CML and myeloproliferative disorders Flashcards
What are the types of polycythaemia?
Relative (low plasma) non malignant
True (high RBC)
What are the types of true polycythaemia?
Secondary (reactive)
Primary Polycythaemia Vera (MPD - neoplasm)
What causes relative polycythaemia?
Alcohol
Obesity
Diuretics
How is EPO different in primary and secondary polycythaemia?
Primary: reduced
Secondary: raised
What are the causes of appropriately raised RBC (true secondary polycythaemia)?
High altitude
Hypoxic lung disease
Cyanotic Heart Disease
High affinity Hb
What are the causes of inappropriately raised RBC (true secondary polycythaemia)?
Inappropriate
Renal disease (cysts, tumours inflammation) uterine myoma
Other tumours (liver, lung)
What are the types of myeloid malignancies?
Acute myeloid leukaemia (Blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders
Chronic myeloid leukaemia
What are the myeloproliferative disorders?
(Ph (philadelphia chromosome) negative) Essential thrombocythaemia (megakaryocyte)
Polycythemia vera (erythroid)
Primary myelofibrosis
(Ph positive)
Chronic myeloid leukaemia
What are the types of lymphoid malignancies?
(precursor cells) Acute lymphoblastic leukaemia
(Mature cell malignancy)
CLL
Multiple myeloma
Lymphoma/ Hodgkins and Non Hodgkins lymphoma
What are the cells created by normal haematopoeisis?
T cell (from Pre T) B cell (from Pre B) RBCs (from BFU-E) Megakaryocyte (from Meg-CFC) Granulocytes (from GM-CFC) Monocytes (from GM-CFC)
What processes are disrupted by mutation?
Cellular proliferation (Type 1) Impair/ block cellular differentiation (Type 2) Prolong cell survival (Anti apoptosis)
What are the mechanisms of mutation?
DNA point mutations Chromosomal translocations (Creation of novel fusion gene, disruption of proto oncogenes)
What do tyrosine kinases do?
Transmit cell growth signals from surface receptors to nucleus
Activated by transferring phosphate groups to self and downstream proteins
Normally held tightly in inactive state
Promote cell growth do not block maturation
What diseases occur as a result of mutationally activated TK in RBCs, PLTs and granulocytes?
Expansion increase in monoclonal mature/end cells
Red cells; polycythaemia
Platelets; essential thrombocythaemia
Granulocytes; chronic myeloid leukaemia
Which gene mutations are associated with myeloproliferative disorders (MPD)?
JAK 2 (many MPD- all polycythaemia vera)
Calreticulin
MPL (some)
Who gets Polycythaemia vera?
Incidence: 2-3/ 100,000
Slightly more male (1.2:1)
60 yo (mean- 5% below 40y)
Incidental finding
How does PV present?
Hyperviscosity
(Headache, stroke, light headed, visual disturbance, fatigue, SOB)
Histamine release (Aquagenic pruritis, peptic ulceration)
What are the clinical findings of PV?
Splenomegaly (79%) Plethora Erythromelalgia Thrombosis Renal vein engorgement Gout (high RBC turnover) Test JAK2 - JAK2 wild type
No other cause
What are the aims of treatment of PV?
Reduce viscosity (hct <45%) >> Venesection >> Hydroxycarbamide (cytoreductive maintenance)
Reduce thrombosis risk
» Aspirin
» Platelets <400 x 10^9/L
What is essential thrombocythaemia (ET)?
Chronic MPN mainly involving megakaryocytic lineage
Sustained thrombocytosis >600x109/L
Who gets ET?
Incidence 1.5 per 100000
Mean age two peaks 55 years and minor peak 30 years
Females :males equal first peak but females predominate second peak
What is the clinical presentation of ET?
Thrombosis (CVA, TIA, gangrene, DVT, PE)
Bleeding (Mucous M and cutaneous)
Minor headaches/ dizzy/ visual disurbance
Splenomegaly (maybe)
What is the treatment for ET?
Aspirin (prevent VTE)
Anagrelide (inhibition of Plt- SE: palpitations, flushing)
Hydroxycarbamide (antimetabolite, mildly leukaemogenic)
What is the prognosis/ complications of ET?
Normal life span may not be changed in many patients.
Leukaemic transformation in about 5% after >10 years
Myelofibrosis also uncommon, unless there is fibrosis at the beginning
What is primary myelofibrosis (PMF)?
A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haematopoieisis
Who gets PMF?
Incidence 0.5-1.5 /100000
Males=females
7th decade. Less common in younger patients
Secondary to other haematological disease: progression from PV or ET
What is the clinical presentation of PMF?
Incidental in 30%
- Blood:
Cytopenias (anaemia/ thrombocytopenia)
Thrombocytosis
- Organ:
Massive Splenomegaly [Budd Chiari]
Hepatomegaly
- Metabolism:
Hypermetabolic state
(wt loss, fatigue, SOB, night sweats, hyperuricaemia)
What are the stages of myelofibrosis?
Prefibrotic
Fibrotic
What happens in the prefibrotic stage of myelofibrosis?
Blood changes mild but may also be confused with ET
Hypercellular marrow
What happens in the fibrotic stage of myelofibrosis?
Splenomegaly and blood changes
Dry tap
Prominent collagen fibrosis
Later Osteosclerosis
What is the prognosis of PMF?
3-5 years
What are bad prognositic signs in PMF?
Severe anaemia <10g/dL
Thrombocytopenia <100x109/l
Massive splenomegaly
Prognostic scoring system (DIPPS)
Score 0 – median survival 15years
Score 4-6– median survival 1.3 years
What is the treatment of PMF?
Transfusions (for anaemia)
Plt transfusions (but often ineffective)
Splenectomy for symptomatic relief (but hazardous and worsens symptoms)
Cytoreductive therapy: hydroxycarbamide for thrombocytosis, may lead to worsening of anaemia
Ruxolotinib JAK2 inhibitor (high prognostic score)
Bone marrow transplant in young patients may be curative (experimental)
Who gets CML?
M:F 1.4:1
40-60 years
What does CML present with?
- Weight loss, lethargy, night sweats
- Splenomegaly
- Features of anaemia
- Bruising/bleeding
- Gout
What would you find in the history and exam with CML?
History
Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA
Exam
Massive splenomegaly +/- hepatomegaly
What would you find on blood investigations with CML?
FBC
Hb and platelets well preserved or raised
Massive leucocytosis 50-200x109/L
Blood film
Neutrophils and some myelocytes (not blasts if chronic phase)
Basophilia
What are the lab features of CML?
Mature myeloid cells
Bi phasic peak Neutrophils and myelocytes
No excess (<5%) myeloblasts
Platelet count raised/upper normal
Basophils
Leucocytosis between 50 – 500x109/l
What is the chronic phase of CML?
-approximately 80% of patients with CML are diagnosed in the chronic-phase
-can last from a few months to about 4-5 years
-nearly 80% of patients with CML will progress from the
chronic-phase to the accelerated-phase
-5% or fewer of the cells in the blood and bone marrow
are blast cells
Median 5–6 years stabilisation
What is the accelerated phase of CML?
10-19% of the cells in the blood and bone marrow are blast cells
Median duration6–12 months
What is the blast crisis in CML?
≥20% of the cells in the blood and bone marrow are blast cells
Median survival3–6 months
What makes the Philadelphia chromosome?
t(9;22) - BCR-ABL (210 kD protein made)
Fusion oncoprotein with tyrosine kinase activity
How do you monitor disease and response to therapy in CML?
FBC and measure leucocyte count
Cytogenetics and detection of Philadelphia chromosome
RT-PCR of BCR-ABL fusion transcript which can be quantified by RQ-PCR to determine response to therapy
How do leukaemia markers correlate with levels of ‘residual’ leukaemia in the body?
Disease detectable:
BCR-ABL / ABL (%)
Disease undetectable:
negative / [no. of ABL transcripts]
Summarise monitoring for CML response to therapy?
FBC
Restored to normal FBC
Cytogenetics
Reduction in percentage of Ph metaphases
RT-PCR
Log reduction in BCR-ABL : ABL ratio
What are the types of response to therapy in CML?
Haematological response
Complete Haematological Response WBC<10x109/l
Cytogenetic response (on 20 metaphases) Partial 1-35% Philadelphia positive Complete 0% Ph positive
Molecular ( reduction in % BCR-ABL transcripts)
BCR-ABL transcripts reduce 100% > 10% > 1% > 0.1%
Major Molecular response (MMR) <0.1% (3 log reduction)
What therapy can be used in CML?
Oral active ABL kinase Inhibitor (TKIs)
1st Generation Imatinib (Glivec)
2nd generation Dasatanib, and Nilotinib
Pathogenesis is an activated Tyrosine Kinase cABL in CML
Pathogenesis is an activated Tyrosine Kinase cABL in CML
Why are the ‘ib’s not a panacea?
Poor response: > Failure to achieve CCyR > Loss of MMR > Acquiring abl point mutations leading to resistance > Evolution to blast crisis
Non compliance
Side effects; fluid retention pleural effusions
What is the clinical course of CML using TKIs?
Average 95% 5 year survival
Annual mortality 2%
Commence on oral TKI 1st generation- Monitor response FBC, Cytogenetics, RQ-PCR
CCyR at 12mo 97% FFP at 6 years (Fail to achieve CCyr 80%)
What happens if there is a loss or failure to respond to TKIs in CML?
Switch to 2nd Generation TKI
Consider allogeneic Stem cell transplant
What is the difference between Type 1,2 and anti apoptotic mutations?
T1: Mutations in Tyrosine Kinase genes cause excess proliferation (no effect on differentiation)
• BCR-ABL1 CML
• JAK2 MPD
T2: Mutations in nuclear transcription factors may block differentiation. If present along with a proliferation mutation can cause acute leukaemia
• PML-RARA in acute promyelocytic
leukaemia
Mutations in apoptosis genes may occur in lymphomas
• BCL2 and Follicular lymphoma
What type of treatment is used for CML?
Imatinib/ TyrK inhibitor
What causes hepatosplenomegaly with no lymphadenopathy?
PMF
CML
What would you find on blood film in PMF?
Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes
What would you find in BM in PMF?
Dry Tap
What would you find in a trephine in PMF?
> Increased reticulin or collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering with abnormalities
New bone formation
What happens in the liver and spleen in PMF?
Extramedullary haemopoiesis in spleen and liver
