Reduced Intensity Conditioning Transplantation Versus Standard of Care in Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional

Summary: 
      This study compares overall survival between patients with acute myeloid leukemia, who are in
      complete remission following initial treatment with chemotherapy and whose remission is
      maintained either with a transplantation of stem cells obtained from a sibling or unrelated
      donor or with standard treatment, which is additional chemotherapy.

      The study hypothesis is that the group transplanted with stem cells from a donor will have a
      superior survival compared with patients treated with standard of care.
    

Detailed description: 
      Objectives:

      The primary objective of this study is to determine whether RICT leads to an improved overall
      survival compared to conventional treatment for AML.

      The secondary objectives of this study are to determine if:

        -  RICT leads to a superior long-term overall survival compared to conventional therapy.

        -  RICT leads to a superior disease-free survival compared to conventional therapy.

        -  Time to relapse is different between RICT and control groups.

        -  Quality of life is different between the two treatment groups.

        -  in RICT patients only:

             -  Safety and feasibility of the procedure

             -  Incidence and severity of acute and chronic Graft versus Host Disease (GvHD)

             -  Rate of complete and partial chimerism

      Study Population:

        -  Newly diagnosed patients with de novo or secondary AML, intermediate or poor risk, in
           first complete remission aged 51-70 years.

        -  Not planned for a full-dose allogeneic transplant.

        -  According to the investigator, fit for a RICT if a suitable donor (sibling or unrelated)
           is found, and also fit for further consolidation chemotherapy in case no suitable donor
           is found.

      Procedures:

      Patients will receive induction therapy according to institutional practice and can be
      included after achieving complete remission. Patients for whom a full-dose conditioned
      allogeneic transplantation is planned will not be approached, neither will patients who are
      for other reasons judged to be ineligible for a RICT. Eligible patients will be informed
      about the study. After the patient's consent has been obtained, potential sibling donor(s)
      will be briefly informed about the study and asked if they are willing to undergo HLA-typing.
      Siblings with evident contraindications to granulocyte colony stimulating factor (G-CSF) or
      collection of peripheral blood stem cells should not proceed to HLA-typing. A search for an
      unrelated matched donor (MUD) will be initiated if there is no potential sibling donor, or if
      sibs are not HLA-identical or otherwise not fit for the donation procedure. A patient's
      inclusion in the study is when blood sampling for tissue typing (HLA-typing) of the first
      potential sibling donor is made, or when a search warrant for a MUD is dispatched.

        -  Note: To enable an early donor search, patients may be registered, but not included, for
           the study prior to CR. These patients will be included at date of achieved CR.
           Registered patients not achieving CR will not be included.

      Included patients with a HLA-identical sibling or with an identified MUD will be assigned to
      the RICT group, and included patients without such a donor will automatically be in the
      control group. This is a HLA-based assignment, and the final intent-to-treat analysis will be
      based on the treatment assignment.

      After treatment assignment, patients on the control arm should receive consolidation therapy
      as per institutional practice, whereas patients on the RICT arm may proceed directly to RICT
      or receive one or maximum two consolidation courses. Patients should be in complete remission
      at the time of transplant. All patients will be followed for relapse and survival for a
      period of at least three years.

      The inclusion of 352 patients in complete remission provides a statistical power of 90 % to
      detect a difference in overall survival at three years of 20 percentage points, ie from 30 %
      of control patients to 50 % in RICT patients.

      Inclusion was terminated 2016-07-19 after 360 registered patients. However, some pts were
      excluded due to grave protocol deviations or withdrawn consent. The data base was locked in
      June 2018 for analysis with 309 pts (after exclusions). Follow-up was >2 yrs fo all pts.
    

Intervention name(s): Reduced Intensity Conditioning Stem Cell Transplantation
Intervention type(s): Procedure
Intervention description(s): One of the following conditioning regimens:
Busulphan (orally or IV), fludarabine
Fludarabine, carmustine, melfalan
Cyclophosphamide, fludarabine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Formally, this is not Phase III study, since there are no new drugs or interventions. Rather - a prospective, controlled study where we include pts aimed for alloSCT before any donor search. Both groups of pts (with or without a matched donor) are followed ≥2yrs. The hypothesis is that pts with a donor do better than those without a donor (sib and/or unrelated).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myeloid Leukemia; Stem Cell Transplantation; Reduced Intensity Conditioning; Survival; Relapse