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Living with CML What should I expect?

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Presentation on theme: "Living with CML What should I expect?"— Presentation transcript:

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 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 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

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