EBMT Slide template Barcelona 7 February 2008 The European Group for Blood and Marrow...

EBMT Slide templateBarcelona

7 February 2008

The European Group for Blood and Marrow Transplantation

CML Learning Programmefor Nurses & Other Allied Health Care Professionals

EBMT Nurses Group



Module 1

Understanding

Chronic Myeloid Leukaemia (CML)


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 chromosomesRowley 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 killingCML 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 9

Chromosome 22

ABL

BCR

ABLBCR

t (9;22)

Philadelphia (Ph)chromosome

9

22 Ph+

Cytogenetics

BCR-ABL(Tyrosine kinase)

Signaling pathways•Ras•AKT•PI3K•Other pathways

Deregulation•Cell proliferation•Cell survival•DNA repair

CML•WBC (myeloid) •RBC •Platelets

+

Tyrosine kinase inhibitors (TKIs)

-

> >


Projection of CML Prevalence up to 2050

Modified from R. Hehlmann

Assumptions: Population: 500 Mill., mortality: 2% per year, Incidence increasing by about 0.01/100.000 per year

20%-25% increase per year in projected prevalence


n = 2830

Year after diagnosis

Su

rviv

al p

rob

abili

ty

Primary imatinib, 2002-2008 (CML IV)5-year survival 93%

IFN or SCT, 1997-2008 (CML IIIA) 5-year survival 71%

IFN or SCT, 1995-2008 (CML III)5-year survival 63%

IFN, 1986-20035-year survival 53%

Hydroxyurea, 1983-1994

Busulfan, 1983-1994 5-year survival 38%

(CML I, II)

Courtesy of the German CML Study Group

Survival 1983-2008


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

causeMoloney 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 /L) ⁹unrelated to therapy, or persistent thrombocytosis (>1000 x 10 / L) unresponsive to therapy⁹


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• 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.)


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)



• 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 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 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



• 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 ofPCR 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 ofPCR 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.)


1010

>1012

106

108

Leukemia cells

CCyR

MMR/CMR

Undetectable range

CHR

Goals of CML Therapy


Criteria for Failure and Suboptimal Response to Imatinib

Time (mo) Response

Failure Suboptimal Optimal

3 No CHR No CG Response <65% Ph+

6 No CHR>95% Ph+ ≥35% Ph+ ≤35% Ph+

12 ≥35% Ph+ 1-35% Ph+ 0% Ph+18 ≥5% Ph+ No MMR MMR

Any

Loss of CHRLoss of CCgR

MutationCE

Loss of MMRMutation

Stable or improving

MMR

Baccarani et al. JCO 2009, 27: 6041-51


Time Failure Subopt. resp. Warnings

Diagnosis - -

High risk

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

Anytime

ACA in Ph+ cells

Loss of CHR

Loss of CCyRMutation (IM-insensit.)

Loss of MMRMutation (IM-sensit.)

Any BCR-ABL transcript level

OCA in Ph- cells

Definition of failure and suboptimal response

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


12 monthly

6 monthly until CCR confirmed

2 weekly until CHR confirmed

ELN Recommendations

Baccarani M. et al. Blood 2006,108:1809-1820

MMR

3 monthly

Haematologic response

Cytogenetic response

Molecular response


loss of MMR

ELN Recommendations

Baccarani M. et al. Blood 2006,108:1809-1820

3 monthly

Molecular response

Cyto responsMutation analysis

no MMR by 18m

5fold rise in BCR-ABL


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

The European Group for Blood and Marrow TransplantationDr. JJWM

Janssen, Chronic Myeloid Leukemia



IRIS: Progression-free Survival Rates With First-line Imatinib by Sokal Risk Group

Estimated rate at 30 months

94% 88% 80%

Low risk

Intermediate risk

High risk

% W

ith

ou

t P

rog

ress

ion

0

10

20

30

40

50

60

70

80

90

100

Months Since Randomization

0 3 6 9 12 15 18 21 24 27 30 33 36

P=0.003

Cervantes F, on behalf of the IRIS study group. Blood. 2003,102:181a. Abstract 633 and oral 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

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