An Intergroup Randomised Trial of Standard Intensity Versus Reduced Intensity TBI-Based Conditioning In Patients with Acute Myeloid Leukemia in First Complete Remission

Abstract 157

Allogeneic hematopoietic cell transplantation (HCT) remains the treatment approach with the lowest risk of relapse in patients with intermediate or high-risk acute myeloid leukemia (AML). The lower incidence of relapse achieved with allogeneic HCT is sometimes offset by the higher rate of transplant-related deaths mainly occurring during the first 12–24 months after the procedure. With the advent of reduced-intensity conditioning regimens, older and less fit patients have become eligible for allogeneic HCT. But still, there is some debate as to the optimum level of conditioning intensity in order to reduce non-relapse mortality without jeopardizing overall cytoreductive efficacy. Stimulated by the promising results of a phase II trial exploring the efficacy and toxicity of a regimen combining Fludarabine 30 mg/m² for four days combined with 800 cGy fractionated total-body irradiation (TBI), we designed this study to compare the mentioned regimen with standard-intensity conditioning.

Adult patients with AML in first complete remission (CR1) with standard or high-risk cytogenetics were randomly assigned with a ratio 1:1 to standard intensity conditioning (6 × 200 cGy TBI (1200cGy) over 3 days and Cyclophosphamide 60 mg/kg per day over 2 days (Arm A)) or TBI 4 × 200 cGy (800 cGy) combined with Fludarabine 30 mg/m² daily over 4 days (Arm B). Antithymocyte globuline was infused at a cumulative dose of 60 mg/kg (3 × 20 mg/kg from day -3 to -1) in recipients of grafts from unrelated donors (UD). Pharmacologic prophylaxis of graft-versus-host disease (GvHD) was performed with CsA starting day -1 and Mtx on days 1, 3, 6 and 11. The primary endpoint was transplant-related mortality (TRM) within the first 12 months after transplantation Secondary end-points included overall as well as disease-free survival and acute and chronic GvHD.

Between November 2004 and December 2009, 198 patients were registered in the trial. Three patients had to be excluded for the violation of inclusion criteria. The intent-to-treat (ITT) population, thus, consisted of 195 subjects (96 Arm A, 99 Arm B). Eleven patients did not receive the study treatment. Therefore, the per protocol analyses involved 184 patients (90 Arm A, 94 Arm B). Median age was 45 years (range 18–60). 46% were female. Intermediate risk and high risk karyotypes were present in 62% and 38% of the patients, respectively. 60% of the patients received grafts from matched sibling donors. Grafts from UD with at least 9 out of 10 HLA alleles (HLA-A, B, C, DRB1, DQB1) were infused in 40%. The majority of patients (89%) received G-CSF mobilised peripheral blood stem cells. Donor type, cytogenetic risk, type of induction regimen and age (18–40 vs. > 40) had been strata for randomisation and were therefore well balanced between both groups. Most patients had received double induction therapy using 3+7 combinations of anthracyclines and cytarabine.

The evaluation of the primary endpoint in the per protocol population showed a lower incidence of TRM after 12 months in Arm B (8%, 95% Confidence interval (CI) 3–14% versus 17%, CI 9–24% in Arm A, p=0.048; ITT p=0.06). The difference in TRM at 12 months was even more pronounced in the subgroup of patients > 40 years (5% Arm B versus 20% Arm A, p=0.01). With a median follow-up of 27 (range 4–81) months for patients alive, the probability of overall survival three years after randomisation was 62 % in the reduced-intensity Arm B versus 59% in Arm A (p=0.28). Probabilities of disease-free survival were 60% and 56% for Arm B and Arm A (p=0.44), respectively. The cumulative incidence of grade II-IV acute GvHD until day 100 was 16% in Arm B versus 23% in Arm A (p=0.15). Cumulative incidences of relapse three years after transplantation were not different between both treatment arms albeit a different kinetic of relapse could be documented.

This trial shows for the first time in a prospectively randomized design in patients with AML in CR1 that reduced-intensity conditioning can result in significantly lower early TRM without increasing relapse risk. Fludarabine combined with 800cGy fractionated TBI can be regarded as a valid alternative to standard intensity conditioning even in younger patients with AML transplanted in first remission.