
L3	1%

Clinical Manifestations of Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia (AML) presents with a spectrum of clinical manifestations, which can be attributed to the replacement of bone marrow by malignant cells and secondary bone marrow failure. The following are common clinical findings associated with AML:

• Marrow Failure in AML: Patients with AML may exhibit findings similar to marrow failure seen in ALL, including anemia, thrombocytopenia, and neutropenia.
• Additional Manifestations: AML can also lead to signs and symptoms that are less frequently observed in ALL:
• Subcutaneous Nodules ("Blueberry Muffin" Lesions): Uncommon but may occur.
• Infiltration of the Gingiva: Gingival involvement can be a distinctive feature.
• Disseminated Intravascular Coagulation (DIC): Laboratory findings and signs indicative of DIC, especially associated with acute promyelocytic leukemia (a subtype of AML).
• Chloromas or Granulocytic Sarcomas: These are discrete masses that may appear even in the absence of apparent bone marrow involvement. Chloromas are typically associated with the M2 subcategory of AML characterized by a t(8;21) translocation.

• CBC Count with Peripheral Smear: Assess for the presence of lymphoblasts, myeloblasts, and check hemoglobin and platelet counts, which may be low.
• PT/PTTK: Coagulation profile evaluation.
• Bleeding Time: Assessing bleeding time.
• Immunophenotyping: A comprehensive examination of bone marrow is crucial to diagnose ALL. Key points include:
• Classification: ALL cases are broadly classified as B- or T-lineage ALL.
• B-Cell Leukemia: Accounts for about 3% of cases and depends on the detection of surface immunoglobulin on leukemic blasts.
• B-Cell Progenitors: Approximately 80% of childhood ALL cases have lymphoblasts corresponding to B cell progenitors. These cases are identified by surface expression of 2 or more B-lineage-associated antigens, including CD19, CD20, CD24, CD22, CD21, or CD79. CD79 is specific for B-lineage ALL.
• T-Cell ALL: Identified by the expression of T-cell-associated surface antigens, with cytoplasmic CD3 being specific. T-cell ALL cases can be classified as early, mid, or late thymocyte.

Cytogenetic and Molecular Diagnosis

In more than 90% of ALL cases, specific genetic alterations can be found in the leukemic blasts. These alterations include:

• Changes in chromosome number (ploidy) and structure; about half of all childhood ALL cases have recurrent translocations.
• Molecular techniques, including reverse transcriptase polymerase chain reaction (RT PCR), Southern blot analysis, and fluorescence in situ hybridization (FISH), have improved diagnostic accuracy.

Clinically Important Genetic Alterations in B-Precursor ALL

Key genetic alterations in B-precursor ALL include:

• Chromosomal translocations (e.g., BCR-ABL, E2A-PBX1, TEL-AML1 gene fusions).
• A variety of MLL gene rearrangements.
• Hyperdiploidy: A DNA index (DI) of 1.16 or higher, occurring in about 20% of B precursor cases and serving as a favorable prognostic factor.

Imaging Studies

Imaging studies can aid in diagnosis and evaluation:

• Chest Radiography: To identify a mediastinal mass.
• Testicular Ultrasonography: If physical examination reveals enlarged testes.
• Echocardiogram and ECG: These are obtained before administering anthracyclines.

Procedures

Key diagnostic procedures for ALL include:

• Bone Marrow Aspirate: To confirm the diagnosis of ALL.
• Lumbar Puncture: Performed before systemic chemotherapy to assess CNS involvement and administer intrathecal chemotherapy. Elevated CSF leukocyte count with lymphoblasts indicates overt CNS (or meningeal) leukemia.

Diagnosing Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML) involves several key diagnostic criteria:

• Blood Count: The following blood count parameters are typically observed:
• Hemoglobin (Hb): Low.
• White Blood Cell Count (WBC): Can be low, normal, or increased.
• Platelets: Low in 92% of cases.
• Blood Smear: Examination of a blood smear often reveals the presence of blasts.
• Diagnosis Confirmation: Diagnosis is confirmed through bone marrow aspirate or biopsy.

Specific criteria for diagnosis based on blast percentages:

• ALL (Acute Lymphoblastic Leukemia): Diagnosis is confirmed when blasts in the bone marrow exceed 25%.
• AML (Acute Myeloid Leukemia): Diagnosis is confirmed when blasts in the bone marrow exceed 30%.

Complications associated with leukemia and its therapy encompass a range of potential issues, including:

• Tumor Lysis Syndrome
• Renal Failure
• Sepsis
• Bleeding
• Thrombosis
• Typhlitis
• Neuropathy
• Encephalopathy
• Seizures
• Secondary Malignancy
• Short Stature (if craniospinal radiation is used)
• Growth Hormone Deficiency
• Cognitive Defects

Acute leukemia treatment strategies vary depending on the specific type of leukemia:

ALL Treatment

• Induction of Remission
• Consolidation (Intensification) of Remission
• Prevention of Overt CNS Leukemia
• Maintenance Therapy

Duration: 2 years in girls and 3 years in boys

AML Treatment

• Chemotherapy: Duanorubicin, Cytarabine (Ara-C), Etoposide (DAE or DAThioguanine)
• Stem Cell Transplant

Induction consists of two cycles, with each cycle involving:

• 7 days of Ara-C (Cytarabine) with 3 days of Duanomycin (Daunorubicin) +/- Thioguanine

Consolidation therapy is administered every three months for two years.

Treatment of M3 (Acute Promyelocytic Leukemia - APML)

The treatment approach for acute promyelocytic leukemia (APML) involves the use of trans-retinoic acid (ATRA) to induce remission. Remission is defined as:

• Less than 5% blasts in a normocellular marrow
• Trilineage recovery of peripheral blood counts
• No evidence of leukemia at other sites

Principles of Management

Management of acute leukemia typically follows several stages:

A. Stage of Induction of Remission (4-6 weeks)

• Fluids
• Allopurinol
• Chemotherapy:
  • Vincristine
  • Prednisolone
  • Asparaginase
• COAP (Cyclophosphamide, Oncovin, Ara-C, Prednisolone)
• Intrathecal (IT) methotrexate/Hydrocortisone/Ara-C
• Cranial irradiation

B. Stage of Consolidation (4-8 weeks)

• Chemotherapy:
• Vincristine and Prednisolone
• Ara-C and Cyclophosphamide

C. Stage of Maintenance (2-3 years)

• Daily 6-Mercaptopurine
• Weekly Methotrexate
• Monthly Reinforcements:
• Vincristine
• Prednisolone

Relapse in ALL

Relapse can occur in patients with ALL, and its location carries different implications:

• Relapse in the bone marrow occurs in 15-20% of ALL patients and is associated with serious implications.
• Relapse in the CNS may present with signs of increased intracranial pressure or isolated cranial nerve palsies.
• Testicular relapse is rare, occurring in 1-2% of boys with ALL, often after completing therapy. It manifests as painless swelling of one or both testes, confirmed by biopsy. Treatment includes systemic chemotherapy and local irradiation.

Management of Relapses

Management strategies for relapsed ALL depend on the location of the relapse:

• CNS Relapse:
  • CNS re-induction chemotherapy
  • Irradiation
  • Intrathecal or intraventricular methotrexate
• Testicular Relapse:
  • Re-induction chemotherapy
  • Irradiation
• Bone Marrow Relapse:
  • Intensive, multidrug re-induction chemotherapy
  • CNS irradiation
  • Bone marrow transplant

Patient Education

Parents or guardians of pediatric ALL patients should be well-informed about the treatment and potential adverse effects:

• Ensure parents/guardians have a reasonable understanding of the expected adverse effects of each medication.
• Teach them to recognize signs and symptoms that require medical attention, including those related to anemia, thrombocytopenia, and infection.
• Empower parents to quickly access medical assistance from the oncology team.

When evaluating a child with suspected leukemia, consider the following differential diagnoses:

• AML (Acute Myeloid Leukemia): AML is a similar type of leukemia but with distinct characteristics.
• Other Malignant Diseases: Some malignant diseases can invade the bone marrow and cause marrow failure, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, and retinoblastoma.
• Primary Bone Marrow Failure: Conditions like aplastic anemia, whether congenital or acquired, can lead to primary bone marrow failure.
• Single Cell Line Failure: Certain conditions, such as transient erythroblastic anemia, immune thrombocytopenia, congenital or acquired neutropenia, can result in the failure of a single cell line.
• Infectious Mononucleosis: Epstein-Barr virus infection, causing infectious mononucleosis, can present with some overlapping symptoms.
• Rheumatoid Arthritis: While rare, rheumatoid arthritis can cause hematologic abnormalities, and its symptoms may overlap with leukemia.

Overall, the cure rate for childhood Acute Lymphoblastic Leukemia (ALL) is nearly 80%. The prognosis for ALL patients varies based on clinical and laboratory features.

ALL: Poor Prognostic Factors

• Demographic factors: Male gender, black ethnicity, age <1 or >10 years old.
• CNS involvement: Central Nervous System (CNS) involvement is associated with a less favorable prognosis.
• Large tumor load: This includes organomegaly (enlarged organs) and mediastinal mass (mass in the chest).
• Hyperleukocytosis: A high white blood cell count (WBC) >50,000/mm³ indicates a poorer prognosis.
• High PCV: Hemoglobin (Hb) >10 g/dL, often referred to as a high packed cell volume (PCV), is linked to a less favorable outcome.
• Abnormal cell characteristics: Cells that are PAS (Periodic Acid-Schiff) negative or show decreased immunoglobulins A, G, M have a less favorable prognosis.
• L3 forms: The presence of L3 lymphoblast forms is associated with a poorer prognosis.
• B-cell dominance: When B-cell ALL (B-precursor ALL) is more prevalent than T-cell ALL, it may indicate a less favorable outcome.
• cALLa status: cALLa negative (common acute lymphoblastic leukemia antigen) cases have a less favorable prognosis compared to cALLa positive cases.
• Hypodiploidy: Hypodiploidy, characterized by fewer than the normal number of chromosomes, is associated with a less favorable prognosis, whereas hyperdiploidy (chromosome number higher than normal) is more favorable.
• DNA index: A DNA index <1.16 is considered a poor prognostic factor.
• Philadelphia chromosome: The presence of the Philadelphia chromosome t(9:22) is associated with a less favorable prognosis. A more favorable translocation is t(12:21) or TEL AML1.
• Slow resolution: Slow response to treatment may indicate a less favorable outcome.
• Minimal residual disease: Detectable minimal residual disease (residual leukemic cells) after treatment completion is linked to a poorer prognosis.