Leukaemia Flashcards
what is acute leukaemia?
Uncontrolled proliferation of partially developed white blood cells, also called blast cells, which build up in the blood over a short period of time.
what are the 2 consequences of the causative mutations in leukaemia?
causes precursor blood cells to lose ability to differentiate into mature blood cells
blast cells divide uncontrollably
what is the consequence of cells not maturing in leukaemia?
stuck as blast cells, don’t function properly
what are the consequence of uncontrollable cell division of blast cells?
Take a lot of space and nutrition in bone marrow
Other cells get crowded out
Causes cytopenia’s = Anaemia, Thrombocytopenia, Leukopenia
what happens when blast cell numbers increase?
they spill into blood:
Lymphoblasts = settle in liver and spleen
Pre-t cell settle in Thymus and Lymphnodes – enlargement
Acute promyelocytic anaemia -
Promyelocytes activate the clotting process, combined with decreased platelets = DIC
what are the shared clinical features of acute leukaemia?
- Fatgie – anemia
- Bleeding – thrombocytopenia
- Increased infections – leukopenia
- Pain and tenderness in the bones – increased cell production
- Abdominal fullness – hepatosplenomegaly
- Pain in lymphnodes (lymphadenopathy)
what are clinical features more indicative of ALL?
hepatosplenomegaly and lymphadenopathy more common
o Thymus enlargement in T-ALL – mass in mediastinum
o Also testicular
o Cranial nerve palsies
what are clinical features more indicative of AML?
monocytic variety causes swelling of guns
Violaceous skin lesions
what are the common investigations done for Acute leukaemia?
FBC, Blood film, Coagulation screen Bone Marrow Aspirate +/- Biopsy CXR and CT scan Lumbar puncture
what is the general management of acute leukaemia?
Chemo
Biological therapy
stem cell transplants
bone marrow transplants
what will FBC show in acute leukaemia?
decreased haemaglobin
increased wcc (tho blasts so not functioning)
decreased platelets
what will the blood film in AML show?
large cells, fine chromatin, auer rods (crystalised aggregates of the myeloperoxidase enzyme), myeloid blasts
what will the blood film in ALL show?
smaller cells, coarse chromatin, little cytoplasm (glycogen granules) – lymphoblasts
what will the morphology of a bone marrow aspirate show?
↓erythropoiesis; ↓megakaryocytes, i.e. platelet precursors; > 20% blast cells
what is the immunophenotyping of B lineage acute leukaemia?
HLA-DR+, TdT-, CD19+, CD10+, surface IgM+
what is the immunophenotyping of T lineage acute leukaemia?
TdT+, cytoplasmic CD3+, CD1a/2/3+, CD5+
what are the additional immunophenotyping findings of acute leukaemia?
Anti-MPO, CD13, CD33, CD45, CDxw65, CD117
what is the epidemiology of ALL?
- Most common childhood cancer (Newborn – 14 yeras)
* Most common leukemia overall
what is the difference between acute and chronic leukaemia
Acute = blast (non mature) Chronic = cytic (slightly more mature)
what can ALL be classified into?
o T cell ALL (proliferation of T cell precursors)
o Pre-B cell ALL (proliferation of B cell precursors)
o B-cell ALL
what are the histological features of lymphoblasts?
no granules, increased N/C ration, scanty cytoplasm, less prominent nucleolus
what is the spread and consequence of ALL?
bone marrow - replaces other cells (pancytopenia)
enter peripheral blood - leukostasis
Metastasize through body - hepatosplenomegaly, lymphadeonpathy, testes enlarge, CNS, bone
what markers are commonly present in ALL?
TdT+
Periodic acid shiff (+ve)
what are the common causes of ALL?
chromosomal translocations
abnormal chromosome number
genetic conditions
Radiation, smoking, viral infections, folate metabolim polymorphisms, chemotherapy, benzne, multiple myeloma
what are the common chromosomal translocations associated with ALL and what does it cause?
12 and 21
22 and 9 (Philadelphia)
Production of abnormal intracellular proteins, affect cell function + division
what geentic conditions are associated with ALL?
trisomy 21, Klinefelters, Fanconi anameia, Blooms syndrom
what are the features, translocations and markers associated with Pre B-ALL?
o Child
o Trisomy
o CD10, CD19, CD20
o t(9:22), t(12:21
what are the features, translocations and markers associated with B cell ALL?
o t(8:!4), t(8:22), t(2:8) = burkitts lymphoma
what are the features, translocations and markers associated with T cell ALL?
o Adult mass in the anterior mediastinum
o CD3+, CD7+
o 14q11, 7q34
what are the clinical features associated with ALL?
acute, anaemia, infection, fever, malasie, sweats, haemorrhage, lecostasis, bone or joint pain, mediastinal involvement, CNS involvement, widespread lymphadeonpathy, hepatosplenamegaly, rhabdomyosarcoma, Ewings sarcoma
what are the signs of haemorrhage seen in ALL?
purpura, menorrhagia, epitaxiss, bleeding gum, retina, rectal
what are the signs of leukostasis in ALL?
hypoxia, retinal haemorraghe, confusion or diffuse pulmonary shadowing
what does mediastinal involvement in ALL cause?
SVC obstruction
what does CNS involvement in ALL cause?
cranial nerve palsy
what investigations should be done in ALL?
morphologic analysis cytogenic studies cell surface markers molecular markers cytochemical analysis peripheral blood smear
what will the peripheral blood smear show in ALL?
Normocytic or macrocytic anaemia
Platelets <100,000
WBC <10,000 -> 100,000
which subsets of ALL can have targeted treatments?
o BCR-ABL+ALL
o Burkitts
o T-cell ALL
o CNH Leukaemia
what is the remission induction treatment of ALL?
vincritin, predinisolone, daunorubicin, aspraraginase
what is consolidation therapy of ALL treatment?
alternating cycles of induction agents and cytotoxic
what CNS prophylaxis is used in ALL?
cranial irradiation plus IT chemotherapy (methotrexate +/- cytarabine, prednisolone)
what is the maintenance therapy used in ALL?
daily 6-MP PO and weekly methotrexate PO
what are the poor prognostic factors of ALL?
- Age > 60
- WBCs > 100,000
- Mature B or early T cell types
- Phildelphia chromosome (ALL bad, CML good)
what is the epidemiology of AML?
more common in the elderly (>60s)
what is AML?
the clonal expansion of myeloid blasts in the bone marrow, peripheral blood, or extramedullary tissues
what is the spread of AML?
- replace most of bone marrow cells crowding out of normal hamatopoeisis
- enter the peripheral blood – leukostasis
- metasiatisze throughout the body – liver, spleen, CNS, lymphnodes, bone, skin, gum infiltration (m5)
what are myeloid cells?
granulocytes
what are the causes of AML?
chromosomal translocations
myelodysplastic
antineoplastic agents, alkylating agents, ionising radiation, benzene
aplastic anaemia, myeloproliferative disorders, Fanconi anaemia, PNH
what is myelodysplastic syndrome?
Defective maturation of myeloid cells
Build of blasts
initially <20% blast, but enough to cause decrease in function of red blood cells, granulocytes and platelets
as disease progresses the blast percentage may >20% resulting in AML with myelodysplasia
what is the classification of AML based on?
the morphology of the myeloblast
what are the different classifications of AML?
AML without maturation AML with minimal maturation AML with maturation (M2) Acute promyelocytic leukaemia (M3) Acute myelomonocytic leukaemia Acute monocytic leukaemia (M5) Acute erythroid leukaemia Acute megakaryoblastic leukaemia
what are the features of AML M2?
caused by t8:21
most common
what are the features of acute promyelocytic leukaemia (M3)
Characterised by translocation of chromosome 15:17 which disrupts retinoic acid receptor gene which is required for normal cell division
Associated with DIC
Treats with Vit A – good prognosis
what feature is associated with AML M5
gum infiltration
what are the clinical features of AML?
acute, anaemia, infection, fever, malaise, sweats, haemorrhage (M3), gum hypertrophy and skin infiltration (M4/M5), leucostasis
what are the diagnostic investigations for
morphologic analysis cytogenic studies cell surface markers molecular markers cytochemical analysis peripheral blood
what will morphological analysis show in posistive AL?
> 20% blasts
what chemical markers are present in AML?
TdT-, MPO+
what will peripheral blood in AML show?
Normocytic or macrocytic anemia
Platekets <100,000
WBC <10,000 – 100,000
Auer rods – myeloperoxidase +
what is the treatment of AML?
• 2-4 cycles of chemotherapy (5-10 days of chemotherapy followed by 2-4 weeks recovery)
what are the poor prognostic factors of AML?
- Age >60
- WBCs >100,000
- Poor performance status
- Mutation of FLT3
- 2ry AML
what are common complications of treatment in AL?
Bone Marrow Suppression - anaemia, neutropenia, thrombocytopenia
Ohers - n+v, hair loss, liver, renal dysfunction, tumour lysis syndrome, infection, hyperviscosity sundrome
late effects - loss of fertility, cardiomyopathy
AL - presence of auer rods in blood?
ALL - none
AML - always
AL- presence of lymphoblast’s in blood
ALL - always present
AML - may or may not be present
AL - bone and joint pain
ALL - more common
AML - less common
AL - hepatosplenomegaly
ALL - more common
AML - less common
AL - organ infiltration
ALL - more common
AML - quite unusual
AL - Immunophenotyping
ALL - B Cell (CD19, cytoplasmic CD22, cytoplasmic CD79a, CD10), T cell (CD4, CD2, CD7)
AML - Anti-MPO, CD13, CD33, CD45, CDxw65, CD117
what is the pathophysiology of chronic leukaemia?
Cells only mature partially
Too many premature cells = accumulate
Leukocytes accumulate in bone marrow and eventually spill out – blood and tissues Accumulated cells causes healthy cells to get crowded out
What is the affect of cell dysfunction in each type of CL?
CML - divide too quickly
CLL - don’t die as they should
most is the epidemiology of CLL?
- Most common type in Western countries
* adults – increased risk with increasing age (>60s)
what type of cells does CLL impact?
T and B cells
what is the underlying pathophysiology of CLL?
• B cell interfere with pathways of B cell receptors, which should only be activated during infection – to activate specific tyrosine kinase
o Brutons tyrosine kinase which stops lymphoids developming developing
o Interaction with each other – causes them to die slowly
what markers are expressed in CLL?
CD5, CD19, CD23
what is the spread of leukocytes in CLL?
• Premature leukocytes build up in bone marrow, spill in blood and move to lymphatic system – primarily lymph nodes – lymphadenopathy then lymphomas
o Richter transformation – small lymphomas collect into masses
What are the consequences of cell spread in CLL?
Autoimmune haemolytic anaemia
Hypogammaglobulinemia
Cytopenia
what are the clinical features of CLL?
asymptomatic
lymphadenopathy
lymphocytosis “smudge cells”
marrow failure – anaemia, neutropenia and thrombocytopenia
recurrent infection
weight loss, night sweats, malaise
massive hepatosplenamegaly
autoimmune haemolytiv anameia – DAT, warm type
10% develop diffuse large cell lymphoma = aggressice (fever, increased LDH and LD size)
what investigations can be done in CLL?
blood count blood film immunophenotyping immunoglobulins cytogenics
what will a blood count in CLL show?
lymphocytosis, platelets normal or low
what will a blood film in CLL show?
increased lymphhocytes, smear cells
what will immunophenotyping in CLL show?
o CD5, CD19 and CD23 +
o CD2 and FMC7 -ve
what will immunoglobulins in CLL show?
hypogammaglobulinemia
what is the cytogenic of CLL?
13q –, 11q –, 12q +, 17p –, 6q –, +12
what staging system is used for CLL?
The RAI system:
o Stage 0 lymphocytosis (low)
o Stage 1 lymphocytosis and adenopathy (mid)
o Stage 2 lymphocystosis and hepatosplenomegaly (mid)
o Stage 3 anemia (high)
o Stage 4 thrombocytopenia (high)
what are the indications for treatment in CLL?
o weight loss of more than 10% over 6 months
o extreme fatigue
o fever related to leukemia for longer than 2 weeks
o night sweats for longer than 1 month
o progressive marrow failure (anemia or thrombocytopenia)
o autoimmune anemia or thrombocytopenia not responding to glucocorticoids
o progressive or symptomatic splenomegaly
o massive or symptomatic lymphadenopathy
o progressive lymphocytosis, as defined by an increase of greater than 50% in 2 months or a doubling time of less than 6 months
What is the 1st line treatment for CLL?
Chlorambucil +/- prednisolone
what is the epidemiology of CML?
elderly
what are the causes of CML?
Translocation that effects granulocytes = Philadelphia chromosome (t(9;22) = 22
Radiation
Chronic myeloproliferative – CML, p.vera, ET, MMM
what cell does CML affect?
myeloid cells:
granulocytes and their precursors
other lineages (platelets)
how does the Philadelphia chromosome cause CML?
• Philadelphia chromosome produces BCR gene sites next to ABL = BCR-ABL gene
• Produces BCR-ABL protein
o Activates tyrosine kinases (causes abnormal phosphorylation = signalling) – on/off switch always on
o Switch on cell division – myeloid cells divide more quickly
causes buildup in bone marrow, spill into blood
what is natural progression of CML?
o chronic phase – increased WCC <10% of blast cells in blood
o aggressive/accelerated phase – more likely to find blast cells in the blood – 10-10%, more systemic symptoms
o blast phase/crisis – blood contains >20% blast cells
increased mutatuons as cells divide more quickly
what are the clinical features of CML?
- presents in chronic phase
- many asymptomatic
- fatigue, lethargy, weight loss, sweats
- hepatospenomegaly – feeling of abdominal fullness (due to build up of cells)
- gout, brusing/bleeding, splenic infarction, priapism
- retinal haemorraghe, dyspnoea and cough
what are the clinical features of a blast crisis?
rapid increase in blast cells, fever, bone pain, fatigue, increased severity of anemia and thrombocytopnia, splenomegaly, large clusters of blasts in bone amrrow
what investigations can be used in CML?
FBC blood film NAP score decreased, ESR reduced BM biopsy cytogenic analysis FiSH
what is the management of CML?
Imatinib
Interferon Alpha
Stem Cell Transplant
SOKAL - prognosis
how does Imatinib work in CML management?
o tyrosine kinase inhibitor that prevents the action of the BCR-ABL fusion protein, i.e.this is the abnormal protein produced by the Ph mutation.
what is the diagnostic feature of blast cells in CML?
<10%
what will the blood film and FBC show in CML?
increased WBC
o normal/↓Hb
o leucocytosis with neutrophilia and myeloid precursors (myelocytes – of all stages), eosinophilia, basophilia
o thrombocytosis
o Rapid turnover – raised uric acid and LDH
what will cytogenic analysis in CML show?
t9:22
what will FiSH anaylsis in CML show?
BCR-ABL
