Acute Lymphoblastic Leukaemia (ALL)

Acute lymphoblastic leukaemia (ALL) is a malignant transformation of a clone of cells from lymphoid progenitor cells. The majority of cases are of B-cell origin, but it can also arise from T-cell precursors. Lymphoid precursors proliferate and replace the normal cells of the bone marrow and blasts spill into the peripheral circulation. It can be distinguished from other malignancies of lymphoid tissue by the immunophenotype of the cells. Cytochemistry and cytogenetic markers are also used to classify the malignant lymphoid clone.

• There are 550 new diagnoses of ALL per year in England, Scotland and Wales, with a standardised incidence rate of 1 per 100,000 general population pa (based on data from 1983-93).¹
• ALL represents 12% of all leukaemia (but 80% in children).²
• It is the commonest cancer in children.
• Peak age of incidence occurs between 2 and 4 years old, decreasing to become a much rarer disease of adulthood. A smaller peak occurs in people over 50 years.
• Equal sex ratios in children, male preponderance in adults.

Aetiology

Many different theories exist but few causal links have been firmly established. Interactions (e.g. environment-genetic, environment-infection) are likely to be important and a sequence of 'hits' may be required for malignant transformation.

• Genetic factors:³
  • ALL occurs is concordant in 25% monozygotic twins within a year of the diagnosis of the first twin.
  • Among dizygotic twins, there is fourfold increase in risk of leukaemia compared to the general population.
  • Patients with trisomy 21 have a 20 fold risk of developing ALL compared to the general population and other disorders with excessive chromosomal fragility are also associated with higher risks (e.g. Fanconi anaemia, ataxia-telangiectasia).
  • 60-70% of adults and about 80%of children have identifiable cytogenetic abnormalities at diagnosis.
• Environmental factors:
  • Leukaemia in adults does appear to be related to high doses of radiation (based on studies following survivors of atomic bomb explosions, other exposures such as the Chernobyl accident and therapeutic radiotherapy) but the position with regard to low doses seems less clear.⁴
  • There is no evidence that non-ionizing radiation is a risk factor for ALL in children and concern about proximity to power lines or mobile telephone masts is without supporting evidence.¹
  • Other suggested environmental risk factors (e.g. hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use) have been found to be weakly and inconsistently associated with ALL.⁵
  • Establishing environmental risk factors is difficult due to problems confirming and quantifying exposure, lack of a prospective cohort, confounding variables etc.
• Infection:⁶
  • The peak age of infection reflects a developmentally immature immune system. Babies who attend day care appear to have a decreased risk of developing ALL. This has been attributed to their earlier routine exposure to infection and increased immunological 'maturity'.⁷
  • Viral aetiologies have been shown for other cancers e.g. EBV and Burkitt's lymphoma.
  • Some studies suggest a seasonal variation in birthdate of patients or diagnosis.
  • Excess of ALL in rural, potentially immunologically naive communities with 'outbreaks' triggered by influx of new population (the population mixing theory).⁵

Usual presentation is with symptoms due to direct infiltration of organs or from the decreased production of normal marrow cells.

Symptoms

• Fatigue, dizziness and palpitations from anaemia
• Severe and unusual bone and joint pain
• Recurrent and severe infections due to neutropenia (oral, throat, skin, perianal infections commonly)
• Fever without obvious infection (but infection should be assumed)
• Left upper quadrant fullness and early satiety due to splenomegaly (10-20%)
• Dyspnoea (due to anaemia or large mediastinal mass in those with T-cell tumours)
• Respiratory distress and altered mental status due to large numbers of blasts in the peripheral circulation (rare presentation)
• Haemorrhagic or thrombotic complications due to thrombocytopenia or DIC (e.g. menorrhagia, frequent nose bleeds, spontaneous bruising)

Signs

• Pallor
• Tachycardia and a flow murmur
• Non-specific signs of infection
• Petechiae (due to thrombocytopenia), may progress into purpura or ecchymoses (with DIC)
• Abdominal distention due to hepatomegaly and splenomegaly
• Lymphadenopathy
• Testicular enlargement
• Gum hypertrophy
• Leukaemia cutis⁸
• Cranial nerve palsy (especially VI, III, IV and VIII) in mature-B cell ALL

Primary healthcare professionals need to be aware that haematological cancer can present with a variety of symptoms with a wide differential, should be prepared to investigate accordingly and urgency of referral should reflect the severity of the symptoms and signs, and findings of investigations.⁹

• Infections e.g. EBV, Parvovirus B19
• Myeloproliferative or lymphoproliferative disorders
• Myelodysplasia
• Aplastic anaemia
• ITP
• Lymphoma
• Metastatic cancer
• Other cancers of childhood e.g. neuroblastoma, rhabdomyosarcoma
• Osteomyelitis
• Juvenile chronic arthritis

Blood tests

• Full blood count:
  • Anaemia is usual and Hb may be below 5 g/l.
  • Thrombocytopenia is also usual, to varying degrees.
  • WBC may be high, normal or low but there is usually neutropenia.
• Blood film is likely to show blast cells.
• Clotting: DIC may occur and this produces an elevated prothrombin time, reduced fibrinogen level and the presence of fibrin degradation products.
• Lactic dehydrogenase levels are usually raised and rapid cell turnover may raise uric acid.
• Liver and renal function must be checked before initiating chemotherapy.
• If fever is present appropriate steps should be taken to identify and treat infection e.g. blood cultures.

Radiology

• CXR may show pneumonia, a mediastinal mass or lytic bone lesions.
• Testicular ultrasound if testes enlarged on examination.
• ECG, ECHO and/or multiple gated acquisition (MUGA) scan prior to use of anthracyclines (due to cardiotoxicity).

Specialist haematology, immunology & genetic tests

• Bone marrow aspiration and biopsy - WHO classification requires that 20% or greater amount of blasts in bone marrow and/or peripheral blood for the diagnosis of ALL.
  
  
  
• Immunophenotyping helps reveal the subtype. Positive confirmation of lymphoid rather than myeloid origin should be sought by flow cytometric demonstration of lymphoid antigens:
  1. B-lineage ALLThe precursor nature of the cells is established by demonstrating lack of surface Ig, the presence of nuclear Tdt and sometimes the expression of CD34. Subclassification is as follows:
     • Pre-pre B-ALL: CD19 CD10- cytoplasmic mu heavy chain negative.
     • Common ALL: CD19 CD10 cytoplasmic mu present in <20% of cells
     • Pre B-ALL: CD19 CD10 cytoplasmic mu present in >20% of cells
     • Blasts of all subgroups will express cytoplasmic CD22 and CD79b.
     • Pre pre-B ALL blast cells lack expression of CD10.
  2. T-lineage ALL
     The precursor nature of the cells is established by demonstrating Tdt and sometimes CD34 positivity and the lack of surface TCR/CD3. T-cell lineage is demonstrated by the expression of CD7 and/or CD1a. Expression of the other pan-T cell markers is variable.

The French-American-British (FAB) Classification is:

• LI - small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm. This subtype represents 25 to 30% of adult cases and 85% of paediatric cases.
• L2 - large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large. This is the commonest subtype at 70% of adult cases but 14% of paediatric cases.
• L3- large and homogeneous cells with cytoplasmic vacuolisation that often overlies the nucleus as the most prominent feature. This is just 1 to 2% of adult cases.

The WHO has proposed that this classification be abandoned because the L1 and L2 morphologies do not predict immunophenotype, genetic abnormalities, clinical behaviour or prognosis.Instead, classification should be as either precursor B lymphoblastic leukaemia or as precursor T lymphoblastic leukaemia. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia.¹⁰

Treatment is divided into induction, consolidation (or intensification) and maintenance (or continuation) therapies, CNS prophylaxis as well as management of relapse.

General supportive treatment

• Replacement therapy of blood cells may be required - pre-existing deficiency due to ALL can be profoundly aggravated by chemotherapy.
• Growth factors may be used to alleviate profound myelosuppression e.g. granulocyte-colony stimulating factor (G-CSF) during induction was associated with faster recovery of neutrophils, platelets and a shorter hospital stay.¹²
• Antibiotics and anti-fungal agents may be required to treat opportunistic infection.
• Allopurinol is often required during induction therapy to control uric acid levels.
• A central venous catheter is usual given the frequent requirements for venous access.
• To reduce the risk of infection, uncooked vegetables and raw/undercooked meat should be avoided.

Remission induction

The goals of induction therapy are:

1. To eliminate more than 99% of the initial burden of leukaemic cells
2. Rapid restoration of normal haematopoiesis
3. To restore previous performance status

Since the 1950s, improvements in chemotherapy and supportive care have resulted in complete remission rates of about 98% for children and 85% for adults. This is in contrast to mature B-cell ALL (an unusual variant, occurring in 5% adult ALL) - with current conventional regimes, only 30 to 40% of these patients gain complete remission and few survive long-term. Minimal residual disease assessment using PCR based strategies appear to be able to predict relapse although they are not yet in routine clinical use.
Current induction treatment phases usually consists of quadruple therapy, given over the course of 4 to 6 weeks:

• Vincristine
• Glucocorticoid (prednisone, prednisolone or dexamethasone)
• Anthracycline
• L-asparaginase

The exception is children with standard-risk ALL for whom such intensive induction therapy may actually increase morbidity and mortality.
Imatinib (a tyrosine kinase inhibitor) has also been used as a single agent or part of combination therapy to induce or consolidate remission. It has been useful extending disease-free survival and improving quality of life, particularly in elderly patients with ALL, but its impact on cure rates remains unclear.^13,14

Consolidation

Once normal haematopoiesis is achieved, patients can undergo maintenance therapy.
Common regimens in childhood ALL include:

• High-dose methotrexate with mercaptopurine
• High-dose asparaginase over an extended period
• Reinduction treatment (a repetition of the initial induction therapy in the first few months of remission).

Those with high risk or very high risk ALL may receive all of these treatment.

Maintenance

Attempts to shorten duration of chemotherapy to 12 to 18 months have produced poor results in children and adults so in most current trial work, patients are treated for two years or more. Maintenance usually consists of weekly methotrexate and daily mercaptopurine. Oral mercaptopurine should be given in the evening and not taken with milk or milk products.

CNS prophylaxis^15,16

Patients with ALL frequently have meningeal leukaemia at the time of relapse (50-75% at one year in the absence of CNS prophylaxis) and a few have meningeal disease at diagnosis (<10%). Cranial irradiation causes acute and late complications (secondary cancers, neurocognitive deficits, endocrinopathy) so has largely been superseded by intrathecal (methotrexate, ara-C, steroids) and high-dose systemic chemotherapy (methotrexate, ara-C, L-asparaginase) except in patients at very high risk of relapse. It is possible to stratify risk and tailor treatment accordingly. CNS relapse risk factors include:

• High-risk genetic factors
• T-cell immunophenotype
• Large leukaemia-cell burden
• Presence of leukaemia cells in the CSF

Stem cell transplantation (SCT)

SCT allows intensification of chemo and radiotherapies as it replaces destroyed stem cells.Adult patients receiving an allogenic transplant obtain a 45-75% long-term disease-free survival rate compared to 30-40% in those only receiving chemotherapy (note, data is difficult to interpret as highly selective criteria determine suitability for transplant and numbers are typically small in studies).¹¹Haemopoietic stem cells are found in:

• Bone marrow
• Peripheral blood stream
• Umbilical cord blood

Bone marrow transplants can be allogenic (sibling donor, HLA matched) or autologous (own peripheral stem cells harvested and 'purged' of cancerous cells). However, in most studies, autologous transplants have been found to be inferior to allogenic ones.
Sadly HLA-matched relatives are only available to about 25% of patients, and the chance of HLA matching an unrelated donor is smaller and dependant on the size of volunteer donor registries.
Optimum timing of SCT is still under study: children usually receive it at the time of their first relapse and adults (because of their poorer prognosis) in their first complete remission.

Treatment of relapse¹⁷

Relapse has a very poor prognosis. Most patients are referred for trial 'salvage' therapies .
Factors predicting a good outcome after salvage therapy were:

• Young age
• Short duration of first remission

Prevention of recurrence is the best strategy for long-term survival in ALL.

Most complications that arise are iatrogenic, due to the toxicity of the therapies. Acutely:

• Key risks are haemorrhage and infection even with blood replacement therapy. Any fever in a neutropaenic patient must be referred immediately back to the unit responsible for care.
• Tumour lysis syndrome, especially in children. Uric acid, phosphate and potassium are raised and calcium is low. Treat with alkaline intravenous fluids to aid renal excretion of these products. Electrolyte status should be closely monitored.
• Stroke from sinus venous thrombosis occurs in about 1 child in 200 but prognosis seems good.¹⁸
• Failure of the leukaemia to respond to chemotherapy usually means that they do not respond to other chemotherapy.
• Graft-versus-host disease with allograft stem cell transplant (can also occur as a chronic condition).

Longer term complications include:

• Cardiomyopathy, arrhythmias
• Lung fibrosis
• Growth delay,¹⁹ hypothyroidism, infertility
• Secondary malignancies^20,21
• Psychosocial effects, impacts on education and occupation^22,23

Increasingly clinical protocols are being developed to reduce side-effects without sacrificing survival benefits. Drugs with carcinogenic or major organ-damaging effects are being reduced in dose or avoided and pre-conditioning therapies investigated, for example, the use of iron-chelating agents to avoid anthracycline-induced cardiotoxicity. Pharmacogenetics is also being used to predict how patients will respond to treatment.²⁴

Prognosis is very much better in children than in adults, the exception being infant ALL which carries a bad prognosis.²⁵
Patients can be divided into 3 groups on the basis of risk:

1. Good prognosis involves:
   • No adverse cytogenetics
   • Under 30 years old,
   • Total WBC count of less than 30x10⁹/l
   • Complete remission obtained within 4 weeks
2. Bad prognosis occurs with:
   • Adverse cytogenetics [(t9;22), (4;11)]
   • Over 60 years old
   • Precursor B-cells with WBC count over 100x10⁹/l
   • Failure to achieve complete remission within 4 weeks
3. Those who do not fit into either of those categories have intermediate prognosis.

A 10 years follow up of adults found that nearly 80% achieved complete remission but the median duration of remission was 20 months with median survival of 21 months. 6 years seemed to be the critical point to indicate cure and at 10 years 25% appeared to be long term survivors.²⁶ Early response to chemotherapy seems to be a good prognostic indicator in both adults and children.²⁷ An extensive review found that although children could obtain remission rates of up to 100% that disease free survival at 10 years was 63% for children and 25 to 35% for adults.² Adolescents have a prognosis between that of children and adults but children under 1 have a cure rate of only about 30%.

There are no widely accepted preventative strategies for ALL. Some studies have suggested that breast-feeding confers protection for childhood ALL but this remains controversial.²⁸