Acute Lymphoblastic Leukemia (ALL)

• Acute Lymphoblastic Leukemia (ALL) is a malignant disease affecting lymphoid progenitor cells in the bone marrow
• In ALL, early lymphoid precursors proliferate and displace normal haematopoietic cells
• ALL leads to lymphoblast accumulation in peripheral blood and bone marrow

Epidemiology

• ALL is the most common malignancy in childhood
• The majority of ALL cases occur in children aged 2-10 years, but adults can also be affected
• Peak incidence of ALL in children is at 4-5 years of age
• ALL has an acute onset with a brief duration
• 85% of ALL cases involve B cells, while 15% involve T cells
• ALL is 5 times more frequent in childhood compared to Acute Myeloid Leukemia (AML)
• ALL affects males more than females

Etiology & Predisposing Factors

• The exact cause of ALL is unknown in most cases
• Environmental factors like ionizing radiation and chemical mutagens are implicated
• Genetic factors are suggested, with Down syndrome children having a higher leukemia risk, specifically precursor B lymphoblastic leukemia
• Chronic exposure to childhood infections, especially viral, has been linked to ALL
• Genetic predisposing factors include Downs, Turners and Klinefelters Syndromes, Fanconi Anemia, Diamond Blackfan Anemia and Bloom Syndrome
• Other genetic links include Ataxia telangiectasia and Paroxysmal nocturnal hemoglobinuria (PNH)
• Environmental predisposing factors include Ionising Radiation, Drugs (chemotherapeutic), Alkylating Agents Other environmental are Nitrosourea, and Benzene Exposure as well as Childhood viral infections

Classification

• ALL is classified using two methods: FAB and WHO
• FAB classification focuses on the morphology of lymphoblasts
• WHO classification is based on immunological markers on lymphoblasts

FAB Morphological Classification

• ALL can be classified morphologically using the French-American-British (FAB) system into L1, L2, and L3 types
• L1 is the small monomorphic type and has small homogeneous blasts, a high N:C ratio, a single inconspicuous nucleolus, and a regular nuclear outline It is the most common subtype
• L2 is the large heterogeneous type and has larger blasts, a low N:C ratio, more pleomorphic and multinucleolate, irregular nuclei and conspicuous nucleoli
• L3 is the Burkitt cell type and has large homogeneous blasts, abundant basophilic cytoplasm with vacuoles. It's associated with a B-cell phenotype

Immunological Classification - B Lineage

• Pro B-ALL: HLA-DR+, TdT+, CD19+ (5% children, 11% adults)
• Common ALL: HLA-DR+, TdT+, CD19+, CD10+ (65% children, 51% adults)
• PreB-ALL: HLADR+, TdT+, CD19+, CD10-, cytoplasmic IgM+ (15% children, 10% adults)
• B-cell ALL: HLA-DR+, CD19+, CD10-, surface IgM+ (3% children, 4% adults)

Immunological Classification - T Lineage

• Pre-T ALL: TdT+, cytoplasmic CD3+, CD7+ (1% children, 7% adults)
• T-cell ALL: TdT+, cytoplasmic CD3+, CD1a/2/3+, CD5+ (11% children, 17% adults)

Clinical Features

• ALL usually presents acutely
• Children with ALL are often critically ill due to bone marrow failure effects
• Symptoms of anemia include weakness, lethargy, breathlessness, lightheadedness, and palpitations
• Susceptibility to infection, particularly in the chest, mouth, peri-anal area, and skin (Staphylococcus, Pseudomonas, HSV, Candida), and can have fever, malaise and night sweats
• Hemorrhage manifests as purpura, menorrhagia, epistaxis, bleeding gums, rectal bleeding, and retinal hemorrhages
• Leucostasis signs include hypoxia, retinal hemorrhage, confusion, or diffuse pulmonary shadowing
• Mediastinal involvement occurs in about 15% of cases, potentially causing Superior Vena Cava (SVC) obstruction
• Central Nervous System (CNS) involvement is seen in 6% of patients, leading to cranial nerve palsies, sensory disturbances, and meningism
• Common signs include widespread lymphadenopathy (55%), mild to moderate splenomegaly (49%), hepatomegaly (45%), and orchidomegaly

Investigations and Diagnosis

• A Full Blood Count (FBC) and blood film examination will show normocytic normochromic anemia, thrombocytopenia, leucocytosis >50 x 10^9/L, along with >20% lymphoblasts on film
• Bone marrow aspirate with biopsy reveals hypercellular marrow with >20% lymphoblasts
• Bone marrow cytogenetics are conducted to identify chromosomal abnormalities
• Lumbar puncture is performed for Cerebrospinal Fluid (CSF) examination to check for CNS involvement
• Biochemical tests include elevated Lactate Dehydrogenase (LDH), Uric acid in serum, Liver Function Tests (LFTs), and renal function tests, done as baseline before chemotherapy
• Chest X-Ray (CXR) may show thymic or mediastinal lymph node enlargement
• Immunophenotyping of blood or bone marrow blasts is also performed

Differential Diagnosis

• Non-Hodgkin's Lymphoma in its leukemic phase
• AML
• Reactive lymphocytosis from infections
• Metastatic tumors in bone marrow

Treatment

• Pre-chemotherapy involves supportive care
• Chemotherapy includes phases of pre-induction, remission induction, CNS preventive therapy, along with consolidation and maintenance therapy
• Allogenic stem cell transplantation is another option
• Newer drugs have also been developed

Supportive Treatment

• Providing explanations and counseling regarding the diagnosis
• Insertion of a central venous catheter to administer drugs and blood products
• Red Blood Cell (RBC) and platelet transfusion support throughout treatment
• Starting a neutropenic regimen for prophylaxis or active treatment for infections, including antibiotics, antifungals, or antivirals
• Allopurinol to prevent hyperuricemia and tumor lysis syndrome
• Antiemetic drugs like metoclopramide or chlorpromazine to prevent vomiting

Specific Treatment

• Treatment for ALL includes five continuous phases
• Pre-induction is the first phase
• Remission induction uses vincristine, prednisolone, daunorubicin, and L-Asparaginase to achieve complete remission
• CNS prophylaxis combines cranial irradiation and/or intrathecal chemotherapy with drugs like methotrexate, cytarabine, or prednisolone, given early in the consolidation phase
• Consolidation therapy is used reduce tumor burden and the risk of relapse and drug-resistant cells are a risk. This may be followed by Allogeneic Stem Cell Transplant (SCT)
• Maintenance therapy is necessary for all patients not proceeding to stem cell transplant

Preinduction

• Prednisolone is administered at 1mg/kg orally for 5 days
• The blast count is rechecked after 5 days; a drop indicates a favorable response

Induction of Remission

• Prednisolone is administered at 1mg/kg orally for 1-28 days
• Vincristine is given intravenously at 1.5mg/m2 weekly for 4 weeks
• Doxorubicin is administered intravenously at 30mg/m2 weekly for 4 weeks
• L-Asparaginase is given at 10,000u daily for 10 days (total dose 100,000 u) in divided doses

Central Nervous System (CNS) Prophylaxis

• CNS prophylaxis for lower-risk patients is achieved with systemic and intrathecal chemotherapy, without cranial irradiation in many cases.
• High-risk features in children increase the risk of CNS relapse, and those children frequently receive prophylactic cranial irradiation
• Features of high-risk include WBC counts of 50,000/μL or higher as well as over 100,000/μL , they are associated with a high relapse risk
• Further high-risk features are also T-cell phenotype, Philadelphia chromosome-positive ALL, and the presence of t(4;11)
• For infants under 12 months with 11q23 abnormalities intensified systemic and intrathecal chemotherapy is commonly utitlized due to the young ages of the infants

Newer Drugs

• Monoclonal antibodies include Rituximab (CD20), Epratuzumab (CD22), Alemtuzumab (CD52), and Gemtuzumab (CD33)
• Antimetabolites include Clofarabine and Nelarabine
• Tyrosine kinase inhibitors include Imatinib, Nilotinib, and Dasatinib
• Other drugs include Vornistat, Sirolimus, Everolimus, and Oblimersen

Allogeneic Stem Cell Transplantation

• Typically performed in second remission
• Can be done in first remission for high-risk patients, specifically those with WBC >25000, Philadelphia chromosome-positive or poor initial response to remission induction

Late Effects of Treatment

• Cranial irradiation can lead cognitive and intellectual impairment and CNS neoplasms
• Chemotherapeutic drugs could lead to secondary AML
• Endocrine dysfunctions include short stature, obesity, and growth retardation
• Anthracycline has the potential to be cardiotoxic
• Steroids can cause avascular necrosis of bone

Relapse

• Blasts reappear at any body site after initial remission during or after chemotherapy completion
• Marrow relapse has a poor outcome, with Hyper CVAD regimen, BM transplantation
• CNS relapse involves Triple IT (Intrathecal Therapy), alternate days until CSF clears, then twice weekly x 6 doses, then one dose every week x 6 doses, with optional cranial irradiation
• Testicular relapse requires chemotherapy plus testicular irradiation

Prognostic Factors in ALL

Biphenotypic Acute Leukemias

• Approximately 7% of acute leukemias exhibit two distinct leukemic cell populations upon phenotyping, characterized as biphenotypic leukemias
• The cell populations commonly express B-lymphoid and myeloid markers
• Variable response rates are common in patients with biphenotypic acute leukemias
• The choice of treatment protocol can become complex and problematic

Key Differences Between ALL and AML

Lymphoblast Vs Myeloblast: Morphology

Summary Points

• Leukemia is a consequence of mutations in bone marrow pluripotent stem cells
• Individuals with acute leukemia will present with variable white counts, anemia, and low platelet counts
• Acute leukemia is classified when blast cells gather within bone marrow and peripheral blood
• Hepato-splenomegaly or lymphadenopathy is more readily found in chronic leukemias than in acute leukemias
• WHO guidelines stipulate that a peripheral smear should contain 20% or greater myeloblasts to diagnose acute leukemia
• Cytochemical staining is used to detect acute leukemias based on the staining patterns of the blasts