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Sibling transplantation with reduced-intensity conditioning fails to improve AML outcomes
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SAN DIEGO — Hematopoietic stem cell transplantation with a sibling donor after reduced-intensity busulfan/fludarabine-based regimen failed to improve outcomes compared with chemotherapy among patients with acute myeloid leukemia in first complete remission, according to results of an intention-to-treat analysis presented at ASH Annual Meeting and Exposition.
Prospective studies comparing reduced-intensity conditioning transplant with chemotherapy have been lacking for patients with AML aged older than 50 years, according to Mats Brune, MD, PhD, associate professor in the department of medicine at Sahlgrenska University Hospital in Gothenburg, Sweden, said during his presentation. “So, we set out do something about this,” he said.
The analysis included 145 patients (median age, 63 years; range 50-70) with high- (n = 48) or intermediate-risk (n = 97) disease who were deemed fit for reduced-intensity conditioning and who had at least one willing and healthy sibling.
After HLA matching, 77 patients with matched sibling donors underwent transplantation with reduced-intensity conditioning — which included 150 mg/m2 to 180 mg/m2 fludarabine and 8 mg/kg oral or 6.4 mg/kg IV busulfan — and 68 patients without a matched sibling underwent consolidation chemotherapy.
The immunosuppression regimen included cyclosporine with (53%) or without (9%) methotrexate, or mycophenolate mofetil (35%). Most transplantations (95%) involved peripheral blood stem cells.
Baseline data showed that the two groups were comparable in terms of gender, age, performance status and risk group.
Median duration from diagnosis to study inclusion was 64 days (range, 29-319) in the transplant arm and 65 days (range, 32-256) for controls. Times from first complete remission to inclusion also were comparable between the two arms, at 19 days (range, 0-131) days for transplant patients and 22 days (range, 0-218) days for controls.
“The most important is that inclusion started at the date of HLA typing of the sibling,” Brune said. “That’s when the clock starts.”
OS served as the primary endpoint. Secondary endpoints included RFS, nonrelapse mortality, and relapse incidence.
Median follow-up was 7.9 years (range, 0.24-14), which is “rather impressive,” Brune said.
Twenty patients in the transplantation group failed to reach transplant, according to Brune. Reasons included 12 relapses, three nonrelapse fatalities, comorbidities for four patients, and one for another reason.
Twenty-five percent of transplanted patients experienced grade 2 to grade 4 graft-versus-host disease, and 39% experienced chronic extensive GVHD.
There were 16 deaths in the control group.
Results showed no difference between the two groups in terms of 3-year OS (transplant, 45% vs. controls, 48%), which persisted through 10 years (27% vs. 25%).
AML was the primary cause of death for the transplant (73%) and control (88%) groups.
Brune added that 3-year RFS (40% vs. 35%), cumulative incidence of relapse (49% vs. 60%), and nonrelapse mortality (12% vs. 4.4%) also were similar between the two study arms.
“In this prospective multicenter study in patients aged 50 to 70 years with AML in first complete remission, we found no clinical benefit of sibling donor search and reduced-intensity allogeneic stem cell transplant compared with standard chemotherapy,” Brune said.
Possible alternative strategies include adapting conditioning to the clinical status and risk category, finding ways to enhance the graft-versus-leukemia effect without causing GVHD, and looking at unrelated young donors, according to Brune.
He expressed uncertainty about what these data mean.
“We’re not sure what’s going to happen,” he said. “Perhaps we should make transplants earlier.” – by Rob Volansky
Reference:
Brune M, et alet al. Abstract 205. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Brune reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Ran Reshef, MD
This is an important abstract from a multi-institutional study. Although AML is currently the leading indication for this type of transplant, we are currently missing a body of prospective, randomized data to support the use of allogeneic transplant in that disease. Also, elderly individuals have not historically been included in these studies because the practice of doing transplant in patients older than age 50 or 60 years has only evolved in the last 20 years with the introduction of reduced-intensity regimens that made these transplants feasible.
This trial was intended to ask that question of whether allogeneic transplant in that elderly age group is a) feasible and b) of benefit to these patients in terms of their OS. The bottom line of this paper is a bit disappointing because there was, in fact, no significant difference in mortality. The OS was fairly identical. The reasons for mortality were different in the two groups. Patients who underwent transplant had higher risk for nonrelapse mortality. The patients who did not have a transplant had a greater chance of dying from their underlying disease. Ultimately, OS was not significantly different.
However, we need to take this study in the context of additional studies in the field. We should also look carefully at the study design. We have seen from previous data comparing reduced-intensity transplant with full ablative transplant that there can be a tremendous survival benefit to ablative transplant. The main conclusion is if you have patient who is able to undergo a full ablative transplant, that should be the right choice.
Patients included in this study were forced to have a transplant that led to a lack of survival advantage. The other issue is that to keep a homogenous population, this trial used a single conditioning regimen. This regimen is known to be associated with a fairly high relapse risk in patients with AML. If we were to design this study today, we would have designed it allowing for different conditioning regimens. Also, we know that patients around age 50 years would get a full ablative transplant, because we know the outcomes are better. This study shows the feasibility of allogeneic transplant up to age 70 years with an acceptable risk.
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