Fludarabine/treosulfan for allo-HCT in patients with MDS

While allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for patients with high-risk myelodysplastic syndromes (MDS), most patients with MDS are older and have comorbidities, rendering them ineligible for standard myeloablative conditioning (MAC) due to high nonrelapse mortality (NRM). Reduced intensity conditioning (RIC) regimens have allowed for transplantation in older patients, although evidence demonstrating their association with reduced NRM comes from retrospective studies that employed purposive sampling, and evidence supporting the use of one regimen over another is inconclusive.

Treosulfan is a bifunctional alkylating agent with durable myeloablative and immunosuppressive characteristics allowing consistent hematopoietic cell engraftment with a lower risk of graft-versus-host disease (GvHD), making it a suitable component of the conditioning regimen given, prior to allo-HCT. The combination of fludarabine and treosulfan (FT) has demonstrated lower risk of GvHD and NRM in patients with acute myeloid leukemia (AML). Shimoni et al.¹ retrospectively compared outcomes following FT versus other RIC and MAC regimens in patients with MDS, which was recently published in the British Journal of Haematology and summarized herein.

Study design

This was a retrospective cohort study using patient data from the Chronic Malignancies Working Party (CMWP) database of the European Society for Blood and Marrow Transplantation (EBMT). Eligibility criteria for patients included de novo or secondary MDS and had undergone an allo-HCT from a human leukocyte antigen (HLA)-matched sibling or an unrelated donor between 2000‒2016. Patients were divided into three groups (FT, RIC, and MAC) based on dose intensity as reported by the participating center.

The primary outcome was overall survival (OS), defined as the day of allo-HCT until death of any cause or last follow-up. Secondary outcomes included:

• NRM: Death without prior disease recurrence
• Relapse mortality
• Acute GvHD (aGvHD) and chronic GvHD (cGvHD)

Results

Baseline characteristics

A total of 1,722 patients with MDS, either from HLA-matched siblings (n = 747) or unrelated donors (n = 975), were included. The median age was 56 years (range, 18‒76) and 60% of the patients were male (Table 1).

• Patients in the FT and RIC group were older compared with those in the MAC group (p < 0.001), but other disease characteristics were well balanced between the three groups (Table 1).
• The most common regimens included high-dose busulfan/cyclophosphamide (37%) and fludarabine/high-dose busulfan (32%) for MAC and fludarabine with reduced-dose busulfan (82%) for RIC. FT regimens included total doses of 30 g/m² (10%), 36 g/m² (17%), 42 g/m² (44%) or other/missing (29%).

Table 1. Baseline characteristics*

OS and NRM

• The median follow-up amongst surviving patients (n = 850) was 64 months and 75, 60, and 64 months after FT, RIC, and MAC, respectively (p < 0.001).
• The 5-year OS rate across all groups was 44%, and 50%, 43%, and 43% after FT, RIC, and MAC, respectively (p = 0.03). Factors predicting OS using univariate analysis are presented in Table 2.
• The major causes of death included disease recurrence (n = 384), GvHD (n = 165), infection (n = 161), organ toxicities (n = 73), and second malignancies (n = 16).
• Improved OS rates were consistent in the multivariate analysis (hazard ratio [HR], 0.72; p = 0.01) for FT.
  • However, lower survival rates were predicted for advanced age (HR, 1.41; p < 0.001), transformation to AML before allo-HCT (HR, 1.43; p < 0.001), secondary MDS (HR, 1.19; p = 0.05), poor cytogenetics (HR, 1.34; p = 0.004), and earlier years of allo-HCT (≤2009, HR, 1.28; p = 0.001).
  • No significant differences were observed in the 5-year OS after conditioning with different dose intensity of FT (p = 0.68).
  • OS improved in all three groups and the improvement associated with FT was mostly observed in patients ≥55 years of age (p = 0.001) compared with younger patients (p = 0.52).
  • OS with FT was also more prominent with active disease at allo-HCT and in patients with poor cytogenetics.
• The 5-year NRM rate was 30% across all groups, and 30%, 27%, and 34% after FT, RIC, and MAC, respectively (p = 0.008) (Table 2).
  • Higher NRM was predicted by MAC (HR, 1.44; p = 0.001), advanced age (HR, 1.51; p < 0.001), allo-HCT from an unrelated donor (HR, 1.21; p = 0.06) and earlier years of allo-HCT (≤2009, HR, 1.21; p = 0.05) in the multivariate analysis.

Table 2. Univariate analysis of factors predicting the 5-year survival and NRM after allo-HCT*

Relapse mortality

• FT, RIC, and MAC showed relapse rates of 25%, 38%, and 25%, respectively (p < 0.001).
• FT (HR, 0.55; p <0.001) and MAC (HR, 0.61; p < 0.001) predicted a lower relapse rate compared with RIC in the multivariate analysis.
  • Higher relapse rate was predicted by advanced age (HR, 1.22; p = 0.06), transformation to AML before allo-HCT (HR, 1.93; p < 0.001), poor cytogenetics (HR, 1.87; p < 0.001), treatment-refractory disease (HR, 1.59; p < 0.001) and earlier years of allo-HCT (≤2009, HR, 1.42; p = 0.001).

GvHD

• A total of 455 patients developed Grade 2–4 aGvHD with a cumulative incidence of 30% at 1 year and 633 patients developed cGvHD with a cumulative incidence of 43% at 2 years after allo-HCT.
  • The cumulative incidences for aGvHD were 26%, 24%, and 34% after FT, RIC, and MAC, respectively (p = 0.001), and 46%, 41%, and 43% after FT, RIC, and MAC, respectively (p = 0.56) for cGvHD.
  • 350 patients of the 633 developed extensive cGvHD with cumulative incidences of 31%, 25%, and 30% after FT, RIC, and MAC, respectively (p = 0.18).
• Deaths related to GvHD occurred in 9%, 10%, and 18% of patients in the FT, RIC, and MAC groups, respectively (p = 0.007).

Conclusion

This large cohort study in patients with MDS demonstrated that the OS with FT was comparable to the OS seen with RIC and MAC, and FT was associated with low relapse rates, like MAC, and low NRM rates, like RIC. The current study had certain limitations in that it was a retrospective study with limited data and no data on comorbidities in the patients. Treosulfan was approved by the European Medicines Agency (EMA) in June 2019 as a conditioning treatment prior to hematopoietic progenitor cell transplantation, and FT may become the preferred regimen for allo-HCT in patients with MDS.