Haematology Flashcards
What is antiphospholipid syndrome?
Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)
What are the complications of anti-phospholipid syndrome in pregnancy?
Recurrent miscarriage
IUGR
pre-eclampsia
placental abruption
pre-term delivery
venous thromboembolism
What is the treatment for antiphospholipid syndrome?
low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing
low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation
these interventions increase the live birth rate seven-fold
How does heparin work?
Heparin works by binding to antithrombin III, enhancing its anticoagulant effect by inhibiting the formation of thrombin and other clotting factors.
What deficiency may cause patients to be resistant to heparin?
Patients with antithrombin III deficiency may therefore by resistant to heparin treatment
What does antithrombin III do?
Antithrombin III inhibits several clotting factors, primarily thrombin, factor X and factor IX. It mediates the effects of heparin
What are the features of antithrombin III deficiency?
ecurrent venous thromboses
arterial thromboses do occur but are uncommon
What is the management of antithrombin III deficiency?
thromboembolic events are treated with lifelong warfarinisation
heparinisation during pregnancy*
antithrombin III concentrates (often using during surgery or childbirth)
What is haemophilia?
Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christmas disease) there is a lack of factor IX
What are the features of haemophilia?
haemoarthroses, haematomas
prolonged bleeding after surgery or trauma
Which blood test would be prolonged in haemophilia?
prolonged APTT
bleeding time, thrombin time, prothrombin time normal
What is the most common cause of antithrombin III deficiency?
CKD
What is burkitts lymphoma? what are the two forms?
Burkitt’s lymphoma is a high-grade B-cell neoplasm. There are two major forms:
endemic (African) form: typically involves maxilla or mandible sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
What gene translocation is burkitts lymphoma assoc. with? What virus is also implicated?
Burkitt’s lymphoma is associated with the c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form.
What is the management of burkitts lymphoma?
chemotherapy
What can chemo for burkitts lymphoma cause? what is given to reduce this risk?
This tends to produce a rapid response which may cause ‘tumour lysis syndrome’. Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring.
What are the complications of tumour lysis syndrome?
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
Which cell transfusion is most commonly associated. With bacterial infection?
Platelets
Stored at room temp
Which antibodies cause delayed extra vascular haemolytic transfusion reactions more than acute intravascular haemolytic transfusion reactions?
IgG
Which antibodies cause acute intravascular haemolytic transfusion reactions?
IgM anti a and anti b
Are anti ABO antibodies and antigens present at birth?
Antigens are present at birth and antibodies are present at about 6months
Which antibody are 1 in 10000 people deficient in?
IgA
About 1 in 10 000 people are deficient in IgA and can form clinically significant, complement
binding, antibodies to IgA.
What is the commonly the cause of apparent anaphylaxis to blood transfusion?
In many cases of apparent anaphylaxis to a blood transfusion, the causative agent is unknown,
but is putatively thought to be due to allergens in the donation, such as penicillin or peanut antigens.
What are delayed transfusion reactions caused by and when do they occur?
occur 5-10 days post transfusion due to the development of red cell alloantibodies:
What are the clinical features of delayed transfusion reaction?
usually minimal but can include unexplained pyrexia, jaundice or unexplained drop in hemoglobin
How do you make the diagnosis for delayed transfusion reaction?
Urinalysis shows urobilinogenuria and a blood shows fragile ballooned spherocytes, diagnosis is confirmed by Coombs test which is done by adding antihuman globulin (AHG) (anti-Ig G and anticomplement) to the patient’s washed RBCs. A positive test results in red cell agglutination.
Autoimmune haemolytic anaemia cold
What antibody causes this?
What mediates haemolysis?
Intravascular or extra vascular?
Causes?
Respond well/less we’ll to steroids?
Cold AIHA is usually by IgM and causes hemolysis best at 4°C. Hemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Reynaud’s and acrocynaosis. Patients respond less well to steroids.
Causes of cold AIHA
• Neoplasia: e.g. lymphoma
• Infections: e.g. mycoplasma, EBV
Autoimmune haemolytic anaemia warm
What antibody causes this?
What mediates haemolysis?
Intravascular or extra vascular?
Causes?
Management options?
Warm AIHA the antibody (usually IgG) causes hemolysis best at body temperature and hemolysis tends to occur in extravascular sites, for example the spleen. Management options include steroids, immunosuppression and splenectomy.
Causes of warm AIHA
• Autoimmune disease: e.g. Systemic lupus erythematosus*
• Neoplasia: e.g. Lymphoma, CLL
• Drugs: e.g. Methyldopa
Which is the most common hereditary haemolytic anaemia in Northern Europe?
Hereditary spherocytosis
What is Hereditary spherocytosis caused by? How does this lead to anaemia?
Autosomal Dominant defect of RBC cytoskeleton
• Biconcave disc → spherocyte
• Red cell survival ↓, destroyed by spleen
What are the clinical features of hereditary spherocytosis?
Presentation
• E.g. Failure to thrive
• Jaundice, gallstones
• Splenomegaly
• Aplastic crisis precipitated by parvovirus infection
• Degree of hemolysis variable
• ↓ MCV - ↑ MCHC - ↑ Reticulocytes
Splenic rupture is an important differential
How is hereditary spherocytosis diagnosed?
the osmotic fragility test was previously the recommend investigation of choice. However, it is now deemed unreliable and is no longer recommended
the British Journal of Haematology (BJH) guidelines state that ‘patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration[MCHC], increase in reticulocytes) do not require any additional tests
if the diagnosis is equivocal the BJH recommend the cryohaemolysis test and EMA binding
for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
What is the treatment for hereditary spherocytosis?
Folate replacement • Splenectomy
How is sickle cell disease inherited?
What is it caused by?
Which chromosome is involved?
Autosomal Recessive. It s caused by mutation in β-globin chain of hemoglobin, causing
hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the 6th
position. The β-globin gene is found on the short arm of chromosome 11.
What is the difference between sickle cell disease and sickle cell trait?
Sickle-cell anemia is a specific form of sickle-cell disease in which there is homozygosity for
the mutation, it is also known as “HbSS”, “SS disease”, “hemoglobin S”.
• Heterozygous: 1 sickle gene and 1 normal gene, it is known as “HbAS” or “sickle cell trait”.
• Other, rarer forms of sickle-cell disease include sickle-hemoglobin C disease (HbSC), sickle
beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0). These other
forms of sickle-cell disease are compound heterozygous states in which the person has only one
copy of the mutation that causes HbS and one copy of another abnormal hemoglobin allele.
What are the four main types of sickle cell crisis?
(TASH)
Thrombotic, ‘painful crises’
• Aplastic
• Sequestration (spleen, liver and kidney)
• Hemolytic
What is thrombotic sickle cell crisis?
Also known as painful crises or vaso-occlusive crises
• Precipitated by infection, dehydration, deoxygenation
• Infarcts occur in various organs including the bones (e.g. avascular necrosis of hip), hand-foot
syndrome in children, lungs, spleen and brain.
What is aplastic sickle cell crisis?
Caused by infection with parvovirus
• Sudden fall in hemoglobin
What is sequestration sickle cell crisis?
Sickling within organs such as the spleen or lungs causes pooling of blood with worsening of
the anaemia
• Acute chest syndrome: dyspnea, chest pain, pulmonary infiltrates, low PO2 - the most common
cause of death in adults (Hydroxyurea ↓ the incidence of acute chest syndrome)
• The most common cause of death in childhood: infraction and infection (Pneumococcus,
Chlamydia, Mycoplasm)
What is haemolytic crisis in sickle cell disease?
Rare
• Fall in hemoglobin due an increased rate of hemolysis
What antibodies are looked for in pernicious anaemia?
Anti gastric parietal cell antibodies in 90% (but low specificity)
• Anti intrinsic factor antibodies in 50% (specific for pernicious anemia)
What kind of anaemia is pernicious anaemia?
-WBC count? platelets?
Macrocytic anemia
• Low WBC and platelets
what do you see in blood films and in the marrow of patients with pernicious anaemia?
Also low serum B12, hypersegmented polymorphs on film, megaloblasts in marrow
What is shillings test for?
Radiolabelled B12 given on two occasions
• First on its own
• Second with oral Intrinsic Factor
• Urine B12 levels measured
used in the past
What is sideroblastic anaemia?
condition where red cells fail to completely form heme, whose
biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria
that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired
What is a congenital cause of sideroblastic anaemia?
Delta-aminolevulinate synthase-2 deficiency
What is an acquired cause of sideroblastic anaemia?
Myelodysplasia
• Alcohol
• Lead
• Chloramphenicol and Anti-TB medications (INH + Pyrazinamide)
What kind of anaemia is present in sideroblastic anaemia?
Hypochromic microcytic anemia (more so in congenital)
• Bone marrow: sideroblasts and ↑ iron stores
what is the management of sideroblastic anaemia?
Supportive
• Treat any underlying cause
• Pyridoxine may help
What is pure red cell aplasia?
is diagnosed when there is unexplained anaemia and reticulocytopenia,
with a complete absence of red cell precursors in the bone marrow, but with preservation of other cell
lines.
What is pure red cell aplasia associated with?
Either spontaneously or associated with
• Thymoma
• Autoimmune
• Lymphoproliferative disorders.
What is the management of pure red cell aplasia?
is supportive with immunosuppression with cyclosporin or related compounds. The
condition can rarely occur where recombinant erythropoietin is administered, where antierythropoietin
antibodies can be detected; these patients respond to withdrawal of erythropoietin with subsequent
falling of the antibody levels
What is Glucose-6-phosphate dehydrogenase (G6PD) deficiency?
is the commonest red
cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in
an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad
(fava) beans
What are the features of G6PD? what is seen on blood film?
Neonatal jaundice is often seen
• Intravascular hemolysis
• Heinz bodies on blood films
How is the diagnosis of G6PD made?
Diagnosis is made by using a G6PD enzyme assay
What drugs can cause haemolysis in G6PD?
Anti-malarials: primaquine
• Ciprofloxacin
• Sulfonamides
• Co-trimoxazole (because it contains sulfa)
What drugs are safe in G6PD?
Penicillins
• Cephalosporins
• Macrolides (Azithro-Clarithro-Erythro mycins)
• Tetracyclines
• Trimethoprim
What is Paroxysmal nocturnal hemoglobinuria (PNH)
-inherited or acquired?
-what is it thought to be caused by?
-what are patients more prone to?
is an acquired disorder leading to
hemolysis (mainly intravascular) of hematological cells. It is thought to be caused by ↑ sensitivity of
cell membranes to complement due to a lack of glycoprotein glycosyl-phosphatidylinositol
(GPI). Patients are more prone to venous thrombosis
What is the pathophysiology of PNH?
-what does a lack of GPI cause?
-why causes thrombosis?
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
• Complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly
bound to the cell membrane due a lack of GPI
• Thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to
platelet aggregation
What are the features of PNH?
Hemolytic anemia
• Red blood cells, white blood cells, platelets or stem cells may be affected therefore
pancytopenia may be present
• Hemoglobinuria: classically dark-colored urine in the morning (although has been shown to
occur throughout the day)
• Thrombosis e.g. Budd-Chiari syndrome
• Aplastic anemia may develop in some patients
How is PNH diagnosed?
Flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test
as the gold standard investigation in PNH
• Ham’s test: acid-induced hemolysis (normal red cells would not)
How is PNH managed?
• Blood product replacement
• Anticoagulation
• Eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being
trialled and is showing promise in reducing intravascular hemolysis
• Stem cell transplantation
What is the treatment for sickle cell disease?
-acute attack
analgesia e.g. opiates
rehydrate
oxygen
consider antibiotics if evidence of infection
blood transfusion
exchange transfusion: e.g. if neurological complications
What is the treatment for sickle cell disease
-prophylaxis
hydroxyurea
increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
NICE CKS suggest that sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years
What are relative causes of polycythaemia?
Dehydration
• Stress: Gaisbock
syndrome
What are the primary causes of polycythaemia?
Polycythaemia Rubra Vera
What are the secondary causes of polycythaemia?
COPD
• Altitude
• Obstructive sleep apnoea
• Excessive erythropoietin: cerebellar
hemangioma, hypernephroma,
hepatoma, uterine fibroids*
How to differentiate between primary and secondary causes of polycythaemia?
Erythroid colony studies:
autonomous growth of erythroid colonies is taken as a sign of primary
polycythaemia, where erythropoiesis has escaped the control of erythropoietin; erythroid colony studies
are thought to have high specificity for detecting primary versus secondary polycythaemia.
How to differentiate between true and relative polycythaemia?
To differentiate between true (primary or secondary) polycythaemia and relative polycythaemia red cell
mass studies are sometimes used. In true polycythaemia the total red cell mass in males > 35 ml/kg and
in women > 32 ml/kg
What is polycythaemia rubra vera?
is a myeloproliferative disorder caused by clonal
proliferation of a marrow stem cell leading to ↑ RBCs, often accompanied by ↑ WBC (neutrophils) and
↑ platelets.
When does the incidence of polycythaemia rubra vera peak?
The incidence
of PRV peaks in the sixth decade (50-60s of age)
What are the main features of polycythaemia rubra vera?
Hyperviscosity (headaches, tinnitus, visual disturbance, cyanosis, joint pain)
• Pruritus, typically after a hot bath
• Splenomegaly ± Hepatomegaly
• Hemorrhage (secondary to abnormal platelet function not number)
• Plethoric appearance
• Low ESR
• Hypertension in a third of patients
what mutation is present in polycythaemia rubra vera?
a mutation in JAK2 is present in approximately 95% of
patients
What investigations are suggested when considering polycythaemia rubra vera - what will you find?
FBC/film (raised hematocrit; neutrophils, basophils, platelets raised in half of patients)
• JAK2 mutation
• Serum ferritin
• Renal and liver function tests
↑ Hemoglobin and hematocrit
• ↑ Leucocyte alkaline phosphatase (LAP) and low ESR
• Additional:
o ± ↑ WBC and ↑ PLT
o ± ↑ Plasma volume
o ↑ Vitamin B12
o ↑ Red cell mass
o ↓ Erythropoietin level
What further investigations are suggested when considering polycythaemia rubra vera and JAK2 is negative
Red cell mass
• Arterial oxygen saturation
• Abdominal ultrasound
• Serum erythropoietin level
• Bone marrow aspirate and trephine
• Cytogenetic analysis
• Erythroid burst-forming unit (BFU-E) culture
What is the management of polycythaemia rubra vera?
• Venesection - first line treatment
• Hydroxyurea -slight ↑ risk of secondary leukemia
• Allopurinol & Phosphorus-32 therapy
What is the diagnostic criteria for polycythaemia rubra vera?
Diagnosis: JAK2-positive PRV - diagnosis requires both criteria to be present
A1 High hematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2
JAK2-negative PRV - diagnosis requires A1 + A2 + A3 + either another A or two B criteria
A1 Raised red cell mass (>25% above predicted) OR hematocrit >0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the hematopoietic cells
B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 109/l in non-smokers; > 12.5109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin
What is the definition of neutropenia?
on a routine full blood count (CBC) is one of the most common enquiries received
by hematologists from primary care physicians and hospital doctors. Neutropenia is defined as an
absolute peripheral blood neutrophil count of <2.0 × 109/l. There is a racial variation: black and
Middle Eastern people may have neutrophil counts of <1.5 × 109/l normally.
What are causes of congenital neutropenia?
• Kostmann’s syndrome
• Chediak–Higashi
• Schwachmann–Diamond syndrome
• Cyclical neutropenia
What are 5 causes of acquired neutropenia?
• Infection: viral e.g. influenza, HIV, hepatitis, bacterial sepsis.
• Drugs: anticonvulsants (phenytoin) – anti-thyroid (carbimazole) – phenothiazines
(chlorpromazine) – antibacterial agents (cotrimoxazole) – ACE-inhibitors (ramipril)
• Immune-mediated: SLE, Felty’s syndrome (Rheumatoid Arthritis + Neutropenia + Splenomegaly)
• Bone marrow failure: leukaemia, lymphoma, Hematinic deficiency
• Splenomegaly: any cause
What are the investigations for neutropenia
• Blood film
• Hematinics: factors that ↑Hb (Iron, TIBC, Vit B12, Folic Acid, Vit D)
• Autoimmune profile bone marrow aspirate/trephine are indicated if there are severe or
prolonged neutropenia or features suggestive of marrow failure
What is a leukemoid reaction?
describes the presence of immature cells such as myeloblasts,
promyelocytes and nucleated red cells in the peripheral blood. This may be due to infiltration of the
bone marrow causing the immature cells to be ‘pushed out’ or sudden demand for new cells
What are the different causes for a leukemoid reaction?
• Severe infection
• Severe hemolysis
• Massive hemorrhage
• Metastatic cancer with bone marrow infiltration
How do you differentiate between leukemoid reaction and CML?
Leukemoid reaction:
• High leukocyte alkaline phosphatase score
• Toxic granulation (Dohle bodies) in the
white cells
• ‘Left shift’ of neutrophils i.e. ↑neutrophils
or ≤ 3 segments of the nucleus
CML:
• Philadelphia chromosome
• Low leukocyte alkaline phosphatase score
Philadelphia chromosome is the most accurate test to distinguish
What is myelofibrosis?
-what is it thought to be caused by?
Abnormal fibrous deposition in bone marrow which = low blood count
• Thought to be caused by hyperplasia of abnormal megakaryocytes [bone marrow cell
responsible for the production of blood thrombocytes (platelets)]
• The resultant release of platelet derived growth factor is thought to stimulate fibroblasts
• Hematopoiesis develops in the liver and spleen
What are the features of myelofibrosis?
• E.g. Elderly person with symptoms of anemia e.g. Fatigue (the most common presenting
symptom)
• Massive splenomegaly
• Hypermetabolic symptoms: weight loss, night sweats etc
What are the investigations for myelofibrosis?
• Anemia
• High WBC and platelet count early in the disease
• ‘Tear-drop’ poikilocytes on blood film
• Unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
• High urate and LDH (reflect ↑ cell turnover)
• leucoerythroblastic change
What is the treatment for myelofibrosis?
• Supportive care (blood transfusion, platelets, antibiotics)
• Allogeneic stem cell transplantation in a select few
• Splenectomy (CONTROVERSIAL)
Who does myelodysplasia effect? What can this transform into?
occurs mainly in the elderly, 30% transforms to AML
What is the presentation of myelodysplasia?
•Anaemia
• Infection
• Bleeding
= Due to pancytopenia
What are the investigations for myelodysplasia?
• Serial blood counts show evidence of increasing bone marrow failure
• Bone marrow shows increased cellularity.
What is the management for myelodysplasia?
• < 5% blasts in the bone marrow → manage conservatively.
• ↑ WBC → gentle chemotherapy.
• < 60 years old → Intensive chemotherapy
What chromosome is evident in CML?
The Philadelphia chromosome is present in more than 95% of patients with CML. It is due to a translocation between the long arm of chromosome 9 and 22 -
t(9:22)(q34:q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with
the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which
has tyrosine kinase activity in excess of normal.
What is the presentation of CML?
Presentation (40-50 years)
• Middle-age
• Anemia, weight loss
• Splenomegaly may be marked (lethargy, anorexia, abdominal discomfort – 75% palpable spleen)
• Hepatomegaly and lymphadenopathy are uncommon
• Spectrum of myeloid cells seen in peripheral blood
• ↓ neutrophil alkaline phosphatase
• May undergo blast transformation (AML in 80%, ALL in 20%)
How to diagnose CML?
• Philadelphia is confirmatory
• Peripheral blood film: (leukocytosis in all stages of differentiation within the myeloid linage)
• Basophilia is important diagnostic marker especially when Philadelphia is absent
• Monocytopenia
• Bone-marrow hypercellularity with ↑ myloid-erythroid ratio
↑ Granulocytes of all types, typically including mature myeloid cells. Basophils and eosinophils are almost universally ↑;
this feature may help differentiate CML from a leukemoid reaction. A bone marrow biopsy is often performed as part of the
evaluation for CML, and CML is confirmed by detecting the Philadelphia chromosome, this can be detected by routine
cytogenetics, by fluorescent in situ hybridization, or by PCR for the bcr-abl fusion gene.
What is the management of CML?
• Hydroxyurea (also used in PRV, painful attacks in sicklers and as antiretroviral in HIV)
• Interferon- α
• Imatinib (inhibitor of tyrosine kinase)
Inhibitor of the tyrosine kinase associated with the BCR-ABL defect, Very high response rate in chronic phase CML
• Allogenic bone marrow transplant (optimum management)
What is acute myeloid leukaemia?
Malignant disease of WBC’s and RBC’s
Is AML common? how does it occur?
is the most common form of acute leukemia in adults. It mayoccur as a primary disease or following a secondary transformation of a myeloproliferative disorder(e.g CML, myelofibrosis).
> 30% blasts are almost diagnostic of AML.
What is the presentation of AML?
• Early signs are vague and non-specific (influenza-like)
• Persistent or frequent infections (due to ↓ WBC)
• Bruising and petechiae (due to ↓ PLT)
• Splenomegaly may occur but typically mild and asymptomatic. Lymph node swelling is rare.
Symptoms are caused by Pancytopenia (↓RBC - ↓WBC - ↓PLT)
What test can distinguish ALL from AML
The combination of a myeloperoxidase or Sudan black stain and a non-specific esterase (NSE)
stain will provide distinction of AML from ALL and in subclassification of AML in most cases.
What is the treatment of AML?
Chemotherapy: divided into two phases
Induction and consolidation phases
What is the induction phase of chemotherapy in AML?
Induction: All types except M3 are given induction with cytarabine (ara-C) and an
anthracycline (such as daunorubicin or idarubicin).This regimen is known as “7+3”, because
the ara-C is given as a continuous IVI for 7 days while the anthracycline is given for 3
consecutive days as an IV push.
What is the consolidation phase of chemotherapy in AML?
Consolidation: even after complete remission, very few leukemic cells likely to remain
undetected with current diagnostic techniques. If no further post-remission therapy is given,
almost all patients will eventually relapse. Therefore, more therapy is necessary to eliminate
non-detectable disease and prevent relapse — that is, to achieve a cure. The specific type of
postremission therapy is individualized based on prognostic factors and general health:
For good-prognosis leukemias [t(8;21), and t(15;17)], patients will typically undergo
an additional 3–5 courses of intensive chemotherapy
For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying
MDS, or therapy-related AML), allogeneic stem cell transplantation is usually
recommended
How to diagnose AML?
The first clue is typically an abnormal
CBC. While ↑ WBC is a common finding, and
leukemic blasts are sometimes seen, AML can also
present with isolated ↓ PLT, ↓ RBCs, or even ↓ WBC.
While a presumptive diagnosis of AML can be made
via examination of the peripheral blood smear when
there are circulating leukemic blasts, a definitive
diagnosis usually requires an adequate bone marrow
aspiration and biopsy.
Auer rod: an esoinophilic needle like inclusion in
cytoplasm of blast cells is pathgenomic of AML
What are the poor prognostic features of AML?
• > 60 years
• > 20% blasts after first course of chemo
• Cytogenics: deletions of chromosome 5 or 7
How many different classifications exist in AML?
7
Which classification of AML is +ve and strongly +ve for NSE
+ve: M4 - Granulocytic and monocytic maturation
strongly +ve: M5 - Monocytic
Which classification of AML is PAS stain positive
M6 - Erythroleukemia
How does Acute Promyelocytic Leukemia (APL) M3 present?
Younger age around 25
Chest infection, ↑WBC and DIC or thrombocytopenia often at presentation
What translocation is assoc with Acute Promyelocytic Leukaemia
• Associated with t(15:17)
• Fusion of PML and RAR-α genes
How is acute promyelocytic leukaemia treated?
• Treated with the ATRA in addition to induction chemotherapy. Care must be taken to prevent
DIC, complicating the treatment of APL when the promyelocytes release the contents of their
granules into the peripheral circulation. APL
How does ATRA work in acute promyelocytic leukaemia?
ATRA (all-trans-retinoic acid):
activates the RAR- α gene thus
helps the WBCs to differentiate
(i.e mature) but it will not
eliminate the leukemia.
What is CLL caused by?
is caused by a monoclonal proliferation of
well-differentiated lymphocytes which are almost always B-cells (99%)
What are the features of CLL?
• Often none
• Constitutional: anorexia, weight loss
• Bleeding, infections
• Lymphadenopathy more marked than CML
What are the complications of CLL? what is the most common cause of death?
• Hypogammaglobulinemia leading to recurrent infections → most common cause of death
• Warm autoimmune hemolytic anemia in 10-15% of patients
• Transformation to high-grade lymphoma (Richter’s transformation)
What is the investigation of choice in CLL?
What is seen on blood film?
• Immunophenotyping (flow cytmetry)
Immunophenotyping will demonstrate the cells to be B-cells (CD19 positive). CD5 and CD23 are also characteristically positive in CLL
• Blood film: smear or smudge cells
What are indications for treatment in CLL?
• Progressive marrow failure: the development or worsening of anemia and/or thrombocytopenia
• Massive (>10 cm) or progressive lymphadenopathy
• Massive (>6 cm) or progressive splenomegaly
• Progressive lymphocytosis: > 50% ↑ over 2 months or lymphocyte doubling time < 6 months
• Systemic symptoms: weight loss > 10% in previous 6 months, fever >38oc for > 2 weeks,
extreme fatigue, night sweats
• Autoimmune cytopenias e.g. ITP
What is the management of CLL?
• None early on (when to start Rx is mentioned above)
• Chlorambucil to ↓ lymphocyte count
• Other options include fludarabine (because fludarabine causes profound lymphopenia, thus
increases the risk of opportunistic infections significantly, prior to commensing fludarabine you
must give co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis
carinii pneumonia)
What is the median survival in CLL?
What are poor prognostic indicators?
3-5 years
• ♂ Sex
• Age > 70 years
• Lymphocyte count > 50
• Prolymphocytes comprising > 10% of blood lymphocytes
• Lymphocyte doubling time < 12 months
• Raised LDH
• CD38 expression positive
What is Veno-occlusive disease? What is the treatment?
Veno-Occlusive Disease (VOD) or Hepatic veno-occlusive disease. It is a complication of high-dose
chemotherapy given before a bone marrow transplant (BMT). The name sinusoidal obstruction syndrome is
now preferred if VOD happens as a result of chemotherapy or bone marrow transplantation. Treatment is primarily supportive.
What are the features of veno-occlusive disease?
Features:
• Fluid retention (weight gain, generalized edema, pleural effusion)
• Hepatomegaly
• ↑ Bilirubin (Jaundice)
• Usually complicated by multi-organ failure
What is the diagnosis of veno-occlusive disease?
Diagnosis:
• U/S abdomen helps in diagnosis
• Liver biopsy shows centrolobar necrosis
What is hairy cell leukaemia?
is a rare malignant proliferation disorder of B cells lymphocytes. It is more common in ♂s (4:1) and is usually classified as a sub-type of chronic lymphoid leukemia. Hairy
cells are abnormal WBCs with hair-like projections of cytoplasm.
What are the features of hairy cell leukaemia?
• Pancytopenia (Monocytopenia is classical)
• Splenomegaly
• Skin vasculitis in 1/3 patients
• ‘Dry tap’ despite bone marrow hypercellularity (also seen in myelofibrrosis)
• Bone marrow biopsy migh show “fried egg appearance”
• Tartrate resistant acid phosphotase (TRAP) stain positive
Lymphadenopathy is very uncommon in hairy cell leukaemia
What is the management for hairy cell leukaemia?
• Chemotherapy is first-line: cladribine, pentostatin
• Immunotherapy is second-line: rituximab, interferon-α
• Splenectomy sometimes required
What is ALL?
What age does it affect people?
Acute lymphoblastic leukaemia
Malignant disease of lymphocytes (can also infiltrate lymph nodes)
causes damage and death by crowding out normal
cells in the bone marrow, and by metastasizing. ALL is most common in childhood with a peak
incidence at 2-5 years of age, and another peak in old age.
What is the cure rate of ALL?
The overall cure rate in children is ≈80%,
and ≈45%-60% of adults have long-term disease-free survival. Acute → relatively short course of the
disease (being fatal in as little as a few weeks if untreated)
What is the clinical presentation of ALL?
• Generalized weakness and fatigue
• Anemia
• Frequent or unexplained fever and infections
• Weight loss and/or loss of appetite
• Excessive and unexplained bruising
• Bone pain, arthralgia.
• Dyspnea due to lung infiltration.
• Lymphandeopathy, hepatosplenomegaly.
• Pitting edema in the lower limbs and/or abdomen
• Petechiae due to thrombocytopenia
The signs and symptoms of ALL are variable but follow from bone marrow infiltration and/or
organ infiltration.
What genetic translocations are assoc. with ALL?
t(12:21) is the most common translocation and portends a good prognosis.
Philadelphia chromosome t(9:22) also has a bad prognosis. t(4:11) is the most common in children
under 12 months and portends a poor prognosis.
What investigations are used for ALL?
• Leukocytosis.
• Blast cells are seen on blood smear in 90% of cases
• Bone marrow biopsy is conclusive proof of ALL
• LP to detect CNS involvement.
• CXR: to look for mediastinal mass (common in ALL).
• U&E to look for Tumor Lysis Syndrome.
• Immunophenotyping, establish whether the “blast” cells origin is B or T lymphocytes
• DNA testing; different mutations reflect prognosis.
Terminal Deoxynucleotide Transferase (TdT) is present in 95% of ALL
What is the treatment of ALL?
Before treating with chemotherapy, if blast cell count is very ↑ (>100 x 109/L), the patient needs Leukapheresis to prevent sludging of capillary beds, this can be life-saving
What are good prognostic factors for ALL?
Good prognostic factors
• Common ALL
• Pre-B phenotype
• Low initial WBC
• FAB L1 type
What are poor prognostic factors for ALL?
Poor prognostic factors
• FAB L3 type
• T or B cell surface markers
• Philadelphia translocation, t(9;22)
• Age < 2 years or > 10 years
• ♂ Sex.
• CNS involvement
• High initial WBC (e.g. > 100 * 109/l)
• Non-Caucasian
What is leukoerythroblastic anaemia?
Any anemic condition resulting from space-occupying lesions in the bone marrow; the circulating blood contains immature cells of the granulocytic series and nucleated red blood cells, frequently in numbers that are disproportionately large in relation to the degree of anemia.
(left-shifted granulocytic series and nucleated red blood cells)
with pancytopaenia. Also defined when there are immature cells (e.g myelocytes, and nucleated red
blood cells) seen on the peripheral blood film.
What are 8 assoc. with a leukoerythroblastic anaemia?
• ↑ Bone marrow turnover e.g. in severe hemolytic anemia (in which case the reticulocyte count
would be high).
• Myelofibrosis and Chronic Myeloid Leukaemia (where there would be splenomegaly, and the
white cell and platelet count would usually be raised).
• Bone marrow invasion. Often in bone marrow invasion the invading malignancy will already
have been diagnosed previously.
• Myeloma
• Polycythaemia Rubra Vera
• Osteopetrosis
• Tuberculous infiltration of the bone marrow
• Sarcoidosis
What is hodgkins lymphoma?
is a malignant proliferation of lymphocytes characterized by the
presence of the Reed-Sternberg cell.
What age does hodgkins lymphoma affect?
It has a bimodal age distributions being most common in the third and seventh decades.
What virus is hodgkins lymphoma assoc. with?
Hodgkin’s lymphoma is associated with EBV.
What do 25% of patients with hodgkins lymphoma suffer?
25% of patients have a constitutional upset, (night sweats, weight loss, fever, pruritus and lethargy)
Describe the staging of hodgkins lymphoma?
Ann-Arbor staging of Hodgkin’s lymphoma
• I: single lymph node
• II: 2 or more lymph nodes/regions on same side of diaphragm
• III: nodes on both sides of diaphragm
• IV: spread beyond lymph nodes
Which is each stage of hodgkins lymphoma further divided into?
Each stage may be subdivided into A or B
• A = no systemic symptoms other than pruritus
• B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)
What features are assoc. with poor prognosis in hodgkins lymphoma?
• Age = 45 years
• Stage IV disease
• Hemoglobin < 10.5 g/dl
• Lymphocyte count < 600/μl or < 8%
• ♂
• Albumin < 40 g/l
• White blood count = 15,000/μl
How can classical hodgkins lymphoma be supclassified?
Classical Hodgkin’s lymphoma (excluding nodular lymphocyte predominant Hodgkin’s lymphoma) can
be subclassified into 4 pathologic subtypes based upon Reed-Sternberg cell morphology and the
composition of the reactive cell infiltrate seen in the lymph node biopsy specimen (the cell composition
around the Reed-Stenberg cell(s)).
What are the 4 pathological subtypes of hodgkins lymphoma?
nodular sclerosing
mixed-cellularity subtype
lymphocyte rich
lymphocyte depleted
Describe nodular sclerosing hodgkins lymphoma?
Is the most common subtype and is composed of large tumor nodules showing scattered
lacunar classical RS cells set in a background of reactive lymphocytes, eosinophils and
plasma cells with varying degress of collagen fibrosis/sclerosis.
Describe mixed-cellularity subtype hodgkins lymphoma?
Is a common subtype and is composed of numerous classic RS cells admixed with
numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma
cells. Without sclerosis. This type is most often associated with EBV infection and may
be confused with the early, so-called ‘cellular’ phase of nodular sclerosing CHL. Good
Prognosis
