Living with CML
What should I expect?
Dr Graeme Smith
Things to discuss
•
Diagnosis and the first few weeks
- I’ve got leukaemia – help!
•
Treatment choices
- which drug and why?
- first line, and later on?
- do’s and don’ts
•
Side effects
- what can I expect?
- how do I cope with them?
•
Monitoring
- how and how often?
- bone marrows?
- can I go on holiday?
•
Special circumstances
- pregnancy and the elderly
Diagnosis and the first few weeks
• Symptoms related to the disease
- from enlarged spleen
- from effect on blood
- shortness of breath
- bruising
- circulatory problems
- sweats
- gout!
- none of the above
• Shock and disbelief!
Peripheral blood film in CML
Normal
CML
Clinical manifestations of CML
• Fatigue 34%
• Bleeding 21%
– platelet dysfunction
• Weight loss 20%
• Excessive sweating 15%
• Abdominal discomfort 15%
– left upper quadrant pain
– feeling full after eating little
– Rarely: severe pain due to
splenic ‘infarction’
• Malaise 3 %
• Tenderness in lower
sternum or limb pain
– expanding bone marrow
• Acute gouty arthritis
– high uric acid levels
• Thrombosis
Treatment choices
• Imatinib or Nilotinib
• Clinical trials
• Other drugs
- allopurinol
- aspirin
- painkillers
- anti-histamines
- water tablets
• Second line therapy
- Dasatinib (or Nilotinib)
- when will they be considered?
Once on treatment, what are the
issues?
• Getting to grips with how best to take the
tablets
• Coping with side effects of treatment
• Avoidance of drug interactions
• Adherence to medications
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
Nilotinib
How to take nilotinib:
• Patients are instructed not to take nilotinib with food
since food can affect levels of nilotinib resulting in
side effects such as the potential to affect heart rhythym
• They should avoid taking grapefruit with nilotinib
• They should take nilotinib at least 2 hours after
eating food and then wait 1 hour before eating again
• N.B. - Nilotinib tablets contain lactose and may not be
suitable for lactose intolerant patients
How to fit nilotinib into
daily life
Imatinib drug interactions
• Imatinib has the potential to interact with several
agents
It is an inhibitor of an enzyme called cytochrome P450
3A4, which is found in the liver and is responsible for
the metabolism of foreign chemicals in the body
Imatinib drug interactions
• Imatinib may decrease metabolic clearance of drugs
that are primarily metabolised by this enzyme
(e.g. simvastatin) and other inhibitors of CYP3A4
may increase imatinib plasma concentrations (e.g.
clarithromycin)
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.
Side effects
Imatinib is a Safe Drug....
IRIS Study: Most Frequently Reported AEs
Most Common
Adverse Events (by
5 Years)
All Grade AEs
Patients, %
Grade 3/4 AE’s
Patients %
Superficial oedema
60
2
Nausea
50
1
Muscle cramps
49
2
Musculoskeletal pain
47
5
Diarrhea
45
3
Rash/skin problems
40
3
Fatigue
39
2
Headache
37
<1
Abdominal pain
37
4
Joint pain
31
3
•
•
Only Serious Adverse Events (SAEs) were collected after 2005
Grade 3/4 adverse events decreased in incidence after years 1-2
IRIS 8 year update
But many patients have low
level side effects...
Which can affect their quality of life…
Common side effects
Imatinib
Oedema (swelling)
Fatigue (tiredness)
Skin rash
Nausea/vomiting, Diarrhea
Myalgias (muscle cramps)
Abdominal Pain
Heartburn
Anaemia
Bleeding (due to low platelet
count)
Neutropenia (low white cell
count)
Subconjunctival hemorrhage
Nilotinib
Headache
Fatigue
Skin rash
Nausea/vomiting
Diarrhea
Constipation
Heartburn
Flatulence
Laboratory abnormalities
Anaemia
Bleeding (due to low platelet count)
Neutropenia (low white cell count)
Prolongation of QT interval/ECG
abnormality
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, worse in the
morning, and at the extremities of legs & arms
• Pleural effusion or ascites (a build up of fluid between the
tissues lining the abdomen) is uncommon. Most common
with dasatinib
Periorbital Oedema
Management of fluid
retention
•
•
•
•
May be identified by regular weighing
Low salt diet
A diuretic (Furosemide) may be needed
On occasions the drug may need to be stopped
until the oedema improves
Eyes:
• Plastic surgery in severe cases
• Artificial tears
Stomach ache
• 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
Other gastro-intestinal side
effects
• Nausea if severe can be managed by the use of antinausea medicine
• It can be helpful to split the drug dose and take twice a
day instead of once a day
• Anti-diarrhoeal medication (eg loperamide) may be used
if diarrhoea occurs
• Dyspepsia (heartburn/reflux) can be managed
symptomatically with antacids or ulcer healing drugs
Fatigue
Fatigue/tiredness
• Fatigue may occur and can have a big impact on the
patient’s quality of life
• Take adequate rest
• Exercise also useful
(anaemia and an underactive thyroid should be excluded)
Muscle cramps
• Muscle cramps may occur in the hands, feet
and/or legs
• They usually occur intermittently, but may
increase with prolonged therapy
Muscle cramps
• Helpful strategies to manage muscle cramps include:
– increasing amount of fluid drunk daily
– electrolyte monitoring (eg potassium and calcium
levels) and supplementation (especially if taking a
diuretic )
– a balanced diet
– tonic water or quinine tablets
• If severe muscle relaxants can be used
Pain
• Some patients will experience joint pain
(arthralgia) and headaches which can be
managed by regular use of non-steroidal antiinflammatory (NSAID’s) drugs
• However, need to be careful about using
certain NSAIDs if the patient has low platelet
counts
Skin rash
• rashes may occur with or without itching or
pustules
• can come and go
• usually resolves with topical or oral
antihistamines
• a severe rash may require an interruption in
therapy and steroid therapy
• skin may just be dry and moisturizing using a
neutral moisturizing cream is helpful
Other skin problems
• Other skin problems can also occur:
– Skin may become thin and tear and bruise
easily
– changes in skin pigmentation may occur
• usually lighter skin colouration with imatinib
– hair discolouration and some hair loss can also
occur
• Patients need to be cautious while in direct
sunlight and use sun protection factor creams
(SPF 15 or above)
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
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
Pleural effusion
• Side effect that is more common with dasatinib
(Sprycel®) than other TKI’s
• Incidence 7-35%
• Symptoms suggestive of pleural effusion, include
shortness of breath and a dry cough
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
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:
– a history of pleural effusions or already has severe lung
problem: would consider nilotinib over dasatinib
– if had history of pancreatitis, or problems with heart rhythm,
would consider dasatinib first
Side Effects
But what about Long Term Toxicity...?
Monitoring
•
•
•
•
Why?
How?
Compliance?
Stopping?
Requirement for monitoring:
CML
The follow-up of CML patients who have achieved a
stable response (MMoR) on TKI therapy is currently
carried out within a hospital outpatient setting.
Patients achieving a MMolR have a very small risk of
disease progression (<1% per year). It is therefore
reasonable to consider reducing the frequency of hospital
visits to just once a year
PCR analysis should still be carried out on a three
monthly basis through samples taken via the GP.
Key features of Outreach service
• IT system for sample tracking and results (HILIS)
• Postal delivery: available anywhere in UK
• All necessary items in Safebox
–
–
–
–
–
Patient information sheet
Symptom check list
Self-assessment questionnaire
Blood tubes
Phlebotomist information sheet
• Pack sent to patient when required
• Returned by pre-paid first class mail
• Results reviewed by clinical scientist & haematology consultant
Symptoms and questionnaire sheets
What is compliance/adherence –
and why is it important?
• 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
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
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
Hammersmith compliance
study
• 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
Hammersmith compliance
study
• 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
Management of special CML
Populations – Pregnancy
and the Elderly
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 have children
Cortes J. et al. Hematol Oncol Clin NorthAm 2004, 18:569-84
Female Pregnancy studies
Preclinical models have shown that imatinib has
teratogenic effects, leading to the manufacturer’s
recommendation that women should avoid
pregnancy
Imatinib and Pregnancy
• Timing of exposure to imatinib by trimester
known in 146/180 cases (81%).
• 71% of these were exposed in the 1st
trimester (includes 4 cases exposed in 1st & 2nd
trimesters)
• 26% exposed throughout pregnancy
• 3% exposed after 1st trimester
Pye et al, Blood. 2008; 111(12): 5505-8
Outcome known for 125/180 (63%)
Pregnancy
outcome
Total
number
Normal live
infant
63
(%) of those with
known outcome
n=125
50
Elective
Termination*
Foetal
Abnormality
Spontaneous
Abortion
35
28
19.5
12
9.6
6.7
18
14.4
10
Pye et al. Blood. 2008; 111(12):5505-8
* Includes 3 terminated following identification of foetal abnormalities
(%) of total
n=180
35
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)
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
Recommendations:
• 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
Pregnancy
• 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, nilotinib and dasatinib have all been
found to be excreted in the milk of rats. Therefore breast
feeding is not advised
Male fertility
• 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
• However - there is increasing evidence that children born
to men taking imatinib at the time of conception are not at
increased risk of congenital malformation
Conclusions: male fertility
• 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
CML in the elderly
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 per100,000 in octogenarians
CML in the elderly
• 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
CML in the elderly
• 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
Conclusions
• A diagnosis of CML is compatible with a full and
healthy life of normal span!
• It is encumbent on us as healthcare professionals
to work with you to optimise your treatment so
that we can get the excellent responses in the
leukaemia that are necessary, while paying close
attention to quality of life issues that impact on
your happiness, compliance and, ultimately,
survival!
• Can we do it?