Regular teaching provided in ED, Paediatric Specialist Trainees Regional Training days and nursing training programmes.

Transcription

1 Iron chelation in Children with Haemoglobinopathy Trust Ref: C19/ Introduction The goal of iron chelation therapy in multiply transfused patients is to prevent morbidity and early mortality from the toxic effects of transfusional iron overload, in particular cardiac deaths. At the same time treatment should be associated with as few drug-related side effects as possible. These guidelines will be revised when the UK Forum on Haemoglobin Disorders publishes National Guidelines (due 2016) 2. Scope Relates to Paediatric haematology teams 3. Recommendations, Standards and Procedural Statements Guidelines based on: National Haemoglobinopathy Peer Review Standards 2014 NHS Sickle Cell and Thalassaemia Screening Programme - Standards for the Care of Children with SCD 2009 Caring for people with Sickle cell and thalassaemia syndromes: RCN competencies: a framework for nursing staff (2011) 4. Education and Training Regular teaching provided in ED, Paediatric Specialist Trainees Regional Training days and nursing training programmes. Assessment and monitoring Iron overload monitoring is essential in management of transfusion-dependent and transfusionindependent anaemias associated with increased iron accumulation. The aim is to assess pre-existing iron load and current rate of transfusion loading, to assess risk of organ toxicity from iron overload and to assess the efficacy of on-going chelation therapy. These assessments should be performed or analysed at the annual review visit and compared with previous years Clinical assessment is done at least annually at the annual review visit Transfusion requirements are assessed annually by automatic calculation of ml/kg transfused from the e-transfusion spreadsheet Special monitoring tests are indicated in Table 1. Results are entered onto the e-transfusion spreadsheet Iron chelation in Children with Haemoglobinopathy Guidelines Page 1 of 9

2 Table 1. Laboratory and radiological monitoring of iron overload HbSS on regular top-up or exchange transfusion Beta thalassaemia major Thalassaemia intermedia and iron loading anaemias (<4 transfusions per year) Serum ferritin R2 MRI (Ferriscan) Monthly From age 8 or 1 year after starting transfusion. Annually thereafter Monthly From age 8. Annually thereafter 6 monthly Annually from age 10 Myocardial T2* MRI Every 5 years from starting transfusion From age 8. Every 2 years if T2*>20 msec, every year if T2* msec, every 6 months if T2*<10 msec Every 5 years from age 10 Liver biopsy and iron quantitation Only if indicated for histology or if having laparotomy Only if indicated for histology or if having laparotomy Only if indicated for histology or if having laparotomy Guidelines for iron chelation therapy Indications Transfusion iron overload in chronically transfused patients with beta thalassaemia major (BTM), sickle cell disease (SCD) and other transfusion dependent anaemias Non-transfusion dependent thalassaemia or other iron loading anaemia, with evidence of significant iron loading on Ferriscan (Liver iron >7 mg/g dry weight) Dosing and prescribing (See sections on individual chelation agents) Initiation of chelation and changes in chelation drugs and dosage discussed with patient/family in MDT clinic Initiation and changes in dosing should be done by consultant All prescriptions dispensed by hospital pharmacy Recording and communication All chelation regimes (including drug, dosage, change of dosage, adverse effects and instructions and monitoring will be done from hospital clinic) to be included in out-patient clinic letter. Copied to GP, patient/family and community haemoglobinopathy team Update chelation section on e-transfusion spreadsheet Iron chelation in Children with Haemoglobinopathy Guidelines Page 2 of 9

3 SPECIFIC CHELATION DRUGS Deferasirox (Exjade Novartis) DFX Indications: 1. Transfusion-dependent anaemia (Beta thalassaemia major, sickle cell disease. Diamond Blackfan anaemia, aplastic anaemia, pyruvate kinase deficiency) receiving at least six transfusions per year. 2. Transfusion iron overload as defined by one or more of the following: Contra-indications: Annual mean serum ferritin >1000mcg/l Ferriscan liver iron >5mg/g dry weight Cardiac MRI T2* 10-20ms Renal disease Decompensated liver disease Pregnancy Breast feeding Baseline investigations: FBC Full serum biochemistry including duplicate creatinine and ALT Urinalysis, urinary protein/creatinine ratio Serum Ferritin Ferriscan (If not done during past year) Cardiac T2* MRI (If not done during past year) Liver biopsy is not necessary routinely, but should be done if patient has pre-existing liver disease (e.g. HCV infection) and liver biopsy not done in previous 2 years Dosage regime Initial dose is usually 20mg/kg. Dose can be increased by 5mg/kg at 3 monthly intervals if increasing/insufficient reduction of iron loading as assessed by above parameters. Usual dosage required for reduction in iron loading is 30mg/kg/day. Dosage may be increased up to 40mg/kg/day if myocardial T2* msec and not improving after 12 months on 30mg/kg. Dose should be reduced if ferritin mcg/l and consider temporary discontinuation if ferritin <500 mcg/l with monthly monitoring. Monitoring Weekly FBC, creatinine, liver function tests for first month, monthly thereafter with regular pre-transfusion tests Serum ferritin monthly Myocardial T2* annually (or 6 monthly if T2*<20 msec) Ferriscan annually Nursing staff should record creatinine, ALT, ferritin monthly e-transfusion spreadsheet and abnormalities communicated immediately to Consultant Iron chelation in Children with Haemoglobinopathy Guidelines Page 3 of 9

4 Clinical and laboratory parameters relating to deferasirox therapy assessed at 3 monthly clinic visit and annual review by consultant Adverse effects and their management Gastrointestinal effects: Nausea, diarrhoea, abdominal pain. Common symptoms at initiation of therapy. May be manageable by dividing the dose into twice daily regimen. If this is not effective, reduce dose by 50%, and gradually increase dose in 5mg/kg increments as tolerated. Rash Fairly common symptom at initiation of therapy. May resolve spontaneously. If more severe, stop until rash subsides and then rechallenge at 50% of initial dose and gradually increase at 5mg/kg increments monthly. Elevated serum transaminase levels. Raised ALT is common. Stop Exjade if >ALT 2X upper limit of normal. Repeat liver function tests after 1 week. Re-introduce at same dosage if ALT normalized, or at 50% dosage if ALT falling but still above 2x ULN. Elevated creatinine. If creatinine > upper limit of normal, stop Exjade. Repeat serum creatinine in 1 week. Reduce dose by 50% and gradually increase at 5mg/kg increments monthly. Renal tubular acidosis. Stop Exjade. Re-introduce at 50% of dose when biochemical abnormalities corrected. Gastro-oesophageal ulceration. For suspected upper GI ulceration, stop Exjade. Arrange upper GI endoscopy. Re-introduce Exjade at 50% dose after 4 weeks and when symptoms have subsided. Lens opacities Rare adverse effect. Seek ophthalmological advice Desferrioxamine (Desferal ) DFO Desferrioxamine was introduced in the 1960 s and became established in the 1980 s as the first effective iron chelation therapy for iron overload in beta thalassaemia major. It has poor oral bioavailability and a short plasma half-life after parenteral administration. Effective chelation is related to the dosage and duration of exposure, and in practice this requires infusion of at least 8 hours 5 times per week. Subcutaneous regimes can be delivered by battery operated syringe driver pump or by disposable elastomeric pumps. The latter is preferred because the drug is reconstituted and ready for infusion on delivery to the patient s home. Also, the infusions tend to be of longer duration and more convenient for the patient s day to day activities. The efficacy in mobilization and excretion of iron is reduced if vitamin C is deficient, and enhanced by taking vitamin C. Indication: 1. Regularly transfused inherited or acquired anaemia (BTM, SCD, aplastic anaemia, myelodysplastic syndrome) or thalassaemia intermedia (TI) 2. Iron overload as defined by one or more of the following Iron chelation in Children with Haemoglobinopathy Guidelines Page 4 of 9

5 Annual mean serum ferritin >1000mcg/l Ferriscan liver iron >6mg/g dry weight Cardiac MRI T2* <20ms (this is the main indication) Contra-indications (these are relative contra-indications. In some cases, the drug may be used at reduced dosage with careful monitoring) Renal failure (egfr <50 ml/min) Decompensated liver failure Severe sensorineural hearing loss Previous retinal toxicity Pregnancy Breast feeding Baseline investigations: FBC Full serum biochemistry Serum ferritin Serum zinc Ferriscan (If not done during past year) Cardiac T2* MRI (If not done during past year) Pure tone audiometry Ophthalmology assessment Liver biopsy is not necessary routinely, but should be done if patient has pre-existing liver disease (e.g. HCV infection) and liver biopsy not done in previous 2 years Dosage regime Desferrioxamine 30-60mg/kg/day at least 5 days per week over hours using disposable infusors Vitamin C (Ascorbic acid) at initiation on infusion Routes of administration Generally self-administered by sub-cutaneous infusion Continuous i.v. desferrioxamine 50-60mg/kg/day over 24 hours per day 7 days per week is used in patients with cardiac failure related to iron overload and other patients with severe iron overload, who have not been able to reduce iron loading with other chelation regimes. Training and supervision in self-administration of desferrioxamine infusions Standard training on insertion of needle, care of infusion site, removal and discarding of needle and infusor, awareness of side effects to be done on Ward 27 Daycare Unit and at home by hospitalbased nurse and community-based nurse specialists Monitoring Iron chelation in Children with Haemoglobinopathy Guidelines Page 5 of 9

6 Clinical assessment monthly (CNS/Consultant) when attending for transfusion. Ask about problems with adherence, local skin reactions (inspect injection sites), rotation of sites, any problems with hearing and tinnitus, any ocular problems. Regular home contact with community-based nurse specialist, who should feedback problems at MDT meeting Adherence and problems assessed at 3 monthly clinic visit and annual review Additional monitoring tests (Ferritin, myocardial T2* and Ferriscan) as per Table 1 Adverse effects and their management: Inconvenience and local tissue reactions are frequent, and the commonest reason for poor adherence and poor control of iron stores. For swelling, itching, erythema and pain at injection sites, rotate injection sites. Hearing loss and visual impairment is encountered in patients who are treated with high doses of desferrioxamine relative to the degree of iron loading. High tone sensorineural hearing loss: Discontinue or reduce dose. Retinal toxicity: Night blindness, disordered colour vision, visual impairment: Discontinue or reduce dose Bone dysplasia is seen in children treated with doses in excess of 30mg/kg. X-rays should be done to assess bone pain, growth retardation. For confirmed pseudorickets or vertebral dysplasia, discontinue or reduce dose Life-threatening sepsis due to Yersinia or Klebsiella is a well recognised complication. Patients and clinicians should be aware of the risk of overwhelming sepsis, and patients advised to discontinue desferrioxamine temporarily if experiencing high fever and/or severe abdominal pain. Cultures should be taken, fluid resuscitation given as needed, and intravenous antibiotics covering these infections (aminoglycoside or tazocin) started promptly Deferiprone (Ferriprox, Apotex) DFP This is an oral iron chelating agent, which must be taken on a three or four times daily regime to be effective. It can be used in combination with desferrioxamine as a high potency chelation regime, and generally has a beneficial effect in chelating cardiac iron, particularly when used in the mg/kg/day dose range. The most important side effects are agranulocytosis (approx 1%) and arthropathy (generally affecting the knees). While agranulocytosis generally occurs during the first six months of therapy, patients need regular monitoring of blood counts. They need to be constantly reminded of the risk of agranulocytosis and the need to seek medical attention and urgent full blood count if they develop a high fever or signs of infection. Indication: Transfusion-dependent anaemia (Beta thalassaemia major, sickle cell disease. Not aplastic anaemia or myelodysplastic syndrome) Severe iron overload as defined by one or more of the following Iron chelation in Children with Haemoglobinopathy Guidelines Page 6 of 9

7 Annual mean serum ferritin >2500mcg/l Ferriscan liver iron >15mg/g dry weight Cardiac MRI T2* <20ms (this is the main indication) Inability to adhere to desferrioxamine regime 30-50mg/kg over at least 10 hours at least 5 times per week. Intolerant of or inadequate control of iron stores with Deferasirox Contra-indications Neutropenia (<1.0x109/l) or past history of agranulocytosis Decompensated liver disease Pregnancy Breast feeding Age <6 Baseline investigations FBC Full serum biochemistry Serum ferritin Serum zinc Ferriscan (If not done during past year) Cardiac T2* MRI (If not done during past year) Liver biopsy is not necessary routinely, but should be done if patient has pre-existing liver disease (eg HCV infection) and liver biopsy not done in previous 2 years Dosage regime Deferiprone mg/kg/day in three doses To manage drug-associated nausea, the initial dose can be given at 25mg/kg, thereafter increasing to 50 and 75mg/kg in 2 week intervals Monitoring Weekly FBC for first month and then monthly FBC with each transfusion. Neutrophil count entered onto e-transfusion spreadsheet and any abnormalities communicated immediately to Consultant Biochemistry (including AST and ALT) weekly first month, then monthly Serum ferritin 3 monthly Serum zinc 6 monthly Myocardial T2* Annually (or 6 monthly if T2*<10 msec) Ferriscan annually Assessed at 3 monthly clinic visit and annual review Adverse effects Gastrointestinal effects: Nausea and vomiting Weight gain Iron chelation in Children with Haemoglobinopathy Guidelines Page 7 of 9

8 Elevated serum transaminase levels Neutropenia (neuts 0.5-1x109/l) Agranulocytosis (neuts <0.5x109/l) Arthralgia and arthritis Zinc deficiency Management of adverse effect Agranulocytosis risk Risk of agranulocytosis explained prior to starting DFP Instructed to stop DFP if develops fever or signs of infection and obtain urgent FBC (all patients have open access to CAU) Discussion documented in clinical notes and letter Agranulocytosis event Stop deferiprone immediately. Hospitalize, barrier nursing, G-CSF daily until neuts>1.0x10 9 /l for two consecutive days. Do not re-challenge Neutropenia (neuts <1.5x109/l) Stop deferiprone. Check FBC daily. Restart at same dose (75mg/kg/day) when neuts >1x10 9 /l for two consecutive days Nausea, vomiting Try anti-emetics. Symptoms usually settle after a few days. It may be necessary to discontinue deferiprone for 1-2 weeks and then re-start at same dose Arthritis and arthralgia Usually affects knees. Discontinue until symptoms settle. If recovery is complete, rechallenge at same dose Combination chelation therapy (ALL patients MUST be discussed in EMSTN Regional Clinical MDT prior to commencing) Desferrioxamine, as above, 2-6 infusions/week plus Deferiprone, as above, 7 days/week This is not a life-long treatment and is intended as intensive chelation to reduce iron stores rapidly and reliably Risks of agranulocytosis and desferrioxamine toxicity are probably increased with combination therapy, and this treatment needs more intensive monitoring, including regular weekly blood counts, 3 monthly biochemistries, ferritin and zinc levels, 6 monthly T2* MRI and audiometry Desferrioxamine frequency should be decreased as ferritin level falls. Patients with consistent ferritin levels below 1000 could be considered for deferiprone monotherapy. Iron chelation in Children with Haemoglobinopathy Guidelines Page 8 of 9

9 Monitoring and Audit Criteria Author / Lead Officer: Reviewed by: Approved by: DEVELOPMENT AND APPROVAL RECORD FOR THIS DOCUMENT Dr Krishna Kotecha Job Title: Consultant Date Approved: Date Issue Number Reviewed by REVIEW RECORD Description of Changes (If Any) DISTRIBUTION RECORD: Date Name Dept Received REVIEW DUE January 2018 Key Words Sickle cell, thalassaemia, transfusion, chelation This table is used to track the development and approval and dissemination of the document and any changes made on revised / reviewed versions Iron chelation in Children with Haemoglobinopathy Guidelines Page 9 of 9