Leukaemia

Original article by Shameena Tamachi and Tom Leach | Last updated on 23/1/2015
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Summary

Acute Leukaemias

  • Acute lymphoblastic leukaemia (ALL) is the most common type in children, primarily affecting 2 to 8 year-olds.  There is equal risk between males and females, while all other leukaemias occur more frequently among males
  • Acute myeloid leukaemia  (AML) in adults is about 4xs more common than ALL in the same population.  It may occur in children, but this is rare. Approximately 2/3s of AML patients are over 60
 

Clinical presentation

These usually represent bone marrow failure, and include the following:
  • Anaemiagenerally feeling tired, SOB on exercise, weakness
  • Bleeding and bruising – as a result of thrombocytopaenia
  • Infection – as a result of leukopaenia
  • Bone pain – as a result of bone marrow infiltration
 
Examination often is normal, but abnormalities may include:
  • Pallor
  • Fever – due to infection
  • Petechiae – these are little purple spots, about 1-2mm diameter caused by rupture of a small blood vessel
  • Lymphadenopathy – in lymphoblastic leukaemia
  • Hepatosplenomegaly – in lymphoblastic leukaemia
  • Violaceous skin lesions – AML
  • Testicular enlargement – ALL
  • Cranial nerve palsies ALL, but quite rare
 

Investigations

  • Blood count – ↓Hb; ↑WCC; ↓platelets
  • Blood film – blast cells nearly always seen; auer rods might also be seen, which are pathognomonic for AML; in ALL there are more likely to be large blast cells, i.e. these cells are smaller and more mature in chronic leukaemias
  • Bone marrow aspirate – ↓erythropoiesis; ↓megakaryocytes, i.e. platelet precursors; > 20% blast cells but may often approach 100%;
  • Following bone marrow aspirate the cells can undergo further testing:
    • The lineage of the tumour (myeloid or lymphoid) is confirmed by flow cytometry immunophenotyping.
    • Further tests to for genetic abnormalities
      • Fluorescent in-situ hybridisation (FISH) which examines chromosome number and translocations, importantly the Philadelphia chromosome (9;22 translocation present in 90% of CMLs), and
      • PCR sequencing for DNA mutations such as JAK-2 (95% of PV, ~50% of ET and myelofibrosis)
  • CXRthere may be mediastinal widening in T lymphoblastic leukaemia
 

Differentiating between ALL and AML

 
ALL
AML
Presence of auer rods in blood
None
Always present
Presence of lymphoblasts in blood
Always present
May or may not be present
Bone and joint pain
More common
Less common
Hepatosplenomegaly
More common
Less common
Organ infiltration
More common
Quite unusual
 

Management

The acute leukaemias are fatal within months if not treated; however, they are generally managed conservatively.  With palliative care, the life expectancy can extend to around a year.  Generally, ALL in children has the highest chance of being curable of all the acute leukaemias.
 
The aim of curative treatment is to destroy clonal cells without destroying normal stem cells, so that the latterwill be able to repopulate after clonal cell destruction.  There are three phases to treatment:
  • Remission induction through which the majority of the tumour will be destroyed by ‘induction chemotherapy’.  This will result in massive bone marrow hypoplasia.  
  • Remission consolidation is carried out if remission induction is unsuccessful; the remaining tumour will be attacked utilising further therapy.  The aim of this phase is to achieve complete remission (CR)*.
  • Maintaining remission. If both of the above treatment phases have been successful, then further therapy, given on an outpatient basis, may be required for up to 3 years.  After the 3-year period no further treatment will be offered but the patient will be closely observed. This is only the case in ALL,and is not thought to be of benefit in patients with AML.
 
Supportive care
This is the proper name given to the basic care given to both palliative and curative patients.  It involves the following:
  • Reducing symptoms of anaemia
  • Prevention/control of bleeding
  • Treatment of infection
 

Prognosis

The prognosis for ALL in childhood is very good.
  • Complete remission is obtained in almost all patients.
  • 80% will still be alive without recurrence after 5 years.
  • Failure of treatment occurs most commonly occurs in those with:
    • a high blast count
    • a T(9:22) translocation
  • The aforementioned factors related to failure increase in frequency with age.
  • The overall CR rate in children and adults is 70-80%.  Failure to achieve remission with first- line therapies carries with it a very poor prognosis.  
  • Most recurrences of the disease occur within 3 years, and recurrence is usually a very poor prognostic factor. CR can be obtained, but again there is likelihood of relapse.
 

Chronic Leukaemias

  • Chronic myeloid leukaemia (CML) is almost exclusively an adult disease, accounting for 14% of all leukaemias. The incidence is 2 per 100 000, being slightly higher in men, and the peak age of incidence is between 40-60 years. It is characterised by the presence of the Philadelphia (Ph) chromosome. CML progresses slowly.  If CML is not treated, death will generally occur within 3-4 years. CML affects the myeloid cells, i.e. basophils, neutrophils and eosinophils. 
The natural progression of CML is as follows: chronic phase → aggressive/accelerated phase → blast phase/crisis.
 
  • Chronic lymphocytic leukaemia (CLL) is the most common of all leukaemias. It occurs mainly in later life, and increases in frequency with older age. Median survival is 10 years, and this is often related to the severity of symptoms at presentation. CLL results from a progressive accumulation of functionally incompetent B lymphocyteshence the name!  Cytogenic and molecular abnormalities carry prognostic significance.
 

Clinical presentation

Many CML and CLL patients have no symptoms, but any of the following may be apparent: SOB due to anaemia, marrow failure and immunosuppression, splenic pain, weight loss, fever and sweats, lymphadenopathy, and hepatosplenomegaly.
CML usually presents in the chronic phase, whereas CLL is often asymptomatic and is discovered incidently.
 

Investigations carried out in CML and CLL

 
CML
CLL
Blood count
Hb low or normal; ↑ WBC; platelets low, normal or raised
 
Same as CML but WCC may be very high
Blood film
Neutrophilia; WBCs bigger, more mature and blast-like
↑lymphocytes, i.e. > 5x109/L
Bone marrow aspirate
↑cellularity
May be heavily infiltrated with lymphocytes
Cytogenetics
Ph chromosome in 97% of cases
13 q deletion; trisomy 12; mutated IgVH
Immunology
 
CD19/20 and CD5+ B cells
Coombs’ test
 
Positive if haemolysis is present
Leukocyte alkaline phosphatise
Usually reduced
 

Management

CML

Imatinib is a tyrosine kinase inhibitor that prevents the action of the BCR-ABL fusion protein, i.e.this is the abnormal protein produced by the Ph mutation.  It is the first-line treatment during the chronic phase.

  • 95% of patients will respond to the drug
  • 70-80% of these have no detectable BCR-ABL in the blood
  • This treatment can be continued indefinitely
  • The drug is usually well tolerated, but side effects can include nausea, headaches, rashes, cytopaenia, cramps, myelosupression; resistance can sometimes develop.
  • 18 months of a ~nib drug will completely eradicate the Ph mutation in 76% of patients 

Interferon-α is sometimes given to patients who don’t have the Ph mutation.
Stem cell transplantation (SCT) will cure approx 70% of patients.  However there is a risk of death from graft versus host disease, and infection.  

 
The use of SCT has declined since the advent of Imatinib,however it is still indicated in those with a poor response to the drug, i.e. those who do not have the Ph mutation.
 

CLL

Chlorambucil has been considered the drug of choice for first-line therapy of CLL, and when combined with prednisone, chlorambucil is associated with an initial response rate of 60-90% and a complete response in up to 20% of all patients.

More Information

Overview of haematological malignancies

The leukaemias, along with lymphomas and myelomas are a related spectrum of haematological malignancies. They are generally uncommon, but not rare, with the lymphomas being the 7th most common cancer in the United Kingdom.
Although the precise aetiology of all these diseases is unknown, it is thought to be multifactorial.
The way in which these diseases are classified is becoming increasingly complicated and diverse.
Treatment often involves immuno- and myelosuppression – which in itself can be life-threatening, but can sometimes be curative.
It is important upon disease onset to discuss with the patient whether a curative or palliative approach is more appropriate and the rationale for this.  Also, the possibility of treatment failure needs to be addressed at the outset, and not at any later point.
 

Epidemiology

  • Leukaemia is relatively rare, having an incidence of about 10 per 100 000
  • Just over half are acute in presentation
  • Males are more commonly affected than females; the ratios vary for different types of leukaemia, but are roughly 3:2 to 2:1
  • Chronic leukaemias generally occur in middle and old age
  • Acute leukaemias can occur at any age; acute lymphoblastic leukaemia is more common in childhood, whilst acute myeloid leukaemia most commonly occurs over the age of 50
 
The leukaemias can be classified as acute or chronic, and sub-classified as myeloid or lymphoid.  Thus, there are four classifications:
  • ALL – acute lymphoblastic leukaemia this is mainly a disease of childhood.  It is the most common malignancy of childhood.
  • AML – acute myeloid leukaemia
  • CLL – chronic lymphocytic leukaemiathis is mainly a disease of the elderly
  • CML – chronic myeloid leukaemia
 

Aetiology

Basically this is unknown, but several factors are thought to be involved:
  • Radiation – this can induce damage to hemopoietic precursors, and ALL, AML and CML are all seen in increased incidence in survivors of Hiroshima and Nagasaki, as well as in those treated with irradiation therapy.  X-rays of the foetus also increase the risk later in life.
  • Chemical and drugs – exposure to benzene can cause marrow damage.  AML occurs after damage with alkylating agents, e.g. melphalan.
  • Genetic factors – the incidence of leukaemia is increased in identical twins, and in syndromes of chromosomal aneuploidy,e.g. Down’s syndrome, Klinefeler’s syndrome.
  • Viruses – leukaemia is associated with human T cell lymphotropic virus type 1 (HLTV-1), which is inherent particularly in Japan and the Caribbean.
 

Genetic abnormalities

Leukaemia essentially arises from acquired genetic abnormalities in a genetically susceptible individual – basically, the leukaemias are cancers.
The genetic abnormality can be of diagnostic and prognostic significance. The abnormalities alter the cell cycle resulting in decreased apoptosis.
The Philadelphia (Ph) chromosome is the most common genetic abnormality. It is associated with 97% of cases of CML. This defect is also found in ALL, with incidence increasing with age.
  • Ph is an abnormal chromosome 22. There is a reciprocal translocation, i.e. a “swap” between chromosomes 22 and 9. The long arm of chromosome 22 becomes shorter.
  • The new “fusion gene” is called BCR-ABL. This gene produces an abnormal protein that allows for excess phosphorylation which ultimately alters cell growth and apoptosis mechanisms.
  • ABL is a proto-oncogene found on chromosome 9.  BCR is a normal gene coding for a protein found on chromosome 22.  After translocation, ABL gets moved next to BCR, culminating in  BCR-ABL
 

Cell surface markers

These can be used to classify acute leukaemias.  Different surface antigens are displayed at different stages of myeloid cell development.  Thus by determining which surface antigens are expressed by a specific type of leukaemia, one can roughly establish at which point in myeloid cell development the defect lies, and classify the leukaemia.
 

Basic pathology

There is proliferation of primitive stem cells, and leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure.   In chronic leukaemia, the malignant clones are themselves able to differentiate, and the accumulated cell population in the bone marrow is made up of a more mature variety of cells, and not just blast cells.
 

Diagnosis

There is usually a raised white cell count, and this is where the abnormality is often first noted.  The actual diagnosis is made from examination of bone marrow where this examination includes:
Remember: The point of this analysis is not just to identify which cell type is present; bone marrow examination is also essential for determining prognosis and treatment.
 

Myelodysplastic syndromes (MDS)

MDS are generally considered precursors to leukaemia. 30% of all individuals suffering with MDS will go on to develop acute myoblastic leukaemia (AML).
This term encompasses conditions that are due to a defect in myeloid stem cells. These syndromes are acquired, and generally occur in the elderly.
There is usually an associated pancytopaenia.
The natural history of MDS is variable, but there is a high morbidity and mortality.
 

Clinical features

  • Mainly occurs in the elderly
  • Presents with symptoms of anaemia, infection, and/or bleeding, due to pancytopaenia
  • Blood films will show:
    • thrombocytopaenia
    • neutropaenia
    • anaemia
    • monocytosis – however, the level does not rise higher than 1 x 1019/L.
  • Bone marrow often decreases in cellularity despite pancytopaenia
  • The number of blast cells in the bone marrow is increased
 

Management

Patients with <5% blast cells in the bone marrow are managed conservatively:
  • Red cell infusions
  • Platelet infusions
  • Antibiotics for infection
  • Hemopoietic growth factors, e.g. EPO and C-GSF are useful in some patients

Patients with >5% blast cells in the bone marrow have a worse prognosis.  Their management may include:

  • Supportive care only – usually for the very old, and those with other, unrelated medical problems
  • Gentle chemotherapy – this is usually a low dose of a single agent, e.g.  azacytidine, helpful if there is a particularly high WBC count
  • Intensive chemotherapy – this will probably involve similar regimens to those used in AML. The remission rate, however, is poor, and because of the defects in stem cells pancytopaenia can be worsened, because the stem cells can’t generate new cells quickly.
  • Bone marrow transplantthis is curative in some patients – however, there must be an HLA match, i.e.usually a sibling, or more unlikely, a matching donor.  Patients must also be under the age of 50 to be considered for this treatment.
 

Acute Leukaemias

Generally, the prognosis for acute leukaemias is poor.  There is a failure of cell maturation, translating into a build-up of immature cells in the bone marrow.  These cells are pretty much useless, occupying marrow space and denying normal cells vital resources. Eventually these cells will accumulate to a point such that they will spill out into the blood.
  • Acute lymphoblastic leukaemia (ALL) is the most common type in children, primarily affecting 2 to 8 year-olds.  There is equal risk between males and females, while all other leukaemias occur more frequently among males
  • Acute myeloid leukaemia  (AML) in adults is about 4xs more common than ALL in the same population.  It may occur in children, but this is rare. Approximately 2/3s of AML patients are over 60
 

Clinical features

These usually represent bone marrow failure, and include the following:
  • Anaemiagenerally feeling tired, SOB on exercise, weakness
  • Bleeding and bruising – as a result of thrombocytopaenia
  • Infection – as a result of leukopaenia
  • Bone pain – as a result of bone marrow infiltration
 
Examination often is normal, but abnormalities may include:
  • Pallor
  • Fever – due to infection
  • Petechiae – these are little purple spots, about 1-2mm diameter caused by rupture of a small blood vessel
  • Lymphadenopathy – in lymphoblastic leukaemia
  • Hepatosplenomegaly – in lymphoblastic leukaemia
  • Violaceous skin lesions – AML
  • Testicular enlargement – ALL
  • Cranial nerve palsies ALL, but quite rare
 

Investigations

  • Blood count – ↓Hb; ↑WCC; ↓platelets
  • Blood film – blast cells nearly always seen; auer rods might also be seen, which are pathognomonic for AML; in ALL there are more likely to be large blast cells, i.e. these cells are smaller and more mature in chronic leukaemias
  • Bone marrow aspirate – ↓erythropoiesis; ↓megakaryocytes, i.e. platelet precursors; > 20% blast cells but may often approach 100%; the lineage of the tumour is confirmed by phenotyping, in a process known as fluorescent in-situ hybridisation (FISH)
  • CXRthere may be mediastinal widening in T lymphoblastic leukaemia
 
 
This image shows a blast cell. Its granular appearance suggests that it is of myeloid origin.
Note its large size and primitive nucleus.
 
 

Differentiating between ALL and AML

 
ALL
AML
Presence of auer rods in blood
None
Always present
Presence of lymphoblasts in blood
Always present
May or may not be present
Bone and joint pain
More common
Less common
Hepatosplenomegaly
More common
Less common
Organ infiltration
More common
Quite unusual
 

Management

Acute leukaemias are fatal within months if not treated; however, they are generally managed conservatively.  With palliative care, the life expectancy can extend to around a year.
Curative therapy can be undertaken, but does not have a significant success rate. This type of treatment will fail either because the patient cannot tolerate it, or because it fails to destroy the causatory cells.
Generally, ALL in children has the highest chance of being curable of all the acute leukaemias.
 
Curative treatment carries considerable risk.  The acute leukaemias can be classified as high risk or low risk.  Low-risk leukaemias include ALL in childhood. AML in an adult with adverse cytogenic features may be considered a high-risk leukaemia.  Generally, the higher the risk, the greater the morbidity/mortality induced by treatment.
 
Factors that suggest high-risk treatment include:
  • antigens expressed on the cell surface, which are suggestive of the mutation involved
  • age greater than 60
  • leukaemia following on from MDS
  • relapsed disease
  • extramedually disease
  • secondary leukaemia
 

Curative treatment

The decision to treat should not be taken lightly. Treatment will greatly impact on the patient’s life for 6 months to a year, requiring admission to a specialist centre, after which he/she “may never feel the same again”.
 
Curative care carries with it significant risks and should only be attempted where there is chance of success.  In most cases, however, the failure rate is very high. If the possibility of cure ceases to exist during therapy, management strategies should be switched to palliative treatment.
 
The aim of curative treatment is to destroy clonal cells without destroying normal stem cells, so that  the latterwill be able to repopulate after clonal cells destruction.  There are three phases to treatment:
  • Remission induction through which the majority of the tumour will be destroyed by ‘induction chemotherapy’.  This will result in massive bone marrow hypoplasia.  The patient will need a great deal of supportive care during this phase, and is likely to be in intensive care.  The treatment greatly reduces the normal white cell count and therefore the patient is at very high risk of life-threatening infection.  Isolation precautions will be exercised whilst they are in hospital with the likelihood of confinement to a single side room
  • Remission consolidation is carried out once normal haematopoiesis is achieved; the remaining tumour will be attacked utilising further therapy. This consists of further courses of chemotherapy, resulting in more bone marrow hypoplasia.  Where prognosis is deemed to be poor this may involve bone marrow transplant.  If phase one was successful and successive treatment is not offered, there will almost certainly be relapse of the disease.  The aim of this phase is to achieve complete remission (CR)*
    • Bone marrow transplantation, i.e. via stem cell transplantation, is not carried out in low risk disease (usually AML), as the risks outweigh the benefits.
    • Complete remission is rare.  It may initially appear to be the case, but to be certain that it is achieved morphological testing of leukaemic cells is carried out.  The presence of leukaemic cells at this stage is a bad prognostic sign.
  • Maintaining remission. If both of the above treatment phases have been successful, then further therapy, given on an outpatient basis, may be required for up to 3 years.  After the 3-year period no further treatment will be offered but the patient will be closely observed. This is only the case in ALL,and is not thought to be of benefit in patients with AML.
 
*Complete remission – there is a bit of confusion over what this actually means.   It may be defined as no signs of disease on microscopy.  However,even when this is deemed the case, there may still be some abnormal cells present which microscopy methods were not able to detect. Thus, complete remission is not synonymous with cure.  People in complete remission can still relapse, and if they do, this is a bad prognostic sign. In this situation the prognosis is no better than if they had had no treatment.  An alternate and more precise method to define complete remission is through examination of cell surface antigens.
 

Palliative treatment

It is important that patients don’t view this as a form of “non- treatment”.   The aim of palliation is to optimise the individual’s quality of life in the remaining time that they have.  Palliative care will often still involve chemotherapy and irradiation treatments, although the focus is provision of supportive care in the patient’s ideal environment. 
 
Supportive care
This is the proper name given to the basic care given to both palliative and curative patients.  It involves the following:
  • Reducing symptoms of anaemiathe patient will likely be subjected to frequent infusions of packed red cells, and, sometimes, irradiation of cells. Therapeutic measures should be aimed at maintaining leukemic patients on a Hb >10.
  • Prevention/control of bleeding – this is carried out by careful platelet count control. The count should be maintained at >10 in uninfected patients, and >20 in infected patients.
  • Treatment of infection – this involves two things: firstly, the education of the patient and the family about hand washing and isolation; secondly, the use of prophylactic antibiotics and anti-fungals.
 
Specific treatments
AML
  • Curative treatment is attempted in almost all patients under 60. Those at low risk are given the initial remission induction which includes chemo + antibiotic, followed by four, 3-4 week cycles of remission consolidation.  Those in high risk groups may only be given treatment if they have an HLA match for marrow transplantation.
  • Complete remission will be obtained in about ¾ of patients under 60.  Failure may be due to a particularly invasive cancer, death from infection, or very rarely, death from bleeding.  About 50% of those who achieve complete remission will be cured,i.e. in about 30% of patients the disease will never come back
  • If recurrence occurs, then prognosis is very poor.  CR may be achieveable again, but this doesn’t carry with it a better prognosis.
  • Long survival is rarely achieved without transplantation

Acute promyelocyte leukaemia (APML)– this is an uncommon variant of AML, which involves a specific translocation mutation, t(15:17). There is almost always coagulopathy, and this is often the cause of death.

  • ATRA is a protein that causes differentiation of promyelocytes which can reduce the bleeding.  Thus, the standard treatment for APML is now ATRA with chemotherapy to induce remission, followed by maintenance therapy with ATRA alone.
  • CR is obtained in about 80% of cases, and 60% of patients can expect to be cured.
  • The outlook is generally good compared to other types of AML, even after a relapse where remission may be achieveable again.

ALL - overall, the treatment is very similar to AML, but the drugs given may vary.

  • Again, transplantation is only recommended for those at high-risk, where ALL is considered generally incurable without transplantation.
  • Some patients will receive maintenance therapy for up to 2 years.
  • The major difference in treating AML and ALL is that ALL patients also get therapy directed at the CNS.
 

Approach to management of leukaemias

 

Prognosis

The prognosis for ALL in childhood is very good.
  • Complete remission is obtained in almost all patients.
  • 80% will still be alive without recurrence after 5 years.
  • Failure of treatment occurs most commonly occurs in those with:
    • a high blast count
    • a T(9:22) translocation
  • The aforementioned factors related to failure increase in frequency with age.
  • The overall CR rate in children and adults is 70-80%.  Failure to achieve remission with first- line therapies has a very poor prognosis.  If second-line therapies achieve remission then they should be backed up with a positive HLA match for marrow transplant, i.e. usually that of a sibling, even though there is a high risk of graft versus host disease.
  • Most recurrences of the disease occur within 3 years, and recurrence is usually a very poor prognostic factor. CR can be obtained, but again are there likelihood of relapse.
 

Complications

Hyperviscosity syndrome results from increased circulating serum immunoglobulins in Waldenstrom macroglobulinaemia and multiple myeloma, but may also occur in hyperproliferative states such as the acute leukaemias, polycythemia and the myeloproliferative disorders in which there are increased cellular blood components. As serum proteins or cellular components rise, the blood becomes more viscous, leading to the following clinical symptoms:
 
Therapeutic leukapheresis is performed in patients with very high white blood cell counts, i.e. > 100,000 cells/mm3and symptoms of leukostasis. Leukapheresis involves the removal of circulating blast cells followed by reinfusion of leukocyte-poor plasma. A single session can reduce the WCC by 20 to 50%. 
 

Chronic Leukaemias

Chronic myeloid leukaemia (CML)
  • Almost exclusively an adult disease.
  • Accounts for 14% of all leukaemias.
  • The incidence is 2 per 100 000, being slightly higher in men.
  • Peak age of incidence is between 40-60 years.
  • Characterised by the presence of the Philadelphia (Ph) chromosome.
  • Whereas acute leukaemias are generally rapidly reversed or rapidly fatal, CML progresses slowly ; if CML is not treated, death will generally occur within 3-4 years.
  • Affects the myeloid cells, i.e. basophils, neutrophils and eosinophils.
 
 

Presentation

CML usually presents in the chronic phase.  
 
Many patients have no symptoms, but may have any of the following:
  • SOB – due to anaemia
  • abdominal discomfort – due to splenomegaly
  • weight loss
  • fever and sweats – these are not due to infection! (unlike in acute leukaemias)
  • headache (uncommon) – due to hyperleukocytosis
  • bruising and bleeding (uncommon)
  • pallor
  • lymphadenopathy – enlarged lymph nodes – this typically occurs only at times of blast crisis
  • retinal haemorrhage
  • goutdue to increased purine breakdown.  Often allopurinol is given for this.
  • splenic pain
  • cerebral problems – confusion and fits
  • dyspnoea and cough – due to pulmonary leukostasis,  i.e. too many white cells in the blood causing hyperviscosity
 

Disease progression

 The natural progression of CML is as follows: chronic phase → aggressive phase (accelerated phase) → blast phase (blast crisis):
  • Chronic phase – there may be an increased WCC; < 10% of blast cells in blood
  • Aggressive phase – more likely to find blast cells in the blood, i.e. approximately 10-20%, and more systemic symptoms
  • Blast phase – blood contains more than20% blast cells
 

Blast crisis

This is essentially the acute terminal phase of CML. Once patients reach this stage mortality is very high.  The patient is said to be in a blast crisis, when there are more than 20-30% blast cells in the blood or bone marrow. Symptoms of a blast crisis include:
  • rapid increase in proportion of blast cells
  • fever
  • bone pain
  • fatigue
  • increased severity of anaemia, e.g. fatigue
  • increased severity of thrombocytopaenia, e.g. bleeding and/or bruising
  • splenomegaly
  • large clusters of blasts on bone marrow film
 

Investigations

  • Blood count Hb low or normal; ↑ WBC; platelets low, normal or raised
  • Blood film neutrophilia, i.e. abnormally high number of neutrophils, with myeloid precursors including blasts; in chronic leukaemia white blood cells are bigger, more mature and blast-like compared to the situation in other chronic disease
  • Bone marrow aspirate increased cellularity, i.e. increased number of cells
  • FISH = fluorescent in-site hybridisation used to look for the cytogenetic abnormality; cytogenetics will show Philadelphia chromosome in 97% of cases
  • Leukocyte alkaline phosphatise (LAP) usually reduced
There is a high cell turnover rate giving a high urate – this is linked to gout.
 

Management

Imatinib is a tyrosine kinase inhibitor that prevents the action of the BCR-ABL fusion protein, i.e.this is the abnormal protein produced by the Ph mutation.
This is first-line treatment during the chronic phase.
  • 95% of patients will respond to the drug
  • 70-80% of these have no detectable BCR-ABL in the blood
  • This treatment can be continued indefinitely
  • The drug is usually well tolerated, but side effects can include nausea, headaches, rashes, cytopaenia, cramps, myelosupression; resistance can sometimes develop.
  • 18 months of a ~nib drug will completely eradicate the Ph mutation in 76% of patients
 
In the acute phase, i.e. blast transformation, the drug is of limited use and patients will have to have additional treatments.
In the aggressive phase, use of the drug can put the disease back into the chronic phase.
 
Interferon-α
This is sometimes given to patients who don’t have the Ph mutation.  It was the first-line treatment before Imatinib.
 
Stem cell transplantation (SCT)
This will cure approx 70% of patients.  However there is a risk of death from graft versus host disease, and infection.  Situation which are more likely to produce a poor outcome with SCT include:
  • old age of patient
  • disease in acute phase
  • poor HLA compatibility of donor
The use of SCT has declined since the advent of Imatinib,however it is still indicated in those with a poor response to the drug, i.e. those who do not have the Ph mutation.
 
Autologous transplant
Some of the patient’s own bone marrow is removed, screened for the disease, and if it is a suitable sample with some non-diseased cells, the stem cells are transplanted back.
There is a lower less mortality associated with this procedure, but is also less likely to cure than a HLA match.
 
SOKAL index
This is the tool used to determine prognosis in CML.
  
Calculate Sokal score
 
 
 
 
 
 
Age (years)
 
 
Spleen (cm)
 
 
Platelet (X 109/L)
 
 
Myeloblasts in blood (%)
 
 
 
 
 

Chronic lymphocytic leukaemia (CLL)

  • The most common of all leukaemias.
  • Occurs mainly in later life, and increases in frequency with older age.
  • Results from a progressive accumulation of functionally incompetent B lymphocyteshence the name!
  • Median survival is 10 years, and this is often related to the severity of symptoms at presentation.
  • Cytogenic and molecular abnormalities carry prognostic significance.
 
 

Presentation

CLL is often asymptomatic and discovered incidentally.  In others it can present with:
  • marrow failure and immunosupression – frequent infections, anaemia
  • painless lymphadenopathy
  •  splenic pain
  • fever – due to infection
  • hepatomegaly / splenomegaly – sometimes very massive!
 

Investigations

  • Blood count – Hb normal or low; ↑WCC and may be very high; platelets normal or low
  • Blood film - ↑lymphocytes, i.e. > 5x109/L
  • Bone marrow - similar to peripheral blood; may be heavily infiltrated with lymphocytes
  • Immunophenotyping – mainly CD19/20 and CD5+ B cells which may weakly express surface immunoglobulins
  • Cytogenetics – most common abnormality is deletion of 13q which translates into relatively benign disease status; trisomy 12 is present in 15% which is associated with progressive disease; mutation of IgVH on B cells is associated with poor prognosis, however IgVH is difficult to measure; intracellular ZAP-70, i.e. zeta-associated protein, correlates closely with IgVH mutated status and can be measured more easily in general laboratory
  • Coombs’ test – may be positive if there is haemolysis
  • Immunoglobulins – may be low or normal
 

Bone marrow aspiration

Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL, but may be necessary in some instances to establish a diagnosis and assess other complicating factors such as anaemia and thrombocytopaenia.
 

Management

Treatment depends on the stage of the disease, although cytogenetic markers are increasingly used. Clinical staging systems such as the Rai or Binet staging systems for CLL can help to determine when and how to treat the patient.
 
Chemotherapeutic intervention in early-stage disease is not usually necessary.  The absolute indications for treatments are:
  • weight loss of more than 10% over 6 months
  • extreme fatigue
  • fever related to leukemia for longer than 2 weeks
  • night sweats for longer than 1 month
  • progressive marrow failure (anemia or thrombocytopenia)
  • autoimmune anemia or thrombocytopenia not responding to glucocorticoids
  • progressive or symptomatic splenomegaly
  • massive or symptomatic lymphadenopathy
  • progressive lymphocytosis, as defined by an increase of greater than 50% in 2 months or a doubling time of less than 6 months
 
According to NICE guidance, fludarabine monotherapy is not recommended for the first-line treatment of CLL.
Chlorambucil has been considered the drug of choice for first-line therapy of CLL, and when combined with prednisone, chlorambucil is associated with an initial response rate of 60-90% and a complete response in up to 20% of all patients.
 

Complications

Richter syndrome or transformation is seen in 3 to 10% of cases, where CLL is transformed into an aggressive, large B-cell lymphomaEpstein-Barr virus may play a role in transformation. Lymph node biopsy is necessary for diagnosis. Patients will often present with:
  • weight loss
  • fever
  • night sweats
  • muscle wasting
  • increasing hepatosplenomegaly
  • lymphadenopathy
Pneumonia and/or septicaemia may occur due to the hypogammaglobinaemia and impaired T-cell function associated with CLL. Prophylactic antibiotics or immunoglobulin replacement therapy may be helpful.
Anaemia secondary to bone marrow involvement, splenic sequestration of RBCs, and autoimmune haemolytic anaemia may be treated with blood transfusion, splenectomy, or steroids respectively. 
Thrombocytopaenia also due to the aforementioned sequelae of CLL is managed as above in the setting of concurrent anaemia.