Transcript CML_Learning_Programme_Modul.1

CML Learning
Programme
EBMT Slide template
for NursesBarcelona
& Other
Allied
Health Care
7 February
2008
Professionals
EBMT Nurses Group
The
The European
European Group
Group for
for Blood
Blood and
and Marrow
Marrow Transplantation
Transplantation
Module 1
Understanding
Chronic Myeloid Leukaemia
(CML)
The European Group for Blood and Marrow Transplantation
Aims of Module 1
This module explains the background to CML,
it aims to:
• Understand the definition of Chronic Myeloid
Leukaemia (CML) and its pathophysiology
• Understand CML’s etiology, increasing
prevalence and symptoms
The European Group for Blood and Marrow Transplantation
Aims of module 1
• Understand the different stages of CML, the
way CML is diagnosed and different prognostic
scoring systems
• Understand historical developments in CML
treatment
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Definition of CML
The World Health Organization (WHO) classifies
chronic myeloid leukaemia (CML) as a myeloproliferative disease characterised by the
presence of the Philadelphia chromosome or
BCR-ABL fusion oncogene
Vardiman J.W. et al. Blood 2002,100:2292-302
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Epidemiology of CML
• CML is a complex disease that occurs in about
1 case per 100’000 of the population
Black R.J. et al. Eur J Cancer 1997, 33: 1075-1107)
• CML is estimated to account for approximately
one of every five cases of adult leukaemia
Sawyers C.L. et al. NEJM 1999, 340: 1330-1340)
• CML affects men slightly more than women
Ratio 1.7:1
Henderson, E.S., Lister, T.A., & Greaves, M.F. (2002.)
Leukemia 7th ed.) New York: Saunders
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Epidemiology of CML
• The median age at diagnosis is 60 to 65 years
ESMO Guidelines Working Group. Ann Oncol (2010) 21 (suppl 5): v165-v16
• There is no significant ethnic or geographical
predisposition
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Epidemiology of CML
• Around 10 % of cases of CML occur in children aged 5 to 20 years
Beutler E., Lichtman M.A., Coller B.S., Kipps T.J., & Seligsohn, U. (2001.)
William’s hematology (6th ed.). New York: McGraw-Hill.
• CML represents around 3% of all cases of childhood leukaemia
Beutler E., Lichtman M.A., Coller B.S., Kipps T.J., & Seligsohn U. (2001)
William’s hematology (6th ed.)
New York: McGraw-Hill
• The number of people living with CML has doubled since 2001 due to the
development of new treatments (such as imatinib)
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
CML Prevalence Estimates
• CML is one of the big success stories in cancer
• With imatinib (and other TKI treatments) the
survival in CML has improved from a median of
3 to 6 years with hydroxyurea and interferon
alpha to an estimated 8 year survival rate of
80 to 90% with imatinib
(Prevalence = incidence x duration of disease)
The European Group for Blood and Marrow Transplantation
CML Prevalence Estimates
• Prior to imatinib the annual mortality rate for CML
was 15 to 20% of patients
• Thus it is estimated that the prevalence of CML in
the US in the next three decades may exceed
200’000 cases
The European Group for Blood and Marrow Transplantation
CML Prevalence Estimates
• Because the highly effective drugs are still
fairly new, the average survival of people
now being diagnosed with CML is not known
• CML is currently undergoing transition from
being a rare cancer to a chronic one
The European Group for Blood and Marrow Transplantation
Epidemiology of CML
• The risk of getting CML increases with age, with
half of all CML patients older than 60
• CML is slightly more common among males than
females. Ratio 1.3:1
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
1845
John Hughes Bennett and Rudolph Virchow describe
the first case of CML
1960
Peter C. Nowell and David Hungerford
identify an abnormal chromosome
called the Philadelphia chromosome
in the blood cells and bone marrow
of patients with CML Nowell & Hungerford. J Natl Cancer Inst 1960, 25: 85-109
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
1973
Janet Rowley determines
that the abnormal
chromosome identified by
Nowell and Hungerford
results from the exchange
of genetic material
between two chromosomes
Rowley J.D. et al. N Engl J Med 1973, 289:220-221)
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Historical Milestones in CML
1982-1985
John Groffen, Nora Heisterkamp, Gerald Grosveld,
E. Cannani, David Baltimore and Owen Witte
show that an abnormal gene and protein called
BCR-ABL is produced as a consequence of the
chromosome rearrangement that characterizes CML
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
1987
Nicholas Lydon and Alex Matter commence a drug
discovery program to target proteins such as BCR-ABL,
in collaboration with Brian Druker, Thomas Roberts and
Charles Stiles
Using a new technique called high throughput screening,
in which thousands of molecules can be tested for their
Biological activity, Lydon identified a compound called
CGP57148B,later renamed STI-571
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Historical Milestones in CML
1993
Brain Druker’s laboratory shows that STI57I
(imatinib) is the best of the compounds developed
by Lyndon’s group at specifically targeting and killing
CML cells
Druker B. et al. Nat Med 1996, 2: 561-566
1998
Brian Druker, Charles Sawyers, and Moshe Talpaz
begin clinical trials of imatinib
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
2001, May 10
Imatinib is FDA approved for use as a first-line
treatment for people with accelerated phase or
blast crisis CML or chronic phase CML patients
who had not responded to interferon-alpha
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
2003
The IRIS trial showed that imatinib was superior to the
standard combination of interferon-alpha/cytarabine
O’Brien S.G. et al . N Engl J Med 2003, 348: 994-1004
Charles Sawyers, Brian Druker, Andreas Hochhaus, and
Francois-Xavier Mahon report that mutations of BCR-ABL are
The major mechanism of imatinib resistance, leading to the
development of second generation tyrosine kinase inhibitors
such as dasatinib and nilotinib
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
2006-2007
Dasatinib and nilotinib are FDA approved for Patients with
imatinib resistance
June 2010
FDA approval granted to nilotinib as first-line treatment in
Ph+ CML
October 2010
FDA approval granted to dasatinib as first-line treatment in
Ph+ CML
The European Group for Blood and Marrow Transplantation
Historical Milestones in CML
December 2010
EMA and Swiss Medic approve nilotinib as first line
treatment in Ph+ CML
EMA approved dasatinib as first-line treatment in
Ph+ CML
(Taken, in part, from “50 Years in Hematology: Research that revolutionized patient care”. Published by the
American Society of Hematology. Chapter 2. Targeted Therapy for Chronic Myeloid Leukemia. P 13.)
The European Group for Blood and Marrow Transplantation
What is Philadelphia
chromosome positive CML?
• Chronic myeloid leukaemia (CML) is a haematopoietic stem cell disease of the bone marrow and
blood
• CML is characterised by a massive overproduction
of white blood cells
The European Group for Blood and Marrow Transplantation
What is Philadelphia
chromosome positive CML?
• The uncontrolled growth of white blood cells in CML
results from an acquired injury to the DNA of a stem
cell in the bone marrow
• The disease is called Philadelphia chromosomepositive CML because it results from the formation of
the Philadelphia chromosome from the translocation
of elements of chromosome 9 and 22
The European Group for Blood and Marrow Transplantation
What is Philadelphia
chromosome positive CML?
The gene that breaks off from chromosome 9 is
called ABL (after Abelson the scientist who first
identified the gene), while the gene that splits
from chromosome 22 is called BCR, short for
breakpoint cluster region
The European Group for Blood and Marrow Transplantation
What is Philadelphia
chromosome positive CML?
• The combination of BCR and ABL leads to the
formation of an abnormal fusion gene responsible for
the pathogenesis of CML
• In the words of Brian Druker the BCR-ABL gene in
CML acts “like the gas pedal in a car stuck in the ‘on’
position fuelling the excess growth of white blood
cells”
The European Group for Blood and Marrow Transplantation
What is Philadelphia
chromosome positive CML?
The presence of BCR/ABL rearrangement is
the hallmark of CML, and responsible for
accelerated cell growth and decelerated cell
death
(ASH, 50 Years in Hematology: Research that revolutionized patient care, 2008)
The European Group for Blood and Marrow Transplantation
Biology of CML
Chromosome 22
Chromosome
9
Philadelphia (Ph)
chromosome
9
t (9;22)
BCR
BCR
ABL
ABL
BCR-ABL
(Tyrosine kinase)
Cytogenetics
+
Signaling pathways
• Ras
• AKT
• PI3K
• Other pathways
>
Deregulation
• Cell proliferation
• Cell survival
• DNA repair
22
>
Ph+
CML
• WBC (myeloid) 
• RBC 
• Platelets 
Tyrosine kinase inhibitors (TKIs)
The European Group for Blood and Marrow Transplantation
Projection of CML Prevalence up to 2050
Assumptions:
Population: 500 Mill., mortality: 2% per year,
Incidence increasing by about 0.01/100.000 per year
400000
350000
Incidence 2000: 1/100.000
Incidence 2000: 1,5/100.000
Prevalence
300000
Incidence 2000: 2/100.000
250000
200000
150000
20%-25% increase per year
in projected prevalence
100000
50000
0
2000
2005
Modified from R. Hehlmann
2010
2015
2020
2025
2030
2035
2040
2045
2050
Year
The European Group for
Blood and Marrow Transplantation
Survival 1983-2008
Primary imatinib, 2002-2008 (CML IV)
5-year survival 93%
Survival probability
n = 2830
IFN or SCT, 1997-2008
(CML IIIA) 5-year survival 71%
IFN or SCT, 1995-2008 (CML III)
5-year survival 63%
(CML I, II)
IFN, 1986-2003
5-year survival 53%
Hydroxyurea, 1983-1994
Busulfan, 1983-1994 5-year survival 38%
Courtesy of the German CML Study Group
Year after diagnosis
The European Group for Blood and Marrow Transplantation
Etiology of CML
• The initiating factor of CML is still unknown, although
exposure to radiation has been implicated
• If people have had radiotherapy for another cancer
this can increase risk of CML
• Agents such as benzene are thought to be a possible
cause
Moloney W.C. et al. Blood 1987, 70 : 905-908
The European Group for Blood and Marrow Transplantation
Etiology of CML
• The risk of getting CML does not seem to be
affected by smoking, diet, or infections
• CML does not run in families since inherited
mutations do not cause CML
• Instead, DNA changes related to CML occur
during the patient’s life time
The European Group for Blood and Marrow Transplantation
Etiology of CML
• People with low immunity after an organ
transplant or due to HIV or AIDS are at
increased risk
• Ulcerative colitis can increase the risk
• Being overweight can slightly increase risk
The European Group for Blood and Marrow Transplantation
Symptoms of CML
The clinical manifestations of CML are insidious
and often discovered incidentally when an
elevated white blood cell count is revealed by a
routine blood count or when an enlarged spleen
is revealed during a general physical
examination
The European Group for Blood and Marrow Transplantation
Common CML symptoms
include
• Feelings of satiety and decreased food intakes due
to the enlarged spleen encroaching on the stomach
• Nonspecific tiredness resulting from anaemia
• Low-grade fever and excessive sweating related to
hyper metabolism
The European Group for Blood and Marrow Transplantation
Symptoms of CML
• Bone pain or joint pain caused by leukaemia cells
spreading from the marrow cavity to the surface of
the bone or into the joint
• In very rare cases, patients with very high white
blood count may present with Hyperviscosity
syndrome, including priapism, cerebrovascular
accidents, tinnitus, confusion and stupor
The European Group for Blood and Marrow Transplantation
Phases of CML
The progression of Ph+ CML that occurs when the
condition is left untreated is described in three phases:
• Chronic Phase CML
• Accelerated CML
• Blast Crisis CML
Chronic
Accelerated
Blast
The European Group for Blood and Marrow Transplantation
Phases of CML
The phases of CML depend on a number of
different factors, mainly the number of
leukaemic blast cells (blasts) that are found
in the blood and bone marrow and the
severity of symptoms that the patient is
experiencing
The European Group for Blood and Marrow Transplantation
Chronic Phase CML
• In the chronic phase of Ph+ CML there are few blasts
• Approximately 90 % of patients with Ph+ CML are
diagnosed in this phase
• Newer forms of therapy aim to delay progression of the
disease from chronic phase to accelerated or blast phase
• Patients usually respond to standard treatments
The European Group for Blood and Marrow Transplantation
Accelerated Phase CML
• Blasts 10 to 19% of WBCs in peripheral and/or
nucleated bone marrow cells
• Peripheral blood basophils (> 20%)
• Persistent thrombocytopenia (<100 x 10 ⁹/L)
unrelated to therapy, or persistent thrombocytosis
(>1000 x 10 ⁹/ L) unresponsive to therapy
The European Group for Blood and Marrow Transplantation
Accelerated Phase CML
• Increasing spleen size and increasing WBC count
unresponsive to therapy
• Cytogenetic evidence of clonal evolution
WHO Criteria. IARC Press: Lyon 2008
• The accelerated phase can last 6 to 18 months,
where it either responds to treatment or progresses
to the next phase
• CML in the accelerated phase does not respond
as well to treatment as CML in the chronic phase
The European Group for Blood and Marrow Transplantation
Blast Crisis
WHO Criteria
• Blasts >20% of
peripheral blood
white cells or of
nucleated bone
marrow cells
• Extra medullary blast
proliferation
• Large foci or clusters
of blasts in the bone
marrow biopsy
(WHO. IARC Press: Lyon 2008)
International Bone Marrow
Transplant Registry
• >30% blasts in the
blood, marrow or both
• Extra medullary
infiltrates of leukemic
cells
(DeVita VT, Hellman S et al.
Cancer: Principles and Practice of
Oncology, 6th Edition. Vol 2. pgs
2433-2447. 2001
Lippincott, Williams & Wilkins.)
The European Group for Blood and Marrow Transplantation
Disease Progression
The exact molecular mechanism by which CML
transforms to more advanced stages of the
disease is unknown
The European Group for Blood and Marrow Transplantation
Disease Progression
However, it is thought likely that one of the drivers of
the progression from chronic phase through
acceleration and blast crisis is the acquisition of new
chromosomal abnormalities in addition to the
Philadelphia chromosome
With modern treatment only about 10% of patients
show progression every year
The European Group for Blood and Marrow Transplantation
Techniques used to
diagnose/monitor CML
• Complete Blood Counts
• Cytogenetic analysis
• More sensitive testing
The European Group for Blood and Marrow Transplantation
Complete Blood Counts
•
Most patients with CML show an increase in the
number of leukocytes in the blood with many
immature cells
•
Sometimes CML patients also have anaemia and
thrombocytopenia
•
•
Even though such findings suggest leukaemia
further tests will be needed to confirm the diagnosis
The European Group for Blood and Marrow Transplantation
Cytogenetic analysis
• Involves looking at DNA from bone marrow under
the microscope to determine how many cells
contain the Philadelphia chromosome
• A complete cytogenetic response occurs when
no cells are found to have the Philadelphia
chromosome
The European Group for Blood and Marrow Transplantation
More sensitive testing
For CML patients who are cytogenetically
Ph-chromosome–negative (Ph-) the following special
techniques can be used to detect BCR-ABL :
• Fluorescence in situ hybridization (FISH)
• Reverse transcriptase polymerase chain reaction
(RT-PCR)
The European Group for Blood and Marrow Transplantation
Fluorescence insitu
hybridization (FISH)
• Uses fluorescent dye probes to bind to specific pieces of DNA
• For CML 2 probes may be used, 1 to bind to the BCR gene,
and 1 to bind to the ABL gene
• When the probes bind to their target genes each dye emits a
fluorescent glow
• Reveals whether BCR and ABL genes are next to each other
(as in the Philadelphia chromosome), or on separate
chromosomes (as in normal cells)
The European Group for Blood and Marrow Transplantation
Fluorescence insitu
hybridization (FISH)
• If copies of the gene are found it means that the
leukaemia is still present even when cells aren’t
visible under the microscope
• Can be used on used on regular blood or bone
marrow samples without culturing the cells first
The European Group for Blood and Marrow Transplantation
Fluorescence insitu
hybridization (FISH)
• The technique looks at 200 to 500 blood cells
attained through bone marrow biopsy
•
Due to the small sample size the test
is not as sensitive as PCR
• FISH has the capacity to detect
1 leukaemia cell in 500 healthy cells
The European Group for Blood and Marrow Transplantation
John Goldman:
CML treatment with imatinib
The European Group for Blood and Marrow Transplantation
Polymerase chain reaction
(PCR)
• PCR, can be performed on bone marrow or peripheral blood
• Allows scientists to exponentially amplify small amounts of
DNA or RNA and increase their quantity so that abnormal
cells can be detected
• It is a highly sensitive test that is capable of detecting one
Philadelphia positive chromosome in a million healthy cells
The European Group for Blood and Marrow Transplantation
Polymerase chain reaction
(PCR)
• PCR is used to help diagnose CML and is also
useful after CML treatment to see if copies of the
BCR-ABL gene are still there
• If copies are found it means that the leukaemia is
still present, even when the cells are not visible
under the microscope
• It is at least 2 to 3 logs more sensitive than
cytogenetic techniques such as FISH
The European Group for Blood and Marrow Transplantation
Polymerase chain reaction
(PCR)
• Since it requires a simple blood draw, PCR is much
less invasive and time consuming
• The ultimate goal of CML treatment is to achieve
undetectable levels of the Philadelphia chromosome
where the PCR test finds no leukemic cells in the
sample
The European Group for Blood and Marrow Transplantation
Need for standardisation of
PCR techniques
• A range of real time quantitative PCR techniques are in
use, leading to variation in BCR-ABL levels reported by
different laboratories
• While such variation does not necessarily represent a
major drawback when tracking the response of an
individual patient in a single centre, it does make
comparisons of BCR-ABL values between laboratories
difficult
The European Group for Blood and Marrow Transplantation
Need for standardisation of
PCR techniques
• Confusion arises when oncologists change labs,
or patients change doctors
• PCR results are best used when viewed over time
- longer term trends are more important than
individual PCR results
The European Group for Blood and Marrow Transplantation
Initiatives underway to improve
standardisation of PCR results
• European Treatment and Outcome Study
(EUTOS) aims to promote quality controlled
molecular monitoring using standardized RQPCR technologies and the establishment of an
international definition of major molecular
response
• The PCR international scale is looking to
reduce confusion by standardizing PCR results
The European Group for Blood and Marrow Transplantation
European LeukemiaNet
Definitions of Responses
Failure was defined as:
• 3 months (no haematologic response [HR])
• 6 months (incomplete HR or no cytogenetic response [CR])
• 12 months (less than partial CR (Ph+ >35%)
• 18 months (less than complete CR response)
• and in cases of HR and CR response loss, or appearance of
Imatinib-highly-resistant BCR/ABL mutations
The European Group for Blood and Marrow Transplantation
European LeukemiaNet
Definitions of Responses
Suboptimal response was defined:
• 3 months (incomplete HR)
• 6 months (less than partial CR)
• 12 months (less than complete CgR),
• 18 months (less than major molecular response)
• and in case of MMolR loss, other mutations or other
chromosome abnormalities
The importance of regular monitoring at experienced
centres was highlighted
(Baccarani M. et al. Blood 2006, 108: 1809-1820.)
The European Group for Blood and Marrow Transplantation
Goals of CML Therapy
Leukemia cells
>1012
CHR
1010
CCyR
108
MMR/CMR
106
Undetectable range
The European Group for Blood and Marrow Transplantation
Criteria for Failure and Suboptimal
Response to Imatinib
Time (mo)
3
6
12
18
Any
Failure
No CHR
No CHR
>95% Ph+
≥35% Ph+
≥5% Ph+
Loss of CHR
Loss of CCgR
Mutation
CE
Response
Suboptimal
No CG
Response
Optimal
<65% Ph+
≥35% Ph+
≤35% Ph+
1-35% Ph+
No MMR
0% Ph+
MMR
Loss of MMR
Mutation
Stable or
improving
MMR
Baccarani et al. JCO 2009, 27: 6041-51
The European Group for Blood and Marrow Transplantation
Definition of failure and
suboptimal response
Time
Failure
Subopt. resp.
Warnings
High risk
Del9q+
ACA in Ph+ cells
Diagnosis
-
-
3 mos
No CHR
No CyR
6 mos
No CyR
< PCyR
12 mos
< PCyR
< CCyR
18 mos
< CCyR
< MMR
ACA in Ph+ cells
Loss of CHR
Loss of CCyR
Mutation
Loss of MMR
Mutation (IM-sensit.)
Anytime
< MMR
Any  BCR-ABL
transcript level
OCA in Ph- cells
(IM-insensit.)
Baccarani M, et al. J Clin Oncol. 2009;27:6041-51.
The European Group for Blood and Marrow Transplantation
Rationale for response
monitoring
• Most patients in CP have a good response to
imatinib. Some patients, however, will still go on
to progress
• Early identification of relapse or progression
provides an opportunity for alternative therapy
• It also allows identification of patients in stable
remission after withdrawal of TKIs
The European Group for Blood and Marrow Transplantation
ELN Recommendations
Haematologic
response
2 weekly until
CHR
confirmed
Cytogenetic
response
Molecular
response
6 monthly
until CCR
confirmed
3 monthly
MMR
Baccarani M. et al. Blood
2006,108:1809-1820
12 monthly
The European Group for Blood and Marrow Transplantation
ELN Recommendations
Molecular
response
Mutation
Cyto
analysis
respons
3 monthly
no MMR by 18m
loss of MMR
5fold rise in
BCR-ABL
Baccarani M. et al. Blood 2006,108:1809-1820
The European Group for Blood and Marrow Transplantation
Adverse prognostic factors
for CML
In addition to the three phases of CML (chronic, accelerated
and blast) other factors are used to predict patient survival
These include:
• Enlarged spleen
• Areas of bone damage caused by growth of leukaemia
• Increased numbers of basophils and eosinophil's in blood
samples
The European Group for Blood and Marrow Transplantation
Adverse prognostic factors
for CML
• Very high or low platelet counts
• Aged 60 years or older
• Additional Philadelphia Chromosomes in
CML cells
American Cancer Society: www.cancer.org
The European Group for Blood and Marrow Transplantation
CML Prognostic scoring systems
Sokal score: devised in 1984 as a prognostic
discriminator of survival in patients treated with
chemotherapy (mainly busulfan and hydroxyurea)
The system considers patient’s age,blast cell
count and spleen size at time of diagnosis
Sokal J.E. et al. Blood 1984, 63:789-799
The European Group for Blood and Marrow Transplantation
CML Prognostic scoring systems
Euro score system: devised in 1998 as a prognostic
discriminator of survival in patients treated with
alpha-interferon
The system considers age, spleen size (measured
from left costal margin), blast cell count, platelet
count, eosinophil count and basophil count
Hasford J. et al. JNTL Cancer Inst1998,90:850-858
The European Group for Blood and Marrow Transplantation
Dr. JJWM
Janssen, Chronic
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
IRIS: Progression-free Survival Rates With
First-line Imatinib by Sokal Risk Group
100
% Without Progression
90
Cervantes F, on
behalf of the
IRIS study
group. Blood.
2003,102:181a.
Abstract 633
and oral
presentation
80
70
60
50
Estimated rate at 30 months
40
Low risk
Intermediate risk
High risk
30
20
94%
88%
80%
P=0.003
10
Months Since Randomization
0
0
3
6
9
12
15
18
21
24
27
30
33
36
The European Group for Blood and Marrow Transplantation
Nursing take home messages
• CML is set to change from a rare cancer to a
chronic one
• This will lead to an increasing role for nurses
in the day to day care of patients living with a
chronic condition
The European Group for Blood and Marrow Transplantation
Coming soon......
Module II:
Exploring treatments in CML
The European Group for Blood and Marrow Transplantation