My Clinical Notes

• Characterised by the accumulation of malignant white cells in the bone marrow and blood
• These abnormal cells can cause symptoms because of bone marrow failure or due to infiltration of organs

 

• Leukaemias can be classified into;
  • Acute myeloid – M0-M7
  • Acute lymphoid – L1-L3
  • Chronic myeloid
  • Chronic lymphoid

 

Acute Leukaemias

• Generally aggressive
• Due to malignant transformation of haematopoietic stem cells or early progenitors
• Increased proliferation, reduced apoptosis and a block in differentiation results in accumulation of blast cells which are early haematopoietic cells in the bone marrow
• The main clinical feature is bone marrow failure due to accumulation of blast cells but organ infiltration does occur
• If untreated they are generally fatal but paradoxically they are easier to cure than chronic leukaemia

 

Differentiation between ALL and AML

• ALL blasts generally show no differentiation (with exception to B cell ALL) whereas AML shows differentiation to granulocytes or monocytes in the blasts
• In a small number of cases blast cells can show features of both AML and ALL, this is called hybrid acute leukaemia and treated based on the dominant pattern

 

Acute Lymphoblastic Leukaemia

 

• Most common malignancy of childhood – incidence higher at 3-7 years with a secondary rise at the age of 40
• The B cell type has an equal sex dominance but the T cell type is more common in males
• In a proportion of cases the first event occurs in utero with a second event possibly precipitated by infection in childhood

 

Classification

• Can be classified based on morphology and immunotyping
  • L1 – show uniform small blast cells with scanty cytoplasm
  • L2 – larger blast cells with more prominent nucleoli and cytoplasm with more heterogeneity
  • L3 – large, prominent nucleoli, with basophilic cytoplasm and vacuoles in the cytoplasm
• Immunotyping can divide ALL into;
  • Early pre-B
  • Pre-B
  • B cell
  • T cell subtypes

 

Clinical features

• Bone marrow failure resulting in; anaemia, neutropenia, thrombocytopenia
• Organ infiltration; tender bones, lymphadenopathy, hepatosplenomagaly, meningeal syndrome, testicular swelling or mediastinal compression

 

Investigations

• Normocytic, normochromic anaemia
• Thrombocytopenia
• Blood film showing blasts
• Hypercellular BM with >20% leukaemic blasts
• Blast cells are characterised by morphology, cytogenetics, immunophenotyping
• LP should be done as CSF may have increased pressure and contain leukaemia cells
• Other biochemical tests may reveal;
  • Raised urate
  • Raised serum lactate dehydrogenase
  • Hypercalcaemia
• Baseline liver and kidney function tests should be done before treatment
• Radiology may reveal lytic bone lesions or a mediastinal mass

 

DDx

• AML
• Aplastic anaemia
• Marrow infiltration by other malignancies e.g. rhabdomyosarcoma, neuroblastoma
• Infections – EBV and pertussis
• Juvenile RA
• Immune thrombocytopenic purpura

 

Cytogenetics

• Hyperdiploid cells have >50 chromosomes and are associated with a good prognosis whereas hypodiploid cases carry a poor prognosis
• The most common genetic abnormality in childhood ALL is the t(12:21) TEL-AML1 translocation
• AML1 is involved in transcriptional control and in inhibits in the TEL-AML1 transcloation
• The Philadelphia chromosome translocation t(9:22) increases with age and is associated with poor prognosis

 

Treatment

• Can be divided into supportive and specific treatments

 

Supportive

• Central venous catheter
• Blood product support – red cells and platelets. Blood should be CMV negative (in case they have a SCT. Avoid blood transfusions in the patient have a very high WCC, because of hyperviscosity and the risk of thrombotic episodes. Blood products given to immunusippressed should be irradiated
• Anti-emetic therapy
• Treatment of tumour lysis syndrome – chemotherapy may trigger an acute rise in plasma uric acid, potassium and phosphate and cause hypocalcaemia due to rapid lysis of tumour cells. Treat with allopurinol, IV fluids and electrolyte replacement
• Pain control
• Psychological support
• Reproductive issues e.g. sperm storage
• Nutritional support
• Prophylaxis and treatment of infection

 

Specific therapy

• Chemotherapy and sometimes radiotherapy
• 4 components of the treatment course
• Vary with age and are risk adjusted to reduce the treatment being given to patients with a good prognosis

 

Remission induction

• Rapidly kills most of the tumour cells and gets the patient into remission – defined as less than 5% blasts in the BM, normal peripheral blood count and no other symptoms and signs of disease
• Drugs used are;
  • Prednisolone or dexamethasone (in children)
  • Vincristine
  • Asparaginase
  • Daunorubicin (may be added in adults)

 

Intensification (consolidation)

• High dose multidrug chemotherapy to reduce or eliminate tumour burden to very low levels
• Doses are close to the limits of patients tolerance
• Typical protocols include;
  • Vincristin
  • Cyclophosphamide
  • Cytosine arabinoside
  • Daunorubicin
  • Etoposide
  • Thioguanine
  • Mercaptopurine
• Generally 2 or 3 intensification blocks in children, more in adults

 

CNS directed therapy

• Few of the drugs given reach the CNS so specific therapy is needed
• Options are;
  • High dose methotraxate given IV
  • Intrathecal cytosine arabinoside or methotrexate
  • Cranial irradiation (avoided in children due to substantial side effects)

 

Maintenance

• Given for 2 years in girls and adults and for 3 years in boys
• Daily oral mercaptopurine and once weekly methotraxate with IV vincristine given in monthly or 3 monthly intervals

 

Other treatments

• BMT in patients who are Ph positive or who have refractory primary disease or who have relapsed
• Imatinib is a tyrosine kinase inhibitor specific for the bcr-abl chimeric protein. Used to treated Ph positive ALL

 

Prognosis

• Approx 90% of children can be cured
• Only 5% of adults over 70 years can be cured
• Factors associated with a poor prognosis;
  • Having a high WCC
  • Being male
  • Having T-ALL in children
  • Being an adult or an infant less than 2
  • Being Ph+
  • Taking more than 1 week to clear blasts from the blood
  • Taking more than 4 weeks to achieve remission
  • Having CNS disease at presentation
  • Having minimal residual disease still present at 3-6mth

 

Acute Myeloid Leukaemia

 

• Occurs in all age groups. The most common form of acute leukaemia in adults and increased with age
• Rare in childhood
• Important to distinguish, primary AML (which arises de novo) from secondary AML which can develop from myelodysplasia, myeloprloferative diseases and following previous chemotherapy
• The most common genetic abnormality is the presence of tandom repeats of the FLT-3 gene which is normally tightly regulated in CD34 cells

 

Classification

• Divided into 8 subtypes based on cytochemical stains, immunotyping and chromosomal changes
• The typical myeloid phenotype is CD13+, CD33+, TdT-.
• Treatment and prognosis of the different types is similar

 

Clinical features

• Resemble ALL – anaemia and thrombocytopenia
• M3 subtype is associated with a bleeding tendency and DIC
• M4 and M5 are associated with tumour cell infiltration of the gums, skin and CNS

 

Investigations

• General haematogical and biochemical findings are similar to ALL

 

Treatment

• Supportive therapy is similar to ALL
• The haemorrhagic syndrome associated with M3 can be treated using platelet transfusions and FFP
• In addition all-trans retinoic acid (ATRA) is given with chemo for patients with M3 disease, this can be associated with ATRA syndrome – fever, hypoxia and fluid infiltrates

 

Specific therapy

• Intensive chemotherapy usually involving 4 blocks of approximately 1 week. Drugs used include;
• Daunorubicin
• Cytosine arabinoside
• Etoposide
• Mitoxantrone
• The drugs are myelotoxic resulting in severe bone marrow failure
• Maintenance therapy is only used for M3 disease and CNS treatment is not used
• Other therapies include anti-CD45 and anti-CD33

 

Stem cell transplantation

• Autologous transplants reduces rate of relapse but is toxic so has no overall benefit
• Allogeneic stem cell transplantation are considered in patients under 65 from HLA matched sibling who have standard or poor risk AML. Can also be saved to be used following relapse

 

Prognosis

• Most patients suffer relapse
• 50% of children and young adults can be cured
• For those over 70, 10% can be cured

 

Factors associated with prognosis

Â	Favourable	Unfavourable
Cytogenetics	t(15;17) t(8;21) inv(16) Nucleophosmin (NPM) gene	Deletions of chromosome 5 or 7 Flt-3 mutation 11q23 t(6;9)
BM response to remission induction	<5% blasts after first course	>20% blasts after first course
Age	<60	>60
Onset	Primary	Secondary

 

Chronic Leukaemia

• Chronic leukaemias have a slower progression than acutes
• Paradoxically they are more difficult to cure

 

Chronic Myeloid Leukaemia (CML)

 

• Accounts for 15% of leukaemias and can occur at any age
• M=F
• Most frequent between the ages of 40-60
• Characterised by the presence of the Ph chromosome t(9:22). The BCR-ABL gene product is a tyrosine kinase with excessive activity
• The Ph chromosome is found in cells of both the myeloid and lymphoid lineages

 

Clinical features

• Mostly due to the increase in total body myeloid cell mass
• In at least 70% of the patients who don’t response well to imatinib, there is a terminal transition to acute leukaemia
• Clinical features;
  • Hypermetabolism – weight loss, might sweats, fatigue
  • Splenomegaly
  • Anaemia
  • Abnormal platelet function resulting in; bruising, menorrhagia, haemorrhage
  • Gout or renal impairment caused by hyperuricaemia caused by purine breakdown
  • Visual disturbance
  • Priapism
• However up to 50% of the diagnosis is made from a routine blood count

 

Laboratory findings

• Leucocytosis
• Increased circulating basophils
• Normocytic normochromic anaemia
• Platelets may be increased, decreased or normal
• Neutrophil alkaline phosphatase is invariably low (it is raised in myeloproliferative diseases and infection)
• Bone marrow is hypercellular with a granulopoietic predominance
• Ph chromosome on cytogenic analysis
• Raised serum uric acid

 

Treatment

• The tyrosine kinase inhibitor Imatinib (Glivec) is a specific inhibitor of the BCR-ABL fusion protein and blocks tyrosine kinase activity by competing with ATP binding. It is the first line treatment of chronic phase disease. At a dose of 400mg/day it is able to produce a complete response in virtually all patients. Side effects include;
  • Skin rash
  • Fluid retention
  • Muscle pains
  • Nausea
  • Neutropenia and thrombocytopenia
• In patients who have a suboptimal response, there are a number of options regarding their treatment;
  • Increase the dose of imatinib
  • Substitution of second generation tyrosine kinase inhibitors – dasatinib or nilotinib
  • Allogeneic stem cell transplant
    • This is the only curative treatment for CML but because of the risk is generally reserved for imatinib failures
    • Only patients below the age of 65 can tolerate SCT
    • The 5 year survival is approximately 50-70% although this is reduced to only 10% if the SCT is delayed for more than 1 year after diagnosis

 

Course and prognosis

• Survival is now much prolonged with imatinib, it is possible that the best responders may never relapse
• Patients may be divided into prognostic groups based on age, spleen size, platelet count, peripheral blood or bone marrow blast cells on presentation
• The most important prognostic marker is degree of response to imatinib

 

Accelerated phase disease and blastic transformation

• Acute transformation with 20% or more blasts in the marrow may occur rapidly over days or weeks
• Patient may have an accelerated phase of anaemia, thrombocytopenia and am increase in basophils, eosinophils or blast cells in the blood and bone marrow
• Spleen may be enlarged and the BM fibrotic
• New chromosome abnormalities may be present
• In around 1/5 of cases acute transformation may be lymphoblastic and may be treated similarly to ALL
• In the majority transformation is myeloid or mixed which are more difficult to treat and survival is rare beyond a few months

 

Chronic lymphoid leukaemias

 

• Characterised by accumulation in the blood of mature B or T cells
• Difficult to distinguish between CLL and Non-Hodkin’s lymphoma, depend on the proportion of disease in soft tissue masses compared to blood and BM
• In general the disease are incurable but tend to run a chronic and fluctuating course
• Diagnosis depend on morphology, immunophenotyping and cytogenetics

 

B cell Diseases

 

Chronic lymphocytic leukaemia

• Most common CLL
• Peak incidence between 60 and 80
• M:F 2:1
• Common in the west but rare in the far east
• In contrast to other forms of leukaemia there is no increased incidence after previous chemotherapy or radiotherapy
• There is a 7 fold increased risk of CLL in the close relatives of patients
• Tumour cell is a relatively mature B cell with weak surface expression of IgM and IgD
• The cells accumulated in the blood, bone marrow, spleen, liver and lymph nodes

 

Clinical features

Most cases are diagnosed by routine blood test

Symmetrical enlargement of cervical, axillary, inguinal lymph nodes is common

Features of anaemia and thrombocytopenia

Splenomegaly, less commonly hepatomegaly

Immunosuppression resulting from hypogammaglobulinaemia and cellular immune dysfunction

 

Lab findings

• Lymphocytosis – between 70 and 99% of white cells in the blood smear appear to be small lymphocytes
• Immunophenotyping – CD19+ B cells, IgM, IgD+. Shown to be monoclonal due to expression of only one form of light chain. The cells are also CD5+, CD23+, CD79b- and FMC7-
• Normocytic normochormic anaemia is present. Thrombocytopenia can also be present
• Bone marrow aspiration shows lymphocytic replacement of normal marrow elements
• Reduced concentrations of serum Ig. Rarely a paraprotein is present
• Autoimmune haemolytic anaemia can occur as can immune thrombocytopenia

 

Prognostic markers

Cytogenetics

• The four most common chromosome abnormalities are;
  • Deletion of 13q14
  • Trisomy 12
  • Deletion of 11q23
  • Structural abnormalities of 17p involving the p53 gene
• Somatic hypermutation – the more mutation the better the prognosis
• Tumour cell phenotype
• ZAP-70 is a tyrosine kinase involved in cell signalling following Ag recognition by T cells. Its expression is associated with an unfavourable outcome

 

Staging

• Via the Rai staging score
  • 0 – absolute lymphocytosis >15 x109/L
  • I – Stage 0 + enlargement of lymph nodes (adenopathy)
  • II – Stage 0 + enlarged liver and or spleen +/- adenopathy
  • III – Stage 0 + anaemia +/- adenopathy +/- organomegalyp
  • IV – Stage 0 + thrombocytopenia +/- adenopathy +/- organomegaly

 

Treatment

• Cure is rare so treatment is conservative aiming at control
• Chemotherapy can shorten rather than prolong life expectancy
• Treatment is given for symptoms such as organomegaly, haemolytic episodes and BM suppression

 

Chemotherapy

• Oral alkylating agent chlorambucil is useful at reducing tumour bulk
  Purine analogues e.g. fludarabine (can be given with cyclophosphamide and rituximab to increase response
• Monoclonal antibodies – Campath- 1H (anti-CD52) and Rituximab (even though CD20 expression on CLL is not high, it appears to be useful when given with fludarabine)
• Corticosteroids – prednisolone for patients in BM failure and autoimmune haemolytic anaemia or thrombocytopenia

 

Other forms of treatment

• Radiotherapy – reduces size of bulky LN groups
• Combination chemo – cyclophosphamide, hydroxydaunorubicin, vincristin, prednisolone (CHOP) with rituximab may be used in late stage cases
• Cicosporin – may help with red cell aplasia
• Splenectomy
• Ig replacement
• Stem cell transplantation

 

Prognostic factors

Â	Good	Bad
Stage	Rai 0 - I	Rai II-IV
Sex	Female	Male
Lymphocyte doubling time	Slow	Rapid
BM biopsy appearance	Nodular	Diffuse
Chromosomes	Deletion 13q11	Trisomy 12, deletion 17p, deletion 11q23
VH Ig genes	Hypermutated	Unmutated
ZAP expression	Low	High
CD38 expression	Negative	Positive
LDH	Normal	Taised

 

Course of disease

• Patients who are Rai stage 0 or I may never need disease
• If patient does need treatment, generally the disease responds well to several courses of chemo before there is a gradual onset of bone marrow infiltration, bulky disease and recurrent infection
• Disease may transform into a high grade lymphoma – Richter’s transformation

 

Other CLL

 

Prolymphocytic Leukaemia

• The prolymphocyte is 2x the size of a CLL and has a round central nucleolus
• B-cell PLL is 3x more common than T-cell PLL
• PLL typically presents with splenomegaly without lymphadenopathy with a high and rapidly progressing lymphocyte count

 

Hairy cell leukaemia

• M:F 4:1
• Peak incidence 40-60 years
• Patients typically present with anaemia, infections, splenomegaly
• The blood film reveals unusual large cell with villous cytoplasmic projections
• Immunophenotyping show is to be CD22+, FMC7 and CD103+
• Can be effectively treated and there is a good prognosis

 

Plasma cell leukaemia

• Associated with high numbers of circulating plasma cells
• Clinical features – as well as general features of leukaemia, also associated with features of myeloma (hypercalcaemia, renal involvement and bone disease

 

T cell diseases

 

Large granular lymphocytic leukaemia

• Characterised by the presence of circulating lymphocytes with abundant, granular cytoplasm – may be T cells or NK cells
• Show variable expression of CD16, CD56 and CD57
• May clinical symptom is cyopenia particularly neutropenia

 

Adult T cell Leukaemia/Lymphoma

• First malignancy to be associated with a retrovirus, human T cell leukaemia virus type I (HTLV-1)
• ATLL cells have a convoluted ‘clover-leaf’ nucleus and express CD4
• Clinical presentation is associated with hypercalcaemia, skin lesions, hepatosplenomegaly and lymphadenopathy

 

Sézary Syndrome

• Present with skin disease – pruritic exfoliative erythoderma affecting the palms, soles and face – ‘red man syndrome’
• Lymphocytic infiltrate of the skin and Sézary cells in the peripheral blood which look like ATLL cells

 

Stem cell transplantation

 

• The principle is to eradicate a persons haematopoetic system and immune system and replace it with stem cells for another individual or with a previously harvested portion of the patients own stem cells
• In bone marrow transplantation the stem cells are collected from the BM
• In peripheral blood stem cell transplantation they are collected from the peripheral blood
• SCT may be;
  • Syngeneic – from an identical twin
  • Allogenic – from another individual
  • Autologous – from the patients own stem cells

 

Procedure

• For allogenic SCT
  • Bone marrow aspiration or leukopheresis of stem cells from peripheral blood after G-CSF injection
  • T cell depletion
  • Donor stem cells transfused into recipient who has had either previous high dose chemo or total body irradiation (this is called conditioning)
  • Intensive support therapy is then given to the recipient in the form of red cells and platelets as well as antibiotics and prophylaxis against GVHD – cyclosporine +/- methotrexate
• For an autologous SCT
  • There are generally attempts made to remove residual tumour cells e.g. by monoclonal antibodies prior to them being re-infused back into the patient

 

• After a period of 1-3 weeks of pancytopenia, the first signs of successful engraftment are monocytes and neutrophils in the blood and a rise in the platelet count
• G-CSf can be used to decreased the period of neutropenia
• Engraftment is generally quicker after PBSC transplantation that BMT

 

Autologous transplantation

• The problem with autologous transplantation is the recurrence of original disease as tumour cells contaminating the harvest may be reintroduced into the patient
• GVHD is not an issue

 

Allogeneic transplantation

• Risk of GVHD as donor T cells react against recipient tissues. The incidence increases the grester the degree of HLA mismatch
• Acute GVHD – occurs in the first 100 days. May be treated with high dose corticosteroids
  • Skin rash – particularly affecting the face, palms, soles and ears
  • Gut – diarrhoea
  • Liver
• Late GVHD
  • Associated with;
    • Scleroderma
    • Sjogren’s syndrome
    • Lichen planus
    • Malabsorption
    • Infection

 

• There is a phenomenon called graft-vs-leukaemia (GVL) effect, which seems to be a donor T cell mediated effect and explains the decreased disease relapse rate is patient with GVHD

 

Myelodysplasia

 

• Group of clonal disorders of multipotent haematopoietic cells resulting in a cytopenia in the presence of BM of normal or increased cellularity
• There is a tendency to progress to AML
• In most cases the disease is primary but some patients have secondary disease following chemotherapy or radiotherapy for another malignancy

 

• In terms of pathogenesis disease is presumed to start following some genetic damage to a haematopoietic progenitor leading to increased proliferation but ineffective differentiation and maturation. A high rate of apoptosis is seen in the BM precursors

 

Clinical features

• 4 in 100,000 incidence. Slight male predominance. Generally seen in the elderly
• Symptoms; anaemia, infections, bruising and bleeding

 

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