Haem - Malignant Conditions Flashcards
ALL Hx
Child – typically 2-5 yrs old Hepatosplenomegaly Bone pain / limp Fevers CNS symptoms Testicular swelling (rare but specific)§
Adults – similar to AML, lymphadenopathy
ALL - Blood Tests
Usually present with thrombocytopenia and anaemia
High white cell count
Some analysers will indicate presence of blasts but sometimes these will be flagged as lymphocytes.
Circulating blasts are not normal.
ALL - Blood Film
High nucleus – cytoplasm ratio
It is not possible to tell ALL from AML on blood film most of the time!
ALL- Diagnosis
Diagnosis usually relies on Bone Marrow & Flow Cytometry
Typical features:
TdT +
CD19 / CD22 = B cells (more common)
CD 2 / CD 3 / CD 4/8 = T cells
ALL - Genetics (Paeds)
ETV6-RUNX1 fusion gene & hyperdiploidy (extra chromosomes) are most common abnormalities
Both have a favourable prognosis
MLL gene mutations (now renamed KMT2A) have bad prognosis but are rare.
ALL- Genetics (Adults)
BCR-ABL1 t(9;22) associated with 20-30% of ALL in adults
This is the genetic mutation which also causes CML (covered later)
ALL - Rx
Chemotherapy:
Remission induction: Chemo agents often given with steroids
Consolidation: High dose multi drug chemotherapy
CNS treatment
Maintenance: 2 years in girls and adults, 3 years in boys –> remission
Consider allo-Stem Cell Transplant
Also use imatinib/other TKI for BCR-ABL1
Supportive: Blood products, ABx, Allopurinol, fluid, electrolytes – to prevent tumour lysis syndrome
AML - Hx
Incidence increases with age
Might have had pre-existing myelodysplastic syndrome (MDS)
Symptoms of cytopenias
AML - Blood Tests
Anaemia – due to bone marrow suppression
Thrombocytopenia – due to bone marrow suppression
Leukocytosis – high numbers of circulating white cells
Neutropenia – lack of mature white cells due to excess of blasts
High number of circulating blasts (not always flagged by analysers)
Normal INR – normal for AML Abnormal INR (increased) – possible DIC due to acute promyelocytic leukaemia
AML - Blood Film
A single Auer rod is enough to diagnose AML* (or MDS)
But sometimes there are lots… “Faggot cells”
AML - Dx
If no Auer rods present, flow cytometry needed to diagnose
Typical expression pattern: MPO – most specific
APML - Rx
T(15;17) Acute Promyelocytic Leukaemia
Presents with DIC. Good prognosis
All-Trans Retinoic Acid (ATRA) –> Forces cells to differentiate, stops proliferation
AML- Rx
Similar to ALL (i.e. various combos of chemo/consider SC allo-transplant) but no CNS prophylaxis/maintenance therapy needed
Possibility of targeted agents in the future.
Poor prognosis, worse with increasing age - particularly in elderly who won’t tolerate stem cell transplant
Essential Thrombocytopenia (an MPN)
Proliferation of megakaryocytic/thrombocytes
Platelet Count >450 consistently
JAK2 mutation in 55%
No evidence of other cause
Treatment:
Aspirin to reduce stroke risk
Hydroxycarbamide to lower count
Causes of thrombocytosis
Acute infection Chronic inflammation Malignancy (5-10%) Essential thrombocythaemia Polycythaemia rubra vera
Polycythaemia Vera
Proliferation of Erythrocytes
Haematocrit >0.52 / 0.48 (M / F)
Often thrombocytosis as well
High risk of thrombotic events e.g. MI, Stroke, Budd-Chiari
JAK2 mutation in 95%
Treatment:
Aspirin to reduce stroke risk
Venesection (taking blood to lower haematocrit)
Hydroxycarbamide to lower count
Causes of polycythaemia
Primary:
Polycythaemia rubra vera
Secondary:
Altitude
Chronic hypoxia: e.g. severe COPD, cyanotic heart disease
Erythropoietin-secreting renal cancers
Myelofibrosis
Clonal proliferation of stem cells in the bone marrow –> cytokine release and fibrosis of the bone marrow –> reduced production of all cell lineages
Features: JAK2 mutation present in 50% Pancytopenia Splenomegaly (can be massive splenomegaly) “dry tap” on bone marrow aspiration “tear drop poikilocytes” on blood film
Treatment:
Stem cell transplant likely only cure
Ruloxitinib - JAK inhibitor
CML - Hx and Ex
CML classified as a MPN
Typically onset age 35-55 in EMQs
LUQ pain - Splenomegaly
Mostly asymptomatic if diagnosed in chronic phase
May have lethargy, fatigue, fever, night sweats
May present with symptoms of acute leukaemia if in accelerated / blast phase (~10%)
CML - Blood Tests
In chronic phase – unlikely significantly anaemic (but can be)
In chronic phase – unlikely thrombocytopenia. 50% have elevated platelet count
Leukocytosis
Neutrophilia
May be elevated basophil count
Monocyte count should be low (high monocyte count would indicated CMML)
May be precursor cells flagged on blood differential e.g. promyleocytes, myleocytes (left shift)
Leukocytosis
Acute bacterial infection - Usually a high neutrophil : lymphocyte ratio
Acute viral infection - Usually a low neutrophil : lymphocyte ratio
Fungal / parasitic infection - Usually a high eosinophil count
Monocytosis - Unusual but seen in: TB, endocarditis, inflammatory conditions
In severe acute infections, there may be some precursor cells (myelocytes, metamyelocytes)
Elevated basophil AND eosinophil counts are concerning for malignancy
CML - Blood Film
“Left shift” - Precursor cells present
Leukocytosis
Eosinophilia
Basophilia
Hypolobated megakaryocytes in bone marrow
CML - Diagnosis
Nearly all CML is associated with the Philadelphia chromosome
BCR-ABL1 fusion gene results from translocation of
t(9;22) and formation of the
Philadelphia chromosome
In exams they may use one of these three descriptions.
Detected by FISH currently.
CML - Phases of Disease
Chronic (85-90%)
Accelerated - Increasing number of blasts in BM
Lack of response to therapy
Additional abnormalities in addition to BCR-ABL1
Blast phase -
>20% blasts in bone marrow
Behaves like an acute leukaemia
CML - Rx
Tyrosine Kinase Inhibitors
1st Generation: Imatinib (mainstay of Rx)
2nd Generation: Dasatinib, Nilotinib, Bosutinib
3rd Generation: Ponatinib
> 90% 10 yr survival
Small percentage of patients will fail treatment and need transplants.
CLL - Hx and Ex
Usually asymptomatic
Picked up on routine blood tests
Age >50 (median 65-70)– incidence increases with age
Twice as common in Men:Women
Can present with lymphadenopathy/splenomegaly
Can present with ITP (immune-mediated thrombocytopenic purpura) / Haemolytic anaemias
CLL - Blood Tests
Normally – no anaemia at presentation
Anaemia at presentation = more aggressive disease or haemolytic anaemia present
Normally – no thrombocytopenia at presentation
High white cell count, often >100 x10^9
Normally – no neutropenia
Lymphocytosis - WCC is made up of mature lymphocytes
CLL - Blood Film
Smear/smudge cells
Lymphocytosis
CLL - Diagnosis
Aided by flow cytometry: - Identifying a “clonal” population of cells, Will express same cell markers e.g. Kappa/Lambda light chains.
Most frequently B-cells but can get T-cell CLL
Same pathology as Small Lymphocytic Lymphoma but different distribution of disease - CLL primarily in BM, SCC primarily in LNs
CLL - Staging/Rx
Binet Staging
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)
CLL - Rx
Options:
Ibrutinib (Brutons tyrosine kinase inhibitor)
FCR (fludarabine, cyclophosphamide, rituximab) – chemo regimen
Stem cell transplant
If p53 deletion - alemtuzumab
Watchful waiting/supportive treatment with transfusions/infection prophylaxis
Lymphomas (Hodkins vs Non-Hodgkins) - Characteristics
HODKINS Age: young LN: mediastinum (anywhere), painful on drinking Course: aggressive Prognosis: mostly curable
NON-HODGKINS Age: increases with age LNs: anywhere Course: variable Prognosis: variable
Lymphomas - Classification
There are ~60 types of lymphoma Broadly classified into: Hodgkins vs Non-Hodgkins B-cell vs T-cell Very high vs High vs Low grade
Hodgkins - 4 types
Non-Hodgkins:
T-Cell - ATLL (adult T-cell leukaemia/lymphoma)
B-Cell - Burkitt’s, DLBCL (diffuse large B-cell lymphoma), mantle cell, follicular
Lymphomas - Classification
Ann-Arbor Staging:
1- 1 set of LN involvement, 1 side of diaphragm
2 - multiple sets of LN involvement, 1 side of diaphragm
3 - LN involvement both sides of diaphragm
4 - bone marrow/splenic involvement
B Symptoms:
Fever >38 degrees
Drenching sweats at night
Unintentional weight loss >10% body weight in 6 months
Hodgkin’s Lymphoma
Affects many young people (second peak in later life)
Presentation with lymphadenopathy or “B”-symptoms
Frequently mediastinal lymphadenopathy - painful on drinking alcohol
Reed-Sternburg cells are diagnostic (only 1 needed)
Nodular sclerosing is the most common type
Can be associated with EBV infection
Treatment is with ABVD chemotherapy usually + radiotherapy
Most patients have a good chance of cure
Stem cell transplants for rare cases who fail treatment
Non-Hodgkin Lymphoma - General
Many sub-types – mostly B-cell origin, can be T-cell.
Present with B-symptoms or lymphadenopathy
Incidence increases with age
May be indolent or high-grade
Non-Hodgkin Lymphoma - Indolent
Most common “indolent” lymphoma is Follicular Lymphoma
Small lymphocytic lymphoma is similar to CLL but with disease in nodes
Present with lymphadenopathy – usually few very large nodes
Risk of transformation to high grade lymphoma
Follicular Lymphoma
- Large numbers of centroblasts on lymph node biopsy
- t(14;18) causes fusion of BCL2 gene
- Treatment is watchful waiting unless high burden of disease.
Non-Hodgkin Lymphoma - High-Grade
Most common “high grade” lymphoma is Diffuse Large B-Cell Lymphoma
Present with lymphadenopathy & frequently B-symptoms
May have Bone Marrow involvement
Risk of Tumour Lysis Syndrome with treatment
Mantle Cell Lymphoma
- t(11;14) causes overexpression of Cyclin D1
- Treatment is with chemotherapy
- May have “leukaemic phase”
- Film will show “mantle cells” - cleft in the nucleus
Diffuse Large B-Cell Lymphoma
- Treatment is with Rituximab-CHOP chemotherapy
- Can be associated with EBV
Burkitt’s Lymphoma
Some lymphomas are very fast growing.
Commonest example is Burkitt’s Lymphoma.
High risk of Tumour Lysis Syndrome with treatment.
- “Starry sky” appearance on histology
- Mostly associated with t(8;14)
- Associated with EBV + HIV
- Large fast growing lymph nodes in neck / elsewhere
Adult T-Cell Leukaemia/Lymphoma (ATLL)
T-cell lymphomas are less common
ATLL is one example
Cutaneous T-cell lymphomas are rare and present with weird rashes
- More common in far east
- Associated with HTLV-1
- “flower cells” on blood film
Multiple Myeloma - Definition
“Plasma cell dyscrasia”
Clonal population of plasma cells which proliferate and produce monoclonal immunoglobulin light chains
Blood - paraprotein
Urine - Bence Jones Protein
Myeloma Progression - Myeloma
Myeloma:
Clonal bone marrow plasma cells >10% in the marrow or plasmacytoma
And end organ damage
1 or more: Calcium: Hypercalcaemia >2.75 Renal: Creatinine clearance <40ml/min / Creatinine >177 Anaemia Hb <100g/l Bone lesions – lytic lesions
Myeloma Progression - Smouldering Myeloma/Aymptomatic Myeloma
Serum monoclonal protein (IgG / IgA) >30g/l or Bence Jones Protein
And/or
Clonal bone marrow plasma cells 10%-60% in the marrow
No end organ damage
Most will progress to myeloma untreated
Myeloma Progression - Monoclonal Gammopathy of Unknown Significance
Serum monoclonal protein <30g/l
Plasma cells <10% on Bone Marrow
No end organ damage
No evidence of other disorder
1-2% per year progress to myeloma
Waldenstrom’s Macroglobulinaemia
Similar to multiple myeloma but rare.
- The paraprotein is always IgM (you can also get IgM Myeloma)
- They present with lymphadenopathy and similar to follicular lymphoma
- There is an abnormality in the lymphoplasmatoid cells as well as plasma cells
- They are at risk of hyperviscosity syndrome
Myeloma - Diagnosis
Blood film - Plasma cells (look a bit like fried eggs), rouleaux formation
Myeloma - Rx
MGUS: annual blood test
Smouldering myeloma / Myeloma – treat in most cases
Rx is changing every year.
PRINCIPLES
Younger patients: chemotherapy then autologous stem cell transplant
Older patients: chemotherapy then maintenance therapy
Commonly used drugs in initial treatment: Velcade (bortezomib) Revlimid (lenalidomide) Dexamethasone Cyclophosphamide
Subsequent treatments:
Pomalidomide
Daratumumab
Melphalan
Haematopoietic Stem Cell Transplant
Autologous or Allogeneic
Principles:
Stem cells harvested from bone marrow / blood
Recipient receives chemotherapy to destroy their marrow
Stem cells infused into recipient
Approximately 10% die in the first year
Long-term SEs include: cataracts, thyroid problems, lung damage, infection, infertility, skin rashes, weakened bones
Myelodysplastic Syndromes - General
Dysplastic changes (abnormal cells) 1 or more myeloid cell lines (erythroid, megakaryocyte, granulocyte)
Usually asymptomatic, but risk of progression to AML
Present with incidental cytopenia
Around 30% would progress to AML. Risk is assessed using IPSS score.
Myelodysplastic Syndromes - Anaemia
Anaemia with normal ferritin (iron), B12, Folate and erythropoitin levels raises suspicion of MDS
Usually this is macrocytic anaemia
MDS with Ring Sideroblasts
> 15% ring sideroblasts
Anaemia
Or multilineage dysplasia
MDS with Multilineage Dysplasia
2-3 cell lineages affected
<5% blasts
MDS with Excess Blasts
> 5% blasts
10-19% blasts = “MDS with excess blasts 2)
20% blasts = AML
MDS with Isolated del(5q)
Del(5q) is a separate but related syndrome
Anaemia
Normal / high platelets
<5% blasts
MDS - Rx
Supportive - transfusions, EPO, G-CSF, ABX
Biological modifiers - immunosuppressive drugs, lenalidomide, azacytidine
(Think don’t worry too much about this - Jack PP says beyond scope of 5th year)
MDS - Prognosis
Depends on International Prognostic Scoring System (IPSS): BM blast %; karyotype; degree of cytopenia
Mortality rule of 1/3: 1/3 die from infection, 1/3 die from bleeding, 1/3 die from acute leukaemia
