CML Learning Programme For Nurses & Other Allied Health Care Professionals

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

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

Definition of CML
The World Health Organization (WHO) classifies

chronic myeloid leukaemia (CML) as a myelo-
proliferative disease characterised by the
presence of the Philadelphia chromosome or
BCR-ABL fusion oncogene
Vardiman J.W. et al. Blood 2002,100:2292-302

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

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

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)

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)

• 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

• 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

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

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
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)

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

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

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

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

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

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

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.)

What is Philadelphia
chromosome positive CML?
• Chronic myeloid leukaemia (CML) is a haemato-

poietic stem cell disease of the bone marrow and
blood
• CML is characterised by a massive overproduction

of white blood cells

• 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 chromosome-

positive CML because it results from the formation of
the Philadelphia chromosome from the translocation
of elements of chromosome 9 and 22

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 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 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)

Biology of CML
Chromosome 22 Chromosome Philadelphia (Ph) Cytogenetics
9 chromosome
9
BCR t (9;22)
BCR
ABL ABL
22 Ph+
BCR-ABL + Signaling pathways Deregulation CML

(Tyrosine kinase) • Ras • Cell proliferation • WBC (myeloid) 
• AKT • Cell survival • RBC 
• PI3K > • DNA repair > • Platelets 
• Other pathways
-
Tyrosine kinase inhibitors (TKIs)
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
300000 Incidence 2000: 2/100.000
Prevalence
250000
200000
150000
20%-25% increase per year
100000 in projected prevalence
50000
0
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Modified from R. Hehlmann
Year
Survival 1983-2008
Primary imatinib, 2002-2008 (CML IV)
5-year survival 93%
n = 2830
Survival probability
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

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

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

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

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

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

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

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

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

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

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

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

Blast Crisis
WHO Criteria International Bone Marrow
• Blasts >20% of Transplant Registry
peripheral blood • >30% blasts in the
white cells or of blood, marrow or both
nucleated bone • Extra medullary
marrow cells infiltrates of leukemic
• Extra medullary blast cells
proliferation
• Large foci or clusters
of blasts in the bone
(DeVita VT, Hellman S et al.
marrow biopsy Cancer: Principles and Practice of
Oncology, 6th Edition. Vol 2. pgs
2433-2447. 2001
(WHO. IARC Press: Lyon 2008) Lippincott, Williams & Wilkins.)

Disease Progression
The exact molecular mechanism by which CML

transforms to more advanced stages of the
disease is unknown

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

Techniques used to
diagnose/monitor CML
• Complete Blood Counts
• Cytogenetic analysis
• More sensitive testing

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

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

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)

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)

Fluorescence insitu
• 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

Fluorescence insitu
• 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

John Goldman:
CML treatment with imatinib

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

(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

(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

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

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

Initiatives underway to improve
standardisation of PCR results
• European Treatment and Outcome Study

(EUTOS) aims to promote quality controlled
molecular monitoring using standardized RQ-
PCR 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

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

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.)

Goals of CML Therapy
Leukemia cells
>1012
CHR
1010
CCyR
108
MMR/CMR
106
Undetectable range
Criteria for Failure and Suboptimal
Response to Imatinib
Response
Time (mo)
Failure Suboptimal Optimal
No CG
3 No CHR <65% Ph+
Response
No CHR
6 ≥35% Ph+ ≤35% Ph+
>95% Ph+
12 ≥35% Ph+ 1-35% Ph+ 0% Ph+
18 ≥5% Ph+ No MMR MMR
Loss of CHR
Stable or
Loss of CCgR Loss of MMR
Any improving
Mutation Mutation
MMR
CE
Baccarani et al. JCO 2009, 27: 6041-51

Definition of failure and
suboptimal response
Time Failure Subopt. resp. Warnings
High risk
Diagnosis - - Del9q+
ACA in Ph+ cells
3 mos No CHR No CyR
6 mos No CyR < PCyR
12 mos < PCyR < CCyR < MMR
18 mos < CCyR < MMR

ACA in Ph+ cells
Loss of CHR Any  BCR-ABL
Loss of MMR
Anytime Loss of CCyR transcript level
Mutation (IM-sensit.)
Mutation OCA in Ph- cells
(IM-insensit.)
Baccarani M, et al. J Clin Oncol. 2009;27:6041-51.
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

ELN Recommendations
Haematologic Cytogenetic Molecular
response response response
2 weekly until 6 monthly 3 monthly

CHR until CCR
confirmed confirmed
MMR
Baccarani M. et al. Blood
2006,108:1809-1820
12 monthly

ELN Recommendations
Molecular Mutation
Cyto
response analysis
respons
3 monthly no MMR by 18m
5fold rise in
loss of MMR
BCR-ABL
Baccarani M. et al. Blood 2006,108:1809-1820

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

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

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

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

Dr. JJWM
Janssen, Chronic The European Group for Blood and Marrow Transplantation
IRIS: Progression-free Survival Rates With
First-line Imatinib by Sokal Risk Group
100
90
80
% Without Progression
70
60
50
Estimated rate at 30 months
40
Low risk 94%
30
Intermediate risk 88%
20 P=0.003
High risk 80%
Cervantes F, on
behalf of the 10
IRIS study
group. Blood. Months Since Randomization
2003,102:181a. 0
Abstract 633
and oral 0 3 6 9 12 15 18 21 24 27 30 33 36
presentation

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

Coming soon......
Module II:
Exploring treatments in CML

CML Learning Programme For Nurses & Other Allied Health Care Professionals

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CML Learning

EBMT Nurses Group

The European Group for Blood and Marrow Transplantation

This module explains the background to CML,

• Understand the definition of Chronic Myeloid

• Understand CML’s etiology, increasing

The European Group for Blood and Marrow Transplantation

• Understand the different stages of CML, the

• Understand historical developments in CML

The European Group for Blood and Marrow Transplantation

The World Health Organization (WHO) classifies

Vardiman J.W. et al. Blood 2002,100:2292-302

The European Group for Blood and Marrow Transplantation

• CML is estimated to account for approximately

• CML affects men slightly more than women

The European Group for Blood and Marrow Transplantation

• The median age at diagnosis is 60 to 65 years

• There is no significant ethnic or geographical

The European Group for Blood and Marrow Transplantation

• CML represents around 3% of all cases of childhood leukaemia

The European Group for Blood and Marrow Transplantation

• CML is one of the big success stories in cancer

• With imatinib (and other TKI treatments) the

(Prevalence = incidence x duration of disease)

The European Group for Blood and Marrow Transplantation

• Prior to imatinib the annual mortality rate for CML

• Thus it is estimated that the prevalence of CML in

The European Group for Blood and Marrow Transplantation

• Because the highly effective drugs are still

• CML is currently undergoing transition from

The European Group for Blood and Marrow Transplantation

• The risk of getting CML increases with age, with

• CML is slightly more common among males than

The European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

Using a new technique called high throughput screening,

The European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

Charles Sawyers, Brian Druker, Andreas Hochhaus, and

The European Group for Blood and Marrow Transplantation

The European Group for Blood and Marrow Transplantation

EMA approved dasatinib as first-line treatment in

The European Group for Blood and Marrow Transplantation

• Chronic myeloid leukaemia (CML) is a haemato-

• CML is characterised by a massive overproduction

The European Group for Blood and Marrow Transplantation

• The uncontrolled growth of white blood cells in CML

• The disease is called Philadelphia chromosome-

The European Group for Blood and Marrow Transplantation

The gene that breaks off from chromosome 9 is

The European Group for Blood and Marrow Transplantation

• The combination of BCR and ABL leads to the

• In the words of Brian Druker the BCR-ABL gene in

The European Group for Blood and Marrow Transplantation

The presence of BCR/ABL rearrangement is

(ASH, 50 Years in Hematology: Research that revolutionized patient care, 2008)

The European Group for Blood and Marrow Transplantation

BCR-ABL + Signaling pathways Deregulation CML

Assumptions: Population: 500 Mill., mortality: 2% per year,

350000 Incidence 2000: 1/100.000