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Clinical Phase III Trial to Compare Treosulfan-based Conditioning Therapy With Busulfan-based Reduced-intensity Conditioning (RIC) Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients With AML or MDS Considered Ineligible to Standard Conditioning Regimens

Phase 3
18 Years
70 Years
Open (Enrolling)
Acute Myeloid Leukemia, Myelodysplastic Syndrome

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Trial Information

Clinical Phase III Trial to Compare Treosulfan-based Conditioning Therapy With Busulfan-based Reduced-intensity Conditioning (RIC) Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients With AML or MDS Considered Ineligible to Standard Conditioning Regimens

To compare efficacy and safety of Treosulfan-based conditioning (test) with i.v.
Busulfan-based reduced intensity conditioning (reference).

The statistical aim of the study is to show non-inferiority with respect to:

Event-free survival (EFS) within 1 year after transplantation. Events are defined as relapse
of disease, graft failure or death (whatever occurs first).

1. Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between
day -6 and day +28

2. Comparative evaluation of overall survival (OS) and cumulative incidence of relapse
(RI) as well as non-relapse mortality (NRM) and transplantation-related mortality (TRM)

3. Comparative evaluation of day +28 conditional cumulative incidence of engraftment

4. Comparative evaluation of day +28 and day +100 incidence of complete donor-type

5. Comparative evaluation of cumulative incidence of acute and chronic GvHD

6. Comparative evaluation of incidence of other CTC grade III/IV adverse events between
day -6 and day +28

Individual patients will be followed-up for at most 1 year after transplantation. Three
confirmatory interim evaluations and one final analysis are planned, which allow to stop the
trial as soon as the question of non-inferiority is answered (as outlined below). In
addition, post-surveillance with respect to OS and EFS will be conducted one year after
inclusion of the last study patient.

Inclusion Criteria:

1. Patients with acute myeloid leukaemia acc. to WHO, 2001 (AML in complete remission at
transplant, i.e. blast counts < 5 % in bone marrow) or myelodysplastic syndrome acc.
to WHO, 2001 (MDS with blast counts < 20 % in bone marrow during disease history)
indicated for allogeneic haematopoietic progenitor cell transplantation but
considered to be at increased risk for standard conditioning therapies according to
the following criteria:

- patients aged ≥ 50 years at transplant and / or

- patients with a HCT-CI score > 2 [acc. to Sorror et al., 2005]

2. Availability of an HLA-identical sibling donor (MRD) or HLA-identical unrelated donor
(MUD). Donor selection is based on molecular high resolution typing (4 digits) of
class II alleles of the DRB1 and DQB1 gene loci and molecular (at least) low
resolution typing (2 digits) of class I alleles (i.e., antigens) of the HLA- A, B,
and C gene loci. In case, no class I and class II completely identical donor (10 out
of 10 gene loci) can be identified, one antigen disparity (class I) and/or one allele
disparity (class II) between patient and donor are acceptable. Conversely, disparity
of two antigens (irrespective of the involved gene loci) cannot be accepted. These
definitions for the required degree of histocompatibility apply to the selection of
related as well as of unrelated donors.

3. Adult patients of both gender, age 18 - 70 years

4. Karnofsky Index ≥ 60 %

5. Written informed consent

6. Men capable of reproduction and women of childbearing potential must be willing to
consent to using a highly effective method of birth control such as condoms,
implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or
vasectomised partner while on treatment and for at least 6 months thereafter

Exclusion Criteria:

1. Patients with acute promyelocytic leukaemia with t(15;17)(q22;q12) and in CR1

2. Patients considered contra-indicated for allogeneic HSCT due to severe concomitant
illness (within three weeks prior to scheduled day -6):

- patients with severe renal impairment like patients on dialysis or prior
renal transplantation or S-creatinine > 3.0 x ULN or calculated
creatinine-clearance < 60 ml/min

- patients with severe pulmonary impairment, DLCO/or FEV1 < 50 % or severe
dyspnoea at rest or requiring oxygen supply

- patients with severe cardiac impairment diagnosed by echocardiography and
LVEF < 40 %

- patients with severe hepatic impairment indicated by hyperbilirubinaemia > 3
x ULN or ALT / AST > 5 x ULN

3. Active malignant involvement of the CNS

4. HIV-positivity, active non-controlled infectious disease under treatment (no decrease
of CRP or PCT) including active viral liver infection

5. Previous allogeneic HSCT

6. Pleural effusion or ascites > 1.0 L

7. Pregnancy or lactation

8. Known hypersensitivity to treosulfan, busulfan and/or related ingredients

9. Participation in another experimental drug trial within 4 weeks prior to day -6 of
the protocol

10. Non-cooperative behaviour or non-compliance

11. Psychiatric diseases or conditions that might compromise the ability to give informed

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival (EFS)

Outcome Time Frame:

within 1 year after transplantation

Safety Issue:


Principal Investigator

Dietrich W. Beelen, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Hospital, Essen


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

November 2008

Completion Date:

March 2019

Related Keywords:

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Treosulfan
  • Busulfan
  • Conditioning
  • Allogeneic
  • Transplantation
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia