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Perth Haematology :: Dr Steven Ward

Chronic Myeloid Leukaemia (CML)

 

CML = clonal increased granulocyte precursor production in the marrow and blood

 

A great deal of research has revealed the mechanism of the disease, down to the molecular level.

 

CML is due to the production of the abnormal fusion gene BCR-ABL and its product the bcr-abl protein.

 

bullet
nOne of the Myeloproliferative disorders (MPD)
bullet
nClonal Stem cell disorder
bullet
nabnormal maturation of progenitor cells - expansion
bullet
nless regulated than normal cells
bullet
naccumulation of mature cells
bullet
nHigh WCC - mainly myelocytes and neutrophils
bullet
nAbnormal basophils and eosinophils
bullet
nHigh platelet count
bullet
nSplenomegaly
bullet
nO2 K+ glucose spurious abnormalities, as metabolically active cells in blood tube
bullet
nBCR-ABL fusion gene
 
bullet
n20% of all leukaemia
bullet
nmortality = 1.5 per 100,000 population/year
bullet
nM>F
bullet
ná with age; only 5% <20 years
 

Symptoms / Signs

bullet

fatigue, “unwell”, anorexia ; sweats

bullet

nabdo discomfort / satiety ; wt loss

bullet

nsplenomegaly ; gout; âconscious level

 

nBCR-ABL fusion gene
bullet
nreciprocal translocation between chromosome 9 & 22
bullet
nBCR normally on chromosome 22        ABL normally on chromosome 9
bullet
nthe shortened chromosome 22 = Philadelphia [Ph+] chromosome
bullet
nABL is translocated next to BCR
bullet
nResultant fusion gene is active – Tyrosine Kinase
bullet
nconstitutively activated
bullet
nUsually a 210kD protein, some have 185 - 190kD
 

nBCR-ABL frequency:
bullet
n100% of CML [now part of definition]
bullet
npreviously 95%+ CML [Other 5% = MPD-unspecified]
bullet
n25% adults with ALL
bullet
n5% children with ALL
bullet
nSome “normal” 80 year olds (very low numbers)
 

Therapy

nCurrent therapy involves the use of Tyroskine Kinase Inhibitors (TKIs). These drugs have revolutionised CML into a chronic disease now.
The need for transplantation is now very rare.
There are currently 3 TKIs licenced and funded for use in CML in Australia
bulletImatinib (Glivec) - the original drug - 1st generation TKI.
bulletDasatinib (Sprycel)
bulletNilotinib (Tasigna)

n


Imatinib (Glivec)

bullet
nOral drug
bullet
n400mg/day (1 tablet)
bullet
nCommoner Side Effects:
bullet
nOedema
bullet nNausea
bullet nMuscle cramp/ arthraliga
bullet nRash
bullet nNeutropenia, thrombocytopenia
bullet
nDrug interactions: paracetamol
bullet
nExpensive: $55,000 pa (400mg/day)
n
 

CML TKI Side Effect Profiles
Side Effect
Imatinib
Nilotinib
Dasatinib
Fluid Retention
+++
(+)
(+)
Nausea, vomiting, Diarrhoea
++
(+)
(+)
Pleural Effusion
-
-
++
Myalgia
+++
(+)
(+)
QTc prolongation
+
+
+
LFT abn
+
++
+
Lipase abn
+
++
+
Glucose
Hypo
Hyper
No change
Hypo PO4
++
+
+
Rash / itch
+
++
(+)
Anaemia
+
+
+
Neutropenia
++
+
+
Thrombocytopenia
+
+
++

 

 
MCR
CCR
Imatinib
83%
63%
IFN   Ara-C
20%
7%

 

CML : Definitions

 

Complete Haematologic Response (CHR)

bullet

Normal FBP, WCC < 10

bullet

Platelets < 450

bullet

No immature cells in blood

bullet

No signs or symptoms of disease with disappearance of palpable splenomegaly

 

 

Partial haematologic Response

As for CHR but:

bullet

Presence of immature cells

bullet

Platelets < 50% of pre-treatment count but > 450

bullet

Persistent splenomegaly, but <50% of pre-treatment size

 

 

Cytogenetic response

bullet

Complete: No Ph+ metaphases (CCR)

bullet

Partial: 1-34% Ph+ metaphases

bullet

Minor: 35-90% Ph+ metaphases

 

 

Accelerated Phase

WHO Criteria:

bullet

Blasts 10-19% in blood or BM cells

bullet

PB basophils ≥ 20%

bullet

Persistent thrombocytopenia < 100 unrelated to therapy, or persistent thrombocytosis > 1000 unresponsive to therapy

bullet

Increasing spleen size and increasing WCC despite therapy

bullet

Cytogenetic evidence of clonal evolution

 

 

Blast Crisis

WHO Criteria:

bullet

Blasts ≥ 20% blood or BM cells

bullet

Extramedullary blast proliferation

bullet

Large foci or clusters of blasts in marrow

 

 

Imatinib (Glivec) potential drug interactions

 

Drug

Interaction

Paracatamol

LFT abn. Limit paracetamol to 1g day max

Aprepitant

5 imatinib conc

Carbamazepine

6 imatinib conc

Clarithromycin

5 inatinib conc

Cyclosporin

5 CyA conc

Dexamathasone

6 inatinib conc

Erythromycin

5 imatinib conc

St John’s Wart

6 inatinib conc

Itraconazole, ketoconazole

5imatinib conc

Phenytoin

6 imatinib conc

Rifampicin, rifaubtin

6 imatinib conc

Simvastatin

5 simvastatin conc

Warfarin

5 warfarin effect, inc INR

Mainly  CYP450 3A4 interactions