Acute Lymphoid

Overview of Acute Lymphoblastic Leukemia (ALL)

Definition: An aggressive hematologic malignancy characterized by the rapid proliferation and accumulation of immature lymphoid cells (lymphoblasts) in the bone marrow, blood, and extramedullary sites. This uncontrolled proliferation crowds out normal hematopoietic cells
Also Known As: Acute Lymphocytic Leukemia
Cell Types Involved: ALL can be classified into subtypes based on the cell lineage:
- B-Cell ALL (B-ALL): Most common type, involving precursor B cells
- T-Cell ALL (T-ALL): Less common type, involving precursor T cells
Key Feature: >20% lymphoblasts in the bone marrow
Epidemiology:
- ALL is the most common type of childhood leukemia, with a peak incidence between 2 and 5 years of age
- It also occurs in adults, but is less common
Prognosis: Varies depending on the subtype of ALL, genetic abnormalities, age, and other factors
Overall, if treated, survival rates are generally higher in children than adults.

Pathophysiology

Genetic Mutations: Acquired genetic mutations in lymphoid progenitor cells disrupt normal differentiation and proliferation, leading to:
- Uncontrolled proliferation of lymphoblasts
- Arrest in cell maturation, with a buildup of immature cells
- Chromosomal translocations, deletions, and other genetic abnormalities are common
Impaired Hematopoiesis: Lymphoblasts accumulate in the bone marrow, crowding out normal hematopoietic cells and leading to:
- Anemia (decreased red blood cells)
- Thrombocytopenia (decreased platelets)
- Neutropenia (decreased neutrophils)
Extramedullary Infiltration: Lymphoblasts can infiltrate extramedullary sites, such as:
- Lymph nodes
- Spleen
- Liver
- Central nervous system (CNS)
- Testes

Etiology and Risk Factors

Genetic Factors:
- Chromosomal abnormalities:
  - t(12;21)(p13.2;q22.1): ETV6-RUNX1 (favorable prognosis, common in childhood B-ALL)
  - t(9;22)(q34.1;q11.2): BCR-ABL1 (poor prognosis, more common in adult B-ALL)
  - t(4;11)(q21;q23.3): KMT2A (MLL) rearrangement (poor prognosis, common in infants)
- Gene mutations:
  - NOTCH1 mutations (common in T-ALL)
  - TP53 mutations (associated with poor prognosis)
Environmental Factors:
- Exposure to ionizing radiation
- Exposure to certain chemicals (e.g., benzene)
- Prior chemotherapy or radiation therapy (therapy-related ALL)
Genetic Syndromes:
- Down syndrome (increased risk of B-ALL)
- Neurofibromatosis type 1
- Fanconi anemia
Age:
- Peak incidence in childhood (2-5 years)
- Incidence increases again after age 50

Classification

WHO Classification:
- B-Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified (B-ALL/LBL, NOS):
  - B-ALL cases that do not meet the criteria for other subtypes
  - Classified based on morphology, immunophenotype, and cytogenetic abnormalities
- B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities:
  - B-ALL with t(9;22)(q34.1;q11.2); BCR-ABL1 (Philadelphia chromosome-positive ALL)
  - B-ALL with t(v;11q23.3); KMT2A rearranged
  - B-ALL with t(12;21)(p13.2;q22.1); ETV6-RUNX1
  - B-ALL with t(1;19)(q23;p13.3); TCF3-PBX1
  - B-ALL with hyperdiploidy (more than 50 chromosomes)
  - B-ALL with hypodiploidy (less than 46 chromosomes)
- T-Lymphoblastic Leukemia/Lymphoma:
  - T-ALL/LBL cases involving precursor T cells
  - Often presents as a mediastinal mass in adolescents and young adults

Clinical Manifestations

Symptoms of Bone Marrow Failure:
- Fatigue, weakness, pallor (anemia)
- Bleeding (e.g., nosebleeds, gum bleeding, petechiae, ecchymoses) - thrombocytopenia
- Infections (e.g., fever, pneumonia) - neutropenia
Symptoms of Extramedullary Involvement:
- Lymphadenopathy (swollen lymph nodes)
- Splenomegaly (enlarged spleen)
- Hepatomegaly (enlarged liver)
- Mediastinal mass (especially in T-ALL, causing cough, shortness of breath, or superior vena cava syndrome)
- Central Nervous System (CNS) Involvement:
  - Headache
  - Vomiting
  - Seizures
  - Cranial nerve palsies
- Testicular Involvement:
  - Painless testicular swelling (more common in males)
Other Symptoms:
- Bone pain (due to bone marrow infiltration)
- Weight loss
- Night sweats

Laboratory Findings

Complete Blood Count (CBC):
- White Blood Cell (WBC) Count: Variable (can be low, normal, or high)
- Hemoglobin (HGB): Decreased (anemia)
- Hematocrit (HCT): Decreased
- Platelet Count: Decreased (thrombocytopenia)
- Neutrophil Count: Decreased (neutropenia)
- Presence of Lymphoblasts in the Peripheral Blood:
  - Lymphoblasts are immature lymphoid cells with:
    - High nucleus-to-cytoplasm (N:C) ratio
    - Fine chromatin
    - One or more distinct nucleoli
    - Scant cytoplasm
Peripheral Blood Smear:
- Lymphoblasts: Predominant cell type
- Cytopenias: Decreased mature RBCs, WBCs, and platelets
Bone Marrow Aspiration and Biopsy:
- Hypercellular Bone Marrow: Replaced by >20% lymphoblasts
- Special Stains:
  - Terminal deoxynucleotidyl transferase (TdT): Positive in lymphoblasts
  - Myeloperoxidase (MPO): Negative in lymphoblasts
- Flow Cytometry Immunophenotyping:
  - Essential for classifying ALL subtypes
  - Identifies cell surface markers on the lymphoblasts
    - B-ALL Markers: CD19, CD22, CD10, CD34, TdT
    - T-ALL Markers: CD2, CD3, CD5, CD7, CD1a, TdT
Cytogenetic Analysis:
- Identifies Chromosomal Abnormalities (e.g., translocations, deletions, inversions)
  - t(9;22)(q34.1;q11.2): BCR-ABL1 (Philadelphia chromosome)
  - t(12;21)(p13.2;q22.1): ETV6-RUNX1
  - t(4;11)(q21;q23.3): KMT2A (MLL) rearrangement
Molecular Testing:
- Detects Gene Mutations and Fusion Genes
  - BCR-ABL1 fusion gene (in Ph+ ALL)
  - FLT3 mutations
  - NPM1 mutations
  - TP53 mutations
  - NOTCH1 mutations (in T-ALL)
Lumbar Puncture:
- To Assess for Central Nervous System (CNS) Involvement
- Cerebrospinal Fluid (CSF) Examination:
  - Cytology: To detect lymphoblasts in the CSF
  - Protein and Glucose Levels: May be abnormal

Treatment

Treatment is Complex and Multi-Phased:
- Induction Therapy:
  - Intensive chemotherapy to achieve complete remission (eradication of blasts from the bone marrow)
  - Common agents: Vincristine, prednisone, daunorubicin, asparaginase, cyclophosphamide
- Consolidation Therapy (Post-Remission Therapy):
  - To eliminate any remaining leukemic cells and prevent relapse
  - Options include:
    - Chemotherapy
    - Hematopoietic Stem Cell Transplantation (HSCT):
      - Allogeneic HSCT (from a matched donor) is the preferred consolidation therapy for patients with high-risk ALL
- Maintenance Therapy:
  - Prolonged, lower-intensity chemotherapy to maintain remission
  - Typically lasts for 2-3 years
- Central Nervous System (CNS) Prophylaxis:
  - To prevent CNS relapse
  - Intrathecal chemotherapy (methotrexate or cytarabine)
  - Cranial irradiation (in some cases)
Targeted Therapies:
- Tyrosine Kinase Inhibitors (TKIs):
  - Used for Philadelphia chromosome-positive (Ph+) ALL to target the BCR-ABL1 tyrosine kinase activity
  - Imatinib, dasatinib, nilotinib
- Monoclonal Antibodies:
  - Blinatumomab: A bispecific T-cell engager (BiTE) antibody that binds to CD19 on B cells and CD3 on T cells, bringing them together to kill the B cells
  - Inotuzumab Ozogamicin: An anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent
Supportive Care:
- Transfusions (RBCs and platelets) to manage cytopenias
- Antibiotics and antifungals to treat infections
- Growth factors (e.g., G-CSF) to stimulate neutrophil production
- Management of tumor lysis syndrome (TLS): A metabolic complication caused by the rapid breakdown of leukemic cells

Prognosis

Factors Influencing Prognosis:
- Cytogenetic Abnormalities: Certain chromosomal abnormalities are associated with favorable or unfavorable outcomes
- Age: Younger patients generally have better outcomes than older patients
- WBC Count at Diagnosis: High WBC count is associated with poorer prognosis
- Response to Induction Chemotherapy: Achievement of minimal residual disease (MRD) negativity is a key prognostic factor
- Minimal Residual Disease (MRD):
  - The presence of a small number of leukemic cells that remain after treatment
  - Measured by flow cytometry or PCR
  - MRD negativity is associated with improved outcomes
Risk Stratification:
- Patients are classified into risk groups (standard, high, or very high risk) based on prognostic factors
- Risk stratification guides treatment decisions and helps predict the likelihood of achieving long-term remission

Key Laboratory Findings

CBC:
- Anemia
- Thrombocytopenia
- Neutropenia
- Presence of lymphoblasts in the peripheral blood
Peripheral Blood Smear:
- Lymphoblasts
Bone Marrow Examination:
- Hypercellular marrow with >20% lymphoblasts
Flow Cytometry Immunophenotyping:
- Identifies cell surface markers on the lymphoblasts
Cytogenetic Analysis:
- Detects chromosomal abnormalities
Molecular Testing:
- Detects gene mutations and fusion genes

Key Terms

Acute Lymphoblastic Leukemia (ALL): An aggressive leukemia characterized by >20% lymphoblasts in the bone marrow
Lymphoblast: Immature lymphoid cell
Cytopenia: Deficiency of blood cells (e.g., anemia, neutropenia, thrombocytopenia)
Complete Remission (CR): Eradication of blasts from the bone marrow and restoration of normal hematopoiesis
Induction Chemotherapy: Initial intensive chemotherapy to achieve remission
Consolidation Therapy: Treatment to prevent relapse after achieving remission
Maintenance Therapy: Prolonged, lower-intensity chemotherapy to maintain remission
Hematopoietic Stem Cell Transplantation (HSCT): Procedure to replace damaged bone marrow with healthy stem cells
Tyrosine Kinase Inhibitor (TKI): A drug that inhibits tyrosine kinase activity
Minimal Residual Disease (MRD): A small number of leukemic cells remaining after treatment

Lymphoid Neoplasia

Chronic B-Cell