Haematology 1 Flashcards
Acute Leukaemias Chronic Myeloid Leukaemia and Myeloproliferative disorders Chronic Lymphocytic Leukaemia Lymphomas Myeloma Myelodysplastic syndromes & Bone Marrow Failure Bone Marrow Transplantation
Leukaemia literal meaning
white blood
Pathophysiology of Leukaemia
What types exist
Caused by mutations in white blood cells or their precursors
Mutations cause proliferation through a variety of mechanisms
Can be rapidly progressive or indolent – (Acute vs Chronic)
List myeloid cell types
Branching off from multipotential haematopoietic stem cell
Common Myeloid Progenitor
Megakaryocyte, Mast Cell, Erythroblast, Myeloblasts: Basophil, Eosinophil, Neutrophil, Monocytes –> Macrophage
List Lymphoid cell types
Branching off from multipotential haematopoietic stem cell
Common Lymphoid Progenitor
Natural Killer Cell, Small Lymphocytes: T Lymphocytes, B Lymphocytes –> Plasma Cells
Which cells does acute leukaemia affect?
The more acute the leukaemia, the higher up it affects the chain of blood cell production
What cell does AML and CML affect?
Common Myeloid Progenitor
What causes CML?
BCR-ABL mutation in the myeloid progenitor or prior stem cell line
What is myeloma?
Myeloma – Plasma cell dyscrasia – proliferation of PLASMA cells in bone marrow
What cells does CLL affect?
Small Lymphocytes: T Lymphocytes and B Lymphocytes
What cell does ALL affect?
Common Lymphoid Progenitor
Clinical Presentation of Leukaemia
anaemia, thrombocytopenia, leukopenia/neutropenia
Splenomegaly less common than chronic leukaemias
Bone pain common
Pathophysiology of Leukaemia:
Rapid proliferation of cells, causing packed bone marrow
Results in bone marrow failure
3 overheading signs of Leukaemia
Anaemia, Thrombocytopenia, Leukopenia
3 overheading signs of Acute Leukaemia and associated symptoms
Anaemia: shortness of breath, chest pain on exertion, fatigue
Thrombocytopenia: easy bruising, petechial rashes, spontaneous bleeding e.g. epistaxis
Leukopenia: frequent or severe infections including opportunistic infections e.g. fungal infections
Additionally, bone pain
How does chronic leukaemia differ from acute leukaemia?
Slower proliferation of malignant cells
Less burden of disease in bone marrow
Clonal cells can pool in lymph nodes or in the spleen
Clinical manifestations – lymphadenopathy, splenomegaly
Key features of ALL in the history
Child – typically 2-5 yrs old
Hepatosplenomegaly (usually in chronic L, but children have small organs so occurs in ALL too)
Bone pain / limp (can be this alone - KEY FACT!)
Fevers
CNS symptoms
Testicular swelling (rare but specific - pooling of cells) (bALLs)
Adults – similar to AML, lymphadenopathy
Key features of ALL on blood tests
LOW PLATELETS (THROMBOCYTOPENIA)
LOW HB (ANAEMIA)
HIGH WCC
CIRCULATING BLASTS
Usually present with thrombocytopenia and anaemia
High white cell count (if severe, will be normal or suppressed)
Some analysers will indicate presence of blasts but sometimes these will be flagged as lymphocytes.
Circulating blasts are abnormal (should be in bone marrow)
https://imgur.com/2ZABq6m
interpret this blood film
High nucleus – cytoplasm ratio
It is not possible to tell ALL from AML on blood film most of the time!
This is Precursor B-cell ALL
What are key Ix for ALL?
Flow Cytometry and Bone Marrow Biopsy
What is Flow Cytometry?
a technique used to detect and measure physical and chemical characteristics of a population of cells or particles. A sample containing cells or particles is suspended in a fluid and injected into the flow cytometer instrument.
What causes ALL?
what is a method of remembering this?
BCR-ABL1 t(9;22) associated with 20-30% of ALL in adults
ALL can affect testicles - Balls - B-ALL spells out BALL.
B standing for BCR-ABL1 t(9:22) mutation
How is ALL treated?
Chemotherapy - Imatinib or other TKI for BCR-ABL1
Induction –> Consolidation –> Maintenance –> Remission
Possible transplant
Key features of AML in the history
Incidence increases with age
Might have had pre-existing MDS (myelodysplastic syndromes can transform into ALL)
Symptoms of cytopenias
Key features of AML on blood tests
anaemia (low haemoglobin) (bone marrow suppression)
high WCC
low platelets (bone marrow suppression)
neutropenia (lack of mature white cells due to xs blasts)
high blasts
normal INR - normal for AML
Abnormal INR - possible DIC due to acute promyelocytic leukaemia
https://imgur.com/ERMjP3z
what is the feature and dx
Auer Rods
AML (one is enough to diagnose AML or MDS)
https://imgur.com/0YTUM0h
what is the feature and dx
Auer Rods
AML (one is enough to diagnose AML or MDS)
https://imgur.com/Oe1u3pi
what is the feature and dx
Auer Rods
AML (one is enough to diagnose AML or MDS)
https://imgur.com/HUniyD6
what is the feature and dx
Auer Rods
AML (one is enough to diagnose AML or MDS)
https://imgur.com/oerYgPF
what is the feature and dx
Faggot Cells (stacks of Auer Rods)
AML
Next steps if suspecting AML but no Auer Rods?
Positive Result?
Flow Cytometry
MPO
Important subtype of AML?
Significance?
Treatment?
T(15;17) Acute Promyelocytic Leukaemia
Presents with DIC. Good prognosis
Treat with: All-Trans Retinoic Acid (ATRA) aka Vitamin A: Forces cells to differentiate, stops proliferation
AML treatment?
Prognosis?
Similar to ALL - Imatinib or similar TKI
Possibility of targeted agents in future
Poor prognosis particularly in elderly who won’t tolerate stem cell transplant
What are myeloproliferative Neoplasms?
These are increased production of the myeloid lineage i.e. anything following the Common Myeloid Progenitor in the chain
What is the myeloproliferative neoplasm affecting megakaryocytes?
Diagnosis? Associated Mutation?
Treatment?
Essential Thrombocytopenia
Platelet count consistently >450
JAK2 Mutation in 55%
Aspirin to reduce stroke risk
Hydroxycarbamide to lower count
What is the myeloproliferative neoplasm affecting Erythrocytes?
Diagnosis? Other features? Risks? Associated Mutation?
Treatment?
Polycythaemia Vera
Haematocrit >0.52 / 0.48 (M/F)
Often thrombocytothaemia as well
High Risk of thrombotic events e.g. stroke, MI, Budd-Chiari Syndrome (very dense, thick blood)
JAK2 Mutation 95%
Aspirin to reduce stroke risk
Venesection (taking blood to lower haematocrit)
Hydroxycarbamide to lower count
What is Haematocrit?
the ratio of the volume of red blood cells to the total volume of blood.
Meaning of ‘Polycythaemia’?
Excess production of Red Blood Cells
What is caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites, and liver enlargement.
Budd–Chiari syndrome
affects 1 in 1 million
What causes proliferation of stem cells in the bone marrow & subsequent fibrosis? Pathophysiology?
Associated mutation? Ix results?
Blood film finding?
Pathagnomonic Ix and Result?
Treatment?
Myelofibrosis
clonal proliferation of stem cells (first cell in the chain)
results in cytokine release and fibrosis of bone marrow
The fibrosis causes reduced production of all cell lineages
JAK2 Mutation in 50%
Pancytopenia
Splenomegaly (can be massive splenomegaly)
Tear Drop Cells
Bone Marrow aspiration - Dry Tap (no aspirate)
Stem cell transplant likely only cure
Ruloxitnib - JAK inhibitor
What is a key type of MPN?
A key type of myeloproliferative neoplasm is CML
Increased production of the Myeloid Lineage
What are key features of CML in the history?
Typically onset age 35-55 in EMQs
LUQ pain - Splenomegaly
Mostly ASYMPTOMATIC if diagnosed in chronic phase
May present with symptoms of acute leukaemia if in accelerated / blast phase (~10%)
Typical age of onset of CML?
35-55
Ahmed - Saeid
Key features of CML on blood tests
Haemoglobin - normal (unlikely v anaemic)
WCC - 30 (v. v. high - Leukocytosis)
Platelets 450 (high - if chronic may have dropped, 50% have elevated platelet count)
Neutrophils 15 (neutrophilia)
Basophils (might be elevated blood count)
Monocytes (
Clinical Presentation of Chronic Leukaemia (4 points)
Slower proliferation of malignant cells
Less burden of disease in bone marrow
Clonal cells can pool in lymph nodes or in the spleen
Clinical manifestations – lymphadenopathy, splenomegaly
CELLS WITH HIGH NUCLEUS - CYTOPLASM RATIO ON BLOOD FILM
ALL (maybe AML - can’t tell apart)
Ix for ALL
Bone Marry Biopsy & Flow Cytometry
BCR-ABL1 t(9;22) associated with?
20-30% of ALL in adults
may indicate CML too
Mx for ALL?
Imatinib
or other tyrosine kinase inhibitor for bCR-ABL1
possibly transplant
Key features of AML on blood tests
low hb high WCC low platelets low neutrophils raised blasts INR normal (AML) INR high (DIC due to acute proteomyelocytic leukaemia)
Auer Rods?
AML
possibly MDS
what are faggot cells?
stacks of auer rods - indicate AML
Ix for AML if no auer rods seen?
Flow Cytometry - (MPO)
What is acute promyelocytic leukaemia?
type of AML with good prognosis and different mx (w/ ATRA) that presents with DIC (clotting and procoagulant depletion - clots & difficulty forming more clots - low PLT and fibrinogen)
AML treatment
Imatinib
similar to ALL - (chemotherapy)
poor prognosis, particularly in elderly who can’t tolderate stem cell transplant
bone marrow transplant if treatment not working
What are myeloproliferative neoplasms?
Excess production of red cells, white cells or megakaryocytes or any other myeloid cell.
What are myeloproliferative neoplasms?
INCREASED PRODUCTION OF MYELOID LINEAGE CELLS
PLATELET COUNT >450 CONSISTENTLY (no hx of recent infection where it can be raised)
KEY COMPLICATION
MX
ESSENTIAL THROMBOCYTHAEMIA
STROKE
HYDROXYCARBAMIDE
& ASPIRIN (to reduce stroke risk)
What are the 4 main myeloproliferative disorders?
Polycythaemia Vera (RBCs)
Essential Thrombocythaemia (PLTs)
CML (granulocytes)
Myelofibrosis (stem cells fibrose bone marrow - all cell lineages REDUCED)
What medication lowers myeloid cell count?
Hydroxycarbamide
Haemocrit >0.5 ±0.2
High PLT
dx
mutation %
important complication
mx
POLYCYTHAEMIA VERA
JAK2 MUTATION 95%
MX
ASPIRIN to reduce stroke risk
VENESECTION to lower haematocrit
HYDROXYCARBAMIDE to lower count
Low RBC
Low WCC
Low PLT
Dx & Ix
Mutation & %
features
Mx
ASSOCIATION ON BLOOD FILM
Myelofibrosis - clonal proliferation of stem cells in bone marrow –> cytokine release and fibrosis of bone marrow –> reduced prod. all myeloid cell lineages
Ix: BONE MARROW BIOPSY - DRY TAP!!
JAK2 MUTATION in 50%
Pancytopenia
SPLENOMEGALY - can be MASSIVE SPLENOMEGALY
Mx:
STEM CELL TRANSPLANT likely only cure
RULOXITINIB - JAK inhibitor!
TEARDROP CELLS
age range of CML?
common presenting complaints?
35-55
LUQ pain & splenomegaly
mildly low Hb v high WCC high PLT high NEUT possibly high basophils low monocytes
CML
Left Shift on blood film
CML
CML blood film features
Features: “Left shift” Leukocytosis Eosinophilia Basophilia
Hypolobated megakaryocytes in bone marrow
The bigger the cells the more _____ they are
immatrure
mutation in CML
which Ix used?
PHILADELPHIA CHROMOSOME
aka BCR-ABL1 fusion gene
translocation t(9;22)
FISH (fluo in situ hybridisation)
What are the phases of CML?
3 phases
Chronic (85-90%)
Accelerated (gradually more blasts in bone marrow)
Blast Phase (20% blasts in bone marrow - behaves like AML)
Management of CML
Prognosis
worst case scenario?
Tyrosine Kinase Inhibitors:
1st gen: Imatinib
2nd gen: Dasatinib, Niltinib, Bosutinib
3rd gen: Pontaninib
> 90% 10 yr survival
Small percentage of patients will fail treatment and need transplants
Signs and Symptoms of CLL
ASYMPTOMATIC dx on bloods AGE >50 - incidence increases w age Men:Women 2:1 can present with lymphadenopathy/splenomegaly, ITP/haemolytic anaemias
Normal Hb (occasionally low) EXTREMELY high WCC (100) PLT normal NEUT normal Lymphocytes 95 (WCC made up of mature lymphocytes)
CLL
Smear cells (blood film)
CLL
Smudge Cells (blood film)
CLL
Ix with CLL?
Flow cytometry
Usually B-cell but can get T-cell CLL
Same pathology as small lymphocytic lymphoma but different distribution: blood/marrow vs lymph nodes - i.e.more lymph nodes than blood
Mx w CLL
STAGE DEPENDENT:
A - no cytopenia, <3 areas of lymphoid involvement
B – no cytopenia, 3+ areas of lymphoid involvement
C – cytopenias
A – watch and wait
B – consider treatment
C – treat
Richters syndrome: transformation of CLL to aggressive disease (ALL / high grade lymphoma)
Treat with either:
IBRUTINIB (Brutons TK Inhibtor)
FCR (fludarabine, cyclophosphamide, rituximab)
Stem Cell Transplant
2 other ways of describing the philadelphia chromosome?
how is it detected?
BCR-ABL1 fusion gene
t(9;22)
by FISH (fluorescene in situ hybridisation)
CML Treatment? if fails?
Imatinib
Transplants
how does CML present?
RUQ pain and splenomegaly
how does CLL present?
asymptomatic - picked up on routine blood tests
What is pathagnomonic for CLL?
Smear Cells / Smudge Cells
Blood film of CLL
Lymphocytosis
SMEAR/SMUDGE CELLS
Treatment of CLL?
(if stage C) Ibrutinib or FCR (fludarabine, cyclophosphamide, rituximab)
if failing, Stem cell transplant
Which leukaemia is associated with very high lymphocytes?
CLL
lymphoid lineage
Which leukaemias are indicated by:
Auer Rods
Smear Cells
Left Shift
Auer rods - AML
Smear/Smudge Cells - CLL
Left Shift (more immature cells, less mature cells) -CML
Way of remembering what smear/smudge cells indicate?
They are chronic
and they are LL
lymphoblastic leukaemia because they are S/S
i.e. double letter
Which leukaemia is associated with high basophils?
CML
myeloid lineage
Which leukaemias are associated with higher levels of blasts in the marrow?
Acute Leukaemias have over 20% blasts in the bone marrow
Which leukaemia can have a high platelet count?
CML (myeloid lineage)
Which leukaemia is associated with high eosinophils?
CML
myeloid lineage
Which leukaemias have blast cells in the blood?
I think all of them can have them, however blasts are more characterisitc of acute leukaemias
What can go on to form AML?
Myelodysplastic Syndromes?
What are Myelodysplastic Syndromes?
Dysplastic changes - abnormal cells
1 or more myeloid cell lines (erythroids, megakaryocyte,
granulocyte)
Usually asymptomatic - however there is risk of progression to AML
Present with incidental cytopenia
Pelger Huet Cells =
Hyposegmented Neutrophils
Pseudo-Pelger Anomally
causes:
Congenital (lamin B Receptor mutation) Acquired (myelogenous leukaemia and myelodysplastic syndromes (granulocytic lineage))
How does MDS present?
Clinical Features
• BM failure and cytopenias – infection, bleeding, fatigue
• Hypercellular BM
• Defective cells:
o RBCs e.g. ring sideroblasts (abn nucleated blast surrounded by iron granule ring)
o WBCs – hypogranulation, Pseudo-Pelger-huet anomaly (hyposegmented neutro)
o Platelets – micromegakaryocytes, hypolobated nuclei
N.B. In the exam – use an ‘investigative approach’ to pick out clues that lead to classification
Key difference between MDS and Leukaemia?
<20% blasts in MDS, >20% blasts acute leukaemia
What are Myelodysplastic Syndromes?
Heterogeneous group of progressive disorders featuring ineffective proliferation and differentiation of abnormally maturing myeloid stem cells.
• Characterised by: peripheral cytopenia; qualitative abnormalities of cell maturation; risk of AML transformation.
• Typically seen in the elderly; symptoms usually develop over weeks/months (incidental)
• By definition all patients have <20% blasts (>20% blasts = acute leukaemia)
Treatment of MDS?
Treatment
• Supportive – transfusions, EPO, G-CSF, ABx
• Biological modifiers – immunosuppressive drugs, lenalidomide, azacytidine
• Chemotherapy – similar to AML
• Allogeneic SCT
Where are the different types of MDS found and what are the types?
BLOOD RBCs: Refractory Anaemia (RA) +/ ring sideroblasts ( RARS ) PLATELETS: MDS w/ 5q deletion MDS unclassified WBCs: Refractory Cytopenia with Multilineage Dysplasia (RCMD) +/ ring sideroblasts ( RCMD RS )
BONE MARROW
Refractory anaemia with excess blasts
(RAEB I) <5% Blasts
(RAEB II) 5-19% Blasts
Explain staging of both Hodgkin’s and Non-Hodgkin’s Lymphoma
Ann-Arbor Staging
Stage I - IV
Stage I - One Group of Lymph Nodes (e.g. axillary, cervical, mediastinal)
Stage II - More Than One Group of Lymph Nodes That Are Above The Diaphgragm
Stage III - More Than One Group of Lymph Nodes That Are Above and Below the Diaphragm
Stage IV - Bone Marrow / Spleen Involement
How are Lymphomas classified?
Hodgkin’s vs Non-Hodgkin’s
Hodgkin’s has 4 types
Non-Hodgkin’s is B-cell vs T-Cell (ATLL)
Very High vs High vs Low Grade
What is pathagnomonic for Hodgkin’s Lymphoma?
Reed-Sternburg Cells
owl eye cells
Hodgkin’s Lymphoma - profile and typical presentation
prognosis
affects young
pc: lymphadenopathy (often mediastinal) or B symptoms
Reed-Sternburg Cells are diagnostic
usually good prognosis, stem cell transplant used if fails
What disease is associated with Hodgkin’s Lymphoma?
EBV
Ebstein Barr Virus infection
What is the most common subtype of Hodgkin’s Lymphoma?
Nodular Sclerosing
What is the most common slow growing (indolent) lymphoma?
Follicular
Lymph node biopsy shows large numbers of centroblasts
Follicular Lymphoma
t(14;18) ?
causes fusion of BCL2 gene
follicular lymphoma
What does centroblast look like on biopsy?
perfect circle of many cells
What are the 4 types of Hodgkin’s Lymphoma?
nodular sclerosis classical Hodgkin lymphoma
mixed cellularity classical Hodgkin lymphoma
lymphocyte-rich classical Hodgkin lymphoma
lymphocyte-depleted classical Hodgkin lymphoma
Features of Follicular Lymphoma
How does it present?
Risk?
Small lymphocytic lymphoma similar to CLL but disease with disease in NODES
Presents with lymphadenopathy, usually few very large nodes
Risk of transformation to high grade lymphoma
Treating Follicular Lymphoma
Is Non-Hodgkin’s Lymphoma subtype
Expectant management unless high burden of disease
Key features of Non-Hodgkin’s Lymphoma
Many sub-types – mostly B-cell origin, can be T-cell (ATLL)
Present with B-symptoms or lymphadenopathy
Incidence increases with age
Treatment of Hodgkin’s Lymphoma
Treatment is with ABVD chemotherapy usually + radiotherapy
Most patients have a good chance of cure
Stem cell transplants for rare cases who fail treatment
