Chronic Myeloid

Leukemia
 Leukemia
 ALL, AML, CLL
 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
 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
 How you are diagnosed
 Usually by accident!  S/SX: lethargy, pallor,
night sweats, weight loss,
 anorexia, fever,
 Routine WBC test shows
lymphadenopathy,
elevated leukocytes
splenomegaly
 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
 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:
 Pharmacotherapy  Stem Cell Transplant
– 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
– 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
 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
 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
 Enzyme that is able to transfer  A great advance in the
a phosphate group from ATP treatment of CML was to
to a tyrosine residue in a develop a tyrosine kinase
protein inhibitor, that “turns off’ the
 Main proponents of signal active TK in the body, specific
transduction of enzymes in to the mutated gene, BRC-ABL
body, in bone marrow, this is  The first generation TK
one of many proteins that inhibitor for CML is imatinib
plays a large role in mesylate
hematopoeisis
 In CML, the BRC-ABL gene is a
tyrosine kinase that is
constituently active, and thus
produces unregulated
granulocytes
 Imatinib mesylate
 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)
 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
 Resistance occurs
 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
 2nd Generation TKIs
 Dasatanib
– 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
 Nilotonib
– Structurally similar to imatanib
– 20 to 50 times more potent
than imatanib
– Binds in the closed
conformation
– Not FDA approved, still under
scrutiny
 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
 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/medical-
monitor/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