Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia Overview

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children, representing approximately 25% of all childhood cancers and surpassing brain tumors and neuroblastoma. It is also the most prevalent leukemia in children, with a peak incidence between 2 and 5 years of age.

Key Clinical Features

Crossing the Blood-Brain Barrier: ALL has a propensity to infiltrate the central nervous system (CNS), leading to CNS leukemia. This infiltration can manifest with symptoms such as meningismus (headache, stiff neck), raised intracranial pressure (ICP), seizures, and cranial nerve palsies. The presence of CNS involvement at diagnosis or relapse significantly impacts treatment strategies.
Testicular Lump: ALL can cross the blood-testis barrier, which normally protects the testes from systemic influences. This can result in a painless testicular mass or enlargement, typically unilateral. While testicular involvement is unusual as an initial presentation, it's a critical site for potential relapse. Histological examination reveals leukemic infiltration within the testicular tissue.

Pathological Background

B-Cell Origin: The majority (approximately 85%) of ALL cases originate from B-cells, specifically precursor B-lymphoblasts. These B-cell ALLs are often characterized by specific immunophenotypic markers and genetic abnormalities that guide classification and risk stratification.
- Common Subtype: Common ALL, also known as precursor B-cell ALL, is the most frequent subtype, accounting for the majority of B-cell ALL cases. It is characterized by distinct immunophenotypic and genetic features.
- Flow Cytometric Marker: CD10 (CALLA - Common Acute Lymphoblastic Leukemia Antigen) is a marker frequently associated with common ALL. However, it is not entirely specific, as it can be found in other lymphoid malignancies. Flow cytometry is essential for identifying cell surface markers, aiding in the diagnosis and classification of ALL subtypes.
- Philadelphia Chromosome: The presence of the Philadelphia chromosome, resulting from the $t(9;22)(q34;q11.2)$ translocation, indicates a high-risk tumor. This translocation leads to the formation of the BCR-ABL1 fusion gene, a tyrosine kinase that promotes uncontrolled cell proliferation. Patients with Philadelphia chromosome-positive ALL require tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, or ponatinib for effective management. The $t(9;22)$ translocation is found in both CML and ALL, but its prognostic significance differs.
T-Cell Origin: T-cell ALL accounts for approximately 15-20% of ALL cases. These leukemias arise from precursor T-lymphoblasts and often present with distinct clinical and biological features compared to B-cell ALL.

T-Cell Tumor Features

Mediastinal Mass: A mass in the mediastinum (the space in the chest between the lungs) is a common presentation in T-cell ALL. This mass represents enlarged thymus and lymph nodes infiltrated by leukemic cells. The mediastinal mass can cause various clinical manifestations due to compression of adjacent structures.
Superior Vena Cava Syndrome: Compression of the superior vena cava (SVC) by the mediastinal mass can lead to SVC syndrome. This manifests as facial swelling, dyspnea, and prominent venous collaterals on the chest wall.
Chylous Ascites: Infiltration of the lymphatic system can result in chylous ascites, which is the accumulation of chyle (lymphatic fluid rich in triglycerides) in the peritoneal cavity. This can cause abdominal distension and discomfort.
Airway Pressure: Compression of the trachea or bronchi by the mediastinal mass can lead to airway obstruction, causing stridor (a high-pitched breathing sound) and respiratory distress.
Testicular Involvement: Similar to B-cell ALL, T-cell ALL can also cause testicular lumps due to leukemic infiltration. Testicular involvement can occur at initial diagnosis or relapse.

Etiology of ALL

A mnemonic (A, B, C, D, I, F, K, N) helps in remembering the causes:

Ataxia-Telangiectasia: A rare autosomal recessive neurocutaneous disorder affecting spinocerebellar pathways, causing ataxia (impaired coordination) and telangiectasia (visible, small, dilated blood vessels in the sclera and skin). Patients with ataxia-telangiectasia have an increased risk of developing ALL and other malignancies due to defective DNA repair mechanisms.

Bloom Syndrome: A rare autosomal recessive disorder of defective DNA repair, characterized by short stature, sun-sensitive skin, and an increased risk of various cancers, including ALL. The defective gene in Bloom syndrome is involved in DNA replication and repair.
Benzene Exposure: Prolonged or high-level exposure to benzene, an industrial solvent, is a known risk factor for developing ALL and other hematological malignancies. Benzene can cause DNA damage and disrupt normal bone marrow function.

Chemotherapy-Induced Secondary Malignancy: Certain chemotherapy drugs, particularly alkylating agents and topoisomerase II inhibitors, can lead to secondary ALL. These agents can damage DNA and disrupt normal hematopoiesis, increasing the risk of developing therapy-related leukemia.
- Nitrosureas and Epipodophyllotoxins: Treatment with these agents, used for other primary malignancies, can result in secondary ALL. This is similar to how topoisomerase II inhibitors and alkylating agents can lead to AML. The latency period between exposure to these agents and the development of secondary ALL is typically 5-10 years.

Down Syndrome: Children with Down syndrome (trisomy 21) have a significantly higher risk (10-20 times) of developing ALL, particularly B-cell ALL. The increased risk is thought to be due to genetic factors related to the extra chromosome 21.
- Specific AML Subtype: If AML develops in children with Down syndrome, it is often the M7 variety (acute megakaryoblastic leukemia). This subtype is characterized by abnormal proliferation of megakaryoblasts, the precursors of platelets.

Ionizing Radiation: Exposure to ionizing radiation, such as from medical imaging or radiation therapy, increases the risk of ALL (except chronic lymphocytic leukemia). The risk is particularly high in individuals exposed at a young age. Radiation can cause DNA damage and chromosomal abnormalities.
Infection: HTLV-1 (Human T-cell Lymphotropic Virus Type 1) is a retrovirus associated with T-cell leukemia, specifically adult T-cell leukemia/lymphoma (ATLL). HTLV-1 infects T-cells and can lead to uncontrolled proliferation.

Fanconi's Anemia: A rare congenital aplastic anemia characterized by bone marrow failure, physical abnormalities, and an increased risk of ALL (not to be confused with Fanconi's syndrome, which is a renal tubular disorder). Fanconi's anemia is caused by mutations in genes involved in DNA repair.

Klinefelter Syndrome: Characterized by a tall male with gynecomastia and small testes (due to XXY chromosomal abnormality), is also associated with an increased risk of ALL. The exact mechanism for this increased risk is not fully understood but may be related to hormonal imbalances or genetic factors associated with the extra X chromosome.

Neurofibromatosis Type 1: A neurocutaneous disorder caused by mutations in the NF1 gene. Can be associated with blood cancers, including ALL, similar to ataxia-telangiectasia. Also associated with pheochromocytoma (a tumor of the adrenal gland). The NF1 gene plays a role in regulating cell growth and differentiation, and mutations can lead to uncontrolled cell proliferation.

Chromosomal Translocations

Philadelphia Chromosome: Indicates high-risk ALL, requiring tyrosine kinase inhibitors. The $t(9;22)(q34;q11.2)$ translocation results in the BCR-ABL1 fusion gene, which drives leukemic cell growth.
$t(8;14)(q24;q32)$ : Seen in both ALL and Burkitt's lymphoma/leukemia. This translocation involves the MYC gene on chromosome 8 and the immunoglobulin heavy chain locus on chromosome 14, leading to overexpression of MYC and uncontrolled cell proliferation.
$t(4;11)(q21;q23)$ : Involves the MLL gene on chromosome 11 and the AF4 gene on chromosome 4. This translocation is associated with a poor prognosis, particularly in infants.
$t(1;19)(q23;p13.3)$ : Creates the E2A-PBX1 fusion gene. This translocation is more common in pre-B cell ALL and is associated with a relatively good prognosis.

The risk stratification (low, standard, high, very high) guides treatment decisions, with high-risk cases often requiring allogeneic stem cell transplantation in the first remission to improve long-term survival. Risk stratification is based on factors such as age, white blood cell count, cytogenetics, and response to initial therapy.

HTLV-1

Adult T-Cell Leukemia/Lymphoma (ATLL): HTLV-1 can cause ATLL, a rare and aggressive T-cell malignancy. ATLL is endemic in certain regions of the world, such as Japan, the Caribbean, and parts of Africa.
- Flower Cells: Peripheral smear shows characteristic lymphocytes with a flower-like or clover-leaf shaped nucleus, which is basophilic with the cytoplasm pushed to the periphery. These cells are pathognomonic for ATLL. Distinguish from Sézary cells in mycosis fungoides (cutaneous T-cell lymphoma), which have constricted nuclei and cerebriform (brain-like) appearance.
Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (TSP/HAM): HTLV-1 is also linked to this chronic progressive neurological condition that affects the spinal cord, causing weakness, spasticity, and sensory disturbances in the lower extremities.

CNS Leukemia

Occurs more frequently in ALL than AML due to ALL cells' greater propensity for CNS infiltration. Prophylactic CNS-directed therapy is a crucial component of ALL treatment to prevent or eradicate CNS leukemia.
Symptoms: Meningismus (headache, stiff neck), nuchal rigidity, and signs of raised ICP (papilledema, vomiting, altered mental status). Cranial nerve palsies may also occur.
Diagnosis: Lumbar puncture (spinal tap) is performed to obtain cerebrospinal fluid (CSF) for analysis. CSF examination includes cell count, differential, protein and glucose levels, and cytological examination for leukemia cells. However, lumbar puncture may cause iatrogenic CNS leukemia due to ruptured blood vessels during the procedure.
Prevention: Intrathecal methotrexate, a chemotherapy drug, is administered during lumbar puncture to prevent iatrogenic CNS leukemia by killing any leukemic cells that may be introduced into the CSF during the procedure. Triple intrathecal therapy (methotrexate, cytarabine, and corticosteroids) is often used for CNS leukemia treatment and prophylaxis.
CSF Findings: Cell count in CSF is typically more than 5 lymphocytes/ $mm^3$ . The presence of any leukemic blasts in the CSF is diagnostic for CNS leukemia. Cancer cells are identified in centrifuged CSF sediment (cytospin).
Imaging: Contrast-enhanced MRI (magnetic resonance imaging) is more sensitive than CT (computed tomography) for detecting leptomeningeal metastases (spread of leukemia to the lining of the brain and spinal cord). MRI can show thickening and enhancement of the leptomeninges.

Clinical Presentation Timeline

Typical Patient: A previously healthy child (2-8 years old) experiences rapid disease progression over a period of weeks to months.
Adult Onset: Can occur in adults, typically after 50 years of age. ALL in adults often has a worse prognosis than in children.
Initial Symptoms:
- Pallor (pale skin) due to anemia
- Epistaxis (nosebleeds) and bleeding gums due to thrombocytopenia
- Bruising and petechiae (small, pinpoint-sized red or purple spots on the skin) due to thrombocytopenia
- Recurrent infections (e.g., pneumonia, cellulitis) due to neutropenia (low white blood cell count)
- Bone pain (sternal tenderness) due to leukemic infiltration of the bone marrow. Bone pain is often described as deep and aching.
Advanced Disease:
- Organomegaly: Hepatomegaly (enlarged liver) and splenomegaly (enlarged spleen) due to leukemic infiltration.
- Lymphadenopathy: Enlarged lymph nodes, which may be painless or tender.
- Mediastinal Mass: May lead to superior vena cava syndrome with facial congestion, edema, dyspnea, and collateral vessel development on the chest wall.
- CNS Leukemia: Raised ICP, vomiting, headaches, seizures, and cranial nerve palsies (e.g., sixth nerve palsy causing double vision).
- Testicular Lump: Painless enlargement of one or both testicles due to leukemic infiltration.

Workup

Complete Blood Count (CBC):
- Anemia (normocytic normochromic): Reduced red blood cell count and hemoglobin levels.
- Variable TLC (total leukocyte count): Can be normal, low (leukopenia), or elevated (leukocytosis). The white blood cell count can vary depending on the extent of bone marrow infiltration.
- Hyperleukocytosis: Markedly elevated TLC, > 100,000/mm^3, indicates a high tumor burden and can cause leukostasis (sludging of white blood cells in small blood vessels).
- Thrombocytopenia: Reduced platelet count, increasing the risk of bleeding.
Bone Marrow Aspiration and Biopsy:
- Needles: Sternal or Klima's needle are commonly used for bone marrow aspiration.
- Site: Posterior superior iliac spine is the preferred site for bone marrow aspiration and biopsy due to its accessibility and safety.
- Anesthesia: Local anesthesia, propofol, or ketamine are used to minimize discomfort during the procedure.
- Diagnostic Cutoff:>20% blasts (immature white blood cells) in the bone marrow is required for the diagnosis of ALL, according to WHO criteria. This percentage may vary slightly based on specific classification systems.
- Morphological Subtypes: L1 (commonest), L2, and L3 (Burkitt's leukemia). These subtypes are based on the French-American-British (FAB) classification system, which is less commonly used now in favor of WHO classification but still relevant.
  - L3 Variety (Burkitt's Leukemia/Lymphoma): Mature B-cell type, CD10 positive, surface immunoglobulin positive, with $t(8;14)$ . This translocation leads to overexpression of the MYC gene.
Immunophenotyping and Cytogenetics:
- Immunophenotyping by flow cytometry is essential for classifying ALL based on cell surface markers. Cytogenetic analysis, including karyotyping and FISH (fluorescence in situ hybridization), is performed to identify chromosomal translocations and abnormalities.
- Philadelphia chromosome: $t(9;22)(q34;q11.2)$
- $t(8;14)(q24;q32)$ (Burkitt's leukemia/lymphoma)
- $t(4;11)(q21;q23)$
- $t(1;19)(q23;p13.3)$
TdT (Terminal Deoxynucleotidyl Transferase) Assay:
- TdT is a DNA polymerase expressed in immature lymphocytes. TdT positivity indicates high DNA polymerase activity and high cell turnover, increasing the risk of tumor lysis syndrome. TdT is a useful marker for distinguishing ALL from other leukemias.
Electrolyte and Renal Function Monitoring:
- To assess the risk, or presence, of Tumor Lysis Syndrome (TLS). TLS is characterized by hyperphosphatemia, hypocalcemia, hyperkalemia, and hyperuricemia due to the rapid breakdown of leukemic cells. Hydration and allopurinol (or rasburicase) may be required to prevent or manage TLS.
Lumbar Puncture: CSF examination for leukemia cells is crucial for diagnosing CNS leukemia. Intrathecal methotrexate is administered to prevent iatrogenic CNS leukemia.
HLA (Human Leukocyte Antigen) Matching: For potential allogeneic stem cell transplantation. HLA matching is performed to identify a suitable donor for patients who require stem cell transplantation.

Risk Stratification

High-Risk ALL

Age: Less than 1 year or more than 10 years at diagnosis.
WBC Count:> 50,000/ $mm^3$ at diagnosis.
Organomegaly: Significant lymphadenopathy, hepatosplenomegaly, mediastinal mass, and related symptoms indicating a high tumor burden.
Mature B-Cell ALL: More aggressive than pre-B ALL.
Hypodiploidy: Fewer than 46 chromosomes in the leukemic cells.
Specific Chromosomal Translocations: $t(9;22)$ , $t(4;11)$ , $t(8;14)$ , $t(1;19)$ .
Peripheral Smear Blasts:> 1,000 blasts after 14 days of chemotherapy (debatable value, but still considered in some protocols).
Absence of CD10: In B-cell ALL, absence of CD10 expression is associated with a poorer prognosis.
MLL Positivity (Mixed Lineage Leukemia): MLL gene rearrangements are associated with high-risk ALL, particularly in infants.

Recommended Treatment: Allogeneic stem cell transplantation in first remission is often recommended for high-risk ALL patients to improve the chances of long-term survival.

Low-Risk ALL

Age: 1-9 years at diagnosis.
WBC Count: < 50,000/ $mm^3$ at diagnosis.
Pre-B Cell ALL
Hyperdiploidy: More than 46 chromosomes in the leukemic cells. Specifically, hyperdiploidy involving certain chromosomes (e.g., chromosomes 4, 10, and 17) is associated with a favorable prognosis.

Standard-Risk ALL

Same features as high-risk, but with normal cytogenetics (no high risk chromosomal swaps/translocations). Patients in this category have an intermediate risk of relapse and are typically treated with intensive chemotherapy.

Very High-Risk ALL

Induction failure: Failure to achieve remission after the initial induction chemotherapy.
Philadelphia chromosome positivity: Presence of the $t(9;22)$ translocation.

Treatment for Low and Standard Risk: Chemotherapy with a multi-agent regimen is the standard approach.

Treatment for High and Very High Risk: Allogeneic stem cell transplantation is often considered for patients with high-risk and very high-risk ALL to improve the chances of long-term survival.

Treatment

Goal: The primary goal of ALL treatment is to achieve complete molecular remission, which means eradicating all detectable leukemic cells from the body.
Timeline for Complete Molecular Remission: Complete molecular remission is typically assessed after 6-16 weeks of chemotherapy initiation using sensitive techniques such as real-time quantitative PCR (RQ-PCR) or flow cytometry.
Success Rates: High-risk (80%), Low-risk (90%). These success rates refer to the probability of achieving complete remission with current treatment protocols.

Definitions of Complete Molecular Remission:

Destruction of 99.99% of cancer cells (less than 0.01% leukemia cells or less than 1 leukemia blast per 10,000 normal cells) as measured by real-time PCR. This indicates minimal residual disease (MRD) negativity.
Less than 5% blasts in bone marrow via light microscopy. This is the traditional definition of complete remission based on morphological assessment.

Philadelphia Chromosome-Positive ALL Treatment

Tyrosine Kinase Inhibitors (TKIs): TKIs are essential for treating Ph+ ALL. Second-generation inhibitors are needed as they cross the blood-brain barrier, providing CNS protection:
- Dasatinib: A potent TKI that inhibits the BCR-ABL1 tyrosine kinase activity.
- Ponatinib: A third-generation TKI that is effective against BCR-ABL1 mutations, including the T315I mutation, which confers resistance to other TKIs.

Targeted Approach

Chimeric Antigen Receptor (CAR) T-cell therapy: A form of immunotherapy that involves engineering a patient's own T-cells to express a CAR that recognizes and targets leukemic cells. CAR T-cell therapy targets only the abnormal cells expressing the specific antigen. It has shown remarkable success in relapsed/refractory ALL.
- Drug: Blinatumomab: A bispecific T-cell engager (BiTE) antibody that binds to CD19 on leukemic cells and CD3 on T-cells, bringing them together to kill the leukemic cells.

Chemotherapy for Low-Risk ALL

Phases: Induction, Consolidation, Maintenance. These phases are designed to eradicate leukemic cells and prevent relapse.

Induction (4-6 weeks)

Induction 1:
- Vincristine: A vinca alkaloid that inhibits microtubule formation, disrupting cell division. Side effect: peripheral neuropathy.
- Daunorubicin (or Doxorubicin): An anthracycline antibiotic that inhibits DNA and RNA synthesis. Side effect: cardiomyopathy (heart damage).
- L-Asparaginase: An enzyme that depletes asparagine, an amino acid required by leukemic cells. Side effects: allergic reactions, pancreatitis, and thrombosis.
- Prednisolone: A corticosteroid that suppresses the immune system and inhibits leukemic cell growth.
- Intrathecal Methotrexate: Given to prevent spread to CNS. Methotrexate is an antifolate drug that inhibits DNA synthesis.
Induction 2: This phase may involve additional chemotherapy agents to further reduce the leukemic burden.
- 6-Mercaptopurine (6-MP): A purine analog that inhibits DNA synthesis.
- Methotrexate: An antifolate drug that inhibits DNA synthesis.
- Cyclophosphamide: An alkylating agent that damages DNA. Side effect: hemorrhagic cystitis (inflammation of the bladder).
- Cranial Irradiation: 18-24 Gy (Gray) in 12 fractions. Used in the past for CNS prophylaxis, but now largely replaced by intrathecal chemotherapy. Side effect: Meningioma (a benign brain tumor).

Consolidation (or Intensification) (14-28 weeks)

This phase aims to eliminate any remaining leukemic cells and prevent relapse. It typically involves high-dose chemotherapy.
Cyclophosphamide
Vincristine
Daunorubicin (or Doxorubicin)
Cytosine Arabinoside (Ara-C): A pyrimidine analog that inhibits DNA synthesis.

Maintenance (2-2.5 years)

This phase aims to maintain remission and prevent relapse. It involves lower doses of chemotherapy given over a prolonged period.
6-Mercaptopurine (6-MP)
Methotrexate

Relapse Definition:>5% leukemia cells in the bone marrow via light microscopy. Relapse can occur in the bone marrow, CNS, or testes. Treatment for relapsed ALL depends on the site of relapse and the patient's risk factors.