Haematological malignancy Flashcards
What is the pathophysiology of ALL?
Proliferation of malignant precursor lymphoid cells in the bone marrow. Either B (most common) or T cells.
The proliferating malignant cells replace normal lines = normal suppressed = anaemia, thrombocytopenia and neutropenia.
Most common in children, 2-4 years.
What is the Philadelphia chromosome?
t(9;22) - associated w a poor prognosis
BCR gene and ABL gene swap (BCR-ABL) = increases tyrosine kinase = tells the cells to keep on proliferating = cancer, particularly in CML
What are the different groups of CF associated w ALL?
Marrow failure
Tissue infiltration
Leucostasis
What are the CF of marrow failure?
Anaemia - fatigue, SOB, angina, palor
Neutropenia - recurrent infections, sore throat, fever
Thombocytopenia - petechiae, nose bleeds, bruising
What are the CF of tissue infiltration?
Lymphadenopathy and hepatosplenomegaly - common at diagnosis
Bone pain
Mediastinal mass - could cause SVCO
Testicular enlargement
What is leucostasis?
Increased WCC in blood = thicker blood/impaired flow through small vessels: alt mental state, headache, breathlessness, visual changes
Also called meningeal syndrome - headache, N+V, blurred vision and diplopia - fundoscopy = papilloedema
What are the blood ix into ALL?
FBC - anaemia, thrombocytopenia, leucocytosis and neutropenia
U+E and LFTs - hypercalcaemia from paraneoplastic sydnrome, also baseline to check func before begin treatment
Coag screen and D dimer - assess for DIC
Uric acid and LDH - non specific markers of tumour burden
BBV screen ?
Blood film - blast cells
What is the imaging into ALL?
CXR - may have mediastinal mass
CT chest, AP - lymphadenopathy and organ involve, lytic lesions, enlarged thymus in T ALL
CT/MRI head - if pt sx indicate neuro involve
What is the diagnostic test in ALL?
Bone marrow aspiration and biopsy:
- Staining
- Review cell morphology
- Immumophenotyping
- Cytogenetics
- Flow cytometry
What are some additional ix into ALL?
- Blood film - blast cells
- Pleural tap
- LP - if concerned about CNS involve (but can promote spread of tumour cells into CNS)
What factors are associated w poorer prognosis in ALL?
(in adult pt):
- Increasing age
- Performance status >1
- High WCC - >30 B cell and >100 T cell
- Philadelphia chromosome
- CNS involvement
What is the classification of ALL?
Morphological
Immunological - surface markers
Cytogenic - chromosomal analysis, used for prognostic assessment
What is the supportive management of ALL and AML?
Blood <80g/l/platelet <10/l transfusion or<20 if bleed/septic
IV fluids, electrolyte replacement + allopurinol - prevent tumour lysis syndrome
Port system or Hickman line inserted
Infection prevention - prophylactic abx, anti virals and anti fungals
Anti emetics - ondansetron and they possible addition of dex, treat before N happens
Fertility treatment eg. freeze sperm/eggs
Macmillan nurse
What is the definitive management of ALL?
Chemo:
- Complex multi drug chemo, have multiple rounds and may take years
- Induce remission - vincristine, preg, L-asparaginase, daunorubicin
- Possible stem cell transplant
- CNS prophylaxis - IT/IV mtx
- Maintenance - prolonged chemo agents for 2 years eg. vincristine, dex, mtx
What is the pathophysiological of AML?
Genetic changes in myeloid precursor cells = proliferating immature cells that don’t respond to normal control mechanisms.
Results in reduced normal haemopoiesis.
What are some RF of AML?
- Myelodysplastic syndrome - blood disorders that affect haemopoiesis
- Down’s syndrome and other congenital disorders
- Radiation exposure
- Prev chemo
- Increasing age ~70 years
What are the CF of AML?
Marrow failure
Leucostasis
Tissue infiltration:
- Lymphadenopathy and hepatosplenomegaly
- Bone pain
- Gum hypertrophy
- Violaceous skin deposits
- Testicular enlargement
What are the blood ix into AML?
FBC - anaemia, thrombocytopenia, reduced reticulocyte, raised WCC
U+E - important when ruling out tumour lysis
Coag screen to rule out DIC
LDH - raised = high cell turnover
BBV screen
Blood film - Auer rods in myeloid blasts = pathognomonic
What are the other ix into AML?
- BM aspirate and trephine biopsy - >20% blast count, then cytogenetics, cytometry, immunophenotyping
- LP
What is the definitive treatment of AML?
Chemo - 5 cycles given in 1 week blocks = daunorubicin, cytarabine, given in blocks to allow blood count to recover in between, takes ~4-6 w
Marrow transplant - eradicate abnormal cells first then repopulate w donor marrow, give immunosuppression to prevent rejection, poor prognosis or relapse
What are the poor prognostic factors of AML?
> 60
20% blasts after 1st round of chemo
Poor performance status/comorbidities
Prev haematological disorders/dysplasia
Prev chemo/RT
What is chronic lymphocytic leukaemia?
Abnormal cloncal expansion of B cells that resemble mature lymphocytes = widespread lymphadenopathy and secondary immune def and cytopenias
What is the timeline of CLL?
Some pt are asymptomatic for many years
Others may get rapidly progressive disease that is symptomatic - progressive lymphadenopathy, hepatosplenomegaly
What are the CF of CLL?
Lymphadenopathy !!
Sx - weight loss, fever, anorexia, night sweats, lethargy
Signs - lymphadenopathy, hepatomegaly, splenomegaly
Features due to complications - autoimmune haemolytic anaemia (pale, SOB, fatigue), ITP (petechiae, bruise, bleed), recurrent infections
What are ix into CLL?
FBC - raised lymphocytes, low Hb then haemolysis, low neutrophils and low platelets = BM failure
Blood film - smudge cells, smear cells !!!!!! most important
Flow cytometry, immunohistochemistry, cytogenetics
LN biopsy
What are the different types of BM biopsy?
Marrow aspirate - liquid sample for cytology
Trephine biopsy - core sample
BM biopsy
What is the staging of CLL?
Binet:
Stage A <3 lymphoid sites - >10yr
Stage B >3 lymphoid sites >8yr
Stage C = anaemia and thrombocytopenia ~6.5yr
Rai staging:
Stage 0 - lymphocytosis
Stage I-II - lymphocytosis + lymphadenopathy + organomegaly
Stage III-IV - lymphocytosis + anaemia or thrombocytopenia + organomegaly + lymphadenopathy
What are some prognosis factors?
- Lymphocyte doubling time, the faster the worse the prognosis
- Genetic abnormalities = TP53, trisomy 21
- B2M
What is the management of CLL?
- Watch and wait for asymptomatic pt w/o poor prognostic factors
- Pharmacotherapy
- Allogenic stem cell transplant - chemo to destroy BM then replace w donor haemopoietic stem cells
- Supportive care
What are indications for treatment of CLL?
- BM failure
- Massive, progressive or symptomatic splenomegaly/lymphadenopathy/lymphocytosis
- Autoimmune complications not responsive to steroids eg. ITP
- Disease related sx
What pharmacotherapy things can be used for CLL?
Chemo - chlorambucil, fludarabine, bendamustine
Small molecule inhib - ibrutinib (tyrosine kinase inhib), idelalisib, venetoclax
Monoclonal ab - rituximab
Steroids in vv frail pt
What is Richter transformation?
CLL to aggressive lymphoma, ~5-8 month survival
What genetic abnormality is found in CML?
Ph chromosome
BCR-ABL blood test for disease response, should be reducing
What is chronic myeloid leukaemia?
Clonal myeloproliferative neoplasm w abnormal expansion of cells of myeloid lineage, most commonly granulocyte
What are the phases of CML?
Chronic - ~5 years, asymptomatic or non specific sx
Accelerated - abnormal blast cells take up ~20% of BM, symptomatic
Blast - 30% of BM is blast cells, causes pancytopenia, often fatal
What are the CF of CML?
- Asymptomatic and picked up on routine bloods
- Splenomegaly - early satiety, abdo pain !!!!! biggest one
- Fatigue
- Weight loss
- Night sweats
- Sx of anaemia, thrombocytopenia, leucostasis
- Bone pain
- Lymphadenopathy
What are the blood ix into CML?
FBC - high WCC, anaemia, thrombocytosis
Blood film - immature and mature myeloid cells
LDH, urate and K = markers of cell turnover
What are the other ix into CML?
BM aspirate +/- trephine = review % of blasts etc
What is the management of CML?
Tyrosine kinase inhib !!
Intensive chemo for pt w blastic transformation
Allogenic stem cell transplant - chronic phase pt who have failed other options or adv disease, not used as much as lots of different TKI to try first
What are some TKIs?
Imatinib - favourite ?
Dasatinib
Nilotinib
What are the myeloid cells?
Megakaryocytes/thrombocytes
Erythrocytes
Eosinophil, basophil, neutrophil, monocyte
What are the lymphoid cells?
Lymphocytes - B or T
What is trephine biopsy?
bone marrow core biopsy
What is remission defined as for AML?
<5% blasts w/o Auer rods
Hodgkin lymphoma vs non Hodgkin lymphoma?
Hodgkin - Reed Sternberg cells
Non Hodgkin - no Reed Sternberg cells, lots of subtypes, most common type of lymphoma
What are the CF of HL?
Gradual lymphadenopathy
B sx
Mediastinal mass - can be incidental or SOB, coug, SVCO
Pruritis
Hepatosplenomegaly
Malaise and fatigue
What are the ix into HL and NHL?
Excision biopsy of affected LN - whole incision or core (not FNA!!)
Bloods - FBC, U+E, LFT, bone, LDH, uric acid, ESR, BBV
Imaging - CXR, CT neck thorax AP w contrast, MRI brain if suspect CNS, PET once you have confirmation of cancer type
What staging system is used for HL and NHL?
Ann Arbor
1 - localised LN
2 - 2+ LN on same side of diaphragm
3 - 2+ LN on either side of diaphragm, inc splenomegaly?
4 - widespread disease, extra nodal involvement
a - no b sx
b - b sx
What is the most common regimen for HL treatment?
ABVD
A - doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Commonly use w RT as well
What are the rules for blood transfusion in HL?
If have HL or have ever had HL need irradiated red cells and platelets for life - reduce risk of transfusion associated graft vs host disease ?
What is the prognosis of HL?
75% + pt cured, prognosis ~90% 5 years
What are the RF of HL?
HIV, EBV, RA, sarcoidosis, FH
What are the CF of non Hodgkin lymphoma?
Lymphadenopathy !!
Fever
Night sweats
Weight loss
Pruritis
Hepatosplenomegaly
Can present w oncological emergency
What is the common chemo regimen to treat NHL?
Only treat once a patient isn’t well or has high grade cancer, otherwise active surveillance
R-CHOP
Rituximab - attacks CD20 = B cell
Cyclophosphamide
Doxorubicin
Vincristine
Pred
What is the most common type of NHL?
Diffuse large B cell lymphoma - rapidly enlarging mass commonly in neck, abdo or mediastinum, high grade
Follicular lymphoma - most common low grade, 20% transform to DLCL
What are some other types of NHL?
B cell low grade - follicular and MALT lymphoma, associated w H.pylori
B cell high grade - Burkitt (children), DLBCL
What are the RF of NHL?
HIV, EBC, H.pylori, Coeliac’s, Hep B or C, FH
What is paraprotein?
If high = myeloma
Plasma cells make one of 5 types of ab = A G M D and E. In myeloma 1 type will be very high, most of the time its G.
The single type of Ab produced by all the cancerous plasma cells is a monoclonal paraprotein.
What is multiple myeloma?
Malignant disorder of plasma cells, they are a type of B lymphocyte that produces Ab. Cancer in a specific type of plasma cell results in large quantities of a single type of ab produced.
Multiple = when myeloma affects multiple areas of the body
What is MGUS?
Monoclonal gammopathy of undetermined significance = too much of a single type of ab w/o features of myeloma/cancer
May progress to myeloma but don’t know
What is smouldering myeloma?
Progression of MGUS w higher levels of ab, is premalignant.
More likely to progress to myeloma than MGUS
What are the CF of multiple myeloma?
Features related to infiltration of plasma cells and ab secretion:
- Bone disease eg. lytic lesions, clonal prolif in bone marrow
- Impaired renal func
- Anaemia - BM infilitration
- Hypercalcaemia - bone demineralisation
- Recurrent infection - suppression of normal plasma cell func
CRAB
What does CRAB stand for?
Calcium levels high
Renal impairment
Anaemia
Bone disease
What specific syndromes can multiple myeloma present with?
Hyperviscosity syndrome - high paraprotein levels eg. IgA or IgG = blurred vision, headaches, mucosal bleed, SOB = urgent plasma exchange needed
Spinal cord compression - 5% of pt get
When should you suspect myeloma?
> 60 years with…
Unexplained bone pain and pathological fractures - feel sternum and spine esp for tenderness
Fatigue
Hypercalcaemia sx
Weight loss
Sx of MSCC
Sx of hyperviscosity
Recurrent infections
What are the tests for myeloma?
Bloods - FBC, Ca, ESR, plasma viscosity
BLIP!
Bence Jones protein via urine electrophoresis - however don’t really care anymore
Light chain assay (serum) - Kappa Lambda
Immunoglobulins
Protein electrophoresis - don’t really care
Bone marrow biopsy
Whole body 1. MRI 2. CT 3. skeletal survey BUT normally do PET scan
What are the XR signs of myeloma?
Punched out lesions
Lytic lesions
Raindrop skull - many lytic lesions
MGUS vs smouldering vs myeloma
MGUS - paraprotein low, BM plasma cells <10%, no organ damage
Smouldering - paraprotein normal, BM plasma cell >10%, no organ damage
Myeloma - paraprotein ++, BM plasma cell >10%, organ damage
What is the management of myeloma?
Control the disease- relapses and remitted, can’t really cure?
1. Chemo - bortezomib, thalidomide, dex
2. Stem cell transplant - from self, not allogenic
VTE prophylaxis
How do you manage myeloma bone disease?
Bisphosphonates
RT
Orthopaedic surgery to stabilise fractures
What is myelodysplastic syndrome?
Myeloid BM cells don’t mature properly and so don’t produce normal blood cells.
More common in >60 and pt who have prev had chemo or RT.
Increased risk of transforming to AML
What is the presentation of myelodysplastic syndrome?
Asymptomatic and incidentally diagnosed on FBC or have sx:
- Anaemia sx
- Neutropenia sx
- Thrombocytopenia sx
What is the management of myelodysplastic syndromes?
Watch and wait
Blood transfusions when severely anaemic
Chemo ?
Stem cell transplant ?
What are the types of myeloproliferative neoplasms/disorders?
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
What is primary myelofibrosis?
Proliferation of haematopoietic stem cells
Causes fibrosis of BM
Teardrop RBC on film poikilocytosis
What is polycythaemia vera?
Proliferation of erythroid cell line
Raised Hb
What is essential thrombocythaemia?
Proliferation of megakaryocytic cell line
>600 plt
What is the worry associated w myeloproliferative disorders and what mutations are associated w them?
Can transform to AML
Mutations - JAK2, (MPL, CALR ??)
What is the presentation of myeloproliferative disorders?
Asymptomatic
Systemic sx - fatigue, weight loss, night sweats, fever
Splenomegaly
Anaemia (except polycythaemia) and thrombocytopenia
Thrombosis - rairsed WBC and platelets
Portal HTN
What are the signs o/e that will make you suspect polycythaemia vera?
- Conjunctival plethroa
- Ruddy complexion
- Splenomegaly
What is the management of primary myelofibrosis?
Allogenic stem cell transplant - can be curative
Chemo - not curative but slow progression and improve sx
Supportive management
What is the management of polycythaemia vera?
1st line = therapeutic venesection
Aspirin used to prevent VTE
Chemo
What is the management of essential thrombocythaemia?
Aspirin to prevent VTE
Chemo
What tests do you do on BM biopsy?
Flow cytometry and immunophenotyping - tell you what type of cell the blast is eg. B or T cell, neutrophil or lymphocyte
Morphology - liquid slide = like a film, can see the cells
Cytogenetics eg. Ph chromosome
How can you differentiate all the leukaemias?
Acute - just blast cells
Chronic - have blast cells and other stages of immature cells
What are poor prognostic factors in lymphoma?
HL - raised ESR
NHL - raised LDH
