Treosulfan Passes Test for AML Conditioning

As a conditioning regimen before allogeneic hemopoietic stem cell transplantation (HSCT), treosulfan plus fludarabine was noninferior to a standard reduced-intensity regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients who are older or have comorbidities.

A randomized, international phase III trial met its primary endpoint, showing that patients treated with treosulfan plus fludarabine had a noninferior 2-year event-free survival (EFS) compared with patients treated with reduced-intensity busulfan plus fludarabine (HR 0.65, 95% CI 0.47-0.90, P<0.0001), Dietrich Wilhelm Beelen, MD, of the University of Duisburg-Essen in Germany, and colleagues reported in Lancet Haematology.

Although the 2-year EFS was considerably higher with the treosulfan-based treatment (64.0% vs 50.4%), the regimen was not shown to be statistically superior to the busulfan-based regimen.

Patients who received treosulfan also had improved 2-year overall survival (87.5% vs 69.0%; P=0.0082) and lower rates of transplantation-related mortality (12.1% vs 28.2%; P=0.020) and non-relapse mortality (11.4% vs 22.6%; P=0.053) compared with patients who received the busulfan. The 2-year relapse rates were similar between treatment groups (24.6% vs 23.3%; P=0.50).

“This regimen has the potential to become a standard preparative regimen before allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome at increased mortality risk for myeloablative conditioning,” the authors asserted.

In a corresponding editorial, Avichai Shimoni, MD, of Chaim Sheba Medical Center in Israel, echoed a similar view, writing that “for patients older than 65 years or frail patients with comorbidities, the new 10 g/m² treosulfan regimen might become the new standard, provided the trial is powered to show a difference in outcome in this more selected patient population.”

Currently, treosulfan is not approved in the U.S. for any disease indication, making the implications of the study unclear for U.S. oncologists. In Europe, treosulfan has been approved for certain cancer types for several years (under the trade name Trecondi) and most recently received approval from the European Medicines Agency for use in combination with fludarabine as a conditioning regimen before allogeneic HSCT.

Asked for his perspective, James Rossetti, DO, of UPMC Hillman Cancer Center/MDS Center of Excellence in Pittsburgh, told MedPage Today that “while treosulfan is not currently FDA-approved in the United States, the improved outcomes demonstrated by this study further highlight the need to continually update standard transplant practices in effort to increase eligibility while improving upon transplant and non-transplant related morbidity and mortality.”

He noted that the regimen used by the comparator arm is a “well-established” standard reduced-intensity form of conditioning.

“These data should encourage transplant teams around the globe to reassess both internal data and their current reduced-intensity preparative regimens for similar patients,” Rossetti said. “Such reassessment may result in changing standard practices and/or the implementation of additional clinical trials.”

In the current study, all patients included in the planned interim analysis described were enrolled after the trial protocol was revised in 2013 to lower the dose of treosulfan from 14 g/m² to 10 g/m² due to concerns about prolonged neutropenia leading to excess infections.

A total of 476 patients with AML or MDS were enrolled in the revised trial protocol from 31 transplantation centers in Europe and randomly assigned conditioning treatment with treosulfan plus fludarabine or reduced-intensity busulfan plus fludarabine.

Randomization was stratified by donor type (matched-related vs matched-unrelated donor), transplantation center, and disease risk group. Patients were eligible for the trial if they were 50 years of age or older and/or had a HSCT-specific comorbidity index above 2, making them at a heightened risk of mortality from standard myeloablative conditioning.

Overall, the toxicity appeared similar between both treatment groups. Incidence of grade 1 or 2 adverse events was similar between the treosulfan group and busulfan group (40% vs 41%), as was the frequency of grade 3 (44% vs 48%) and grade 4 events (6% vs 5%). The frequency of serious adverse events (8% vs 7%) and drug-related serious adverse events (3% vs 3%) was also similar between the treosulfan and busulfan groups, respectively. No patients in either treatment group needed to stop treatment due to toxicity or have the dose reduced.

For patients who received treosulfan-based conditioning, 52 patients (24%) died, of which 26 (12%) deaths were due to relapse, 23 (10%) due to causes related to transplantation, and 2 (1%) due to other causes. For patients who received busulfan-based conditioning, 82 (34%) died, of which 36 (15%) deaths were due to relapse, 45 (19%) were due to causes related to transplantation, and 1 (<1%) was due to a secondary malignancy.