The primary aim of this innovative immunotherapeutic study is to determine whether the antileukemic effects seen in our previous phase I/II study can be confirmed in a large cohort of patients and whether dendritic cell vaccination can significantly prevent relapse and increase survival of acute myeloid leukemia (AML) patients by eradicating minimal residual disease.

Together with the Transplant Committee of the Belgian Hematological Society (BHS), we will perform a multicenter randomized open-label phase II clinical study in 130 patients with acute myeloid leukemia (AML). Adult patients (> 18 years) with AML who have entered morphological CR or CRi after (1) intensive chemotherapy (i.e (i) at least one cycle of induction and one cycle of consolidation chemotherapy or (ii) one to two cycles of CPX-351 induction treatment and up to two cycles of CPX-351 consolidation treatment) or (2) low-intensity chemotherapy (i.e (iii) at least two cycles to maximum six cycles of hypomethylating agents whether or not combined with venetoclax or (iv) at least two cycles to maximum six cycles of low-dose cytarabine combined with venetoclax); and fulfilling all other eligibility criteria will be randomized to be vaccinated with dendritic cells or to receive regular follow-up care. After randomization, patients receiving low-intensity chemotherapy are allowed to continue this treatment in combination with DC vaccination or the follow-up care. The primary aim of this innovative immunotherapeutic study is to determine whether the antileukemic effects seen in our previous phase I/II study can be confirmed in a large cohort of patients and whether dendritic cell vaccination can significantly prevent relapse and increase survival of AML patients by eradicating minimal residual disease. Patients will be recruited at 8 different centers in Belgium. Recruitment will start in the second half of 2013 and will last for 10 years or until 130 efficacy-evaluable AML patients are included. In the interventional group, 65 patients will be treated during two years with autologous dendritic cells loaded by messenger RNA electroporation with the Wilms' tumor antigen (WT1). The dendritic cell therapy product will be generated and generally administered in the coordinating center, which is the Antwerp University Hospital, more specifically the Center for Cell Therapy and Regenerative Medicine (CCRG) and the Division of Hematology, both headed by Prof. Zwi Berneman. After inclusion of 130 efficacy-evaluable patients, relapse rate, relapse-free survival and overall survival analysis will be performed. Tumor marker levels and immune activation will also be monitored to compare the 2 groups at a molecular and immunological level. General and disease-specific quality of life will be evaluated using quality of life questionnaires at regular time points.

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia (AML) according to the 2008 criteria of the World Health Organization (WHO).

  • all French-American-British (FAB) subtypes, except:

    - M3 (acute promyelocytic leukemia)

  • all cases of de novo AML or secondary AML with ≥ 20 % blasts in peripheral blood and/or bone marrow, except:

    • AML secondary to myeloproliferative neoplasms (MPN)
    • AML secondary to exposure of leukemogenic agents (t-AML) unless treated with CPX-351 chemotherapy or hypomethylating agents combined with venetoclax.

• Completion of one of the following treatment options:

  • I) Intensive chemotherapy:

    • (1) at least one cycle of induction chemotherapy and one cycle of consolidation chemotherapy (low-dose cytarabine as consolidation therapy is allowed) OR
    • (2) one to two cycles of CPX-351 induction treatment and up to two cycles of CPX-351 consolidation treatment OR

  • II) Low-intensity chemotherapy:

    • (3) at least two cycles to maximum six cycles of hypomethylating agents whether or not combined with venetoclax OR
    • (4) at least two cycles to maximum six cycles of low-dose cytarabine combined with venetoclax;

  • resulting in:

    • morphological complete remission (CR), i.e. bone marrow blast count <5% with neutrophil count >1000 cells/µL and platelet count >100,000 cells/µL OR
    • morphological complete remission with incomplete blood recovery (CRi), i.e. bone marrow blast count <5% with neutrophil count <1000 cells/µL or platelet count <100,000 cells/µL.

For the purpose of this study protocol, platelet count must be >50,000 cells/µL.

• Adult (≥ 18 years) at very high risk of relapse according to:

  • Age ≥ 60 years, and/or
  • Adverse biological features (e.g. adverse cytogenetics, adverse morphological features, adverse molecular features, hyperleukocytosis (> 100000 cells/µL)), and
  • Ineligible for or unwilling to receive hematopoietic stem cell transplantation.

• WHO performance status: grade 0, 1 or 2 at the time of enrollment. For definition of performance status, see: http://www.ecog.org/general/perf\_stat.html

• Absence of any psychological, familial, sociological, geographical or physical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before study entry.

Exclusion Criteria:

• Participation in any other interventional clinical trial during the study period.

• History or concomitant presence of any other malignancy, except for:

  • non-melanoma skin cancer
  • carcinoma in situ of the cervix
  • any other effectively treated malignancy that has been in remission for >5 years or that is highly likely to be cured at the time of enrollment.

• Concomitant presence of any immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo.

• Concomitant use of systemic corticosteroids in immunosuppressive doses (>1 mg/kg/day of prednisone, or equivalent dose for other corticosteroid preparations) or any other immunosuppressive agent. A minimum of 4 weeks must have elapsed between the last dose of immunosuppressive therapy and the first vaccination. Topical corticosteroids are permitted, except if applied at the sites of DC injection.

• Pregnant or breast-feeding