Transcript Chronic Myeloid Leukemia

Chronic Myeloid
Leukemia
Leukemia
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ALL, AML, CLL
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Chronic Myelogenous Leukemia
– Cancer of the granulocytes or
monocytes, compared to
leukocytes in lymphocytic
leukemias
– Comprises about 14% of all
adult leukemias
– Males slightly higher than
females
– One of the first cancers to
have a specific genetic link to
a chromosomal mutation
identified for the disease
 Philadelphia Chromosome
Pathophysiology
Disorder of the stem cells in bone
marrow
 General infection fighting cells are
the most harmed > granulocytes
and monocytes (aka, neutrophils)
 These immature cells take over
the body’s mature neutrophils and
hinder the body’s ability to fight
infection properly
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CML is caused by a genetic
mutation with chromosomes 9 and
22 in the body
 Abl on chromosome 9 is
translocated to chromosome 22
and fuses with Bcr
 This ABL-BCR protein is an
unregulated tyrosine kinase and
thus, is the source of the
reproduction of immature
granulocytes
 Other functions include: upstream
changes of DNA repair
mechanisms, suppression of the
body’s programmed cell death
proteins, and changes in
cytoskeletal structures
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How you are diagnosed
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Usually by accident!
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Routine WBC test shows
elevated leukocytes
Confirmed with bone marrow
biopsy and FISH and/or PCR
that shows presence of
Philadelphia Chromosome
Presence of myeloid cells in
peripheral blood determines
staging of disease
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S/SX: lethargy, pallor,
night sweats, weight loss,
anorexia, fever,
lymphadenopathy,
splenomegaly
STAGING OF CML
-
Three main stages, determined by
percentage of blast cells in the blood
- Chronic Phase
- Patient usually diagnosed
- Fewer than 10% of cells in blood and bone marrow are
granulocytes
- Prognosis: (with imatinib) 5yr: 70%, 10yr: 30-40%
- Accelerated Phase
- 10-19% of cells are granulocytes
- Blastic Phase, aka “blast crisis”
- Fulminant symptoms of disease, multiple organ involvement
- 20-30% or more granulocytes in bone marrow and blood
- Prognosis: UNPROMISING, 2 months, may extend survival with
newer drugs or chemotherapy
Treatment Options:
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Pharmacotherapy
– Newer drugs are
prolonging chronic phase
and increasing the number
of patients who enter into
remission
– They are easier on the
body versus SCT
– Old Standard: hydroxyurea
(no possible cytogenic
response) or interferon
alpha + cytarabine
– New Standard: tyrosine
kinase inhibitors
 Imatinib, dasatanib,
nilotonib
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Stem Cell Transplant
– Using bone marrow from a
donor to “resupply” the
patient
– Can be the only “curative”
measure, although many
drawbacks
 Must be good candidates
for surgery
 Must have a relatively
short time from diagnosis
to transplant
 Matching donor
 Possible relapse of CML
 Rejection (GVHD)
How to measure treatment
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Hematologic response
– The response that reflects a
decrease in white blood cell
count and platelets
– A hematological response in
CML would be shown when a
patient went from about a
10% granulocyte count to a
4% granulocyte count
– Good prognostic sign
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Cytogenic response
– Reduction or elimination of
Ph+ cells in bone marrow
– Can be Complete, Major or
Minor
 0%, 1-34%, 35-90%
respectively in bone marrow
cells
– Done by FISH and/or PCR
– Chronic phase patients who
have cytogenic responses
have a significant increase in
survival and a deterrence to
progression to accelerated or
blast phases
– Better prognostic sign
New Treatments: Tyrosine Kinase
Inhibitors
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Enzyme that is able to transfer
a phosphate group from ATP
to a tyrosine residue in a
protein
Main proponents of signal
transduction of enzymes in
body, in bone marrow, this is
one of many proteins that
plays a large role in
hematopoeisis
In CML, the BRC-ABL gene is a
tyrosine kinase that is
constituently active, and thus
produces unregulated
granulocytes
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A great advance in the
treatment of CML was to
develop a tyrosine kinase
inhibitor, that “turns off’ the
active TK in the body, specific
to the mutated gene, BRC-ABL
The first generation TK
inhibitor for CML is imatinib
mesylate
Imatinib mesylate
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First generation TK inhibitor
Dosed in 400mg and 800mg
tablets
Binds the closed form of the
ATP binding site in BRC-ABL
IRIS study: 97% pts in
hematological remission and
major cytogenic remission was
87% compared to interferon
alpha + cytarabine after 19
months
IRIS Follow-up five year study:
if patient shows a 3-log
molecular response to
imatanib, then probability of
progression-free survival at 4
years is 98% (Frame 2006)
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Side Effects: Fluid retention
(76%), diarrhea (30-60%),
nausea (43-73%), fatigue,
muscle cramps, bone pain,
rash, neutropenia,
thrombocytopenia (although
might be signs of
effectiveness)
– Most can be alleviated with
common medications and are
not a cause of discontinuation
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Resistance occurs
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A small number of patients
show some resistance to
Imatanib
The BRC-ABL transcript has the
ability to mutate and thus
make imatinib ineffective
Imatinib binds to the closed
conformation and BRC-ABL can
mutate to the open
conformation and thus makes
imatanib ineffective
Two 2nd generation TKIs have
proven to be more potent and
are in trials to determine
effectiveness against
resistance to imatanib
nd
2
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Dasatanib
Generation TKIs
– aka Sprycel; 300 times more
potent than imatanib
– Binds to multiple
conformational states (open
and closed), unlike imatanib
– Very new drug, approved in
July, 2006 for further clinical
trials
– Side Effects:
myelosuppression which can
lead to bleeding, infection and
fatigue, fluid retention,
headache, skin rash, nausea
– Can be used in patients who
are resistant to imatanib
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Nilotonib
– Structurally similar to imatanib
– 20 to 50 times more potent
than imatanib
– Binds in the closed
conformation
– Not FDA approved, still under
scrutiny
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COMBOS with dasatanib,
nilotonib and imatinib have
proven that they do not inhibit
each other, and prove useful in
pilot experiments with
resistant cell clones
Treatment Algorithm
References
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Faderl S, Kantarjian HM. Chronic Myelogenous Leukemia and Other
Myeloproliferative Disorders. [ BOOK, check citing!]. ACP Medicine. 2006.
vol 2(2570-79)
Fausel C. Novel treatment strategies for chronic myeloid leukemia. Am J
Health-Syst Pharm. 2006 Dec 1; 63(Suppl 8): S15-S20.
Grigg A, Hughes T. Role of Allogenic Stem Cell Transplantation for Chronic
Myeloid Leukemia in the Imatinib Era. Biol Blood Marrow Transplant. 2006
Mar 29; 12:795-807.
http://www.gleevec.com/info/page/safety_info
http://www.cmlmedicalmonitor.com/medicalmonitor/education/ayd_response.asp?trial=show
http://www.pharmcast.com/Patents/Yr2002/Mar2002/032602/6362162_CM
L032602.htm
http://images.google.com/images?q=PHILADELPHIA+CHROMOSOME+imag
e&hl=en&sa=X&oi=images&ct=title
http://commons.wikimedia.org/wiki/Image:Bcr-abl_fusion_gene.jpg