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
- Small-cell lung cancer
- 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
- 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
Managementa) 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) surgicalPrognosis- 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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