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HOUSTON — Using a treosulfan-based myeloablative regimen in place of one based on busulfan may improve survival in vulnerable patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) about to undergo allogeneic hematopoietic cell transplantation (HSCT), say German researchers reporting results from a phase 3 study.

The researchers compared the effect of treosulfan/fludarabine regimens with those containing busulfan/fludarabine prior to HSCT in more 550 patients with AML or MDS who were either aged 50 to 70 years or who had comorbidities.

The results showed that not only was a treosulfan-based regimen noninferior to one containing busulfan in terms of event-free survival, but that it was associated with significantly improved overall survival and complete donor-type chimerism.

The study was presented here at the Transplantation & Cellular Therapy (TCT) 2019 meetings by Dietrich Beelen, MD, PhD, from the West German Cancer Center at the University Hospital of Essen in Germany.

He said that the trial “establishes the new treosulfan/fludarabine regimen as a relatively well tolerable and effective regimen prior to allogeneic hematopoietic stem cell transplantation in elderly and comorbid ALL and MDS patients”.

“This new regimen thereby has the potential to become the standard regimen prior to allogeneic hematopoietic stem cell transplantation in this target population,” he added.

Elderly and Vulnerable Patients

Beelen began his presentation by noting that HSCT is a particular challenge in elderly and comorbid patients owing to an increased nonrelapse mortality risk with standard myeloablative regimens.

However, he pointed to a dose-range finding study and two phase 2 trials published since 2010 showing that treosulfan in combination with fludarabine is well tolerated in AML and MDS patients.

Indeed, as far back as 2004, Casper et al showed in a study of 30 HSCT patients that the combination could represent a “safe and efficient” conditioning regimen.

Beelen and colleagues therefore conducted a prospective, randomized phase 3 trial in AML or MDS patients ages 50 to 70 years or patients age 18 years and older but with a Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) >2.

All patients were required to have a Karnofsky Performance Scale Index score of at least 60%.

The patients were randomly assigned in a 1:1 fashion to a treosulfan- or busulfan-based reduced intensity conditioning regimen, with the primary objective being to show at least the noninferiority of the treosulfan-based regimen in terms of event-free survival.

The final analysis set consisted of 283 patients who received the busulfan-based regimen and 268 who were treated with treosulfan prior to HSCT.

The median age of the final patient cohort was 60 years, with approximately 95% aged at least 50 years, and approximately 39% of patients female.

The median HCT-CI score was 3, with approximately 58% having a score of at least 3.

Patients given treosulfan were more likely to have AML (70.5%) than MDS (29.5%), but the spread was more even in the busulfan group, at 57.5% with AML and 42.5% with MDS.

Beelen reported that the rates of early adverse events were comparable between the treosulfan and busulfan groups, whether looking at all grades, grades III–IV, or regimen-related grade III–IV events.

A similar pattern was seen for serious adverse events, although treosulfan patients had more life-threatening serious adverse events than those given busulfan, at 4.8% and 2.8%, respectively, and had more fatal events, at 3% vs 2.1%, respectively.

Neutrophil recovery post-transplant was almost identical between the two treatment groups.

Patients given a treosulfan-based regimen prior to HSCT were significantly more likely to achieve complete hematopoietic chimerism after transplantation than those treated with a busulfan-based regimen, at 93.2% vs 83% (adjusted P = .0159).

Rates of primary and secondary graft failure were lower with treosulfan-based treatment than busulfan-based regimens (3% vs 0.4%), which was driven by no secondary graft failures with treosulfan.

Treosulfan-based treatment was also associated with a nonsignificant lower rate of extensive chronic graft versus host disease (GVHD) than busulfan-based regimens (19.8% vs 28.6%).

Event-free survival was significantly higher with treosulfan vs busulfan, at 65.7% vs 51.2% at 24 months (adjusted hazard ratio [HR] for mortality, 0.64; P = .0012).

Overall survival was also significantly better, with 2-year survival rates of 72% with treosulfan vs 60.2% for busulfan (adjusted HR, 0.64, P = .0037).

The results also showed that treosulfan was associated with a significantly lower rate of nonrelapse mortality than busulfan at 24 months, at 12% vs 20.4% (adjusted HR, 0.63; P = .0343).

There was, however, no significant difference in relapse/progression between the two regimens at 24 months 22% for treosulfan and 25.2% for busulfan. During the postpresentation discussion, Beelen said that his team had wondered why there was no difference in the relapse rate, when there was a clear survival benefit.

He said that the answer may lie in the lack of difference in rates of acute deaths between the two treatment groups, with the survival benefit only emerging later on, after about 6 months.

“The reason for that is unclear, for [the] time being, but that’s really a big difference [in survival] between the two groups,” he commented.

Beelen noted that there was a difference in relapse-free survival rates at 24 months between the two regimens when they looked at only those patients with chronic GVHD, at 51.4% for treosulfan vs 37.2% with busulfan (HR 0.73, P = .0030).

Beelen concluded that the trial demonstrated that the combination of treosulfan and fludarabine was significantly noninferior to the busulfan/ fludarabine combination with regard to event-free survival.

“In terms of the secondary endpoints of overall survival, nonrelapse mortality, and complete donor chimerism, the study points to a potential benefit of the treosulfan/fludarabine regimen” he said.

Beelen declared honoraria for consultancy, travel support, and trial documentation support from medac GmbH.

Transplantation and Cellular Therapy (TCT) 2019: Abstract 4. Presented February 22, 2019.

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