Living with CMLWhat 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 CMLNormal 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

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

IRIS Study: Most Frequently Reported AEs

• 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

Imatinib is a Safe Drug....

But many patients have low level side effects...

Which can affect their quality of life…

Common side effects

Imatinib

Oedema (swelling)Fatigue (tiredness)Skin rashNausea/vomiting, DiarrheaMyalgias (muscle cramps)Abdominal PainHeartburnAnaemiaBleeding (due to low platelet count)Neutropenia (low white cell count)Subconjunctival hemorrhage

Nilotinib

HeadacheFatigueSkin rashNausea/vomitingDiarrheaConstipationHeartburnFlatulenceLaboratory abnormalitiesAnaemiaBleeding (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 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

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 anti-inflammatory (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)

• Severe myelosuppression is managed by temporary dose reduction and/or treatment interruptions

TKI

In CML, the majority of hematopoiesis is

contributed by Ph+ cells.

TKI eliminates Ph+ cells.This therapeutic effect may result in myelosuppression.

Ph-positive

Ph-negative

Myelosuppression(low blood counts)

Neutropenia (low white cell

count)

Febrile neutropenia

Anaemia (low red cell count)

Tiredness and breathing problems

Thrombocytopenia (low platelet count)

Risk of bleeding and haemorrhage

Risk of infection

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%)

Pye et al. Blood. 2008; 111(12):5505-8

* Includes 3 terminated following identification of foetal abnormalities

Pregnancy outcome

Total number

(%) of those with known outcome

n=125

(%) of totaln=180

Normal live infant

63 50 35

Elective Termination*

35 28 19.5

FoetalAbnormality

12 9.6 6.7

SpontaneousAbortion

18 14.4 10

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?