Overview

Treatment options for older adults with Acute Myeloid Leukaemia (AML) and Myelodysplasia (MDS) are limited. Although stem cell transplantation remains one of the most effective treatments it is associated with severe side effects which have until recently prevented its use in older adults. In the last decade the use of reduced intensity transplants has allowed the extension of the potentially curative effect of transplantation to older patients in whom it was previously precluded. Although a major advance such transplants are associated with a high risk of disease relapse particularly in patients with high risk disease.

This study will evaluate new transplant strategies with the aim of improving the outcome of patients with AML and high risk MDS after stem cell transplantation. Three approaches to improve transplant outcome will be studied:

1. Comparing the new pre-transplant consolidation therapy vyxeos with the standard consolidation therapy
2. Comparing new conditioning therapies in patients under the age of 55 years
3. Comparing new conditioning therapies in patients aged 55 and over

All patients will be followed up for a minimum of 2 years.

Eligibility

Eligibility Criteria for Randomisation 1 Inclusion Criteria for Randomisation 1

1. Patients ( 18 years old) with a morphological documented diagnosis of AML or MDS who are deemed fit for allo-SCT with one of the following disease characteristics:

AML

• Patients in 1st complete remission (CR1) defined as < 5% blasts
  • Patients in 2nd complete remission (CR2) defined as < 5% blasts
  • Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as < 5% blasts MDS
  • Patients with advanced or high risk MDS with an IPSS-R of 3.5 (intermediate 3.5 or higher) 2. Patients with an identified HLA identical sibling or suitable matched unrelated donor (suitable match defined as no greater than a single allele mismatch at HLA-A, -B, -C or DR1) 3. Patients must be considered suitable/fit to undergo allo-SCT as clinically judged by the Local Investigator 4. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 6 months after treatment 5. Patients have given written informed consent 6. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 1
    1. Patients with contraindications to receiving allo-SCT
    2. Patients who have already received Vyxeos in their most recent treatment schedule
    3. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment
    4. Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period
    5. Patients with renal or hepatic impairment as clinically judged by the Local Investigator
    6. Patients with active infection, HIV-positive or chronic active HBV or HCV.
    7. Patients with a prior malignancy, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ. Cancer treated with curative intent 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed
    8. History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the Vyxeos formulation.
    9. Known history of Wilson's disease or other copper-related metabolic disorder since copper gluconate is a component of the Vyxeos formulation

Eligibility Criteria for Randomisation 2 Inclusion Criteria for Randomisation 2

1. Patients aged between 18 - 54 years with a morphological documented diagnosis of AML or MDS who are deemed fit for a MAC allo-SCT with one of the following disease characteristics: AML
   • Patients in 1st complete remission (CR1) defined as < 5% blasts
   • Patients in 2nd complete remission (CR2) defined as < 5% blasts
   • Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as < 5% blasts
   • Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances MDS
   • Patients with advanced or high risk MDS (with an IPSS-R of 3.5 (intermediate 3.5 or higher) who have < 10% blasts at the time of randomisation following intensive chemotherapy (including R1 randomisation) or hypomethylating agents if necessary
2. Patients with an identified HLA identical sibling or suitable matched unrelated donor (suitable match defined as no greater than a single allele mismatch at HLA-A, -B, -C or DR1)
3. Patients with an ECOG performance status of 0, 1 or 2
4. Patients considered suitable/fit to undergo a MAC allo-SCT as clinically judged by the Local Investigator including:
5. Adequate hepatic and renal function as determined by full blood count and biochemistry assessment
6. Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures)
7. Performance of cardiac or pulmonary function tests (where there is a previous history of cardiac or pulmonary impairment)
8. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after treatment
9. Patients have given written informed consent
10. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 2
11. Patients with contraindications to receiving a MAC allo-SCT 2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment 3. Adults of reproductive potential not willing to use appropriate, effective, contraception during the specified period 4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator 5. Patients with active infection, HIV-positive or chronic active HBV or HCV 6. Patients with a prior malignancy, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ. Cancer treated with curative intent 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.

Eligibility Criteria for Randomisation 3 Inclusion Criteria for Randomisation 3

1. Patients aged between 55 years or older with a morphological documented diagnosis of AML or MDS who are deemed fit for a RIC allo-SCT with one of the following disease characteristics

AML o Patients in 1st complete remission (CR1) defined as < 5% blasts

• Patients in 2nd complete remission (CR2) defined as < 5% blasts
• Secondary AML (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or 2 defined as < 5% blasts
• Must have received at least two courses of prior intensive chemotherapy prior to transplant unless there are exceptional circumstances MDS
  • Patients with advanced or high risk MDS (with an IPSS-R of 3.5 (intermediate 3.5 or higher) who have < 10% blasts at the time of randomisation following intensive chemotherapy (including R1 randomisation) or hypomethylating agents if necessary 2. Patients with an identified HLA identical sibling or suitable matched unrelated donor (suitable match defined as no greater than a single allele mismatch at HLA-A, -B, -C or DR1) 3. Patients with an ECOG performance status of 0, 1 or 2 4. Patients considered suitable/fit to undergo a RIC allo-SCT as clinically judged by the Local Investigator including:
    1. Adequate hepatic and renal function as determined by full blood count and biochemistry assessment
    2. Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures)
    3. Performance of cardiac or pulmonary function tests (where there is a previous history of cardiac or pulmonary impairment
    4. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after treatment
    5. Patients have given written informed consent
    6. Patients willing and able to comply with scheduled study visits and laboratory tests Exclusion Criteria for Randomisation 3
    7. Patients with contraindications to receiving a RIC allo-SCT 2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment 3. Adults of reproductive potential not willing to use appropriate, effective, contraception during the specified period 4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator 5. Patients with active infection, HIV-positive or chronic active HBV or HCV 6. Patients with a prior malignancies, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ. Cancer treated with curative intent 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.