Transcript Diapositiva 1

CML Learning
EBMT Slide template
Programme
for nurses &Barcelona
other allied
health
7 care
February 2008
The
The European
European Group
Group for
for Blood
Blood and
and Marrow
Marrow Transplantation
Transplantation
Module 3
Managing TKI treatments
and special CML populations
The European Group for Blood and Marrow Transplantation
Aims of Module 3
To understand:
•
The consequences for patients of living with CML
The challenges involved with taking the different
TKI treatments, side effects of treatments,
drug interactions
•
The importance of drug adherence
•
The management of special CML populations including issues
around fertility, pregnancy, paediatric and elderly populations
The European Group for Blood and Marrow Transplantation
Many treatment issues exist for
CML patients prescribed TKIs
• Getting to grips with how to take complex
treatment regimens
• Coping with side effects of treatment
• Avoidance of drug interactions
• Adherence to medications
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There can be different
issues for the different TKIs
• Imatinib (glivec®/gleevec®)
• Dasatinib (sprycel®)
• Nilotinib (tasigna®)
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Imatinib
How to take imatinib:
It is recommended that imatinib should be taken
with a meal and large glass of water since it is
sometimes associated with GI irritation
Patients should avoid taking imatinib with
grapefruit
The European Group for Blood and Marrow Transplantation
Dasatinib
How to take dasatinib:
- Patients should be instructed to take dasatinib orally
once daily, either in the morning or in the evening
- Tablets should be swallowed whole and can be taken
with or without food
- Patients should avoid taking dasatinib with grapefruit
N.B.: Dasatinib tablets contain lactose and may not be
suitable for lactose intolerant patients
(Bristol-Myers Squibb Company 2009)
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Nilotinib
How to take nilotinib:
- Patients are instructed not to take nilotinib with food
since food can affect levels of nilotinib resulting in
serious side effects such as QT prolongation
- Patients should avoid taking grapefruit with nilotinib
- Patients should take nilotinib at least 2 hours after
eating food and then wait 1 hour before eating food
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Nilotinib
 Patients usually take two daily doses of nilotinib per day,
separated by 12 hour periods
 Patients may take the drug with water, and drink water
while fasting
N.B.: Nilotinib tablets contain lactose and may not be
suitable for lactose intolerant patients
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Nilotinib: Black Box Warning
• Prescribing information for nilotinib carries a blackbox warning regarding the risk of QTc prolongation
and sudden death
• Nilotinib should not be used in patients with
hypocalcemia, hypomagnesaemia, and long QTc
syndrome
From FDA, only in US
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Nilotinib: Black Box Warning
• Potassium and magnesium levels can be corrected
in patients prior to starting nilotinib and monitored
very closely
• Electrocardiograms need to be obtained prior to
starting patients on nilotinib
From FDA, only in US
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How to fit nilotinib into
the daily life
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Tips for taking nilotinib
• Take nilotinib at the same time every day
(This helps it to become part of the patient’s
daily routine)
• Use a watch or alarm to help you take it on an
empty stomach
Suggest patient uses a stopwatch to count down the 2 hours
since they last ate and the 1 hour until they can eat again
The European Group for Blood and Marrow Transplantation
Tips for taking TKIs
- Put a mark in your diary or calendar
- Suggest the patient makes a mark every time they
take their medication. This will help them to see
how compliant they are
- Make use of mobile phone or computer reminders
(Make use of alarms on electronic equipment)
The European Group for Blood and Marrow Transplantation
Imatinib drug interactions
• Imatinib has the potential to interact with several
agents
It is an inhibitor of cytochrome P450 3A4
(CYP3A4), an important oxidase predominantly
found in the liver that is responsible for
metabolism of foreign chemicals in the body
The European Group for Blood and Marrow Transplantation
Imatinib drug interactions
• Imatinib may decrease metabolic clearance of
drugs that are primarily metabolised by CYP3A4
(e.g. simvastatin and pimozide) and other
inhibitors of CYP3A4 may increase imatinib
plasma concentrations (e.g. clarithromycin and
traconazole)
The European Group for Blood and Marrow Transplantation
Imatinib drug interactions
• Conversely, drugs that induce CYP3A4 activity (e.g.
carbamazepine and dexamethasone) may decrease
serum concentrations of imatinib
These interactions are shared by dasatinib and
nilotinib, the following slides report the most
frequent drug interactions of the 3 TKIs
(Novartis PharmaceuticalsCorporation 2007a, NCCN 2008)
The European Group for Blood and Marrow Transplantation
Potential drug interactions with
imatinib
May ↓plasma
Rifampin
levels of imatinib Rifabutin
Dexamethasone
Phenobarbital
Phenytoin
Carbamazepine
May ↑plasma
levels of imatinib
Atazanavir
Clarithromycin
Indinavir
Itraconazole
Ketoconazole
Nefazodone
Nelfinavir
Ritonavir
Saquinavir
Telithromycin
Voriconazole
Grapefruit juice
Drugs whose
plasma levels
may be altered by
imatinib
Acetaminophen
Alfentanil
Cyclosporine
Diergotamine
Dihydropyridine
Ca+ channel
blockers
Ergotamine
Fentanyl
Select statins
Pimozide
Quinidine
Simvastatin
Sirolimus
Tacrolimus
Triazolobenzodiaz
epines
Warfarin
L. Luciano: Living with CML, 2009
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
Examples of drugs that should be avoided
during treatment with nilotinib include, but
are not limited to, the following list:
• Quinidine, amiodarone: antiarrhythmics used to treat an
irregular heart beat
• Verapamil, diltiazem: used to treat high blood pressure
• Ketoconazole, itraconazole, voriconazole, clarithromycin,
telithromycin, erythromycin, ritonavir: used to treat bacterial
or fungal infections
• Cyclosporine, tacrolimus: used as immunosuppressants
• Carbamazepine, phenobarbital, phenytoin: used to treat
selzure disorders e.g. epilepsy
• Rifampin: used to treat a type of infection called
tuberculosis(TB)
The European Group for Blood and Marrow Transplantation
Examples of drugs that should be avoided
during treatment with nilotinib include, but
are not limited to, the following list:
• St. John`s Wort: a herbal product used to treat
depression and other conditions ( also known as
Hypericum Perforatum)
• Midazolam: used to relieve anxiety before surgery
• Warfarin: used to treat blood coagulation disorders (such
as blood clots or thrombosis)
The European Group for Blood and Marrow Transplantation
Nursing take home message
on drug interactions
• Nurses should provide clear instructions about
the ways to take the different TKIs
• Patients need to be reminded of the importance
of taking medication and not making up for
missed doses by doubling the next dose
The European Group for Blood and Marrow Transplantation
Nursing take home message
on drug interactions
• To avoid drug interactions patients should provide
a list of their concurrent medications (including
prescriptions, over the counter medicines,
vitamins, antacids and herbal supplements)
• Information should be provided to patients about
contraindications and potential drug interactions
for each TKI
The European Group for Blood and Marrow Transplantation
Nursing take home message
on drug interactions
• Patients should be educated to identify and report
symptoms of adverse events so they can be
addressed promptly
• Patients should be asked if they are lactose
intolerant since nilotinib and dasatinib contain
lactose
• Patients with a history of cardiac problems should
not be prescribed nilotinib; whereas dasatinib
should be avoided in patients with lung problems
The European Group for Blood and Marrow Transplantation
Common side effects of TKIs
(definition of common >1/100 <1/10)
Imatinib
Nilotinib
Oedema (swelling)
Fatigue (tiredness)
Skin rash
Nausea/vomiting, Diarrhea
Myalgias (muscle cramps)
Abdominal Pain
Heartburn
Anemia
Bleeding (due to low platelet
count)
Neutropenia (low white cell
count)
Subconjunctival hemorrhage
Headache
Fatigue
Skin rash
Nausea/vomiting
Diarrhea
Constipation
Heartburn
Flatulence
Laboratory abnormalities
Anemia
Bleeding (due to low platelet
count)
Neutropenia (low white cell count)
Prolongation of QT interval/EKG
abnormality
The European Group for Blood and Marrow Transplantation
Common side effects of TKIs count
Dasatinib (Sprycel)
•
•
•
•
•
•
•
•
•
•
Fluid retention (including pleural
effusion)
Dyspnea (breathing problems)
Diarrhea
Skin rash
Headache
Haemorrhage (due to low platelet
count)
Infection (due to low white cell count)
Fatigue
Nausea/vomiting
Joint and muscle pain
The European Group for Blood and Marrow Transplantation
Fluid retention
• Fluid retention is the most common side effect of imatinib.
Occurs less frequently with the other drugs
• Superficial oedema occurs around the eyes and extremity
areas
• Pleural effusion or ascites (build up of fluid between the
tissues lining the abdomen) is uncommon. Most common
with dasatinib
The European Group for Blood and Marrow Transplantation
How to deal with TKI
side effects
•
•
•
•
•
•
•
•
•
•
•
•
Fluid retension
Mouth problems
GI problems
Fatigue
Muscle cramps
Pain
Skin problems
Myelosuppression
Neutropenia
Thrombocytopenia
Anaemia
Pleural effusions
The European Group for Blood and Marrow Transplantation
Management of fluid
retention
• Weigh patient 2x week and notify healthcare
provider if weight gain is more than 5 pounds
(2.27kgs) from baseline
• Low salt diet
• A diuretic (Furosemide) may be needed
• On occasion the drug may need to be stopped
until the oedema improves
The European Group for Blood and Marrow Transplantation
Problems with the mouth
• Stomatitis (mouth sores) can be managed
symptomatically
– Good oral hygiene is recommended
– Avoid alcohol based mouth wash
– Avoid spicy food, acidic food, and carbonated
and alcoholic beverages
• Taste may be altered
The European Group for Blood and Marrow Transplantation
Stomach pain
• Imatinib is known to be a GI irritant
• Symptoms can be minimized if:
– Pills are taken with meals or immediately after
meals
– Drink a large glass of water
– Remain upright for about an hour after taking
– Take evening dose at least 2 hours before
bedtime
The European Group for Blood and Marrow Transplantation
Other GI side effects
• Nausea if severe can be managed by the use of antinausea medicine
• It can be helpful to split the TKI dose and take twice a
day instead of once a day
• Anti-diarrheal medication (loperamide hydrochloride or
atropine sulfate/diphenoxylate hydrochloride) may be
used if diarrhea occurs
• Simethicone – a gas reducing agent – is useful for
managing flatulence/excess gas
• Dyspepsia (heartburn/reflux) can be managed
symptomatically with antacids or proton pump inhibitors
(need to be careful with interactions)
The European Group for Blood and Marrow Transplantation
Fatigue/tiredness
• Fatigue may occur and can have a huge impact on the
patient’s life
– Fatigue can be caused by anaemia
• Take adequate rest
• Exercise also useful
Thyroid function tests should be monitored every 3 to 6
months to monitor for hypothyroid
If necessary thyroid replacement therapy should be started
The European Group for Blood and Marrow Transplantation
Muscle cramps
• Muscle cramps may occur in the hands, feet
and/or legs
• They usually occur intermittently, but may
increase with prolonged therapy
The European Group for Blood and Marrow Transplantation
Muscle cramps
• Helpful strategies to manage muscle cramps include:
– Increasing amount of fluid drunk daily
– Electrolyte monitoring and supplementation
(especially if taking a diuretic )
– A balanced diet and calcium in divided doses of 500
mg each 2 to 3 times a day
– Tonic water
• If muscle cramps are very bad muscle relaxants can be
used
The European Group for Blood and Marrow Transplantation
Pain
• Some patients will experience joint pain (arthralgia)
and headaches which can be managed by regular
use of non-steroidal anti-inflammatory (NSAID’s)
medication
• Need to be careful about using certain NSAIDs if the
patient has low platelet counts
The European Group for Blood and Marrow Transplantation
Skin rash
• Rash may occur with or without itching or pustules
• Rash can come and go
• It usually resolves with topical or oral
diphenhydramine hydrochloride and/or steroids
• Severe rash may require an interruption in therapy
and steroids by injection
• Skin may just be dry and moisturizing using a
neutral moisturizing cream is helpful
The European Group for Blood and Marrow Transplantation
Other skin problems
• Other skin problems can also occur:
– Skin may become thin and tear and bruise easily
– Blood blisters may come and go
– Skin discolouration may occur with changes in
pigment
• Lighter pigment with imatinib
– Hair discolouration can also occur
• Patients need to be cautious while in direct sunlight
and use sun protection factor creams (SPF 15 or
above)
The European Group for Blood and Marrow Transplantation
Myelosuppression
(low blood counts)
TKI
Ph-positive
Ph-negative
In CML, the majority of
hematopoiesis is
contributed by Ph+ cells.
TKI eliminates Ph+ cells.
This therapeutic effect may
result in myelosuppression.
• Severe myelosuppression is managed by temporary dose
reduction and/or treatment interruptions
• Low blood cell counts are also seen in GIST but are not as
severe
The European Group for Blood and Marrow Transplantation
Myelosuppression
(low blood counts)
Neutropenia
(low white cell
count)
Risk of
infection
Febrile
neutropenia
Anaemia (low
red cell count)
Tiredness and
breathing
problems
Thrombocytopenia
(low platelet count)
Risk of
bleeding and
haemorrhage
The European Group for Blood and Marrow Transplantation
Low blood counts
• Counts may fall quickly
• Most in first 1-2 months
• Much higher rates in accelerated phase &
blast crisis in CML
• Low blood counts less of a problem in GIST
but can occur
The European Group for Blood and Marrow Transplantation
Neutropenia
(low white cell counts)
• TKI generally stopped if absolute neutrophil counts (ANC)
less than 1,000 (normal count 2,000-7,000)
• In advanced phase CML stop treatment only if less than 500
• May use G-CSF (white cell growth factor) to support
neutrophil count
• Important to stay on TKI while this is being done
• In chronic phase often start at 2-3 times a week, to keep
ANC above 1000
The European Group for Blood and Marrow Transplantation
Preventing infection when
white cell counts are low
• Hand hygiene - hand washing probably most effective
measure
– Key points: friction and drying
– Can use soap and water or alcohol sanitizers
• Avoiding individuals with flu or colds
• Vaccination (especially against influenza)
Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices Advisory Committee, 2007 Guideline
for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings
http://www.cdc.gov/ncidod/dhqp/pdf/isolation2007.pdf ; Zitella et al. (2006) Putting evidence into practice: prevention of
infection. Clinical Journal of Oncology Nursing. 10, 6, 739-750.
The European Group for Blood and Marrow Transplantation
Other precautions
• Dietary restrictions not well researched
– Avoid uncooked meats, seafood, eggs
– Avoid uncooked, unwashed fruits and vegetables;
peel if possible
• Wearing of masks often seen, effectiveness controversial
• Fever over 38°, get medical evaluation immediately; have
thermometer
Zitella et al, op.cit
The European Group for Blood and Marrow Transplantation
Thrombocytopenia
(low platelet count)
• Platelets can become very low quickly with risk of
bleeding
• Temporarily stop drug if platelets less than 50,000
(normal count 150-400,000)
• May require dose reduction if recovery prolonged or
happens more than once
• In advanced disease may use lower threshold stopping at 20,000
The European Group for Blood and Marrow Transplantation
Preventing bleeding when
platelet count is low
• In patients with low platelets, medications that
inhibit platelet function may worsen bleeding (e.g.
aspirin, warfarin; non-steroidal anti-inflammatory
drugs to lesser extent)
• Avoid contact sports, activities where injury likely
(danger of intracranial hemorrhage-bleeding inside
head, puts pressure on brain)
• Use electric razor, not blade
The European Group for Blood and Marrow Transplantation
Low red counts - anaemia
• Check ferritin (a measure of iron stores)
– Dietary, red meat; oral agents such as ferrous
sulfate; intravenous iron if severely deficient
• ESA’s—(erythrocyte stimulating agents) stimulate red
cell production, erythropoietin or darbepoetinexpensive, some dangers e.g. blood clots, stroke.
Now closely regulated and controversial in U.S.
• Pacing activities, may need naps
The European Group for Blood and Marrow Transplantation
Pleural effusion
• Side effect that is more common with dasatinib
(Sprycel®) than other TKI’s
• Incidence 7-35%
• Symptoms suggestive of pleural effusion, include
dyspnoea, dry cough, or abnormal blood oxygen
levels
• Reports have suggested that inhibition of PDGFR
by dasatinib may be responsible
The European Group for Blood and Marrow Transplantation
Pleural effusion
• More common with
• Advanced phase disease
• 2 x day dosing
• Hypertension
• Skin rash
• History of autoimmune disease or high cholesterol levels
• Can happen any time during therapy, perhaps months after
starting
Kelly, K et.al. Serosal Inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Targ Oncol 2009, 4:99-105
The European Group for Blood and Marrow Transplantation
50 Transplantation
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Management of pleural effusion
• Perform chest x-ray when symptoms such as shortness of
breath and dry cough observed
• If mild:
• Stop dasatinib until symptoms improve
• Consider use of diuretics (e.g. furosemide)
• Short-term steroids such as prednisone 40 mg daily for 4
days
• If severe:
• Thoracentesis (removes fluid from the pleural space)
• Oxygen
SPRYCEL® (dasatinib) Full Prescribing Information. Bristol-Myers Squibb. Kelly et al. Targ Oncol (2009) 4:99-105.
The European Group for Blood and Marrow Transplantation
TKI side effects and
changing therapy
• Having intolerable side effects on one drug DOES NOT
mean a patient will have it on another drug
• Consider potential side effect profile in deciding what to use
next. For example:
– History of pleural effusions or already has severe lung
problem: would consider nilotinib over dasatinib
– If had history of pancreatitis, or problems with QTc
interval, would consider dasatinib first
The European Group for Blood and Marrow Transplantation
Adherence
The European Group for Blood and Marrow Transplantation
What is compliance/adherence?
• Compliance
– A medical term that is used to indicate a
patient's correct following of medical advice
• Adherence
– The extent to which a patient follows a
prescribed regimen, agreed with the health
care provider, including medication, diet and
exercise
The European Group for Blood and Marrow Transplantation
What is compliance/adherence?
Concordance:
An agreement reached after negotiation between a patient
and a health care professional that respects the beliefs and
wishes of the patient in determining whether, when and how
medicines are to be taken
Although reciprocal, this is an alliance where health care
professionals recognize the primacy of the patient's
decisions about taking the recommended medications
The European Group for Blood and Marrow Transplantation
What is compliance/ adherence
Persistence:
Medication compliance refers to the act of conforming to a
recommendation of continuing treatment for the prescribed
length of time
Therefore, medication persistence may be defined as “the
duration of time from initiation to discontinuation of therapy”
Sabate E. WHO Report, 2003.
http://www.who.int/ chronic_conditions/en/adherence_report.pdf
The European Group for Blood and Marrow Transplantation
An adherent patient takes the right medications,
in the right dose, at the right time, over time
Takes the
prescriptio
n to the
pharmacy
but doesn’t
pick it up
Doesn’t get
as far as
the
pharmacy
Doesn’t persist
with their
treatment
Doesn’t take the
medication
correctly
Persists with their
treatment over
time
Doesn’t persist
with their
treatment
Non Adherent
Patient
The Patient
agrees a
therapeutic
regimen
with the
doctor &
gets a
prescription
Persists with their
treatment
Adherent
Patient
Fills the
prescription
Takes the
medication
correctly - at
the right time,
in the right
dose
The European Group for Blood and Marrow Transplantation
Adherence
• A WHO study estimates that only 50% of patients
suffering from chronic diseases in developed
countries follow treatment recommendations
Geneva, WHO 2003
• Imatinib non-adherence is widespread, with the
ADAGIO study suggesting that less than 15% of
patients are perfectly adherent
Noens L. et al. Blood 2009, 113: 5401-5411
The European Group for Blood and Marrow Transplantation
Adherence
• Adherent patients are 3 x as likely to have
good treatment outcomes compared with
non adherent patients
DiMatteo. MR et al Medical Care 2002, 40:794-811
The European Group for Blood and Marrow Transplantation
Adherence studies in CML
• Adagio Study
Noens L. et al . Blood 2009, 113: 5401-5411
• Hammersmith Study
Mann J.D. et al. JCO 2010, 28:2381-2388
The European Group for Blood and Marrow Transplantation
ADAGIO study
(Adherence Assessment with Glivec:
Indicators and Outcomes)
Aims:
- To examine prospectively over a 90-day period, in a “real
practice” setting, the prevalence of imatinib non adherence
in patients with CML in Belgium on imatinib treatment for at
least 30 days
- To develop a multivariate “canonical correlation” model of
how various determinants may be associated with various
measures of non adherence
- To examine whether treatment response is associated with
adherence levels
The European Group for Blood and Marrow Transplantation
ADAGIO study
(Adherence Assessment with Glivec:
Indicators and Outcomes)
Study:
A total of 202 patients were recruited from 34 centres
in Belgium, of who 168 were evaluable
The European Group for Blood and Marrow Transplantation
ADAGIO study
(Adherence Assessment with Glivec:
Indicators and Outcomes)
Results:
- One-third of patients were considered to be non adherent
- Only 14.2% of patients were perfectly adherent to 100% of
prescribed imatinib taken
- On average, patients with suboptimal response had
significantly higher mean percentages of
imatinib not taken -23.2%, versus 7.3 % for
patients with an optimal response (P=.005)
The European Group for Blood and Marrow Transplantation
ADAGIO study
(Adherence Assessment with Glivec:
Indicators and Outcomes)
Conclusions:
Non adherence is more prevalent than patients, physicians,
and family members believe it to be, and therefore should
be assessed routinely
It is associated with poorer response to imatinib
Several determinants may serve as alert signals, many of
which are clinically modifiable
Noens L. et al. Blood 2009, 113:5401-541
The European Group for Blood and Marrow Transplantation
ADAGIO study:
additional findings
Within the patient-physician relationship:
Patients rated the following as important:
• Communication and interpersonal style of the physician
(96.1%)
• Continuity of care (96.1% )
• Time the physician spends with the patient (91.2%),
• Physician empathy and assistance (89.2%)
• Patient involvement in planning (88.3%)
The European Group for Blood and Marrow Transplantation
ADAGIO study:
additional findings
The highest effectiveness, feasibility, and applicability ratings
by physicians were given to:
• Improved patient physician communication
• Patient education
• Simplifying the medication regimens
• Regular physician contact
• Spouse/family involvement
• Monitoring of patient adherence by the physician
Noens L. et al. Blood 2009, 113: 5401-5411
The European Group for Blood and Marrow Transplantation
Hammersmith Adherence
Study I
Method:
• 87 patients with chronic phase CML treated with
imatinib 400mg/d for a median of 59.7 months
(range 25 to 104 months) who had achieved
complete cytogenetic response had adherence
monitored for three months. The study used a
monitoring device fitted with an electronic chip
registering when patients opened the pill bottle
The European Group for Blood and Marrow Transplantation
Hammersmith Adherence
Study I
Results:
• 26.4% of patients had adherence rates less
than 90%
• 14% of patients had adherence rates less than
80%
• The 6 year probability of achieving a major
molecular response (3-log reduction) was
28.4% for patients with less than 90%
adherence versus 94.5% for patients with more
than 90% adherence (P<.001)
The European Group for Blood and Marrow Transplantation
Hammersmith Adherence
Study I
Conclusion:
• Poor adherence may be the predominant reason
for the inability of CML patients to obtain an
adequate molecular response
Mann J.D. et al. JCO 2010, 28:2381-2388
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
The consequences
of poor adherence
As a result of the widespread problems of adherence,
substantial numbers of patients do not get the
maximum benefits from medical treatment, resulting in
– Poor health outcomes
– Lower quality of life
– Increased health care costs
van Dulmen S et al. 2007. BMC Health Serv Res 2007, 17:55
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Hammersmith
compliance study II
Study:
• In a second study investigators conducted
interviews with 21 of the original Hammersmith
patients to investigate their reasons for non
adherence to therapy
The European Group for Blood and Marrow Transplantation
Hammersmith
compliance study II
Results:
• One of the most common reasons patients gave
for non adherence was hoping to minimize adverse
effects
• One patient said that he stopped taking the drug
when he went on holiday because he wanted to
enjoy himself and felt he had more energy when he
was not taking treatment
The European Group for Blood and Marrow Transplantation
Hammersmith
compliance study II
Conclusion:
• Factors that seemed to favour adherence were
finding ways to deal with side effects and using
prompts as reminders to take the medicine
Eliasson L.et al. Leukemia Research 2011, 35: 626-630
The European Group for Blood and Marrow Transplantation
Adherence Barriers
Two General Types of Adherence Barriers
Reminder Interventions (if deployed in
isolation) address Unintentional Adherence
Barriers
1)
Unintentional -capacity/resource constraints
•
Easiest to identify and address
•
Focus of past adherence research with
minimal to moderate results
•
•
•
•
•
Forgetfulness/memory problems
Complex regimens
Increased number of medications
(pill burden)
Cognitive deficit
Difficulty in opening package
2)
Intentional - beliefs, motivation and preferences
•
Difficult to identify and change
•
Thought to be the primary reason for nonadherence
 Unconvinced of need for therapy
• Never needed it
• Competing health priorities
 Unconvinced of effectiveness
 Fear of side effect or safety
issues
 Perceived Affordability
Reference: AHRQ / IMS Adherence Backgrounder 2008
• Of subject medication
• Of other medications
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Monitoring compliance
• Patient self reports (communication with physician and
responses to questionnaires)
• Frequency of repeat prescriptions
• Pill counts at hospital or home visits
• Drug plasma levels
• Microelectronic monitoring systems (MEMS), which
monitor when the pill bottle is opened
All methods have significant limitations
The European Group for Blood and Marrow Transplantation
Improving patient motivation:
the importance of good communication
• Patient decisions are highly correlated with their
provider’s perception of them and concerns for
their welfare
• Respectful and supportive communication is
fundamental to gaining information for determining
best management strategies
The European Group for Blood and Marrow Transplantation
Improving patient motivation:
the importance of good communication
• It also enhances the patient’s understanding of the
disease and its treatment
• Increase motivation by exploring and resolving
ambivalence
• Educate patients. Emphasize the importance of
adherence to successful therapy
• Discuss expectations and goals
The European Group for Blood and Marrow Transplantation
Improving compliance
• Monitoring doses
– Monitor at hospital visits, bottle cap counters,
blister packs, electronic monitoring
• Reminder to patient
– Passive: patient views bottle counter or used
blister
– Active: patient diary, electronic reminders,
phone, SMS, internet
The European Group for Blood and Marrow Transplantation
Improving compliance
• Individual feedback to patient
– Device gives signal that the dose was taken
– Give the patient updates on disease response
• General feedback to patient
– Provide information on the disease, how it is
being treated and why, and the goals of the
therapy
The European Group for Blood and Marrow Transplantation
Nursing take home
messages on adherence
• Helping CML patients to understand the importance
of adherence throughout their treatment journey
represents a major role for nurses
• Spend time soon after diagnosis helping patients to
understand CML and the consequences of not
taking their medication
• Be particularly alert to the possibility of adherence
difficulties among patients experiencing side effects
The European Group for Blood and Marrow Transplantation
Nursing take home
messages on adherence
• Find out what side effects bother individual patients
and offer them tailored advice on coping strategies
• Choosing the most appropriate second-line treatment
should involve consideration of each patient’s previous
side-effect profile
• Teach patients strategies to help remember their
medications
The European Group for Blood and Marrow Transplantation
Nursing take home
messages on adherence
• Get family members on board to help
• Non-adherence should be examined as a possible
reason for non or a reduced response to TKIs
before considering patients to be resistant
• If in doubt monitor adherence
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Management of special CML Populations,
Pregnant, paediatric and elderly
• Fertility and Pregnancy
• Paediatrics
• Elderly
The European Group for Blood and Marrow Transplantation
Fertility and Pregnancy
• The transformation of CML from a fatal disease with
a median life expectancy of 6 to 7 years to a
chronic condition has raised issues for CML patients
of child bearing age about their ability to parent
children
• 10% of CML cases occur in patients during
the child-bearing period
Cortes J. et al. Hematol Oncol Clin NorthAm 2004, 18:569-84
The European Group for Blood and Marrow Transplantation
Fertility and Pregnancy
• CML gives rise to special issues during
pregnancy since the condition requires life
long therapy
• The situation differs for male and female
patients
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Management of fertility
For patients of childbearing age who have yet to start a
family/ complete their family provision for maintenance
of fertility should be considered
Options include:
• Sperm freezing (cryopreservation)
• Embryo freezing
• Egg Freezing
• Ovarian Tissue Freezing
The European Group for Blood and Marrow Transplantation
Female Pregnancy studies
Preclinical models have shown teratogenic
effects of imatinib, leading to the manufacture
recommending that women should avoid
pregnancy
The European Group for Blood and Marrow Transplantation
Female Pregnancy studies
The largest clinical experience on safety of imatinib during
pregnancy reported on 180 women, of whom around 80 %
were CML patients
Outcomes have been reported for 125 of them (69%) of whom:
• >70% received imatinib in the first trimester only
• 26% received imatinib throughout the pregnancy
Pye S.M. et al. Blood 2008, 111:5505-5508
The European Group for Blood and Marrow Transplantation
Outcomes of pregnancies
associated with use of imatinib
•
•
•
•
•
•
•
•
Elective abortion (foetal abnormalities identified)
Elective abortion (foetal abnormalities unknown)
Spontaneous abortion
Still birth with foetal abnormalities
Live birth with foetal abnormalities
Normal live birth
Outcome unknown
Total
3
32
18
1
8
63
55
180
Pye S.M. et al. Blood 2008, 111:5505-5508
The European Group for Blood and Marrow Transplantation
Pye SM Blood 2008:111:5505-8 .
3/180 cases of Exomphalos found in study is higher than the general incidence of 1 in 3-4,000 live births
The European Group for Blood and Marrow Transplantation
Fetal abnormalities (n=4)
• The expected incidence of exomphalos in the
general population is 1 in 4,000
• The finding of 3 cases of exomphalos out of 125
with known outcome is approximately 100 fold
greater than expected and cause for significant
concern
Pye S.M. et al. Blood. 2008, 111: 5505-5508
The European Group for Blood and Marrow Transplantation
L. Luciano: Living with CML, 2009
The European Group for Blood and Marrow Transplantation
Options for women
considering pregnancy
• Discontinue imatinib (possibility of suffering CML
relapse and poor outcomes)
• Discontinuing imatinib, but take alternative therapies
such as interferon α (not associated with any
teratogenic effects in animals)
The European Group for Blood and Marrow Transplantation
Options for women
considering pregnancy
• Continue imatinib with close monitoring of pregnancy
(consider termination if significant abnormalities are found)
• The greatest risk to the foetus occurs in the first trimester
since this correlates with organ development
In the first trimester white cell and platelet counts can be
controlled by leucapheresis, which can be continued into the
second and third trimester
The European Group for Blood and Marrow Transplantation
Female Conclusions:
fertility and pregnancy studies
• At the time of CML diagnosis women of child bearing age
should consider embryo cryopreservation or oocyte retrieval
and storage
• Women treated with imatinib should be aware of the
potential for teratogenicity and use contraception to prevent
pregnancy
The European Group for Blood and Marrow Transplantation
Female Conclusions:
fertility and pregnancy studies
• Normal pregnancies have resulted despite imatinib
exposure
• Virtually no data exists regarding use of dasatinib and
nilotinib in pregnancy
• Pregnant women should therefore be advised to
discontinue these drugs
The European Group for Blood and Marrow Transplantation
Female Conclusions:
fertility and pregnancy studies
• In cases of accidental or desired pregnancy risk/ benefits
evaluations should be carried out, with careful counselling of
patients. The needs of mothers who require optimal cancer
therapy need to be balanced against the potential
teratogenicity to foetus
• Pregnancy itself does not appear to affect CML prognosis
• Breast feeding: imatinib, nilotinb and dasatinib have all been
found to be excreted in the milk of rats. Therefore breast
feeding is not advised
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Male fertility and pregnancy
studies
• Studies in male rats showed imatinib treatment in early
life reduced testicular size and altered reproductive
hormones, leading to the conclusion that imatinib before
puberty has deleterious effects
• Animal studies suggest spermatogenesis is impaired in
rats, dogs and monkeys leading to concerns that men
treated with imatinib may have decreased sperm counts
• There is increasing evidence that children born to men
taking imatinib at the time of conception are not at
increased risk of congenital malformation
The European Group for Blood and Marrow Transplantation
Male fertility and pregnancy
studies
• A study of 8 reported pregnancies fathered by 8 men with CML
(median age 35 years) reported 7 successful pregnancies and
1 spontaneous abortion. One baby was born with gut
malrotation requiringsurgical intervention.
Ault P. et al. J Clin Oncol 2006, 24: 1204-8
• 5 healthy pregnancies in the partners of 4 male patients who
had taken prolonged high-dose imatinib
Ramasamy K. et al. British Journal of Haematology 2007, 137:374-375
• Novartis has indicated awareness of more than 60 pregnancies
in the partners of imatinib treated men without any suggestion
of increased risk for congenital abnormalities.
Personal communications
The European Group for Blood and Marrow Transplantation
Male conclusions fertility and
pregnancy studies
• Due to possible adverse effects on male fertility
sperm banking should be discussed at diagnosis
as an option
• Studies show no suggestion of any problems in
pregnancy, delivery or any increase in congenital
abnormalities when the father is being treated for
CML
• For male patients fathering children can be
achieved without interruption of treatment
The European Group for Blood and Marrow Transplantation
CML in childhood
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp
The European Group for Blood and Marrow Transplantation
Meinolf Suttorp: Treatment of Pediatric CML in the Year 2010:
Use of Tyrosine Kinase Inhibitors (TKI)
and Stem Cell Transplantation (SCT)
The European Group for Blood and Marrow Transplantation
CML in childhood - conclusions
• Based on the adult data and what little is known in children,
a reasonable approach appears to be initial treatment with
imatinib in children and adolescents with CML-CP
• A change to a second-generation TKI if there is an
incomplete response or recurrence after an initial response.
• At the time of a change to the second generation TKI, an
allogeneic HCT from either a matched sibling or closely
matched unrelated donor should be implemented
The European Group for Blood and Marrow Transplantation
CML in childhood - conclusions
• Monitoring recommendations of BCR-ABL for CML on TKI
therapy or after HCT can at this time only be extrapolated
from adult data with the caveat that these populations should
be more closely monitored until additional data are obtained
• The long-term effects of TKI usage lasting for a number of
decades represent a very big unknown factor
• Randomized international trials are urgently needed to
evaluate the best therapies for paediatric CML
Taken From Meinolf Suttorp Biol Blood Marrow Transplant 2011, 17: S115-S122
The European Group for Blood and Marrow Transplantation
CML in the elderly
The European Group for Blood and Marrow Transplantation
CML in the elderly
• CML is a condition that occurs most commonly in
older age groups
• The median age at diagnosis for CML is 65 years
• The incidence of CML rises from less than 1 per
100, 000 under the age of 40 years to 5 per
100,000 at the age of 65 and exceeds 11 per
100,000 in octogenarians
The European Group for Blood and Marrow Transplantation
G. Rosti: Elderly and children, 2009
The European Group for Blood and Marrow Transplantation
G. Rosti: Elderly and children, 2009
The European Group for Blood and Marrow Transplantation
G. Rosti: Elderly and children, 2009
The European Group for Blood and Marrow Transplantation
Reality Check: Patients receiving
imatinib, stratified by age and sex
Age group
- 40
41 - 50
51 - 60
61 - 70
71 - 80
81 - 90
Women
93 %
76 %
70 %
68 %
48 %
29 %
Men
81 %
75 %
76 %
67 %
44 %
33 %
Source: CML-Incidence and treatment survey, Hasford/Tauscher/Hochhaus,
Europ. Leukemia Net (2009)
The European Group for Blood and Marrow Transplantation
Median age for patients in
CML clinical trials
– Median age at diagnosis for CML is 65 years
– Nilotinib 1st line study (ASCO 2010): median age
47/46
– Dasatinib 1st line study (ASCO 2010): median age
46/49
Sources:
"Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia", Saglio et al, 10.1056/nejmoa0912614,
June 2010
"Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia", Kantarjian et al,
10.1056/nejmoa1002315, June 2010
The European Group for Blood and Marrow Transplantation
CML in the elderly conclusions
• The incidence of CML increases with age
• Older patients appear more likely to have high risk CML
• There appear to be no differences in achieving CCR and
MMR in clinical trials between older and younger patients
• Older patients are less likely to be prescribed the latest
treatments
The European Group for Blood and Marrow Transplantation
CML in the elderly conclusions
• Older patients have been less represented in clinical trials. One
consequence is that trial results may not reflect the side effect
reality
• Special memory issues may arise in elderly patients around
taking medications
• For elderly patients who typically have more medical problems
and are taking additional medications special consideration
needs to be given about drug to drug interactions
The European Group for Blood and Marrow Transplantation
Coming soon....
Module 4
• Understanding the CML patient journey
The European Group for Blood and Marrow Transplantation