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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 The European Group for Blood and Marrow Transplantation There can be different issues for the different TKIs • Imatinib (glivec®/gleevec®) • Dasatinib (sprycel®) • Nilotinib (tasigna®) The European Group for Blood and Marrow Transplantation 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) The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation How to fit nilotinib into the daily life The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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 The European Group for Blood and Marrow Transplantation 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