Leukaemia Flashcards
What are the main types of leukaemia?
Acute myeloid leukaemia
Acute lymphoblastic leukaemia
Chronic myeloid leukaemia
Chronic lymphoid leukaemia
What is the pathophysiology of ALL?
Arises from lymphoid progenitor cells that undergo malignant transformation
Most are B cell in origin
May arise from T cells
As clonal expansion occurs, these precursors replace other haematopoietic cells in the bone marrow
Classified as B cell lineage
T cell lineage
What cytogenic features are seen in ALL?
t(12;21) most common translocation seen in children - TEL-AML fusion gene
t(9;22) Philadelphia chromosome - BCR-ABL
t(4;11) in infants <12 months, rare in adults
Hyperdiploid karyotype
Hypodiploid karyotype
What are the clinical features of ALL?
Marrow suppression symptoms and lymphadenopathy
Marrow failure:
Anaemia - fatigue, SOB, angina
Neutropenia - recurrent infections
Thrombocytopenia - petechiae, nose bleeds, bruising
Tissue infiltration Lymphadenopathy Hepatosplenomegaly Bone pain Mediastinal mass - may result in SVCO Testicular enlargement
Leucostasis
May occur due to large numbers of WCs entering blood stream
Organ dysfunction due to impairment through small vessels
Altered mental state, headache, SOB, visual changes
What is the presentation of T cell ALL?
Rarer than B cell form
Typically present in adolescent males
With lymphadenopathy or a mediastinal mass
What are the investigations for ALL?
Bloods
FBC, U&Es, LFTs, clotting
DDIMER, bone profile,
uric acid, LDH, BBV
Most will present with pancytopenia
Uric acid and LDH non specific markers of tumour border
DDIMER and coag for DIC
Imaging
CXR - mediastinal mass
CT chest, abdo pelvis for lympadenopathy and organ involvement
CT/MRI head exclude differentials, neurology
Bone marrow aspiration and biopsy, staining and review of cell morphology
Immunophenotyping
Blood smear
Pleural tap if pleural effusion
LP if CNS involvement
What are high-risk factors for adult patients, indicating a poorer prognosis?
Age - worse with advancing age Performance status > 1 WCC - >30 for B, >100 for T Cytogenetics - 9;22, 4;11 Immunophenotype - proB, early and mature T CNS involvement
What is the management of ALL?
Referral to haemato-oncology specialists
- Pre-phase therapy - steroids, with allopurinol and IV hydration, reduces risk of TLS
Can give rasburicase to prevent TLS as helps clears uric acid from body
Leucopheresis can help reduce WCC for TLS.
Anaemia and thrombocytopenia may need treatment, G-CSF for neutropenia.
- Induction chemotherapy
For complete remission or molecular complete:
Complete - not in bone marrow, peripheral blood or CSF
MolecularCR - minimal disease not detectable by sensitive molecular probe - Maintenance therapy
Daily 6-mercaptopurine
Weekly methotrexate
Reduce risk of recurrence - Stem cell transplant
Allogenic
Myeloablative transplant = high dose chemo, then stem cell transplant - Palliative care
What complications are ALL patients at risk of?
TLS
Neutropenic sepsis
SVCO - dyspnoea, facial swelling, cough secondary to mediastinal mass
Chemo side effects - early mucositis, nausea, vomiting, hair loss or late - cardiomyopathy, secondary malignancies
What do you look for in a cytochemical stain in acute leukaemias?
TdT+ in lymphoblasts - ALL
Myeloperoxidase in myeloblasts - AML
How is philadelphia + ALL managed?
Stem cell transplant
Imatinib
TKI’s - tyrosine kinase inhibitors
What is APL? What genetics is it associated with?
Acute Promyelocytic Leukaemia
translocation of chromosome 15 and 17 t(15;17)
How does APL normally present? Describe the pathophysiology of this
Younger than AML and it’s other subtypes (age 25 ish)
build up of promyelocytes –> lots of Auer rods –> high coagulation risk –> DIC
Medical Emergency!
How is APL treated?
It responds to retinoic acid (ATRA)
What is myelodysplastic syndrome?
What would the bone marrow look like?
How would it present?
Condition which is a precursor of AML
Blasts build up in marrow but <20%
Same signs - cytopaenia, bruising etc.
Describe the age presentation of ALL vs AML
ALL is childhood (2-5)
AML is adults (65)
What are the blood results in ALL?
normocytic, normochromic anaemia
thrombocytopenia
leukocytosis but with neutropenia
reduced reticulocytes
Renal failure: raised K and phosphate
raised LDH
What is the bone marrow like in ALL?
hypercellular
blast cell infiltration
On cytochemical staining, what is seen in ALL? Compare this to AML?
blasts are TDT+ve
In AML it is myeloperoxidase +ve
What is ALL associated with?
Most common in children
Associated with Down’s
What is CLL associated with?
Most common leukaemia in adults overall
Associated with warm haemolytic anaemia
Richter’s transformation in lymphoma
Smudge/smear cells
What is CML associated with?
Has three phases
A 5 year - ‘asymptomatic chronic phase’
Associated with the Philadelphia chromosome
What is AML associated with?
Most common adult acute leukaemia
Can be the result of a transformation from a myeloproliferative disorder
Associated with Auer rods
What are the differentials for petechiae?
Leukaemia Meningococcal sepsis Vasculitis Henoch Schonlein Purpura Idiopathic Thrombocytopenia Purpura Non accidental injury
What is the pathogenesis of a haematological malignancy?
Cause - environment, toxin, virus infection, drug, genetic predisposition: translocation, deletion, duplication, point mutation
Pathogenesis - altered gene expression, change in oncogene or tumour suppressor gene
Leads to decrease in apoptosis and differentiation, and proliferation increase
What are lymphoid haematological malignancies?
Acute - lymphoblastic leukaemia
Chronic Lymphocytic leukaemia Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma
What are myeloid malignancies?
Acute myeloid leukaemia
Chronic myeloid leukaemia
Myelodysplasia
Myeloproliferative disorders e.g. polycythaemia vera, essential thrombocytopenia, primary myelofibrosis
What would be shown on a blood film in T-ALL?
Bone marrow showing large number of lymphoblasts with a high nuclear/cytoplasmic ratio
What would be shown on a blood film in B-ALL?
Large blasts with characteristic vacuoles and blue cytoplasm
What are prognostic indicators in AML suggesting a better outcome?
Cytogenic changes - 8;21, 15;17, inversion 16
Remission after one course of chemotherapy
What indicates poor risk in AML?
Cytogenic changes - monosomy 5, monosomy 7, complex charyotypes, 11q23 abnormalities
Aged over 70
How can AML be classed?
Primary or secondary; as may follow a previous myeloproliferative or myelodysplastic event
What is the aetiology of AML?
Not completely understood
Myelodysplastic syndrome and high risk features e.g. excessive blasts
Congenital disorders e.g. Down’s, Fanconi anaemia
Radiation exposure
Prev chemo
Toxins - bezene, organochloride insecticides
What are the clinical features of AML?
Pancytopenia
Fatigue, SOB, angina, recurrent infections, petechiae, nosebleeds
Tissue infiltration
Leucostasis
What are the investigations for AML?
Normocytic normochromic anaemia is common
As is thrombocytopenia and reduced reticulocyte count
Usual blood panel
Clotting and DDIMER - DIC
Bone profile, Mg
Blood smear:
Auer roads - azurophilic structures seen in myeloid blasts (also seen in myelodysplastic syndrome)
Bone marrow aspirate
Myeloid blast count of >20%
LP if concern of CNS involvement
What is the management of AML?
Education and support
Cytoreduction considered in signs of leukostasis and WBC count >100 with hydroxycarbamide
Intrathecal chemo - cytarabine if CNS involved
TLS - prophylaxis where indicated
Chemo:
Induction - cytarabine, daunorubicin and gemtuzumab
Consolidation - IDAC
Allogenic haematopoietic stem cell transplant following myeloablative conditioning regimes +- total body irradiation
What factors indicate poorer prognosis in AML?
‘Secondary leukaemia’ following a preceding haematological disorder e.g. MDS
Age >60 Poor performance status Multiple significant co-morbidities Prev haematological disorders, dysplasia Prev exposure to chemo/radio Certain disease subtypes
What are the phases of treatment for leukaemia?
First phase remission induction with high dose intensive combination chemo
to re-establish normal haemopoiesis
Then post induction chemo initially intensive
Then for ALL less intensive maintenance chemo
Requires 4-6 weeks in hospital
What is chronic lymphocytic leukaemia?
Lymphoproliferative disorder of B lymphocytes
Results from abnormal clonal expansion of B cells
Leads to widespread lymphadenopathy
Due to genetic alterations and changes to the bone marrow microenvironment
What genetic alterations are associated with CLL?
TP53 mutation, major tumour suppressor gene 11q and 13q14 deletions Trisomy 12 Overexpression of BC12 proto-oncogene NOTCH1 mutation
What is monoclonal B cell lymphocytosis?
Premalignant disorder
Genetic alterations allow the formation of a clone of B lymphocytes
Overtime further mutations and bone marrow microenvironment changes allows progression to CLL
What are the clinical features of CLL?
Hallmark feature is lymphadenopathy
due to infiltration of malignant B lymphocytes
Large proportion may be asymptomatic so detected on routine blood tests or finding of abnormally enlarged but painless lymph nodes
Weight loss, anorexia
Fevers, night sweats
Lethargy
Lymphadenopathy, most commonly cervical, supraclavicular, axillary
Hepatomegaly
Splenomegaly
What features occur in association with complications of CLL?
Autoimmune haemolytic anaemia - pallor, SOB, weakness, dizziness
Immune thrombocytopenia - petechiae, bruising, mucosal bleeding
Hypogammaglobulinaemia - recurrent infections, organ specific
How can a diagnosis of CLL be made?
Excess lymphocytes found to be clonal (of same type)
Assessed by flow cytometry
Absolute B lymphocyte count of >5x10^9 for > 3 months or >1 cytopenia due to bone marrow infiltration
And characteristic immunophenotype features and presence of disease manifestations
What is done for investigations for CLL?
Clinical examination to determine presence or absence of lymph node involvement inc specific sites, splenomegaly and hepatomegaly
Bloods - FBC, routine biochemistry, blood film, haemolysis screen, immunoglobulins
Cytogenetics and immunophenotyping
Blood film
Lymphocytes, smudge cells
Bone marrow assessment not usually required unless alternative diagnosis
CT imaging if concerned about lymphomatous transformation
CXR
Lymph node biopsy
Virology
What is the staging of CLL?
Binet Staging
Based on number of lymphoid sites affected on clinical examination
Stage A < 3 sites
Stage B >3 lymphoid sites
Stage C - presence of anaemia or thrombocytopenia
An area is counted as one regardless of whether unilateral or bilateral
Rai Staging
Based on expected natural progression to marrow failure
Stage 0 - lymphocytosis
Stage I-II lymphocytosis, lymphadenopathy, organomegaly
Stage III-IV lymphocytosis, anaemia, thrombocytopenia, lymphadenopathy, organomegaly
What are some prognostic factors for CLL?
Lymphocyte doubling time
Genetic abnormalities e.g. TP53, trisomy 12
Beta 2 microglobulin
Mutated immunoglobulin heavy chain variable genes
What is the management for CLL?
Watch and wait if asymptomatic indolent
Assessment and FBC at 3 monthly intervals
Front line therapy with no TP53 mutations - Fludarabine, cyclophosphamide, Rituximab
Front line therapy with mutations Ibrutinib, Rituximab
Chemo - e.g. chlorambucil
Small molecule inhibitors e.g. venetoclax, Ibrutinib
Monoclonal antibodies e.g. Rituximab
Corticosteroids
Allogenic stem cell transplantation
Supportive care - vaccination, abx, intravenous immunoglobulins, PJP and herpes zoster prophylaxis
What is Richter transformation?
CLL becomes a form of aggressive lymphoma
Associated with rapid deterioration
What are some of the complications of CLL?
May transform into another lymphoproliferative disorder
Prolymphocytic leukaemia
Hodgkin lymphoma
Multiple myeloma
Secondary infections - herpes, PJP, bacterial
Autoimmune complications
Hyperviscosity syndrome
Secondary malignancies
What are the indications for treatment of CLL?
Bone marrow failure - Hb <100, plts <100 x 10^9 g/L
Massive, progressive or symptomatic splenomegaly
Massive progressive or symptomatic lymphadenopathy
Progressive lymphocytosis
Autoimmune complications not responsive to steroids
Symptomatic/functional extra nodal sites
Disease related symptoms
What disease related symptoms should you be on the look out for, for CLL?
Significant weight loss
Severe fatigue
>2 weeks of fever
>1 month of night sweats, without infection
What is chronic myeloid leukaemia associated with?
Philadelphia chromosome - translocation of 9 and 22
Results in a constitutively activated tyrosine kinase
What are the clinical features of CML?
Some asymptomatic, or non vague features, picked up on other tests
Fatigue, weight loss
Night sweats, anaemia
SOB, angina
Thrombocytopenia - petechiae, nose bleeds, bruising
Splenomegaly - early satiety, abdominal pain
Bone pain
Leucostasis - headache, breathlessness, visual changes, priapism
Splenomegaly
Hepatomegaly
Lymphadenopathy
Leucostasis - altered mental state, priapism
What are the investigations for CML?
Bloods - excessive granulocytosis with typical left shift
Bloods
FBC - raised WCC
Blood film - immature and mature myeloid cells
LDH, urate and potassium useful markers of disease
Renal function, LFTs, bone profile, Mg, lipids, HbA1c
Cytogenetics, FISH to identify Ph chromosome - BCR-ABL1 fusion
Bone marrow aspirate
Marrow is hyper cellular with myeloid hyperplasia
Why is allopurinol given in chemo treatments?
Reduce level of uric acid and risk of tumour lysis syndrome
What are the disease phases of CML?
1. Chronic phase Most present at this point Features non-specific Fatigue, weight loss, NSs Prior to advance tx, this phase would last 3-5 years
- Accelerated phase
Features more apparent and severe, harder to treat
Lasts 6-18 months untreated
Blasts in blood or marrow15-29%, basophils in blood
Persistent thrombocytopenia
Clonal chromosome abnormalities in Ph cells
3. Blast crisis Resembles an acute leukaemia Without tx, survival is a few months Blasts in blood or bone marrow >30% Extramedullary blast proliferation
What is the management of CML?
Tyrosine kinase inhibitors - block the enzyme created by BCR-ABL1 fusion gene
Invasive chemo reserved for patients with plastic transformation
Allogenic stem cell transplant for chronic patients
What tyrosine kinase inhibitors are used in the treatment of CML?
Imatinib
Dasatinib
Nilotinib
What are some side effects of tyrosine kinase inhibitors used in CML?
Nausea, vomiting Oedema, cramps, rashes GI symptoms, headache Fatigue Derangement of LFTs Pleuro-pulmonary toxicity
What are the phases of CML?
Chronic phase
May need emergency cytoreduction if WCC v high
Good oral hydration and allopurinol to reduce risk of TLS, use of TKIs
Advanced phase
May have undergone blastic transformation
Second generation TKI with or without intensive chemo
What are the complications of CML?
Thrombotic event
Blast transformation to an acute leukaemia
What cytogenetic findings suggest CML?
Philadelphia!! Seen in 95% of patients with CML
What is seen on a blood film of CML? and what is seen in the bone marrow?
Granulocytes at all different stages of development
BM: hypercellular with ++ granulocytes
Blood results seen in CML?
+++ leukocytosis
normocytic, normochromic anaemia
Thrombocytosis progresses to penia
What is Richter transformation? What is the pathophysiology? How does it present?
Transformation of CLL to a high grade lymphoma
Due to leukaemia cells infiltrating the lymph node
SUDDEN deterioration of symptoms
- B symptoms
- lymph node swelling
- abdo pain and nausea
What is hypogammaglobulinaemia and what does it lead to?
It results in a lack of antibodies and therefore infections
What is seen on a blood film in CLL?
Smudge/smear cells
Lymphocytosis
NOT blasts
Poor prognostic features of AML?
> 60
20% blasts after first chemo
chromosome deletions
Characteristics of the bone marrow in AML?
Hypercellular
>20% Blast cells
What is seen on the blood film of AML?
Blast cells with Auer rods
What is myelodysplastic syndrome?
What would the bone marrow look like?
How would it present?
Condition which is a precursor of AML
Blasts build up in marrow but <20%
Same signs - cytopaenia, bruising etc.
When are most CML’s diagnosed?
in the chronic phase - incidentally found on routine bloods
What is a blast crisis?
No ability to differentiate so resemble acute leukaemia
Bone marrow exhaustion and large tumour burden - systemically unwell and rapidly fatal
What is regularly monitored throughout management of CML?
FISH studies - show % bone marrow cells Ph+
