Pathophysiology

ALL is a malignancy of immature lymphoid haematopoietic cells, resulting in production of lymphoid blast cells.

 

The WHO classifies ALL into B cell type and T cell type. 85% of cases are B-cell ALL.(1)

 

Epidemiology

ALL is the most common malignancy in children, with a median age of 3.5 years.

It rarely occurs in adults, with a peak in 15-24 year olds, and in people >80 years old. Elderly patients with ALL have a poorer prognosis.(1)

 

Risk Factors

Certain conditions carry an increased risk of ALL, including Down’s Syndrome, Klinefelter syndrome, and Fanconi syndrome.(1)

 

Signs/Symptoms

Because leukaemic blast cells accumulate in the bone marrow, the production of healthy red blood cells, white blood cells, and platelets is reduced, resulting in bone marrow failure. Patients present with symptoms of anaemia, thrombocytopenia, infection as a result.

• Anaemia - palpitations, lethargy, fatigue, dyspnea, pallor

• Infection - chest, mouth, skin, perianal, fever

• Thrombocytopenia - easy bruising, bleeding - petechiae, menorrhagia, epistaxis

 

ALL can spread to the Central Nervous System, which can present with cranial nerve palsies, or meningism. Infiltration in organs can result in hepatomegaly, splenomegaly, and orchidomegaly (enlargement of the testis).

 

B cell ALL may cause abdominal lymphadenopathy, while T cell ALL tends to cause mediastinal lymphadenopathy.

 

If the blast count is extremely high, the accumulation of these white cells can obstruct blood and oxygen delivery to organs, resulting in symptoms of “leucostasis” such as confusion, retinal hemorrhages, and diffuse pulmonary infiltrates seen on chest imaging, and hypoxia.(1)

 

Investigations

 

 

 

 

 

 

 

 

 

 

 

 

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Management

Supportive treatment:

• broad spectrum antibiotics, anti-fungals for infection prophylaxis

• if leucostasis then may need leucopharesis

• RBC and platelet transfusions as needed

• hydration, allopurinol to prevent Tumor Lysis Syndrome(1) 

 

Chemotherapy: delivered through central venous catheter.

Consists of 4 stages:

1. Remission induction - aim to achieve complete remission (ex. vincristine, prednisolone, daunorubicin/doxorubicin and aspariginase)

2. Consolidation therapy - reduce the risk of relapse (ex. methotrexate, cytarabine)

3. CNS Prophylaxis - Intrathecal chemotherapy to reduce risk of CNS relapse (ex. IT methotrexate)

4. Maintenance therapy - ongoing oral and IV chemotherapy for 2 years in girls, and 3 years in boys(1)

 

Stem Cell Transplant

All patients with Philadelphia chromosome positive ALL in 1st complete remission are offered an allogenic stem cell transplant (if they meet eligibility criteria).

 

Patients with high risk disease (determined by cytogenetics) are offered transplant if they relapse after 1st complete remission.

 

New Emerging Therapies

CAR-T cell therapy

Chimeric Antigen Receptor T cell therapy is a a growing form of individualized cancer treatment. The patient’s T cells are modified so that they express a receptor specific to the tumor antigen. These specially modified T cells are then re-introduced into the patient. It has promising results in ALL.(2) It is available on the NHS for children and young people with B cell-ALL. It has also been approved for the treatment of other haematological disorders - diffuse large B cell lymphoma which has not responded to 2 or more treatments.(3)

 

Blinatumomab

This is a monoclonal antibody drug. It binds to both CD3 positive cytotoxic T cells and CD19 positive B cells. This allows killing of the CD19 positive malignant B cells in B cell-ALL.(4) It is used in philadelphia chromosome negative precursor B-ALL which is refractory to other treatments, or in complete remission with minimal residual disease. (5,6)

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References

1. Provan D, Dokal I, Vos J, Baglin T. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015.

2. Miliotou, Androulla N., and Lefkothea C. Papadopoulou. “CAR T-Cell Therapy: A New Era in Cancer Immunotherapy.” Current Pharmaceutical Biotechnology, vol. 19, no. 1, 2018, pp. 5–18., doi:10.2174/1389201019666180418095526.

3. NHS England. CAR T Therapy. Available at: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/.

4. Blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia. National Institute for Health and Care Excellence 2017 2017,.

5. Blinatumomab for treating acute lymphoblastic leukaemia in remission with minimal residual disease activity. National Institute for Health and Care Excellence, 2019.

6. Lee KJ, Chow V, Weissman A, Tulpule S, Aldoss I, Akhtari M. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. Therapeutics and clinical risk management 2016;12:1301-1310.

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