Microsoft word - 1.33 aida (aml17).doc

1 Acute Promyelocytic Leukaemia
1.33 AIDA – Clinical Trial AML17
Induction and Consolidation of APL – Arm A of AML 17 Clinical Trial Pre-treatment Evaluation
Morphology of blood and bone marrow aspirate. Trephine biopsy and ‘roll preparations’ should be made if the aspirate is difficult 6ml bone marrow or 30ml peripheral blood in EDTA to be collected from trial patients and sent by courier to Haematology Department at Royal Free Hospital. Cytochemistry: myeloperoxidase, PAS, acid phosphatase – note this may not be done routinely in some labs where immunophenotyping is readily available. Trial patients should have 4ml bone marrow in tissue culture medium with preservative free heparin/ 30ml of heparinised blood sent to local lab for cytogenetic analysis. FISH analysis for common translocations and mono/trisomies may be useful. Molecular analysis for relevant chimaeric genes, especially PML/RARA, BCR-ABL and (AML/ETO if available). Trial patients should have 4ml of bone marrow in culture medium, and 30ml heparinised blood sent to Guy’s St Thomas’ Hospital. Lumbar puncture (glucose, protein, microbiological culture, cytospin, gene rearrangement studies). This is not performed unless clinical suspicion of CNS disease. Serological tests for: Hepatitis B & C, CMV, and HIV (with consent). ECHO/ MUGA if cardiac history, elderly or previous history suggestive of potential cardiac disease (inc diabetes and hypertension) Check any previous anthracycline exposure, particularly if AML is 2nd malignancy. Maximum cumulative dose of mitoxantrone = 160mg/m2 Maximum cumulative dose for IV idarubicin not clearly defined, but 5% cardiomyopathy risk with doses of 150 to 290mg/m2. Renal/liver/bone panel, LDH, CRP, uric acid, serum glucose and blood cholesterol level. Document WHO performance status of patient. Document height, weight and body surface area. Give adequate verbal and written information for patients and relatives concerning patient’s disease, treatment strategy and side effects. Obtain written consent from patient or guardian. If appropriate, discuss the possibility of pregnancy with female patients of child-bearing age and the need for contraception with both male and female patients. Women of child-bearing potential must have a negative pregnancy test within 2 weeks of trial entry. If appropriate, discuss potential risk of infertility with patient and relatives. Sperm banking if appropriate and time allows. Retinoic acid syndrome (or ATRA syndrome) includes fever, dyspnoea, respiratory distress, hypotension, oedema, pleural or peri-cardial effusion, hepatic, renal and multi-organ failure. It is frequently associated with a raised WBC and may be fatal. If the patient presents any signs of this syndrome (eg unexplained respiratory distress): 1. Immediately discontinue tretinoin until clinical condition improves. 2. Initiate dexamethasone 10mg every 12 hours for up to maximum of 3 days or 3. Furosemide may be clinically require 4. Within 4 days of disappearance of symptoms, re-introduce tretinoin at 50% dose. In absence of return of symptoms, full dose may then be resumed. If symptoms do return, tretinoin should be discontinued permanently. Pseudotumour cerebri, defined as severe headache with nausea, vomiting and visual disorders, may occur with tretinoin. It may be necessary to temporarily discontinue retinoin and treat with opiates. In such a case, within 4 days of disappearance of symptoms, re-introduce tretinoin at 50% dose. In absence of return of symptoms, full dose may then be resumed. Drug Regimen
1. Induction
Day1 until Complete
Remission or up to
If WBC > 10 x 109/L, all idarubicin doses should be brought forward by one day, with the first dose given within a few hours after starting tretinoin (ATRA)

Patients should have a bone marrow re-assessment at 30 days which should include molecular
assessment. Patients should enter consolidation treatment if they are in complete remission which is define as
the bone marrow is regenerating normal haemopoietic cells and contains <5% blast cells by morphology in an
aspirate sample with at least 200 nucleated cells. Additionally there is an absolute neutrophil count of more than
1000/µL and platelet count of at least 100,000/µL. If haematologic Complete Remission is not achieved by 60
days after start of induction, patient will go off-study and would be eligible for “High risk” APL protocols.
2. Consolidation
Orally in TWO equally divided Rounded to the Orally in TWO equally divided Rounded to the Orally in TWO equally divided Rounded to the Day 1 ONLY
Comment: Marrow samples will be collected around day 60 (i.e. following course 1 in patients requiring
prolonged ATRA to achieve CR, or following course 2 in those with earlier documentation of CR) and on
regeneration following each consolidation course for testing by real-time quantitative PCR (RQ-PCR) by the
reference laboratory for assessment of molecular remission. Patients who do not achieve molecular remission by
the end of the 3rd consolidation cycle will be considered as molecular resistant and will go off study. Marrow
samples collected at earlier time points are used to measure disease response and provide early indication of
patients at risk of failing first line therapy. If the patient has achieved a molecular remission arrangements should
be made to undertake autologous stem cell transplant. Patients who remain in remission but are molecularly
positive should be assessed for allogeneic stem cell transplant. If no transplant option is available the patient
should commence maintenance chemotherapy.
Dose Modifications
Renal Impairment:

Limited information – SPC advises that the dose be decreased to 25mg/m2 as a precautionary measure. Liver Impairment:

If serum bilirubin, transaminases or ALP > 5 x ULN, tretinoin should be temporarily withheld. Once serum bilirubin, transaminases or ALP < 4 x ULN, tretinoin may be resumed at 50% dose. If liver enzymes do not worsen after a trial period at this dose, full dose tretinoin may be resumed. Monitor with care Bilirubin 40-85 micromol/l Concurrent Medication
Allopurinol should be given as soon as possible after diagnosis at a daily oral dose of 300 mg daily (adjusted as above for renal failure). Patients with high counts at diagnosis or an allergy to allopurinol can be considered for treatment with Rasburicase to reduce the effect of tumour lysis at induction. Anti-emetics
This regimen has high emetic potential - refer to local protocol.
Adverse effects
Adverse effects
The most common adverse effect of ATRA has been headaches of mild to moderate severity. Bone pain, occasionally requiring analgesic treatment, has also been observed. Biochemical abnormality of liver function has occasionally been reported, specifically raised transaminases, alkaline phosphatase and bilirubin, but these are reversible on stopping the drug. The most serious adverse event has been a syndrome characterised by fever, respiratory distress and episodic hypotension, usually in association with leucocytosis (now known as "Differentiation Syndrome"). The onset of this syndrome has usually been in the first 1-2 weeks of drug treatment. Should this occur the ATRA should be stopped and steroids commenced as detailed above. Some cases are reported to respond well to high-dose corticosteroid therapy (dexamethasone 10 mg i.v. 12 hourly for 3 or more days). Prolonged ATRA treatment may cause dryness of the skin and other dermatological side effects, like erythema, rash, pruritus, alopecia, hyperhidrosis. ATRA is also believed to be highly teratogenic and advice regarding contraception should be given as appropriate. The major side effect is myelosuppression. Cardiac toxicity may occur, manifested by cardiac failure, arrhythmias or cardiomyopathies, either during therapy or several weeks later. The cumulative dose associated with cardiotoxicity is not known, but it is believed that a total dose of 60-80 mg/m2, which is considerably higher than that used in AML15, is not problematic. Idarubicin may cause a red discoloration of the urine for 1-2 days after administration. Reversible alopecia will occur, and some nausea or vomiting and oral mucositis should be expected. Elevation of liver enzymes and bilirubin may occur in a minority of patients. Idarubicin should not be given to patients with severe renal or liver impairment High extravasation risk - Tissue necrosis following extravasation outside a vein. It is probably slightly less cardiotoxic than daunorubicin but care should be taken to avoid low serum potassium levels. Anorexia, diarrhoea, stomatitis, fatigue and mild alopecia have also been described. References
WLCN. Treatment of Chemotherapy induced nausea and vomiting prescribing guidelines. May 2002. Patient information
Leukaemia Research Fund - Adult Acute Myeloid Leukaemia booklet CancerBACUP - Acute myeloid leukaemia booklet Written by:
Authorised by:
WLCN Haematology TWG
Date for review by Haematology TWG:


ANTRAG Zusammenfassung und HTA-Literatur ASA Assoziation Schweizerischer Ärztegesellschaften für Akupunktur und Chinesische Medizin Sekretariat: Postfach, CH-8575 Bürglen Telefon 071 634 66 19, Telefax 071 634 66 18 E-MaiInterne Zusatzinformationen im Schlussbericht Programm Evaluation Komplementärmedizin PEK: Summary Traditional Chinese Medicine (TCM) was reimbursed by th

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