Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic hemopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is most often used to treat acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).¹ However, AML and MDS are more prevalent in the elderly, who often cannot tolerate the myeloablative conditioning (MAC) needed prior allo-HSCT. An alternative option for this patient population is the use of a reduced intensity conditioning (RIC), which can increase the number of eligible patients in the 50–70 age range with or without comorbidities, due to a more acceptable toxicity profile. Busulfan plus fludarabine is a well-established RIC regimen for patients who are not able to undergo MAC, but may be associated with an increase in relapse incidence². Treosulfan plus fludarabine is referred to as a reduced-toxicity MAC regimen, which, with its lower toxicity, may be better tolerated by older or comorbid patients than traditional MAC, and may be comparable or better than existing RIC regimens.³  

In his recent publication,³ Dietrich Beelen from the University Hospital of Essen, Essen, DE, and colleagues, presented the final confirmatory results of their open-label, randomized, non-inferiority phase III study (NCT00822393) of treosulfan or busulfan plus fludarabine conditioning prior allo-HSCT in a cohort of patients with AML or MDS. Interim data were previously presented at the 44^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in 2018, which was summarized by the AML Global Portal here. The trial was terminated early due to reaching its primary endpoint (event free survival [EFS] at 2 years) at the second interim analysis.

Study design

• Included adults aged 18–70 years (N= 476) with Karnofsky index of ≥60%, and availability of a matched-related donor or matched-unrelated donor
• AML or MDS in first or consecutive complete hematological remission (AML: blast counts <5% in bone marrow; MDS blast counts <20% in bone marrow) indicated for allo-HSCT
• All patients were considered at increased risk for standard MAC based on age (≥50 years), HSCT comorbidity index (CI) score >2, or both
• Patients were 1:1 randomized to conditioning with either:
  • Treosulfan (10g/m² daily, 2-hour infusion, days -4 to -2) plus fludarabine (30mg/m² daily, days -6 to -2)
  • Busulfan (0.8mg/kg, 2-hour infusion, every 6 hours days -4 and -3) plus fludarabine (30mg/m² daily, days -6 to -2)

Findings

• In total, 470 patients were enrolled and randomly assigned. Of these 220 were treated and transplanted in the treosulfan arm (221 were included in safety analysis) and 240 patients remained in the busulfan arm
• Median follow-up was 15.4 months in the treosulfan arm and 17.4 months in the busulfan arm
• Two-year EFS was:
  • Treosulfan arm: 64.0%
  • Busulfan arm: 50.4%
  • Comparison: HR= 0.65, (95% CI, 0.47–0.90); p< 0.0001 for non-inferiority; p= 0.0051 for superiority) (Table 1)
• Transplant related mortality (TRM) occurred in:
  • Treosulfan arm: 10% of patients
  • Busulfan arm: 19% of patients
• TRM was due to GvHD in:
  • Treosulfan arm: 5% of patients
  • Busulfan arm: 8% of patients
• Engraftment of neutrophils (>0.5x10⁹ cells per L), leucocytes (>1.0x10⁹ cells per L), and platelets (>20x10⁹ cells per L) was 99%, 99%, and 98%, respectively in the treosulfan arm, and 98%, 99%, and 97% in the busulfan arm
• In terms of safety, 93% of patients in the treosulfan arm had an adverse event, and 95% in the busulfan arm. Most adverse events were grade 1–3. The most common adverse events of grade ≥3 were:
  • Abnormal blood chemistry: 15% in both arms
  • Gastrointestinal disorders: 11% vs 16% in the treosulfan and busulfan arms, respectively
• Serious adverse events were similar across the two arms:
  • Treosulfan arm: 8%
  • Busulfan arm: 7%

Although Dietrich Beelen and colleagues highlighted some limitations of this study—lack of measurable residual disease assessment for stratified randomization, and the open-label nature of the trial—the study showed that treosulfan plus fludarabine results in a better two-year OS than busulfan plus fludarabine in older or comorbid patients (estimated 71.3% vs 56.4%; p= 0.0082). Dietrich et al. concluded that pre-allo-HSCT conditioning with treosulfan plus fludarabine has the potential to become a new standard, as it seems efficacious and tolerable from a difficult to treat population of patients with AML or MDS.