Acute Lymphoblastic Leukaemia

Question 1

Acute lymphoblastic leukaemia is the most common malignancy of ….

Answer 1

Acute lymphoblastic leukaemia is the most common malignancy of childhood.

Question 2

Leukaemia refers to a group of malignancies that arise in the bone marrow. They are relatively rare but together are the 12th most common cancer in the UK, responsible for around 9,900 cases and 4,700 deaths a year.

Answer 2

Leukaemia refers to a group of malignancies that arise in the bone marrow. They are relatively rare but together are the 12th most common cancer in the UK, responsible for around 9,900 cases and 4,700 deaths a year.

Question 3

There are four main types of leukaemia

Answer 3

Acute myeloid leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)
Chronic myeloid leukaemia (CML)
Chronic lymphocytic leukaemia (CLL)

Question 4

Acute lymphoblastic leukaemia

Answer 4

ALL arises from a clone of lymphoid progenitor cells that undergo malignant transformation. Most are B-cell in origin though ALL may arise from T-cell precursors.

As clonal expansion occurs lymphoid precursors replace other haematopoietic cells in the bone marrow. With time, infiltration into other body tissues occurs.

Question 5

There are approximately … cases of ALL in the UK each year.

Answer 5

There are approximately 800 cases of ALL in the UK each year.

Question 6

ALL is rare accounting for less than 1% of all cancers and causing approximately 250 deaths in the UK each year. It may occur at any age but is more common …

Answer 6

ALL is rare accounting for less than 1% of all cancers and causing approximately 250 deaths in the UK each year. It may occur at any age but is more common in early childhood with incidence peaking in those aged 0-4.

Question 7

Aetiology and pathophysiology

ALL

Answer 7

ALL occurs due to the proliferation of malignant lymphoid progenitor cells in the bone marrow. Broadly it can be classified as:

B cell lineage (majority)
T-cell lineage

Question 8

Cytogenetic features

ALL

Answer 8

t(12;21): the most common translocation seen in ALL affecting children. Results in TEL-AML fusion gene.
t(9;22): known as the Philadelphia chromosome, seen in around 33% of adults and 2-5% of children. Associated with a poor prognosis. Results in BCR-ABL fusion gene.
t(4;11): common in infants < 12 months but rare in adults. Results in the MLL-AF4 fusion gene.
Hyperdiploid karyotype: seen in 30-40% of children, less common in adults.
Hypodiploid karyotype: may also be seen, associated with a poor prognosis.

Question 9

ALL Patients often present with a short history of features consistent with marrow suppression or lymphadenopathy

Answer 9

Anaemia:
Fatigue
Breathlessness
Angina
Neutropenia:
Recurrent infections
Thrombocytopenia:
Petechiae
Nose bleeds
Bruising

Question 10

Tissue infiltration - ALL

Answer 10

Lymphadenopathy
Hepatosplenomegaly
Bone pain
Mediastinal mass (may result in SVCO)
Testicular enlargement

Question 11

ALL

Lymphadenopathy and hepatosplenomegaly are common at diagnosis. Hepatomegaly and splenomegaly are seen in upwards of 60% of children at diagnosis. The enlargement itself may be noticed or cause anorexia or discomfort.

Answer 11

Lymphadenopathy and hepatosplenomegaly are common at diagnosis. Hepatomegaly and splenomegaly are seen in upwards of 60% of children at diagnosis. The enlargement itself may be noticed or cause anorexia or discomfort.

Question 12

ALL

May occur due to large numbers of white cells entering the bloodstream. Organ dysfunction may result due to impairment of flow through small blood vessels. Features include:

Answer 12

Altered mental state
Headache
Breathlessness
Visual changes

Question 13

What is the definitive diagnostic test in ALL?

Answer 13

Bone marrow aspiration and biopsy is the definitive diagnostic test.

Question 14

Bloods in suspected ALL

Answer 14

The majority of patients will have abnormal haematology labs at diagnosis. Anaemia and thrombocytopenia are common as is leucocytosis. Though the overall WCC may be elevated neutropenia is often seen.

Uric acid and LDH are non-specific markers of tumour burden. Electrolyte derangement may occur and can be multifactorial. Hypercalcaemia may result from the release of a PTH-like hormone or bony involvement.

Coagulation screen and DDIMER are important to evaluate for features of disseminated intravascular coagulation (DIC), a potential complication of ALL.

Question 15

Imaging in ALL

Answer 15

CXR: may demonstrate a mediastinal mass.

CT chest, abdomen and pelvis: assess for lymphadenopathy and organ involvement

CT/MRI head: in patients with symptoms indicative of neurological involvement or to exclude differentials.

Question 16

The following are high-risk factors for adult patients (ALL)

Answer 16

Age (worse with advancing age)
Performance status > 1
White cell count (> 30 for B-cell ALL, > 100 for T-cell ALL)
Cytogenetics
t(9;22) - Philadelphia chromosome
t(4;11)
Immunophenotype (pro-B/early and mature-T)
CNS involvement

Question 17

ALL is a rare condition with complex treatment protocols that differ depending on the patients age and underlying disease type.
Management?

Answer 17

Patients should be referred to a specialist haemato-oncology unit for specialist management. Most patients will be enrolled in a clinical trial as part of their treatment.

Treatment aims to halt disease progression and return normal marrow function. Chemotherapy represents the mainstay of treatment with stem cell transplant used in select patients.

Question 18

ALL
Patients are transferred to a specialist haemato-oncology unit. It is essential patients are cared for by appropriate medical specialists and nursing staff with access to HDU/ITU if required. Key aspects of management include:

Answer 18

Pre-phase therapy: patients may be commenced on steroids (at times with other medications), often in conjunction with allopurinol and IV hydration. This pre-phase helps reduce the risk of TLS. Rasburicase may be required depending on the risk of TLS.
Leucopheresis: not commonly used but may be required to reduce the white cell count, helps to mitigate the risk of TLS.
Supportive therapy: anaemia and thrombocytopenia may require treatment if severe. Neutropenia is common and G-CSF may be given.

Question 19

ALL

The aim of induction chemotherapy is to achieve complete remission or ideally complete molecular remission:

Answer 19

Complete remission (CR): leukaemia not seen in bone marrow, peripheral blood or CSF (less than 5% blasts in bone marrow).
Molecular complete remission (MolCR): as per CR, minimal residual disease not detectable by sensitive molecular probe.

Question 20

Maintenance therapy

ALL

Answer 20

This aims to reduce the risk of recurrence. Regimens normally include daily 6-mercaptopurine and weekly methotrexate though there is considerable variation.

Question 21

Complications

ALL

Answer 21

Patients (particularly after the commencement of chemotherapy) are at risk of neutropenic sepsis and tumour lysis syndrome.

Question 22

.. … syndrome: significant metabolic disturbances arising from the rapid breakdown of malignant cells, normally after therapy has been initiated. It should be anticipated and when appropriate prophylaxis may be given with close monitoring and HDU/ITU availability if needed.

Answer 22

Tumour lysis syndrome: significant metabolic disturbances arising from the rapid breakdown of malignant cells, normally after therapy has been initiated. It should be anticipated and when appropriate prophylaxis may be given with close monitoring and HDU/ITU availability if needed.

Question 23

…: characterised by fever and neutrophils < 0.5 (or expected to fall below 0.5). A medical emergency requiring early identification and management.

Answer 23

Neutropenic sepsis: characterised by fever and neutrophils < 0.5 (or expected to fall below 0.5). A medical emergency requiring early identification and management.

Question 24

SVCO: patients may present with features of … (e.g. dyspnea, facial swelling, cough) secondary to a mediastinal mass.

Answer 24

SVCO: patients may present with features of superior vena cava obstruction (e.g. dyspnea, facial swelling, cough) secondary to a mediastinal mass.

Question 25

Chemotherapy side-effects: depends on the therapy and intensity, can be early (e.g. mucositis, nausea and vomiting, hair loss) or late (e.g. cardiomyopathy, secondary malignancies)

Answer 25

Chemotherapy side-effects: depends on the therapy and intensity, can be early (e.g. mucositis, nausea and vomiting, hair loss) or late (e.g. cardiomyopathy, secondary malignancies)