AML18 - A trial for older patients with Acute Myeloid Leukaemia and high risk myelodysplastic syndrome
Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS)
Current interventions as of 02/10/2019: The AML18 trial will evaluate several therapeutic questions in Acute Myeloid Leukaemia (AML). The trial will recruit 1600 patients primarily over the age of 60 who are considered fit for an intensive approach to treatment. At diagnosis: For patients not known to have adverse risk cytogenetics DA chemotherapy plus two doses of 3 mg/m2 (maximum 5mg per dose) of Mylotarg versus CPX-351. Patients ineligible for Mylotarg can enter the randomisation but receive DA alone or CPX-351. Patients ineligible for CPX-351 will receive DA alone For patients who were allocated DA chemotherapy (with or without Mylotarg) in course 1 but are not in CR or who are MRD +ve, or for whom MRD is not assessable post-course 1. DA versus DAC versus FLAG-Ida All patients at second course who have were allocated DA induction and who have a FLT3 mutation in the diagnostic sample. AC220 versus no AC220 for a maximum of 3 cycles; then with or without maintenance for 1 year for patients allocated AC220 For patients who are in CR or CRi and MRD -ve post course1 and have completed 2 courses of DA. DA versus intermediate-dose Cytarabine (IDAC) For patients who were allocated CPX-351 chemotherapy in course 1 but are not in CR or who are MRD +ve, or for whom MRD is not assessable post-course 1. Course 2 : CPX-351 100 units/m2 x 3 doses (CPX-351 300) versus CPX-351 100 units/m2 x 2 doses (CPX-351 200). Course 3: CPX-351 65 units/m2 given on days 1 and 3 (CPX-351 130) Previous interventions: The AML18 trial will evaluate several therapeutic questions in Acute Myleoid Leukaemia (AML). The trial will recruit 1600 patients primarily over the age of 60 who are considered fit for an intensive approach to treatment. A randomisation will compare standard chemotherapy schedule Daunorubicin/Ara-C(DA) combined with 1 or 2 doses of Mylotarg in course 1, patients who fail to achieve CR or are MRD positive after course 1 will be randomised to compare DA with DA plus Cladribin
Current participant inclusion criteria as of 22/02/2023: 1. They have one of the forms of acute myeloid leukaemia, (except Acute Promyelocytic Leukaemia) as defined by the WHO Classification (Appendix A). This can be any type of de novo AML (including patients with AML with morphological MRC who do not have a history of MDS or known MDS-related cytogenetics) or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2). Patients with a prior history of a myeloproliferative neoplasm may be included provided they meet none of the exclusion criteria. 2. Patients should normally be over the age of 60 years, but patients under this age are eligible if they are not considered eligible for the MRC AML19 trial. Please contact the trial team for further information. 3. They have given written informed consent 4. Serum creatinine ≤1.5 × ULN (upper limit of normal) 5. Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if them or their sexual partners are women of childbearing potential (WOCBP). These measures must be in place for 6 months for patients receiving CPX-351 and 7 months (females) or 4 months (males) for Mylotarg – more comprehensive guidance is included in the current Summary of Product Characteristics (SPC) for these agents. Men should be advised to not father a child while receiving trial treatment. Similarly women must agree to adequate contraceptive measures and avoid becoming pregnant while on protocol treatment. In the event of pregnancy at any point during the trial, the IMPs should be immediately stopped and the Trial Team should be contacted and pregnancy reporting procedures followed 6. ECOG Performance Status of 0-2 _____ Previous participant inclusion criteria as of 02/10/2019: 1. They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de no
Current participant exclusion criteria as of 22/02/2023: Patients are not eligible for the AML18 trial if: 1. Patients that are known to either have adverse risk cytogenetics as defined by Grimwade or cytogenetic changes that meet the WHO definition of AML-MRC 2. They have therapy–related AML (t-AML) with documented history of prior cytotoxic therapy or radiotherapy 3. They have a documented history of CMMoL prior to transformation to AML 4. They have a documented history of MDS prior to transformation AML 5. They have previously received cytotoxic chemotherapy for AML. (Hydroxycarbamide, or similar low-dose therapy, to control the white cell count prior to initiation of intensive therapy, is not an exclusion. 6. They are in blast transformation of chronic myeloid leukaemia (CML) 7. They have a concurrent active malignancy excluding basal cell carcinoma 8. They are pregnant or lactating 9. They have Acute Promyelocytic Leukaemia 10. Known infection with human immunodeficiency virus (HIV) 11. Patients with prior cumulative anthracycline exposure (from prior treatment of a non-AML cancer) of greater than 300 mg/m2 daunorubicin (or equivalent) 12. History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry Mylotarg-specific exclusion criteria: 1. Pre-existing liver impairment with known cirrhosis 2. Total bilirubin >2.0 x the upper limit of normal (ULN) 3. Aspartate aminotransferase (AST) >2.5 x ULN 4. Alanine aminotransferase (ALT) >2.5 x ULN CPX-351-specific exclusion criteria: 1. Hypersensitivity to cytarabine, daunorubicin or liposomal products 2. History of Wilson’s disease or other copper-metabolism disorder In addition patients are not eligible for the AC220 randomisation if they have these cardiovascular system exclusion criteria: 1. Known serious cardiac illness or medical conditions, including but not limited to: 1.1. Clinically unstable cardiac