13 - Haematological 2 Flashcards
What is leukaemia and what is the difference between acute and chronic leukaemia?
- Leukaemia are a group of malignancies that arise in the bone marrow that cause excessive amount of one type of WBC
- Classified as acute or chronic and by the lineage of stem cells they affect (myeloid or lymphoid)
- Acute is due to impaired cell differentiation, so large numbers of malignant precursor cells in the bone marrow; on the other hand, chronic leukaemia is the result of excessive proliferation of mature malignant cells, but cell differentiation is unaffected
Why does leukaemia lead to a pancytopenia?
Excessive production of a single type of cell can lead to suppression of the other cell lines
What ages do each of the types of leukaemia tend to affect?
“ALL CeLLmates have CoMmon AMbitions”
45-75 in steps of 10 years
- Under 5 and over 45 – acute lymphoblastic leukaemia (ALL)
- Over 55 – chronic lymphocytic leukaemia (CeLLmates)
- Over 65 – chronic myeloid leukaemia (CoMmon)
- Over 75 – acute myeloid leukaemia (AMbitions)
Leucostasis may occur in leukaemia due to the increased number of white cells in the blood. How may this present?
- Altered mental state
- Headache
- Breathlessness
- Visual changes
When a bone marrow aspirate/biopsy is done, what are they sent off for?
- Staining (Wright or Giemsa) to look at cell morphology
- Cytogenetics
- Immunophenotyping for cell lineage
- Flow cytometry
What is the most common leukaemia in adults?
(image really important)
CLL!!!!!
What is the epidemiology and aetiology/risk factors of AML?
Epidemiology
- More common in men and diagnosis age 70
Aetiology
- Myelodysplastic syndrome: increased risk
- Down’s syndrome
- Congenital neutropaenia
- Fanconi anaemia
- Radiation exposure
- Previous administration of chemotherapy
- Toxins: benzene and organochlorine insecticides
How does leukaemia present?
Marrow failure
- Anaemia: fatigue, breathlessness, angina
- Neutropenia: recurrent infections
- Thrombocytopenia: petechiae, nose bleeds, bruising
Tissue infiltration
- Lymphadenopathy
- Hepatosplenomegaly: early satiety and reduced appetite
- Bone pain
- Gum hypertrophy
- Violaceous skin deposits
- Testicular enlargement
What investigations are done if you suspect a patient to have leukaemia, how urgently do you do this and what features would warrant this referral
48 hours FBC
- Bleeding, bruising or petechiae
- Bone pain
- Persistent unexplained fatigue
- Unexplained fever
- Hepatosplenomegaly
- Persistent recurrent infections
- Unexplained lymphadenopathy
- Pallor
What will be seen on a FBC if there is leukaemia?
- Normocytic normochromic anaemia
- Reduced reticulocyte count
- Thrombocytopenia
- Raised white cell count
- Circulating myeloblasts
What further investigations should be ordered for leukaemia?
Bloods
- FBC
- U+Es
- LFTs
- Clotting screen: for baseline and to look for DIC
- DDIMER
- Bone profile & Mg
- Uric acid
- LDH
- Blood borne virus screen
- Blood smear should be completed in all patient!!!!
Bone marrow aspirate and biopsy
For a definitive diagnosis
Imaging
- CT CAP for staging
- CXR for mediastinal mass
Lumbar puncture
If there is concern of CNS involvement
What is LDH a marker of?
Increased cell turnover
What is seen on blood film with AML?
Auer rods - Azurophilic structures seen in myeloid blasts
Also seen in myelodysplastic syndrome
What is diagnostic of AML on bone marrow aspirate/biopsy?
Myeloid blast count of > 20% (of 500 bone marrow cells).
Aspirate and biopsy samples are used for cytogenetics, immunophenotyping and flow cytometry
How is AML managed?
Initial management
Managed in specialist centres and offered any clinical trials if suitable
- Education and support: coordinated by designated nurse
- Supportive care: monitored for infections and coagulopathy
- Cytoreduction
- CNS involvement: started on intrathecal chemotherapy (cytarabine)
- Tumour lysis syndrome: Should be anticipated, prophylaxis should be given
Chemotherapy or Haematopoietic stem cell transplantation
- Induction and consolidation (and occasionally maintenance) stages
- Allogenic stem cell transplant
When is cytoreduction done and how?
Patients with signs of leukostasis and WBC > 100 × 109/L
Hydroxycarbamide
How does an allogeneic stem cell transplant work for AML?
- High dose chemotherapy (+/- radiotherapy) is given to destroy diseased bone marrow and suppress immune system.
- Healthy stem cells from donor are infused intravenously, generating a graft-versus-leukaemia effect.
- Immunosupressive medications are used to prevent GVHD.
What are some poor prognostic indicators in AML?
- Age (> 60)
- Poor performance status
- Multiple significant co-morbidities
- Previous haematological disorders / dysplasia
- Previous exposure to chemo/radio-therapy
- Certain disease subtypes
What is the prognosis with AML if left untreated?
2 months
If treated 20% 5 year survival
How common are leukaemias?
12th most common cancer in the UK
What is the epidemiology of ALL and aetiology/risk factors?
Peak incidence is 1-5 years
- Genetics - Trisomy 21, Klinefelter’s syndrome, Fanconi Anaemia.
- Environment - Viral exposure and radiation exposure
What are the most common presenting symptoms of ALL?
- Bone pain (secondary to bone marrow infiltration)
- Lymphadenopathy
- Symptoms of pancytopenia (pallor, fatigue, dyspnoea, tachycardia)
What are some genetic mutations in ALL?
Philadelphia chromosome t(9:22)
What are the different subtypes of ALL and what is the most common?
- B-cell ALL (75%): associated with Philadelphia chromosome.
- T-cell ALL (25%): usually in adolescent males with mediastinal mass due to thymic involvement.
B cell is most common!
What do you see on a blood smear with ALL?
Blast cells
What are poor prognostic factors with ALL?
Typical cure rate 70 to 90%
- Age (<2 or >10)
- Male
- Non-caucasian
- Performance status > 1
- White cell count > 20 at diagnosis
-
Cytogenetics
- t(9;22) - Philadelphia chromosome
- t(4;11)
- CNS involvement
How is ALL managed?
Chemotherapy +/- Bone Marrow transplant
- Refer to specialist centre and enrol in clinical trials
Pre-phase and supportive therapy
- Pre-phase therapy: commenced on steroids with allopurinol and IV hydration to reduce risk of TLS
- Leucopheresis: helps to mitigate the risk of TLS.
- Supportive therapy: anaemia and thrombocytopenia may require treatment if severe. G-CSF may be given.
Induction chemotherapy
Those with CNS disease require intrathecal chemotherapy and prophylactic therapy may be used in those without to reduce the risk of CNS relapse
Maintenance therapy
Daily 6-mercaptopurine and weekly methotrexate
Stem cell transplant
Allogeneic stem-cell transplant may be considered. Reduces risk of relapse
What are some of the complications of ALL?
- Tumour lysis syndrome
- Neutropenic sepsis
- SVCO
- Chemotherapy side-effects: early (e.g. mucositis, nausea and vomiting, hair loss) or late (e.g. cardiomyopathy, secondary malignancies)
What is the characteristic pathophysiology of CML?
Philadelphia (Ph) chromosome
An abnormal chromosome 22 (t 9:22) that results in a constitutively activated tyrosine kinase
BCR-ABL protooncogene
How does CML tend to present?
- In 50s and 60s with non-specific symptoms like fatigue, fever, night sweats
- Lots are diagnosed incidentally by FBC showing raised WBC in all cell lines
- Often have splenomegaly
How is CML definitively diagnosed?
Bone marrow biopsy/aspirate: allows review of percentages of blasts, promyelocytes, basophils and other haematological cell types for staging of phase as well as material for cytogenetics. Proportion of blasts and basophils help to categorise the phase of disease.
Marrow tends to be hypercellular with myeloid hyperplasia in chronic phase
Cytogenetic or FISH: find Philadelphia chromosome
Blood film: Immature and mature myeloid cells all at different stages of maturation
What white cell is a prognostic marker for CML?
Basophil
What are some baseline investigations you should do with CML?
What are the three stages of CML, how do they present and how long do they last for?
1. Chronic phase
> 85%) present in the chronic phase. Clinical features non-specific e.g fatigue, weight loss and night sweats. Without treatment lasts 3-5 years
2. Accelerated phase
Features more apparent and severe and more difficult to treat and outcomes worse. Untreated this phase lasts around 6-18 months.
3. Blast crisis
Resembles an acute leukaemia with the rapid expansion of blasts. Without treatment survival is typically a few months. It is defined by ELN as:
How can you tell the difference between the accelerated phase and blast crisis in CML?
Accelerated:
- 10-19% blastic leucocytes in peripheral blood and/or bone marrow
- ≥ 20% basophils in peripheral blood
- ≥ 30% of peripheral blood myeloblasts and promyelocytes (combined)
Blast Crisis:
- ≥ 20% blastic leucocytes in peripheral blood and/or bone marrow
- Evidence of extramedullary blast proliferation, apart from spleen
- Clusters of blasts may be seen on bone marrow aspirate analysis
How is CML treated?
IT S CURABLE
- First-line: Tyrosine kinase inhibitor (imatinib), good response in chronic phase
- Chemotherapy: Hydroxyurea or Interferon-alpha
- Allogenic bone marrow transplant
Give some examples of Tyrosine Kinase inhibitors used in CML and the side effects of these?
- Imatinib: Side effects include nausea & vomiting, oedema, cramps, rashes, GI symptoms, headache and fatigue
- Dasatinib: Can cause pleuro-pulmonary toxicity
- Nilotinib: Side effects include cytopenias, headache, nausea, change in bowel habit, rash, pruritus, fatigue and derangement of LFTs. May cause prolonged QT
How is CML management different between chronic and advanced phase?
Chronic phase
- Emergency cytoreduction with very elevated WCC at diagnosis (e.g. > 100 ×109/L)
- Good oral hydration and allopurinol to reduce risk of TLS
- TKIs
- Allogenic SCT if failed initial TKI therapy
Advanced phase
- All patients should be treated as part of a clinical trial
- Second generation TKI with or without intensive chemotherapy
- Allo-SCT offers potential cure in appropriate patients
What is the prognosis with CML?
- If newly diagnosed chronic phase CML have a near normal life-expectancy
- Ages of 15-64: 90% 5-year survival
- 65 and older: 40% 5-year survival
CLL is the most common leukaemia in adults over 55. What is the aetiology and pathophysiology of this?
Chronic proliferation of a single type of well differentiated lymphocyte, usually B-lymphocytes
Genetic alterations
- TP53 mutation: major tumour suppressor gene, linked to a poor response to treatment.
- 11q and 13q14 deletions
- Trisomy 12: presence of an extra 12th chromosome
- Overexpression of BCL2 proto-oncogene
- NOTCH1 mutation
What is the natural disease history of CLL?
RELAPSING AND REMITTING
Initial event or abnormal reaction to an antigen leads to genetic alterations that allow the formation of a clone of B lymphocytes. This is a premalignant disorder, monoclonal B cell lymphocytosis (MBL)
Overtime, further genetic mutations and bone marrow microenvironment changes promote the progression to CLL. This transformation from MBL to CLL occurs at a rate of 1% per year
May remain asymptomatic for many years. The symptomatic stage of CLL is characterised by progressive lymphadenopathy, which includes splenomegaly and hepatomegaly, that occurs due to the accumulation of incompetent lymphocytes.
How does CLL present?
- Lymphadenopathy: hallmark feature due to infiltration of malignant B-lymphocytes
- Asymptomatic: detected on routine blood tests
- Recurrent infections: due to low IgG
What investigations are done to diagnose CLL? (different to other leukaemias)?
DO NOT NEED BONE MARROW ASSESSMENT
- FBC: persistent lymphocytosis and normocytic anaemia
- GOLD STANDARD: Cytogenetics and Immunophenotyping. done by flow cytometry, proves lymphocytes are clonal. Can also look for mutations like TP53
- Blood film: smear or ‘smudge’ cells. These are artefacts due to damaged lymphocytes
What are some further investigations you should do with a diagnosis of CLL and why?
- Routine biochemistry: U&E, bone profile, LFTs
- Haemolysis screen (at risk of AIHA): Direct antiglobulin test (DAT), haptoglobin, LDH, unconjugated bilirubin, reticulocytes
- Immunoglobulins: at risk of secondary hypogammglobulinaemia
- CXR: look for pulmonary lymphadenopathy.
- Lymph node biopsy: if concern about lymphomatous transformation.
- Virology: important prior to initiation of treatment. Hepatitis B, hepatitis C, HIV,CMV
How is CLL staged?
Binet or Rai
Binet staging
Lymphoid sites are cervical nodes, axillary nodes, inguinal nodes, spleen, and liver
- Stage A: <3 lymphoid sites
- Stage B: ≥3 lymphoid sites
- Stage C: presence of anaemia (<100 g/L) and/or thrombocytopaenia (<100 x10^9/L)
Rai staging
Based on natural progression of CLL
- Stage 0 (lymphocytosis): 25% at initial diagnosis
- Stage I-II (lymphocytosis + lymphadenopathy + organomegaly): 50% at initial diagnosis
- Stage III-IV (lymphocytosis + anaemia or thrombocytopaenia +/- lymphadenopathy/ organomegaly): 25% at initial diagnosis
What are some prognostic indicator in CLL?
- Binet and Rai stage
- Lymphocyte doubling time
- Genetic abnormalities on cytogenetics: TP53, del(11q), trisomy 12, and del(13q)
- Beta-2-microglobulin: correlates with disease stage and tumour burden
If patients with CLL are asymptomatic how are they treated?
Watch and wait
If asymptomatic, indolent disease without poor prognostic factors and Binet stage A/B or Rai stage <3
Full blood count at 3 monthly intervals
At 12 months, treatment decisions can be decided based on the trajectory of the condition or develop of active/symptomatic disease
What are indications for treatment with CLL?
Need active disease. Need one of iwCLL criteria:
- Bone marrow failure (Hb < 100 g/L, plts <100 x10^9/L)
- Massive, progressive or symptomatic splenomegaly (≥6 cm)
- Massive, progressive or symptomatic lymphadenopathy (≥10 cm)
- Progressive lymphocytosis (≥50% over 2 months or doubling time < 6 months)
- Autoimmune complications not responsive to steroids (e.g. ITP/AIHA)
- Symptomatic/functional extranodal sites (e.g. skin, kidney, lung, spine)
- Disease-related symptoms (e.g. significant weight loss, severe fatigue, >2 weeks of fever or ≥1 month of night sweats without infection)
What does treatment depend on in CLL?
- Patient fitness and performance status
- Co-morbidities
- Mutational analysis (e.g. TP53 mutations)
- First-line treatment or treating relapse/refractory disease
How is active CLL treated medically/surgically?
Pharmacotherapy
-
Chemotherapy
- Chlorambucil: cross-links DNA leading to damage and apoptosis.
- Fludarabine: purine analog that inhibits DNA synthesis
- Bendamustine: alkylating agent that cross-links DNA
-
Small molecule inhibitors
- Ibrutinib: tyrosine kinase inhibitor. TP53 mutations
- Idelalisib: phosphoinositide 3-kinase inhibitor.
- Venetoclax: BCL2 inhibitor
-
Monoclonal antibodies
- Rituximab/Obinutuzumab/Ofatumumab: Anti-CD20 antibodies that target B lymphocytes
-
Other
- Corticosteroids: in extremely frail patients or to treat autoimmune complications including haemolytic anaemia and immune thrombocytopaenia
Allogenic stem cell transplantation
- If fail chemotherapy and BCR inhibitor therapy
- TP53 mutations that do not respond to treatment or relapse
- Richter’s transformation
What supportive care is done in CLL?
- Vaccination: influenza, pneumococcal
- Antibiotics for infections
- Consider IVIG: treatment of secondary hypogammaglobulinaemia (i.e. IgG < 5g/L)
- Consider (PJP) and herpes zoster prophylaxis: in patients on treatment for relapsed CLL
What autoimmune complications are patients with CLL at risk of?
- AIHA
- ITP
What are some of the complications of CLL?
Histological transformation
- Richter transformation: aggressive lymphoma, 5-8 month survival
- Prolymphocytic leukaemia
- Hodgkin lymphoma
- Multiple myeloma
Other complications
- Secondary infections: herpes zoster, PJP, bacterial infections
- Autoimmune complications: AIHA, immune thrombocytopaenia
- Hyperviscosity syndrome
- Secondary malignancies
How may you know that Richter’s transformation has happened in CLL?
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma
Ritcher’s transformation is indicated by one of the following symptoms:
- lymph node swelling
- fever without infection
- weight loss
- night sweats
- nausea
- abdominal pain
What is the prognosis with CLL?
1/3 of cases don’t progress, 1/3 of cases progress slowly, and 1/3 of cases progress actively
Why is ESR massively elevated in myeloma?
Increase in proteins within the plasma, either due to an abnormal protein such as a paraprotein in myeloma, or a polyclonal increase in proteins secondary to some other underlying inflammatory pathology
When is Rasburicase given over Allopurinol?
When patients are high risk for TLS e.g haematological malignancy
What are myeloproliferative disorders and what are the three main ones? What cell line do they come from?
Uncontrolled proliferation of a single type of stem cell, type of bone marrow cancer
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
What gene mutations are associated with myeloproliferative disorders and what is the risk with these disorders?
Risk of transformation to AML
- JAK2
- MPL
- CALR
What is myelofibrosis?
Can be result of primary myelofibrosis, polycythaemia vera or essential thrombocythaemia
Proliferation of the cell line leads to fibrosis of the bone marrow due to cytokines that are released from the proliferating cells. Usually fibroblast growth factor
Extramedullary haematopoiesis occurs in other areas such as the liver and spleen leading to hepatomegaly and splenomegaly. This can lead to portal hypertension. If it occurs around the spine it can lead to spinal cord compression.
How may myeloproliferative disorders present?
Myelofibrosis leads to low RBC, WBC and platelets
- Firstly asymptomatic
- Systemic symptoms: fatigue, weight loss, night sweats, fever
- Anaemia (except in polycythaemia)
- Splenomegaly (abdominal pain + early satiety)
- Portal hypertension (ascites, varices and abdominal pain)
- Low platelets (bleeding and petechiae)
- Thrombosis is common in polycythaemia and thrombocythaemia
- Raised red blood cells (thrombosis and red face)
- Low white blood cells (infections)
What are the three main symptoms of polycythaemia vera?
What are the FBC findings in myeloproliferative disorders?
If you suspect myelofibrosis what investigations should you order and what will these investigations show?
Blood film
- Teardrop shaped RBCs
- Varying sizes of RBCs
- Immature red and white cells (blasts)
Diagnosis
Bone marrow biopsy as bone marrow aspiration is usually dry as scar tissue
Testing for the JAK2, MPL and CALR genes can help guide management
How is primary myelofibrosis managed?
- Patients with mild disease with minimal symptoms might be monitored and not actively treated
- Allogeneic stem cell transplantation is potentially curative but carries risks
- Chemotherapy can help control the disease, improve symptoms and slow progression but is not curative on its own
- Supportive management of anaemia, splenomegaly and portal hypertension
- JAK2 inhibitors and hydroxycarbamide
How is polycythaemia vera managed?
- Venesection is first line, aim is to bring Haematocrit to <0.45
- Aspirin 75mg daily to reduce risk of VTE
- Cytoreductive therapy/Hydroxycarbamide to control the disease
How is essential thrombocythaemia managed?
- Aspirin
- Chemotherapy/Cytoreductive therapy if high risk of transformation
What are some causes of polycythaemia?
Raised haemtocrit
Primary: Polycythaemia Vera
Secondary: see image
Relative: Decrease in plasma volume e.g dehydration, diuretics
What is the main mutation in polycythaemia vera?
JAK2 - Tyrosine Kinase
How is polycythaemia vera usually detected?
(image important)
- Incidental finding on FBC and asymptomatic
OR
- Symptoms of raised haematocrit with gradual onset e.g hypertension
What is erythromelalgia?
What investigations are done to find out the underlying cause of polycythaemia?
Iron deficiency can mask polycythaemia vera
What is the diagnostic criteria for polycythaemia vera?
- High haematocrit (> 0.52 in men, > 0.48 in women) OR raised red cell mass (>25% above predicted)
- AND*
- Mutation in JAK2
What is the prognosis with polycythaemia vera?
- If untreated survival is 18 months
- If treated can live several decades
- 5% transform for AML
- 5-15% progress to myelofibrosis by 15 years
What are some causes of thrombocythemia apart from essential thrombocythaemia?
- Do bone marrow biopsy
- Do iron studies
- Blood film
How does essential thrombocythemia present and what investigations would you do and what would they show?
- Burning sensation in hands
- Thrombosis
- Haemorrhage – more common if plt count >1500
- Splenomegaly
- Platelet count > 600 * 109/l
- JAK2 mutation in 50% of patients
What is myelodysplasia?
Pre-Leukaemia - may progress to AML
Myeloid bone marrow cells not maturing properly. Bone marrow hyper cellular but peripherally pancytopenic
Cause anaemia, neutropenia, thrombocytopenia
What types of patients is myelodysplasia more common in?
- Above 60
- Previous radio/chemotherapy
There is an increased risk of transforming into acute myeloid leukaemia
How may myelodysplasia present and how is it diagnosed?
Presentation
- Asymptomatic and found incidentally on FBC
- Symptoms of anaemia (fatigue, pallor or shortness of breath), neutropenia (frequent or severe infections) or thrombocytopenia (purpura or bleeding)
Diagnosis
- FBC abnormal
- Blasts on blood film
- Confirmed by bone marrow aspiration and biopsy
How is myelodysplasia managed?
- Watchful waiting
- Supportive treatment with blood transfusions if severely anaemic
- Chemotherapy
- Stem cell transplantation
What is the logic behind watch and wait in early CLL and CML?
- The use of alkylating agents or aggressive chemotherapy in patients with early-stage disease does not prolong survival
- There are risks of early treatment, including potential side effects and treatment complications.
- Patients may build up a resistance to the drugs used and would not be able to use them again when treatment for progressive disease is necessary.
What is the most common leukaemia in children?
ALL
(AML if Downs)
