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Addition of High-Dose Treosulfan and Melphalan to Consolidation in High-Risk Ewing Sarcoma


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In a phase III trial (Ewing 2008R3) reported in the Journal of Clinical Oncology, Koch et al found that the addition of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells to consolidation did not improve event-free survival vs no further treatment in patients with metastatic Ewing sarcoma who had received standard induction and consolidation chemotherapy.

Study Details

The open-label trial enrolled 109 patients aged ≥ 4 to < 50 years between 2009 and 2018 from sites in 12 countries. Patients had disseminated disease with metastases to the bone and/or other sites; patients with only pulmonary metastases were excluded. All patients received six cycles of induction with VIDE (vincristine, ifosfamide, doxorubicin, and etoposide) and eight cycles of consolidation with VAC (vincristine, actinomycin D, and cyclophosphamide). Patients were randomly assigned to further consolidation with TreoMel-HDT (n = 55) or no further treatment (n = 54). TreoMel-HDT consisted of treosulfan at 12 g/m2 once daily on days –5 to –3 before autologous stem cell reinfusion (cumulative dose = 36 g/m2) and melphalan at 140 mg/m2 once on day –2 before stem cell reinfusion. The primary outcome measure was event-free survival.

Median ages were 16.6 years (range = 4.4–43.8 years) in the TreoMel-HDT group and 15.1 years (range = 4.8–45.4 years) in the control group; 31 (56%) and 23 (43%) of patients were male, respectively.

Event-Free Survival

Median follow-up was 3.3 years (maximum = 8.0 years). Event-free survival did not significantly differ between the TreoMel-HDT group vs the control group, with a hazard ratio (HR) of 0.72 (95% confidence interval [CI] = 0.46–1.12, P = .37); rates at 1 and 3 years were 51.8% (95% CI = 39.7%–67.5%) vs 39.8% (95% CI = 28.6%–55.4%) and 20.9% (95% CI = 11.5%–37.9%) vs 19.2% (95% CI = 10.8%–34.4%).

KEY POINTS

  • The addition of high-dose treosulfan and melphalan followed by reinfusion of autologous hematopoietic stem cells to consolidation did not improve event-free survival among all patients.
  • A significant benefit was observed in patients aged < 14 years.

A significant improvement was observed in male patients in the TreoMel-HDT group vs male patients in the control group, with a median event-free survival of 1.0 years (95% CI = 0.8–2.2 years) vs 0.6 years (95% CI = 0.5–0.9 years; HR = 0.52, 95% CI = 0.28–0.97, P = .035). Among 19 vs 22 patients aged < 14 years, 3-year event-free survival was 39.3% (95% CI = 20.4%–75.8%) vs 9% (95% CI = 2.4%–34%; HR = 0.40, 95% CI = 0.19–0.87, P = .016).

No significant difference in overall survival was observed between the TreoMel-HDT group and control group (HR = 0.96, 95% CI = 0.58–1.58, P = .87). Rates at 3 and 5 years were 43.4% (95% CI = 30.7%–61.3%) vs 37.4% (95% CI = 25.5%–54.7%) and 26.8% (95% CI = 14.8%–48.6%) vs 33.6% (95% CI = 21.8%–51.9%).

Toxicity

During consolidation, grade 4 hematologic adverse events were more common the TreoMel-HDT group compared with the control group (97.7% vs 82.5%), as were grade ≥ 3 toxicity affecting the gut (47.7% vs 9.5%) and general condition (25.6 vs 6.3%) and grade ≥ 3 infection (38.6% vs 12.7%).

The investigators concluded, “In patients with very high-risk Ewing sarcoma, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.”

Uta Dirksen, MD, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Deutsche Krebshilfe. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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