1. Living with CML What should I expect?
Dr Graeme Smith

2. 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

3. 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!

4. Peripheral blood film in CML
Normal
CML
High numbers of circulating white cells
Predominantly granulocyte lineage
Include mature cells and also immature representing the differentiation pathway from HSC to mature granulocytes

5. Clinical manifestations of CML
Vary among reported series
Depend upon the stage of disease at diagnosis
20-50% of patients are asymptomatic
disease first suspected on routine blood tests

6. Clinical manifestations of CML
Splenomegaly %
Anaemia %
WBC > 100 x1012/L 52-72%
Platelets > 600 x1012/L 15-34%

7. 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

8. 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?

9. 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

10. 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

11. 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

12. How to fit nilotinib into daily life

13. 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

14. 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)

15. 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.
Conversely, drugs that induce CYP3A4 activity (e.g. carbamazepine and dexamethasone) may decrease serum concentrations of Imatinib (Table 2)

16. Side effects

17. IRIS Study: Most Frequently Reported AEs
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
Musculoskeletal pain 47 5
Diarrhea 45 3
Rash/skin problems 40
Fatigue 39
Headache 37
<1
Abdominal pain 4
Joint pain 31
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

18. But many patients have low level side effects...
Which can affect their quality of life…

19. Common side effects Imatinib Nilotinib Headache 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

20. Common side effects Dasatinib (Sprycel)
Fluid retention (including pleural effusion)
Dyspnoea (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

21. 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

22. Periorbital Oedema

23. 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

24. 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

25. Other gastro-intestinal side effects
Nausea if severe can be managed by the use of anti- nausea 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

26. Fatigue

27. 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)

28. Muscle cramps Muscle cramps may occur in the hands, feet and/or legs
They usually occur intermittently, but may increase with prolonged therapy

29. 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

30. Pain
Some patients will experience joint pain (arthralgia) and headaches which can be managed by regular use of non-steroidal anti-inflammatory (NSAID’s) drugs
However, need to be careful about using certain NSAIDs if the patient has low platelet counts

31. 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

32. 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)

33. 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

34. Myelosuppression (low blood counts)
Neutropenia (low white cell count)
Anaemia (low red cell count)
Thrombocytopenia (low platelet count)
Risk of infection
Tiredness and breathing problems
Risk of bleeding and haemorrhage
Febrile neutropenia

35. 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

36. 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

37. Management of pleural effusion
Perform chest x-ray when symptoms such as shortness of breath and dry cough are 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:

38. 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

39. Side Effects

40. But what about Long Term Toxicity...?

41. ENESTnd: arterial Events by 4 Years
Patients, n (%)
Nilotinib 300 mg BID
n = 279
Nilotinib 400 mg BID
n = 277
Imatinib 400 mg QD
n = 280
IHD (3 yrs in brackets)
11 (9)
14 (11)
3 (3)
PAOD (3 yrs in brackets)
4 (4)
5 (3)
Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm)
1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation
Data cutoff: 27Jul 2012. 41 41 41

43. Monitoring
Why?
How?
Compliance?
Stopping?

44. Recommended testing for disease monitoring adapted from NCCN (2013) and ELN (2009 and 2013).
Oehler V G Hematology 2013;2013:
©2013 by American Society of Hematology

45. 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.
Similar to the CLL/MGUS story the follow up of patients with CML who have achieved a stable response to TKI therapy is almost exclusively carried out in a hospital out patient setting.
Patient who have achieved a a major molecular response have a very small risk of progression. It is therefore reasonable to consider reducing their hospital visits to once a year. Regular monitoring of there disease would still be carried out but the sample taken via the GP practice and sent to HMDS in the post.

46. 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
In a very similar manner to the existing outreach service we would use our in-house HILIS IT system to track the samples and report the results rapidly. The pack can be sent out anywhere in the uK. Each pack contains etc. Read from slide

47. Symptoms and questionnaire sheets
There are two of the sheets that will accompany the postal packs. The first a list of symptoms the patient should look out for which differ from some of the common side effects they may experience normally on these therapies. The second sheet is an in-depth questionnaire completed by the patient relating to these and other potential problems

49. What is compliance/adherence – and why is it important?
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
Teaching Note: What is compliance?
Compliance and adherence are used synonymously by many health providers and authors.
However, some feel that the term compliance partitions too much blame on the patient for lack of adherence to prescribed therapy and leads to reduced accuracy of many adherence monitoring methods.
Persistence refers to taking medication for the agreed duration, and is inherent to good compliance.
The World Health Organisation prefers the term adherence, which may imply more patient-provider agreement in treatment choice and a larger role in decision-making by the patient.
Adherence behaviour is also influenced by the clinician and the health care system, the disease and its treatment, and economic and social factors

50. 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:

51. 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:

52. Teaching Note: Again at ASH 2009 Alex Bazeos showed that achieving both MMR and CMR was linked to adherence.

53. 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

54. 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:

55. Management of special CML Populations – Pregnancy and the Elderly

56. 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

57. 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

58. Female Pregnancy studies
Preclinical models have shown that imatinib has teratogenic effects, leading to the manufacturer’s recommendation that women should avoid pregnancy

59. 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):

60. (%) of those with known outcome
Outcome known for 125/180 (63%)
Pregnancy outcome
Total number
(%) of those with known outcome
n=125
(%) of total
n=180
Normal live infant 63 50 35
Elective
Termination* 28
19.5
Foetal
Abnormality 12
9.6
6.7
Spontaneous
Abortion 18
14.4 10
Pye et al. Blood. 2008; 111(12):5505-8
* Includes 3 terminated following identification of foetal abnormalities

61. 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)

62. 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

63. 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

64. 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

65. 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

66. 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

67. CML in the elderly

68. 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

69. 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

70. 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

71. 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?

73. The European Group for Blood and Marrow Transplantation
CML Learning Programme
for nurses & other allied health care
The European Group for Blood and Marrow Transplantation