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Acute lymphocytic leukaemia

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
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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