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Definition
Malignant clonal disease that develops when a lymphoid progenitor cell becomes genetically altered through somatic changes and undergoes uncontrolled proliferation
This progressive clonal expansion eventually leads to ALL
Characterised by early lymphoid precursors replacing the normal haematopoietic cells of the bone marrow and further infiltrating various body organs
Risk Factors
Strong
Children less than 6 years of age
Age in mid to late 30s
Age in mid 80s
Weak
Genetic factors
Family history of ALL
Viruses
Environmental factors
History of malignancy
Treatment with chemotherapy
Male gender
White population
Differential diagnosis
Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable
Skin infiltration and gum hypertrophy are more common in AML
CNS, testis, and mediastinal involvement are more common in ALL
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly
Parvovirus may present with anaemia
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.
Clinical findings of clubbing or Horner's syndrome.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Rhabdomyosarcoma
Disseminated disease can mimic ALL
May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
Epidemiology
Worldwide, the incidence of ALL is projected to be between 1 and 4.75 per 100,000 people
This represents 12% of all leukaemia cases diagnosed
A higher incidence is seen in males compared with females and in white people compared with black people.
Adult acute leukaemias are rare diseases
In the US, about 1,600 new cases are diagnosed every year
This represents 20% of adult leukaemias and 1% to 2% of all cancers
The prevalence of ALL in the US is 1.5/100,000 in white people and 0.8/100,000 in black people
The male-to-female ratio is 1.4:1.0.
In children, leukaemia is the most common malignancy diagnosed
In Europe, ALL represents approximately 75% of all leukaemias diagnosed in children under 14 years
It is more prevalent in western European countries than eastern European countries.
Age:
First peak in children younger than 5 years of age (5.3/100,000)
Incidence of ALL decreases until a second peak around the age of 35 years (2/100,000)
Third peak at the age of 80 to 84 years (2.3/100,000)
Aetiology
The cause of ALL is unknown
Certain factors have been noted to contribute to the development of ALL:
Genetic factors
Diagnosis of ALL in a monozygotic twin is associated with a 20% to 25% likelihood that the second twin will also develop ALL within 1 year
ALL is associated with other genetic disorders:
Trisomy 21
Klinefelter's syndrome
Inherited diseases with excessive chromosomal fragility such as Fanconi anaemia, Bloom's syndrome, and ataxia-telangiectasia
Environmental factors
Exposure to atomic bomb explosions
Radiation
Smoking
Use of hair dyes
Employment in electrical occupations
Viral infections
Have been suggested as a possible cause of ALL
Folate metabolism polymorphisms has also been suggested
Clinical features
Lymphadenopathy
Involvement of the lymphatic nodes is common in ALL, and enlarged lymph nodes are frequently the initial cause for seeking medical attention by the patient
Lymphadenopathy is classically generalised and the enlarged nodes are painless and freely movable
Hepatosplenomegaly
This is common at the time of initial diagnosis
These organs tend to be diffusely enlarged due to infiltration by leukemic lymphoblasts
Pallor, ecchymoses, or petechiae
The most common findings on physical examination are pallor due to anaemia and ecchymoses or petechiae due to thrombocytopenia
Fever
Many patients present with fever and symptoms of infection related to their immune suppressive state
Fatigue, dizziness, palpitations, and dyspnoea
Many patients have fatigue, dizziness, palpitations, and dyspnoea
These symptoms are caused by bone marrow infiltration, anaemia, or systemic inflammatory cytokines
Epistaxis, menorrhagia
These symptoms are caused by bone marrow infiltration, anaemia, or systemic inflammatory cytokines
Papilloedema, nuchal rigidity, and meningismus
CNS infiltration by the leukemoid cells presents as papilloedema, nuchal rigidity, and meningismus
Although the meninges are the primary site of disease, the brain parenchyma and spinal cord may be involved less commonly
Focal neurological signs
In some cases, the cranial nerves (mainly the seventh, third, fourth, and sixth) may be an isolated site of CNS leukaemia at the time of diagnosis or relapse
Painless unilateral testicular enlargement
ALL may involve the testicles presenting with painless unilateral enlargement
Although uncommon at the time of initial diagnosis, recurrent ALL frequently involves the testes, and bilateral wedge biopsy is warranted in such a case
Renal enlargement
Renal enlargement is common at the time of initial diagnosis
This is caused by infiltration of the renal cortex by leukemic blast cells
Despite that, renal function is rarely affected except in the case of urate nephropathy
Bony pain
Related to bone marrow infiltration by blast cells
Abdominal pain
Mainly left upper quadrant in location and is caused by splenomegaly
Mediastinal or abdominal mass
The findings of stridor, wheezing, pericardial effusion, and superior vena cava syndrome may be associated with mediastinal masses caused by T-lineage ALL.
Mature B-cell ALL may initially present as a palpable large abdominal mass from a rapidly proliferating tumour
Pleural effusion
Pleural effusions should be tapped and samples sent for cytology and immunophenotyping
Pleural fluid analysis may yield the diagnosis without the need for an invasive procedure
Skin infiltrations
Caused by infiltration by leukaemic blast cells
Pathophysiology
Normal lymphoid cell populations undergo diverse clonal rearrangements of their IG or T-cell receptor (TCR) genes
Cells that successfully complete these genetic changes undergo a highly regulated process of proliferation that results in the production of normal B and T cell populations
Genetic alteration of a lymphoid progenitor cell through somatic changes results in uncontrolled proliferation and clonal expansion
The leukemic blasts infiltrate the bone marrow and other organs, thus disrupting their normal function and eventually leading to the development of ALL
The leukemic blasts represent a clonal expansion of a single cell
This has been demonstrated by cytogenetics, glucose-6-phosphate dehydrogenase characterisation, and analysis of antigen-receptor gene rearrangements and X-linked restriction fragment-length polymorphisms
The leukemic cells duplicate most of the features of normal lymphoid progenitor
Genetic abnormalities in ALL include microscopically evident chromosomal rearrangements or lesions detectable only by molecular analysis
In addition, chromosomal translocations or aneploidy are found in 75% of ALL cases
These translocations are commonly recurring and are rarely classified as random translocations
Molecular abnormalities seen in ALL can be classified according to the functional consequence of oncogenic mutation
Activation of the ABL protein kinase via rearrangement with the BCR gene is an example of a mutation that results in a proliferative advantage
The most common cytogenetic abnormality in adult ALL results from chromosomal translocation t(9;22)(q34;q11), the Philadelphia chromosome
Other gene rearrangements may result in loss or gain of function mutations involving transcription factors that play a role in haematopoietic development
An example of such gene rearrangement is the t(12;21)(p13;q22) chromosomal translocation that juxtaposes the TEL genes
Other mechanisms of cancer formation involve loss or inactivation of tumour-suppressor genes via deletions and gene rearrangements
Examples of such mechanisms involve p16(INK4A) and p53
Other genetic features:
FLT3 and NOTCH1 have been identified as genes mutated in MLL/hyperdiploid and T ALL, respectively
CREBBP mutations seen in 18% of relapsed ALL and may confer resistance to therapy
PAX5 gene is mutated in up to 30% of paediatric patients with ALL
IKZF1 mutations may be a predictor of relapse
PHF6 mutations are seen in 38% adult T-ALL samples
CDKN2A mutations are seen in 42% of cases of T-ALL
Much of this data has yet to lead to risk stratification or alternative therapies
Investigations
FBC with differential
Over 90% of patients with ALL have clinically evident haematological abnormalities at the time of initial diagnosis
Normocytic normochromic anaemia with low reticulocyte count is present in 80% of patients
Leucocytosis is found in 50% of patients
In one quarter of the patients, WBC is greater than 50 x 10^9/L (50,000/microlitre), thereby indicating a poorer prognosis.
Despite the elevation in WBC, many patients have severe neutropenia (<500 granulocytes/mm^3), thus placing them at high risk of serious infections
Thrombocytopenia is common, affecting 75% of patients
Peripheral blood smear
The finding of lymphoblasts on peripheral blood smear is not sufficient to establish the diagnosis of ALL, and bone marrow biopsy is required
Serum electrolytes
The degree of uric acid elevation reflects the extent of tumour burden
Hypercalcaemia may be caused by bony infiltration or ectopic release of a parathormone-like substance
Phosphorus may be elevated due to ineffective leukopoiesis or as a result of chemotherapy-induced tumour lysis
Hyperkalaemia may also occur as a result of extensive leukemic cell lysis
Renal function
Important baseline investigation
Urea may be normal or elevated
Liver function
Important baseline investigation
Liver enzymes may be normal or elevated
Lactic dehydrogenase
Important baseline investigation
May be elevated
Coagulation profile
Prothrombin time, partial thromboplastin time, and levels of fibrinogen and D-dimers should be measured in any patient with bleeding or petechiae
Results are variable
Bone marrow biopsy or aspiration
Morphology, cytochemical stains, immunophenotyping, chromosome analysis, fluorescence in situ hybridisation (FISH), PCR for t(9;22), and other molecular studies can be performed
Slides should be stained with either Wright or Giemsa stain
The diagnosis of ALL is made when at least 30% lymphoblasts (French American British classification) or 20% lymphoblasts (WHO classification) are present in the bone marrow and/or peripheral blood
Furthermore, the slides should be stained with myeloperoxidase (or Sudan black) and terminal deoxynucleotidyl transferase (TDT)
Flow cytometry and cytogenetics should be performed
Approximately 15% of patients with ALL have a t(9;22) translocation (Philadelphia chromosome)
Other chromosomal abnormalities may also occur, such as t(4;11), t(2;8), and t(8;14)
Immunophenotyping (on bone marrow, or peripheral blood if cell count is raised)
Normally, leukemic cells exhibit markers of one cell type
Rarely, simultaneous expression of lymphoid and myeloid markers occurs in ALL
Monoclonal antibodies allow determination of whether leukaemia is lymphoid or myeloid in origin
Thiopurine methyltransferase (TPMT) phenotype
Affects the pharmacokinetics of mercaptopurine
Cytogenetics
Cytogenetics abnormalities are common in ALL and may be of prognostic and therapeutic significance
BCR/ABL molecular studies
May confirm the presence of the Philadelphia chromosome and therefore require the use of a tyrosine kinase inhibitor with chemotherapy
Complementary test to cytogenetics
HLA-typing
HLA-typing is performed in order to locate suitable donor for stem cell transplantation
Class I typing also allows HLA-matched platelets to be provided in the event of platelet refractoriness
CXR
Mediastinal lymphadenopathy is seen as a widened mediastinum
Lumbar puncture
Lumbar puncture for cytology is done if there is evidence of focal neurology or meningism (this should only be done once raised intra-cranial pressure has been excluded)
All protocols include an intrathecal chemotherapy component.
This initial LP is classified as
CNS1: negative
CNS2: non-traumatic, ≤5 WBC/microL CSF with blasts
CNS3: non-traumatic, >5 WBC/microL CSF with blasts
TLP(+): traumatic (>10 red cells/microL or visibly blood stained) with blasts
TLP(-): traumatic without blasts
The outcome of CNS1, CNS2, and TLP(-) is similar
TLP(+) has an inferior event-free survival and CNS3 has an even poorer outcome
Pleural tap
Pleural effusions should be tapped and samples sent for cytology and immunophenotyping
A mediastinal biopsy should be avoided if possible
A marrow or pleural fluid analysis may yield the diagnosis without the need for an invasive procedure
MRI brain
CNS imaging should be performed in the event of lowered conscious level, meningism, or focal neurology
CT thorax
The findings of stridor, wheezing, pericardial effusion, and superior vena cava syndrome may be associated with mediastinal masses caused by T-lineage ALL
CT thorax should be performed in the presence of a widened mediastinum
Minimal residual disease (MRD) molecular samples
Important baseline investigation that enables depth and speed of remission to be assessed
This is prognostically important and may guide therapeutic decisions
The exact test depends on patient
Management
a) conservative
Semen cryopreservation should be offered to male patients post-puberty
Female patients should be discussed with the fertility centre, but options are limited
Ovarian wedge biopsy is a research procedure and there are risks of reintroducing tumour at reimplantation
There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation
Norethisterone or a similar product should be given to women of menstruating age in order to suppress menses during the period of severe thrombocytopenia
Leukapheresis is indicated in cases with symptomatic leucostasis prior to initiation of therapy
b) medical
Induction chemotherapy
Standard induction therapy for ALL includes prednisone (or dexamethasone), vincristine, anthracyclines, and/or L-asparaginase (crisantaspase in the UK)
Other drugs, such as cyclophosphamide, cytarabine, mercaptopurine, or intrathecal methotrexate may be added as part of early intensification protocols
Patients should be closely monitored for tumour lysis syndrome after the start of therapy
CNS prophylaxis
All patients receive CNS prophylaxis
Prophylactic treatments of CNS leukaemia may result in acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions
Tyrosine kinase inhibitors
E.g., imatinib and dasatinib
Target the BCR/ABL fusion protein associated with Ph+ ALL
Their use alongside chemotherapy has been shown to improve the morphological and molecular complete remission (CR) rates and ensure that more patients proceed to allograft
Fluid therapy + allopurinol or rasburicase
There should be sufficient fluid intake to guarantee urine output of 100 mL/hour, in order to prevent dehydration, electrolyte abnormalities, and urate nephropathy during induction therapy
In addition, patients should receive allopurinol to reduce the formation of uric acid or rasburicase to catalyse the breakdown of uric acid
Prophylactic antimicrobials
Most infections are caused by gram-negative micro-organisms, gram-positive bacteria (mostly staphylococci), Pneumocystis jiroveci, and, less commonly, invasive fungal infections or viral infections
Haematopoietic growth factor
Prophylactic use of colony-stimulating factors (CSF) is indicated in patients at high risk (>20%) of developing febrile neutropenia
Platelet + red cell transfusions
Platelet transfusions should be given when indicated in an actively bleeding patient or those with platelet counts less than 10 x10^9/L
In addition, febrile patients and those with bleeding tendency should receive platelet transfusion at platelet counts less than 20 x10^9/L
Consolidation chemotherapy
This is achieved by the use of high-dose chemotherapy, multiple new agents, or readministration of the induction regimens
The role of this treatment phase is to eliminate clinically undetectable residual leukaemia, hence preventing relapse and the development of drug-resistant cells
Consolidation therapy is based on cytarabine combined with anthracyclines, epipodophyllotoxins, or anti-metabolites
Stem cell transplant
Allogeneic stem cell transplantation (SCT) from sibling or unrelated donors or autologous SCT is now the major approach for intensive post-induction therapy in high-risk patients
The stem cells are obtained either from bone marrow or peripheral blood
c) surgical
n/a
Prognosis
With the current treatment modalities, outcome is heavily age dependent in adult ALL
For the age groups under 30 years, 30-60 years, and over 60 years, complete remission rates are 90%, 81%, and 52%, and overall survival at 3 years is 58%, 38%, and 12%, respectively
Younger patients with WBC less than 30 x 10^9/L (30,000/microlitre) and who respond to treatment within 4 weeks have the best prognosis
An individual’s risk depends on a variety of clinical and biological factors, including:
Age
There is no clear cut-off with regards to age
Children under 1 year and children over 10 years are deemed high risk
Adults over 30 to 35 years are deemed high risk, although the impact of age is a continuous variable
WBC at presentation
White count is also a continuous variable and the arbitrary cut-offs are over 30 x 10^9/L for B- and over 100 x10^9/L for T-cell ALL
Cytogenetic profile has been used to split patients up into risk groups:
very high: t(9;22), t(4;11), complex, low hypodiploid, near triploid, iAMP (intrachromosomal amplification of chromosome 21)
high: MLL other, -7 non-complex, t(1;19), del(17p)
intermediate: normal, low hyperdiploid, del(9p), other
standard: high hyperdiploid.
presence of extramedullary disease (e.g., CSF involvement)
speed of response (i.e., time to achieve a complete remission)
presence of minimal residual disease (MRD): a marker of adverse outcome.
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