ALL - acute lymphoblastic leukemia

Question 1

What is ALL? (Definition)

Answer 1

ALL is a malignant neoplastic disease that arises from lymphoid cell lines and is characterized by the proliferation of immature, nonfunctional cells (blasts) in the bone marrow that are released into the bloodstream. The excessive proliferation of immature blasts in the bone marrow impairs all other cell lines, resulting in anemia, clotting disorders (thrombocytopenia), and increased susceptibility to infections (neutropenia).

Question 2

What is the epidemiology of ALL?

Answer 2

Peak incidence is between 2–5 years. It is the most common malignant disease in children. ∼ 80% of acute leukemias during childhood are lymphocytic. ♂ > ♀.

Question 3

Name some aetiologies or risk factors for ALL.

Answer 3

No identifiable cause or risk factors in most cases. Prior bone marrow damage due to alkylating chemotherapy or ionizing radiation is a risk factor. Adult T-cell leukemia/lymphoma is linked to infection with HTLV.

Genetic or chromosomal factors:

• Down syndrome
• Neurofibromatosis type 1
• Ataxia telangiectasia

Question 4

Explain basic pathogenesis of ALL? What happens?

Answer 4

Acute leukaemia forms, when a malignant transformation (eg. due to mutation) of one blast cell occurs. The cell continues to divide, but looses the ability to mature. When the total amount of blast cells in the bone marrow increases, the amount of normal cell elements decreases (giving the manifestations).

Question 5

How do we classify ALL? What is the name of the classification system?

Answer 5

French-American-British (FAB) historical classification of ALL:

• L1 ALL with small cells (20–30%)
• L2 ALL with heterogeneous large cells (70%)
• L3 ALL with large cells, i.e., Burkitt lymphoma (1–2%)

Question 6

What are clinical manifestations of ALL?

Answer 6

Common manifestations:

• Palpable liver or palpable spleen (∼60%)
• Lymphadenopathy (∼50%)
• Pallor, fatigue (due to anemia)
• Fever (due to infection or the leukemia itself).
• Bruising (due to thrombocytopenia)
• Musculoskeletal pain (∼40%, can present as limping in children)

Hematologic abnormalities are common.

• About half of children present with bleeding (eg, petechiae, purpura).
• Anemia
• 3/4 have a platelet count <100,000/microL at diagnosis.
• WBC count may be low, normal, or high (most commonly low)

Less common: Headache, testicular enlargement, SVC syndrome (superior vena cava syndrome)

Question 7

How do you diagnose ALL?

Answer 7

1. Initial test: CBC and peripheral blood smear.
   - Leukocytes: The WBC may be elevated, normal, or low.
   - Thrombocytopenia.
   - Anemia. Normocytic, normochromic anemia that can vary in severity.
   - Blood smear: ↑ Lymphoblasts.
2. Confirmatory test:
   Bone marrow aspiration and biopsy with subsequent cytogenetic analysis and immunophenotyping to confirm the diagnosis (examine morphology, histochemistry, cytogenetics, and immunophenotyping). Confirmatory diagnostic tests: > 20% lymphoblasts in the bone marrow.

• Histochemistry:
  A. A myeloperoxidase reaction is a simple test to determine if the blasts are myeloid. In this case they will be negative since the cells are lymphoblasts.
  B. Terminal deoxynucleotidyl transferase (TdT) - positive.
  C. Periodic acid-Schiff (PAS) - may be positive.
• Immunophenotyping:
  By flow cytometry to look for T-ALL or B-ALL (most common). We can for example see CD10, CD19 or CD3.
• Cytogenetics:
  Looking for translocations (eg. Philadelphia translocation).

Additional laboratory studies:

• Coagulation studies: rule out DIC
• Electrolytes and metabolic markers: ↑ PO43-, ↓ Ca2+, ↑ K+, ↑ LDH, and ↑ uric acid indicate increased cell lysis.

Further tests:
- Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis.

• Chest x-ray: mediastinal mass in the case of thymic infiltration (occurs primarily in T-cell ALL) or mediastinal lymphadenopathy.
• Abdominal ultrasound: organ enlargement (especially the liver and/or spleen).

Question 8

What is the approach (steps) for treatment of ALL? (Do not name the drugs).

Answer 8

A. Aggressive chemotherapy is the mainstay of treatment.- Chemotherapy regimens are comprised of induction, followed by consolidation, and finally maintenance therapy.

1. Induction therapy (goal: massive reduction of tumor cell count). The goal of induction treatment is complete remission, defined as < 5% blast cells in the bone marrow.
   - 4-6 weeks, usually high dose.
2. Re-induction therapy (goal: massive reduction of tumor cell count). Only indicated in case of relapse or failure of primary induction therapy.
   Duration: 4–6 weeks.
3. Consolidation therapy (goal: destruction of remaining tumor cells). Begin after complete remission is achieved. Always indicated, even if no tumor cells are detected after induction therapy. Duration: several months. Medium doses. ALL regimen: variable drug regimens, such as alkylating agents, anthracyclines, methotrexate.
4. Maintenance therapy (goal: maintaining remission)
   Duration: up to 24 months. Low doses. ALL regimen: may include methotrexate, vincristine, glucocorticoids.

B. Preventive (prophylaxis) CNS treatment

• Intrathecal chemotherapy: chemotherapeutic therapy administered directly into the subarachnoid space via spinal tap or a device placed under the scalp.
• Indicated for all children to prevent meningeal leukemia (even if no CNS involvement is detected).
• CNS radiotherapy: only if the intrathecal chemotherapy is not working.

C. Allogeneic stem cell transplantation.
Indication: poor prognostic factors (e.g., unfavorable cytogenetics) or patients who do not achieve remission through chemotherapy (often not used if over 65).

D. Supportive treatment:

• Neutropenia+fever=antibiotics
• PCP (Pneumocystis jirovecii) prophylaxis with TMP-SMX in all neutropenic patients.
• Mucositis prophylaxis with local antimycotics.
• Herpes simplex prophylaxis with acyclovir.
• Colony-stimulating factor administration can be considered for febrile neutropenia.
• Moreover, anemia and thrombocytopenia must also be compensated by RBC transfusion and PLT transfusion if indicated.

Question 9

Name some common chemotherapy agents in ALL.

Answer 9

Standard regimen includes:
Vincristine
Glucocorticoids
Cyclophosphamide
Doxorubicin
L-asparaginase

Question 10

How many percent of children achieve remission after chemotherapy?

Answer 10

85%

Question 11

What is prognosis of ALL?

Answer 11

5-year survival rate following treatment:

ALL: generally better than with AML (varies from ∼ 20% in elderly patients to ∼ 80% in children and adolescents).