- Myelodysplastic syndromes (MDS)
- Acute Leukaemias
- Approach to management of leukaemias
- Chronic Leukaemias
Leukaemia is a broad term, applied to a range of blood cell cancers.
- 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 leukaemia – this is mainly a disease of the elderly
- CML – chronic myeloid leukaemia
Leukaemia (mostly ALL) is the most common malignancy of childhood – accounting for about 30% of childhood malignancy. The other main three forms of leukaemia – AML, CLL and CML can occur in childhood, but are primarily diseases of adulthood, and most commonly present in patients over 55.
- 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
- 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.
- 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
- morphology of the cells
- analysis of surface markers, aka immunophenotyping
- clone-specific chromosomal abnormalities
Myelodysplastic syndromes (MDS)
- Mainly occurs in the elderly
- Presents with symptoms of anaemia, infection, and/or bleeding, due to pancytopaenia
- Blood films will show:
- 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
- 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 transplant – this 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 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
- Accounts for 80% of all childhood leukaemias
- Peak age of incidence in children is age 2-3
- Acute myeloid leukaemia (AML) in adults is about 4xs more common than ALL in adults. It may occur in children too, but this is rare. Approximately 2/3s of AML patients are over 60
- Accounts for about 15% of childhood leukaemias
- Peak age of incidence in children is <2
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.
- More common in caucasians
- Boys at slightly higher risk
- Wide range of genetic mutations have been implicated
- Risk is greatly increased when another genetic disorder s present (e.g. 20x greater in Down Syndrome)
- Exposure to ionising radiation increases the risk (e.g. maternal abdominal x-ray during pregnancy)
- Anaemia – generally 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
- 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
- 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)
- CXR – there may be mediastinal widening in T lymphoblastic leukaemia
Differentiating between ALL and AML
Presence of auer rods in blood
Presence of lymphoblasts in blood
May or may not be present
Bone and joint pain
Curative therapy has a varible success rate depending in the type of leukaemia and prognositc factors.
- Curative therapy may fail either because the patient cannot tolerate it, or because it fails to destroy the causatory cells.
- 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
In cases deemed unsuitable for curative treatment (or in cases where the patient decides against curative treatment), then palliative treatment can be undertaken. This can extended life expectacny, typically to 12-18 months.
- 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.
- Reducing symptoms of anaemia – the 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.
- 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, asin these cases 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
- 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 cure 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.
- spontaneous gum bleeding
- rectal bleeding
- hearing loss
- visual changes
- headaches/seizures/ somnolence
- heart failure
- Chronic Myeloid Leukaemia
- 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.
- Chronic lymphocytic leukaemia
- 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 lymphocytes –hence 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.
Investigations carried out in CML and CLL
Hb low or normal; ↑ WBC; platelets low, normal or raised
Same as CML but WCC may be very high
Neutrophilia; WBCs bigger, more mature and blast-like
↑lymphocytes, i.e. > 5×109/L
Bone marrow aspirate
May be heavily infiltrated with lymphocytes
Ph chromosome in 97% of cases
13 q deletion; trisomy 12; mutated IgVH
CD19/20 and CD5+ B cells
Positive if haemolysis is present
Leukocyte alkaline phosphatise
Chronic Myeloid Leukaemia (CML)
- 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)
- lymphadenopathy – enlarged lymph nodes – this typically occurs only at times of blast crisis
- retinal haemorrhage
- gout – due 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
- 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
- rapid increase in proportion of blast cells
- bone pain
- increased severity of anaemia, e.g. fatigue
- increased severity of thrombocytopaenia, e.g. bleeding and/or bruising
- large clusters of blasts on bone marrow film
- 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
- 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
- old age of patient
- disease in acute phase
- poor HLA compatibility of donor
Calculate Sokal score
Platelet (X 109/L)
Myeloblasts in blood (%)
Chronic Lymphocytic Leukaemia (CLL)
- marrow failure and immunosupression – frequent infections, anaemia
- painless lymphadenopathy
- splenic pain
- fever – due to infection
- hepatomegaly / splenomegaly – sometimes very massive!
- Blood count – Hb normal or low; ↑WCC and may be very high; platelets normal or low
- Blood film – ↑lymphocytes, i.e. > 5×109/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
- 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
- weight loss
- night sweats
- muscle wasting
- increasing hepatosplenomegaly