Week 11. Neoplastic Blood Disorders of Myeoloid Cells Flashcards Preview

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Flashcards in Week 11. Neoplastic Blood Disorders of Myeoloid Cells Deck (26):

What are myeloid cells?

Granulocytes- neutrophils, eosinophils, basophils

Monocytic, erythroid and megakaryocitic cells lineages- platelets, leukaemias not just WBCs


What are acute myeloid leukaemias due to?
Why is it called acute?

Due to the presence of myeloblasts.

Acute: group of malignant disorders in which the haemopoietic blast cells are greater than 20%. (usually no more than 2% in circulation)


Where can malignant cells accumulate in AML?
What ages does AML affect?

Bone marrow, blood and infiltrate other organs. Crowds out bone marrow.
Affects all ages, but most common in 65+ yrs. 25% of cases happen to under 25s.


What is AML caused by?

Not just one disease! Because in myeloid cell line, many cell lineages.
:Can be caused by lots of different genetic mutations in stem cell or myeloid precursor cell.
-Translocations between chromosome 8 and 21 t(8;21)
-Translocations between chromosome 15 and 17 t(15;17)

Prior myelodysplastic syndrome or myeloproliferative disease (MPD) that transforms into AML: elderly/poor prognosis.


What are the AML classification?

FAB classifications- 8 sub-categories m0-m7

M0- undifferentiated blasts (just myeloids)
M1- lightly granulated blasts
M2- Granulated blasts often with Auer rods (projections in cytoplasm not seen in healthy cells.)
M3- Promyelocytic leukaemia
M4- Myelomonocytic leukaemia
M5-Monocytic leukaemia
M6- Erythroleukaemia
M7- Megakaryocytic leukaemia-> platelets leukaemia


What is FAB class M3 acute promyelocytic leukaemia caused by?

A translocation between chromosome 15-> 17. The PML gene on chromosome 15 fuses with the retinoic acid receptor alpha gene (RARalpha) on chromosome 17.
Retinoic acid=vitamin A.
The PML-RARalpha fusion product blocks differentiation of cells. So accumulation of the blasts.
(This causes 98% of M3 which is good because we can treat it.)


Treatment for FAB class M3 acute promyelocytic leukaemia

Treated with all-transretinoic acid (ATRA) Induces differentiation of the leukaemic cells t(15;17)


Why is m3 acute promyelocytic leukaemia good now?

How do you detect the translocations?

M3 AML (makes up 10% of AMLs) we've identified the translocation and then found a specific treatment so it won't affect healthy cells.

Detected by cytogenetics or PT-PCR


What causes M2 AML: granulated blasts with Auer rods?

translocation between chromosomes 8 and 21. t(8;21) brings together a transcription factor RUNx1 with a co-repressor RUNA1t1.
This fused gene product blocks differentiation.-> accumulation of blasts, again looking for more than 20% of those blasts.
Granulated blasts with Auer rods.

For m0-m7 will have particular translocation. May not be good prognosis.


Clinical features of AML?

Bone marrow failure: blasts overcrowd bone marrow

Anaemia, thrombocytopenia, infections.

Skin infiltration and CNS disease: the malignant cells invade tissues. WBCs in myeloid leukaemias accumulate in the GONs (mucous membranes) which tend to cause what look like ulcers but are an accumulation of WBCs.


Lab findings of AML?

Diagnosis based on;
-Full blood count (FBC) very important look whether normal count and normal cells, types and morphology.
-Morphology: blood film-blasts, bone marrow smear-> 20% blasts.

If blood film showed lots of blasts, would ask to do bone marrow biopsy. Not done unless you suspect it because harder to do.
These would tell you probably if it was AML or ALL.


What are the next lab findings of AML?

After blood counts and films, to identify the particular subset need to do some immunophenotpying.

Immunophenotyping- uses monoclonal antibodies to identify cell antigens which define lineage and maturity, (whether a mature cell or blast). (uses flow cytometry).

On myeloid blasts-> CD33 IS EXPRESSED.

Chromosomal abnormalities


What is the treatment of AML?

Treatment quite good.
Start with:
1. supportive and specific. Treat bone marrow failure e.g. anaemia. Need to be healthy enough to undergo chemotherapy.

2. Chemotherapy divided into: induction-> remission reduction.
consolidation-> get into minimal residual phase.

Induction therapy aims to achieve complete remission (


Describe drugs in AML treatment?

These are cytotoxic drugs so have an effect on healthy cells too, especially in induction chemo.
All AML are given inductino chemotherapy with cytarabine and an anthracycline (danorubicin)

Then you can target the specific translocation but the specific treatments are always given in combination with chemo. e.g. M3 is treated with ATRA and chemo. ATRA causes differentiation of immature cells-> mature granulocytes.

Consolidation therapy-> depends on prognosis. May be short or long consolidation


What is immunotherapy?

uses the antigens identified on the malignant cells e.g. CD33.
Cancer immunotherapy stimulates our own immune system to reject and destroy tumours.


Example of immunotherapy

Myolotarg- drug which is anti-CD33. Destroys Granulocytes and macrophage precursors. Very targetted.
Unfortunately had to be taken out of circulation beause unsafe with other chemotherapeutic agents. Some people died.


Side effects of cytotoxic drugs?

Cytotoxic= no selectivity
Myelotoxic: limited selectivity between leukaemia and normal narrow cells.
Bone marrow failure from chemo.

Emerging development: basing treatment schedule on individual patient on their risk group.


If cytotoxic drugs give you bone marrow failure what do you need next?

Stem cell transplant

Autologous- patients own marrow, collected when patient is in remission. Low risk but usually patient not healthy enough.

Allogenic- most common. ask siblings with same tissue type. Then national marrow donor programme.


What's the prognosis of AML?

Very variable.
More likely to be cured if you're younger.
A shame because more common with +65. Approx 50% young people cured.


Chronic Myelogenous (myeloid) Leukaemia CML

Can transform from CML into AML.

Clonal disorder of a pluripotent stem cell. Proliferation of mature granulocytes and their precursors. Neutrophils, eosinophils and basophils.

15% of leukaemias.
Occurs at any age.
Diagnosis quite straight forward. By blood count. Most commmon translocation = philadelphia chromosome t(9;22)- BCR-ABL1 fusion.


How does the philadelphia chromosome cause CML?

Reciprical translocation 9+22
Results: fusion between protooncogene ABL and BCR gene on chromosome 22.

Resulting BCR-ABL gene encodes for a 210KDa protein- causes production of tyrosine kinase, stimulates production of abnormal cells.

Leads to increased cell cycling and resistance to apoptosis.


What are the clinical features of CML?

Presenting features: weight loss and night sweats.


Anaemia and bleeding and bruising- bone marrow failure.

In up to 50% cases, diagnosis made incidently from a routine blood count.


What are the lab findings of CML?

Increased basophils- usually less than 1%. BUt lots here.
Bone marrow usually hypercellular with a raised myeloid/erythroid ratio.

In blood sample spun, can see loads of WBCs on top of RBCs. Usually can only see a thin layer if any.

Philadelphia chromosome BCR-ABL fusion is detectable by FISH.


What is the disease progression of CML?

3 phases:
1. Chronic phase (CML-CP)
-usually respond well to chemo
-continues on average 4-6 years.

2. Accelerated phase (CML-AP)

3.Blast Phase (CML-BP)
Fatal acute leukaemia.
When it has transformed into acute leukaemia and no treatment available.


What's treatment of CML?

You have the overall chemo so have the induction chemo to put you into remission.

Imnatib/Glivec (targetted therapy)- BCR-ABL tyrosine kinase inhibitor. BLocks the binding of ATP to this BCR-ABL.
Inhibits the activity of the kinase produced which normally increases the proliferation of the cells.
So inhibits proliferation of the BCR-ABL cells.

INcreases the chronic phase and reduces the risk of acute transformation. Resistance to drug is developing now! More being made,


Treatments for CML extra reading

Since imnatib is starting to be resisted to:

Broad multikinase inhibitor
effective in many cases where BCR-ABL1 has acquired mutations rendering it resistant to Imatinib

Similar mechanism of action to Imatinib
Higher affinity for BCR-ABL1 kinase