myeloid malignancy Flashcards by Evie withington

what cells do myeloid malignancies involve

red cells
platelets
granulocytes
monocytes

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what happens to the cells in AML

proliferation w/o differentiation

involves myeloid progenitor cells

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what are the 4 main myeloid malignancies

acute myeloid leukaemia (AML)

chronic myeloid leukaemia (CML)

myelodysplastic syndromes (MDS)

myeloproliferative neoplasms (MPN)

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acute vs chronic myeloid leukaemia

ACUTE:

leukaemic cells don’t differentiate
bone marrow failure
rapidly fatal if untreated - ~50% of pts survive the yr
potentially curable

CHRONIC:

leukaemia cells retain ability to differentiate
proliferation w/o bone marrow failure
survival for a few yrs previously
long term survival/possible cures w/ modern therapy

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what can be seen here

normal bone marrow

heterogeneity of cells

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what can be seen here

AML

useless, immature cells and no differentiation

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clinical features of AML

bone marrow failure (triad)

anaemia (fatigue, SOB, HF)
thrombocytopenic bleeding (purpura and mucosal membrane bleeding)
infection - due to neutropenia, predominantly bacterial and fungal

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essential investigations for AML

blood count and film
bone marrow aspirate/trephine
- blasts >20% of marrow cells in acute leukaemia
cytogenetics (karyotype) from leukaemic blasts
immunotyping of leukaemic blasts
CSF examination if symptoms

targeted molecular genetics for associated acquired mutations e.g. FLT3 and NPM1

increasing use of extended next generation sequencing myeloid gene panels

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what is important for getting prognostic info about AML

cytogenetics (karyotype) - looks for growth abnormalities in the leukaemia cells

e.g. abnormality where there is exchange of material between Chr 15 and 17 –> acute myeloid leukaemia, >90% of pts cured

one whole loss of Chr 5 and one whole loss of Chr 7 and other bits missing = complex karyotype –> probably incurable in all pts

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what is immuophenotyping used for

use antibodies to identify the leukaemic blasts as myeloid or lymphoid

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CSF examination in AML

done when you think pts have CNS involvement

more common in children w/ AML than adults

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treatment of AML

supportive care
anti-leukaemic chemotherapy
-remission induction
-consolidation
-maintenance (new)

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anti-leukaemic chemotherapy - remission induction

to achieve remission - 1-2 cycles
remission = normal blood counts and <5% blasts
- daunorubicin and cytosine arabinoside (DA)
- gemtuzumab ozagamicin
- CPX-351

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anti-leukaemic chemotherapy - consolidation

1-3 cycles

high dose cytosine arabinoside
allogenic stem cell transplantation - to consolidate remission/potential cure

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anti-leukaemic chemotherapy - maintenance

low level treatment for a long period of time to prevent relapse

midostaurin (FLT3 inhibitor)

oral azacitidine (hypomethylating agent)

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treatment of low risk acute promyelocytic leukaemia

chemotherapy free regimen

all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)

high cure rate ~90%

clinical features of CML

anaemia (of chronic disease rather than bone marrow failure)
splenomegaly - often massive
weight loss (hypercatabolic state)
hyperleukostasis - fundal haemorrhage and venous congestion, altered consciousness, cardiac and resp failure
gout (due to lots of proliferation and lots of uric acid production)

CML blood count

high WCC
low Hb
normal MCV
high plts

high neuts
normal lymphs
high monos
high eos - hallmark of CML
high basos

high blasts
high promyelocytes
high myeloctes
high metamyelocytes
- looks like the bone marrow has been moved out of the blood 
high nucleated RBC

laboratory features of CML

high WCC - can be very high
high platelet count
anaemia

blood film shows all stages of WBC differentiation w/ increased basophils
bone marrow is hypercellular
bone marrow and blood cells contain the Philadelphia chromosome - t(9;22)

Philedelphia chromosome

translocation where a bit of chromosome 9 is put onto 22 and vice versa

puts BCR gene next to ABL gene (breakpoint plus abelson oncogene)

BCR-ABL is produced as a protein
overproduction of abnormal fusion gene leads to the leukaemia

treatment of CML

tyrosine kinase inhibitors of BCR-ABL:

imatinib (glivec)
dasatinib (sprycel)
nilotinib (tasigna)
bositinib
ponatinib

direct inhibitors of BCR-ABL): 1st line in all pts

allogenic transplantation - few now, only in TKI failures

how do TKI inhibitors of BCR-ABL work

inhibits tyrosine kinase binding domain

blocks phosphorylation process of tyrosine

stops downstream process that drives cml

what are the 3 main myeloproliferative neoplasma

polycythaemia vera (PV)

essential thrombocythaemia (ET)

idiopathic myelofibrosis - often advanced stage of PV and ET

mutations in MPN

JAK2 V617F gene mutation in 95% of PV - marked by red cell production
50% of ET and myelofibrosis

CALR mutation in 25% of ET

what happens as a result of the mutations in MPN

normal JAK2 - w/o erythropoietin there is no signal, when erythropoietin binds to JAK2 receptor there is phosphorylation of the downstream proteins and you get activation and red cell proliferation and production mutation w/ JAK2 - even w/o erythropoietin signal there is independent stimualtion of red cell produciton

clinical features of PV

``` headaches itch vascular occlusion thrombosis TIA, stroke - high haematocrit splenomegaly - high red cell proliferation ```

laboratory features of PV

raised Hb conc and raised haematocrit tendency to also have raised WCC and plt count raised uric acid true increase in red cell mass when the blood vol is increased

normal haematocrit levels and levels for investiagtions

NORMAL: M 45%/0.45 F 43%/0/43 INVESTIGATE IF: M >52% F >48%

PV typical blood count

``` high WCC high Hb high HCt low MCV high plts ``` ``` high neuts normal lymphs normal monos normal eos high basos ``` film: microcytosis: large and abnormal; platelets present

treatment of PV

venesection to keep the haematocrit <0.45 aspirin - reduce risk of thrombosis cytoreduction: hydroxycarbamide (HC)/alpha interferon (reduce WCC and plts) ruxolitinib (JAK2 inhibitor) in HC failures w/ systemic symptoms

natural hx of PV

stroke and other arterial/venous thromboses if poorly controlled bone marrow failure from development of 2y myelofibrosis transformation to AML

what is ET

myeloproliferative disease w/ predominant feature of raised platelet count

mutations in ET

50% +ve for JAK2V617F mutation 25% +ve for calreticulin (CALR) mutation

clinical features of ET

arterial and venous thromboses digital ischaemia gout headache mild splenomegaly

treatment of ET and complications

aspirin and hydroxycarbamide or anagrelide can progress to myelofibrosis or AML