Canterbury DHB

AML 19

For AML and high risk myelodysplasia age 16–60 or up to 65 if fit enough to be considered for an allogeneic transplant.

AML (other than APML) comparisons

Induction phase

Randomisation between:

• Fractionated (2 doses of 3 mg/m² but capped at a total of 5 mg/m²) versus a single dose of 3 mg/m² gemtuzumab (mylotarg)

  AND

• Daunorubicin and Ara C (standard arm) versus FLAG-Ida

  (i.e. randomisation to one of four possible arms in induction)

• After course 1 of treatment, patients will be segregated based on their molecular-genetic characteristics, and a validated risk score.
• Patients who are at high risk of relapse based on the AML Risk Score, or who are deemed refractory (<50% reduction in blast percentage, and resistant disease) will be eligible for an allogeneic stem cell transplant (if a donor is available) and to enter a study of a novel combination. These patients will be randomised between FLAG-Ida (standard arm) vs CPX-351 with the aim of allowing patients to proceed to allogeneic transplant. One randomisation to one of two arms.
• Patients can also be randomised between FLAG-Ida (standard arm) and CPX-351 at trial entry if known adverse cytogenetics. One randomisation to one of two arms.
• In high risk patients, allogeneic SCT of either myeloablative or reduced intensity from sibling or alternative donors is recommended.

  In consolidation:

• Patients who have received FLAG-Ida and are not CBF leukaemia or high risk will be randomised to receive two, or one, or no further treatment courses of HDAC. One randomisation to one of three arms.
• Patients receiving DA induction chemotherapy will receive two courses of HDAC consolidation.
• Patients who exhibit a suitable molecular marker will be invited to enter a randomisation between minimal residual disease monitoring or not. One randomisation to one of two arms.

Relapse

• Patients who relapse can also enter the high risk randomisation. For patients who have received 2 courses of FLAG-Ida and relapsed within 6 months of achieving remission, the treatment will be Fludarabine plus CPX-351. All other patients will enter the FLAG-Ida vs CPX-351 randomisation.

  APML

• Patients with APML can be registered to receive the Italian AIDA anthracycline plus ATRA-based chemotherapy approach.

  During the course of this 6-year trial, not all randomisation options will be open at all times. Some additional options may be included by protocol amendment.

Flowchart for Adult Patients

AML 19 Trial Information

AML 19 is the treatment offered to all patients from 16–60 or up to 65 if fit enough to be considered for an allogeneic transplant. Many patients over the age of 60 find it too intensive and it is preferable to use a less intensive regimen. For patients not being entered into (the patients less than 60 who opt not to be entered into AML 19), DA 3+10 or Flag Ida would usually be used.

Please consult the trial protocol before entering patients into this study.

Inclusion criteria for the AML19 trial

• Patients with one of the forms of acute myeloid leukaemia as defined by the WHO 2016 Classification – this can be any type of de novo or secondary AML or high risk Myelodysplastic Syndrome (defined as >10% bone marrow blasts) of MDS but with 5%–9% blasts if IPSS-R very high, high, or intermediate (providing that the IPSS-R is >3.5). The IPSS-R calculator is available from the UK MDS forum. These patients enter the high risk randomisation.
• Patients with acute promyelocytic leukaemia (APML). These patients should be entered into the treatments specifically for APML.
• Patients who have WHO performance status 0–2.

  Note: The patient information, consents, and details of registering patients will be on the trials page of the Red Book. Contact the Clinical Trials office on 80377 to let them know about the patient.

• Patients who are considered suitable for intensive chemotherapy.
• Patients aged 16 to 60 years. However, patients older than 60 are eligible if intensive therapy including an allogeneic transplant is considered a suitable option.
• Patients whose serum creatinine is ≤1.5 x ULM (upper limit of normal).
• Women of child-bearing potential with a negative pregnancy test within 2 weeks before trial entry. Pregnancy tests are to be repeated throughout the trial before each course of protocol treatment.
• Sexually mature males who agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child-bearing potential (See AML19 protocol). This applies to APML and AML patients. In both males and females these measures must be in place for at least 30 days after the last administration of all investigational drugs.
• Patients who have given written informed consent.

Exclusion criteria for the AML19 trial

• Patients who have previously received cytotoxic chemotherapy for AML. Hydroxycarbamide, or similar low-dose therapy, to control the white count before initiating intensive therapy is not an exclusion.
• Patients who have received demethylation therapy for AML or high risk MDS defined as marrow blasts >10%. Patients treated for lower risk MDF who progress to have AML are eligible.
• Patients who are in blast transformation of chronic myeloid leukaemia (CML).
• Patients who have a concurrent active malignancy requiring treatment.
• Patients who are pregnant or lactating.
• The physician and patient consider that intensive therapy, including possible allogeneic transplantation, is not an appropriate treatment option.
• Patients who have a known infection with Human Immunodeficiency Virus (HIV).
• Patients with AST and/or ALT more than 2.5 times the local upper limit of normal or Bilirubin more than twice upper limit of normal are not eligible for the Mylotarg randomisations.

  Note: Patients who do not comply with the liver inclusion criteria are eligible to enter the trial but will be excluded from the Mylotarg randomisation.

Randomisation

• Before randomisation, patients need to agree to enter the trial and sign the consent form (contact the Clinical Trials office 80377 or 80386). Fax the signed consent to the trial office (80064).
• Telephone randomisation (tel: +4429 2074 5397) is available Monday to Friday, 09.00 – 17.00 UK time; internet randomisation is available seven days a week at trials.cardiff.ac.uk/HCTU
• The Christchurch Haematology Trials Coordinators will usually do the randomisation. Details of how to randomise are on the Clinical Trials page of the intranet. However if they are unavailable use the login and password that have been emailed to you.
• Induction chemotherapy allocation will be given once the required patient details have been supplied.

Information required at first randomisation

In the first screen once you have logged on, enter the following patient details:

• Title
• First initial
• Middle initial
• Last initial
• Sex
• Date of birth
• Trial centre Doctor
• Check ‘adult’ patient box.
• DO NOT enter patient name or hospital/NHS number.
• WHO performance status:

  0=normal activity

  1=restricted activity but able to look after self and do light work/household chores

  2=in bed <50% waking hours

  3=in bed >50% waking hours

  4=completely disabled.

  Type of disease: de novo AML / secondary AML /High Risk MDS

  Whether APML (FAB type M3) or not

  Baseline White Blood Count

  Confirmation that diagnostic samples of bone marrow and/or blood will be sent for mutation analysis and immunophenotyping.

Remission Criteria

Follow-up Bone Marrows

Eighteen to 21 days after the end of course 1, carry out a bone marrow aspirate to assess remission status:

• If the bone marrow is of adequate cellularity for the assessment of haematopoiesis, assess the patient's remission status.
• If the marrow is hypoplastic and it is not possible to assess the remission status, perform a repeat marrow aspirate after a further 7–10 days and assess remission status.

Minimal Residual Disease

This is monitored after cycle 1 and cycle 2 by either:

• molecular methods if there is a molecular marker (done through Guys Hospital, London, UK), or
• flow MRD. This requires 2 tugs of 1 mL of the first 2 pulls of the bone marrow in EDTA (not transport medium), which is sent to Auckland.

The transport of both types of samples is organised by the Molecular Oncology Lab (Geraldine Duncan or Kym Drake – 86008). If in doubt as to what should be collected, contact the them or Helen McDermott because they have the spreadsheet detailed with all the patient's relevant results and which samples need to be sent.

If there is a molecular marker, then the Guys lab is happy to continue monitoring on a 3-monthly basis as required for 36 months free of charge.

Request cytogenetics if there is sufficient material with the remission marrow if there was an abnormal cytogenetic result at diagnosis.

Definitions of Complete Remission, Partial Remission, and Resistant Disease:

• Complete Remission (CR): 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/microlitre and platelet count of at least 100/microlitre (<100,000/microlitre).

• Complete Remission with incomplete recovery (CRi): Fulfilling all criteria for CR except for residual neutropenia (<1000/microlitre) or thrombocytopenia.
• Partial Remission (PR): The bone marrow is regenerating normal haemopoietic cells and blast count has reduced by at least half, to a value between 5 and 15% leukaemic cells.
• Resistant Disease (RD): The bone marrow shows persistent AML, and patient survives at least 7 days beyond end of course.

Topic Code: 32083