RIC allo-SCT vs HMA or best supportive care in older patients with high-risk MDS

To date, allogeneic stem cell transplantation (allo-SCT) remains the only curative treatment for patients with myelodysplastic syndrome (MDS) and provides better outcomes in patients with high-risk MDS when compared with hypomethylating agents (HMAs).¹ Although, early allo-SCT is widely offered to younger patients, its potential benefit versus non-transplant therapy has not been fully addressed in older patients with high-risk MDS.¹ To address this, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) designed the phase II randomized trial 1102 (NCT02016781), to assess the benefits of reduced intensity conditioning (RIC) allo-SCT vs non-transplant therapies (HMAs or best supportive therapy) in older patients with high-risk MDS.¹

The first results from this trial were presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition and are summarized below.

Study design

• Randomized, open-label, multicenter, biological assignment, phase II trial in patients aged 50–75 years with International Prognostic Scoring System (IPSS) high- or intermediate-2-risk de novo MDS
• Enrolled patients (N = 384) were assigned to arms based on the availability of a fully human leukocyte antigen (HLA)-matched related (6/6) or unrelated (8/8) donor, into:
  • Donor arm (n = 260): patients expected to undergo RIC allo-HCT within 6 months of enrollment. The specific RIC regimen used was at the discretion of each treating physician, or;
  • No donor arm (n = 124): patients receive either HMA or best supportive care at the discretion of the treating physician
• Patients with prior HMA therapy were allowed but those with mismatched or haploidentical donors or umbilical cord blood were excluded
• Primary endpoint was adjusted 3-year overall survival (OS)
• Secondary outcomes include leukemia-free survival (LFS), number of relapsed patients in the donor arm, cost-effectiveness, and quality of life (QoL) assessments
• The arms were well-balanced with regards to baseline patient characteristics (Table 1)

Table 1. Patient baseline characteristics from the BMT CTN 1102 trial¹

Results

• At data cutoff:
  • Donor arm (n = 260): 62 patients completed the 3-year follow-up, 71 are currently alive and on study, 125 died
  • No donor arm (n = 124): 14 patients completed the 3-year follow-up, 23 are alive and on study, 86 died
• Primary outcomes are shown in Table 2. Overall, the intention-to-treat (ITT) analysis (N = 380) showed an absolute improvement in OS of 21.3% in the donor arm vs the no donor arm (p = 0.0001). In the sensitivity analysis, where patients who died or withdrew within the 90 days donor search period were excluded, the 3-year adjusted OS was similarly higher in the donor arm (p = 0.0004)
• Secondary outcomes are also shown in Table 2. From the ITT analysis, a statistically significant absolute improvement in 3-year LFS of 15.2% was observed in the donor arm vs the no donor arm (p = 0.003). This statistical significance between the arms was also maintained in the sensitivity analysis (p = 0.0074)
• The non-compliance trial rate was 26%:
  • Donor arm:
    • 44 patients did not undergo allo-SCT due to disease progression, subject preference, progressive comorbidity, or donor/insurance issues
    • 26 patients underwent myeloablative conditioning allo-SCT
  • No donor arm:
    • 31 patients underwent transplantation, including nine who found a donor after the 90-day search window
• Taking the noncompliance cases into consideration, the as-treated analysis, compares RIC allo-SCT with best supportive care in patients who actually underwent allo-SCT. The results of this analysis are shown in Table 2. Overall, this analysis indicated an even greater benefit of RIC allo-SCT in terms of OS and LFS in patients with MDS

Table 2. Primary and secondary outcomes from the BMT CNT 1102 trial¹

• Further subgroup analysis, showed that the following had no effect on OS or LFS:
  • Response to prior HMAs (either no or any response)
  • Prior HMA treatment
  • Age (≤ 65 or > 65 years)
  • MDS duration (< 3 or ≥ 3 months)
  • IPSS intermediate-2 or high-risk
  • Revised IPSS score very low, low, intermediate, high, or very high
• No clinically meaningful differences in QoL scores were identified between the arms
• The cost-effectiveness analysis is anticipated

Conclusions

The results of this phase II trial indicate that the early use of RIC allo-SCT in older patients (50–75 years) with advanced MDS results in improved outcomes when compared with HMAs or best supportive care. Irrespective of age, RIC allo-SCT led to significantly improved 3-year OS and LFS rates without any associated posttransplant QoL detriments. According to the trial investigators, early allo-SCT referral should be considered as a standard of care not only in younger patients but also in those with advanced age and high-risk de novo MDS.