Standard vs. Reduced-Intensity Conditioning in Patients With Acute Myeloid Leukemia in First Remission

• Disease-free and Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Proportion of patients alive without relapse
• Grade 3-4 extramedullary toxicity [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
  Percentage of patients with grade II-IV acute GvHD

• Disease-free and Overall survival
• Grade II-IV acute Graft-versus-Host disease
• Grade 3-4 extramedullary toxicity

The primary goal of the study is to show that the treatment-related mortality of allogeneic hematopoietic stem cell transplantation an be significantly reduced by using a combination of 8 Gy total-body-irradiation and fludarabine in comparison to the conventional combination of 12 Gy TBI and 120 mg/kg Cyclophosphamide.

Transplant-related deaths because of extramedullary toxicity and graft-versus host disease remain the major causes for treatment-failure in patients with AMl receiving allogeneic hematopoietic stem cell transplantation.

In phase II study, M . Stelljes and coworkers could show, that a reduced dose of total-body- irradiation and fludarabine can be safely used in patients with AML at various disease stages. The best results could be achieved in patients who had been in complete remission by the time of inclusion.

Therefore this prospective trial was initiated to compare the new conditioning regimen with the standard regimen of 12 Gy TBI/Cyclophosphamide 120 mg/kg in patients ith AML in first remission.

After having achieved complete remission, and giving informed consent, patients are stratified according to marrow cytogenetics, age and type of induction therapy and subsequently randomized to receive on of the mentioned conditioning therapies.

The primary end-point will be non-relapse mortality. The hypothesis would be, that the one-year mortality can be reduced from 25 to 15%. Given a power of 0.8 and a first-error of 5%, 252 patients will have to be randomized.

Secondary endpoints include:

3 year overall-and disease-free survival Rate of grade II-IV acute GvHD Rate of grade 3-4 extramedullary toxicity

• 12 Gy/Cyclophosphamide
  Standard intensity conditioning
  Intervention: Other: Conditioning therapy
• Experimental: 8 Gy /Fludarabine
  Reduced-intensity conditioning
  Intervention: Other: Conditioning therapy

• Stelljes M, Bornhauser M, Kroger M, Beyer J, Sauerland MC, Heinecke A, Berning B, Scheffold C, Silling G, Buchner T, Neubauer A, Fauser AA, Ehninger G, Berdel WE, Kienast J. Conditioning with 8 Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005 Jul 14; [Epub ahead of print]
• Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. doi: 10.1016/S1470-2045(12)70349-2. Epub 2012 Sep 7.

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia in first remission
• Standard-or high-risk marrow cytogenetics
• HLA-matched related or unrelated donor available (in case of high-risk disease)
• Age 18 to 60
• Informed consent
• Consent of donor to donate peripheral blood stem cells
• sufficient liver function (elevation of transferases < 2.5 x upper limit)

Exclusion Criteria:

• AML with t(5;17)
• AML with t((8;21)
• clinically relevant heart failure (NYHA II-IV)
• Renal failure (creatinine > 200 µg/ml)
• Liver function failure (bilirubin > 3 mg/dl)
• Concomitant Neurological or psychiatric disease
• Contraindications to receive prescribed study medication
• HIV infection
• Pregnancy