Haem

Question 1

what is leukaemia + how does it present

Answer 1

leukaemia = uncontrolled proliferation of primitive/stem cells in bone marrow

causes bone marrow failure so:
fatigue/SOBOE = anaemia
bleeding = thrombocytopenia
infections common = neutropenia

Question 2

what are the types of leukaemia

Answer 2

myeloid = myeloid precursors affected, neutrophils
lymphocytic = lymphoid precursors affected, B cells

acute = immature cells - malignant precursors, as cell differentiation impaired
chronic = mature cells, as cell differentiation normal but excessive proliferation of malignant mature cells

ALL = most common cancer in children
CLL
CML = philadelphia chr 9:22 (BCR-ABL)
AML = poor prognosis if DNMT3A gene present, good risk if CEBPA gene present

Question 3

what gives good + poor risk/prognosis for AML

Answer 3

good = CEBPA gene present, myeloid transcription factor

poor = DNMT3A gene present, DNA methyl transferase gene

Question 4

what is Philadelphia chr

Answer 4

gene mutation in CML

translocation of long arms of Chr9 + Chr22
BRC-ABL oncoprotein forms, increases tyrosine kinase activity

FISH identifies t(9:22)
PCR identifies BRC-ABL

Question 5

what identifies t(9:22) + BCR-ABL

Answer 5

FISH identifies t(9:22)
PCR identifies BRC-ABL

BCR-ABL = oncoprotein increasing tyrosine kinase activity

Question 6

how do the different leukaemia present

Answer 6

ALL = children, painless lymphadenopathy, CNS palsy
CLL = B symptoms (weight loss, anorexia, night sweat)
CML = gout, B symptoms
AML = gum hypertrophy

ALL = most common cancer in children
CLL
CML = philadelphia chr 9:22 (BCR-ABL)
AML = poor prognosis if DNMT3A gene present, good risk if CEBPA gene present

Question 7

how is leukaemia investigated

Answer 7

FBC, peripheral blood film

definitive diagnosis = biopsy

BM aspirate = morphology
BM trephine = histology to confirm diagnosis

Question 8

what are blood film findings for leukaemia

Answer 8

ALL = leucocytosis, blast cells

CLL = smudge/smear cells
antibodies specific for CD5/19/20/23

CML = excess neutrophil/basophil (myeloid lineage)
FISH identifies t(9:22), PCR identifies BCR-ABL oncoprotein

AML = auer rod (red needle-like crystals containing peroxidase)

Question 9

what determines prognosis + management of CLL

Answer 9

prognosis = IvGH mutation
management = p53 mutation or deletion

if p53 mutated/deleted (17p deletion):
1 - ibrutinib (bruton tyrosine kinase inhibitor)
2 - venetoclax if not tolerated

if p53 wild type:
FCR chemotherapy - fludranib, cyclophosphamide, rituximab (anti-CD20)

if complicated - due to ITP/AIHA (autoimmune haemolytic anaemia):
prednisolone

Question 10

how are the leukaemia managed

Answer 10

ALL = chemotherapy

CLL = chemotherapy + watchful waiting (rising WCC + lymph nodes in 12months)
if 17p deletion (so p53 mutated/deleted) = ibrutinib (Bruton tyrosine kinase inhibitor)
if p53 wild type = FCR chemotherapy
if complicated by ITP/AIHA = prednisolone

CML = chemotherapy
1 - imatinib (tyrosine kinase inhibitor) + 3monthly PCR to monitor BCR-ABL
to reduce WCC = hydroxyurea/hydroxycarbamide
allogenic bone marrow transplant

AML = chemotherapy or bone marrow transplant
for fever, broad spectrum antibiotics (tazocin - piperralicin/tazobactam)

Question 11

what is allogenic transplant

Answer 11

donated from another person

to reduce risk of graft vs host disease (as donor + host mismatches in HLA minor/major loci):
T cell depletion in donor + immunosuppressive host with cyclosporin

Question 12

with chemotherapy, what is given

Answer 12

supportive antibiotic/antifungal therapy to prevent opportunistic infections

neutropenic sepsis due to pseudomonas bacteria (gram -ve) = tazocin (piperralicin/tazobactam) +/- gentamicin
coag -ve staph, staph aureus, strep pneumonia, group A strep

pneumocystis pneumonia due to PJP fungus from HIV

Question 13

what is APML + how is it treated

Answer 13

APML = acute form of AML
translocation of Chr15 + Chr17 t(15:17), mutating RAR receptor that depends on retinoid acid

definitive diagnosis = PCR showing PML-RARA protein + FISH showing t(15:17)

treat with ATRA - all-trans retinoid acid (acid form of VitA)

Question 14

what is myeloma

Answer 14

plasma cell dyscrasia (abnormal/disordered state)
so abnormal proliferation of post-germinal B cells = plasma cells (B cells that make monoclonal antibodies)

so myeloma causes excess amounts of that type of antibody to be made + its fragments secreted into serum/urine
also relative deficiency in functional antibodies, causing relative hypogammaglobulinaemia

Question 15

what is multiple myeloma + MGUS

Answer 15

multiple myeloma = myeloma affects many areas of body

MGUS (monoclonal gammopathy of undetermined significance) = excess of 1 type of antibody, but no CRAB features present so not myeloma

waldestorm macroglubinaemia - progression of MGUS to higher levels of IgM antibodies

Question 16

what immunoglobulin is most common in myeloma

Answer 16

usually IgG

waldestorm macroglobulinaemia is excess IgM instead

Question 17

what are CRAB features of myeloma

Answer 17

at least 1 feature present for myeloma diagnosis:

hyperCalcaemia

Renal impairment

Anaemia

Bone pathology - more osteoclast activity, suppressed osteoblast so osteolytic lesions occur causing pathological + vertebral compression fractures

also plasma hyperviscosisty as too many immunoglobulins
so bruise/bleed easily, purple

Question 18

why does hypogammaglobulinaemia occur if excess antibody made in myeloma

Answer 18

there is relative deficiency in functional antibody

Question 19

what is antibody in myeloma called + what is protein in urine called

Answer 19

antibody referred to as monoclonal paraprotein

in urine, bence jones proteins found (contains light chains of antibody)

Question 20

how is myeloma investigated

Answer 20

FBC - anaemia, hyperCa
CT/MRI for osteolytic lesion
high Cr/CRP/LDH = poor prognosis

serum protein electrophoresis - monoclonal paraprotein spike
urine bence-jones protein test - high amount of free light chains

definitive = bone marrow aspirate/biopsy, shows >10% plasma cells in bone marrow

Question 21

how is multiple myeloma managed

Answer 21

if young pt with few comorbidities = haematopoetic stem cell transplant

1st line - chemotherapy = bortezomid, thalidomide, dexamethasone

manage myeloma bone disease:
bisphosphonate to suppress osteoclast
radiotherapy, surgery