Nearly 10 years after allogeneic hematopoietic cell transplantation (HCT), patients with acute myeloid leukemia (AML) who received either reduced-intensity conditioning or myeloablative conditioning had comparable rates of efficacy and late complications, though younger patients may derive benefit from reduced-intensity conditioning, according to results published in The Lancet Haematology.1
The findings, reported by Frederick Fasslrinner, MD, of the University Hospital Marburg in Germany, and co-authors, build on earlier results from the trial published in 2012, which suggested that both regimens had similar relapse rates, but that reduced-intensity conditioning was superior to myeloablative conditioning with respect to early toxicity and morbidity at three years post-HCT.2
The multicenter, prospective, open-label, randomized, phase III study enrolled 195 adult patients from 13 centers in Germany between November 15, 2004, and December 31, 2009. Eligible patients had adequate renal, cardiac, pulmonary, and neurologic function; intermediate- or high-risk AML in first complete remission; and a human leukocyte antigen-matched sibling donor or unrelated donor.
The investigators collected data from medical reports and interviews with treating physicians, using a modified Minimum Essential Data-A form developed by the European Society for Blood and Marrow Transplantation. When possible, the researchers also conducted patient interviews.
Patients were randomized 1:1 (based on age, cytogenetic risk, induction therapy, and donor type) to receive:
- reduced-intensity conditioning: fludarabine 30 mg/m2 4-6 days before HCT plus four 2 Gy doses of total-body irradiation (TBI; 8 Gy) with lung shielding 2-3 days before HCT (n=99)
- myeloablative conditioning: six 2 Gy doses of TBI (12 Gy) with lung shielding 4-6 days before HCT (2 doses/day) and cyclophosphamide 60 mg/kg per 2-3 days before HCT (n=96)
Five patients in the reduced-intensity group and six in the myeloablative cohort were not included in the per-protocol analysis.
The primary endpoint of the study was incidence of non-relapse mortality (NRM), and all analyses in this long-term follow-up were considered exploratory because they were not specified prospectively in the original protocol, the authors noted.
After a median follow-up of 9.9 years (range = 8.5-11.4 years), the 10-year cumulative incidence of relapse among the surviving patients was 30 percent in both the reduced-intensity and myeloablative cohorts (p=0.99). The median time to response was nearly doubled in the myeloablative group: 9.5 months (range = 4.5-20.5 months) versus 5.0 months (range = 3.0-8.8 months; p=0.12).
Myeloablative conditioning was also associated with a trend toward a lower risk of 10-year NRM than reduced-intensity conditioning: 26 percent versus 16 percent, for a sub-distribution hazard ratio (SHR) of 0.60 (95% CI 0.32-1.11; p=0.10). However, incidence of NRM was significantly lower with reduced-intensity conditioning in the subgroup of 125 participants aged 41 to 60 years (13% vs. 32%; SHR=0.44; 95% CI 0.20-0.95; p=0.034).
These findings appear to confirm the conclusion drawn in the 2012 report, in which the authors recommended reduced-intensity conditioning for patients younger than 60 years.
Rates of 10-year event-free survival were 55 percent in the reduced-intensity cohort and 43 percent in the myeloablative cohort (HR=0.76; 95% CI 0.51-1.14; p=0.19), while rates of 10-year overall survival were 60 percent and 47 percent, respectively (HR=0.71; 95% CI 0.47-1.07; p=0.10).
conditioning is not
associated with an
increased risk of late
—Frederick Fasslrinner, MD
The incidence of transplant-related mortality was similar in both cohorts: 14 patients in the reduced-intensity group (15%) and 21 patients in the myeloablative group (23%; p=0.67). An increased number of early in-hospital fatalities were reported in the myeloablative group (7 vs. 0 deaths), but no other differences in HCT-related deaths were observed.
The incidence of chronic graft-versus-host disease five years after HCT was also similar between the groups: 42 percent in the reduced-intensity cohort and 48 percent in the myeloablative cohort (odds ratio [OR] = 0.80; 95% CI 0.37-1.72; p=0.64).
More patients in the myeloablative group appeared to be on immunosuppressive therapy five years after HCT, compared with reduced-intensity conditioning, though this finding was not statistically significant (29% vs. 19%; OR=0.56; 95% CI 0.22-1.37; p=0.29).
“The incidence of late toxicities was relatively low and similar between the two groups, except for the higher incidence of cataracts in the myeloablative conditioning group,” the authors wrote, reporting that five patients (5%) in the reduced-intensity cohort and 11 (12%) in the myeloablative group developed cataracts (p=0.16). Six patients (6%) in the reduced-intensity cohort and five (6%) in the myeloablative group reported secondary malignancies (p=1.00).
“This long-term follow-up suggests that 8 Gy of TBI combined with fludarabine was not associated with an increased late relapse incidence when compared with 12 Gy of TBI and cyclophosphamide,” the authors concluded. “Taken together [with results from the 2012 report], these observations indicate that reduced-intensity conditioning is not associated with an increased risk of late relapse when compared with myeloablative conditioning.”
The study is limited by its retrospective design and reliance on data from medical records and patient feedback, which could have introduced bias or inaccurate information. In addition, the landmark cohort was small and not randomized.
The corresponding authors report no financial conflicts.
- Fasslrinner F, Schetelig J, Burchert A, et al. Long-term efficacy of reduced-intensity versus myeloablative conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: retrospective follow-up of an open-label, randomised phase 3 trial. Lancet Haematol. 2018 March 14. [Epub ahead of print]
- Bornhäuser M, Kienast J, Trenschel R, et al. 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;13:1035-44.