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).

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.