Comparison of Myeloablative Versus Reduced-Intensity Fludarabine/Busulfan Regimen in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for myelodysplastic syndrome (MDS) but is associated with high non-relapse mortality (NRM). Its use was originally limited to younger patients eligible for myeloablative conditioning (MAC). Introducing reduced-intensity conditioning (RIC), such as a combination of fludarabine with reduced doses of busulfan (Flu/Bu2), increased the number of elderly patients suitable for allo-HSCT. Additionally, a combination of fludarabine and myeloablative doses of busulfan (Flu/Bu4) was developed to retain the antitumor activity of MAC and reduce the NRM to the level of RIC. However, few published reports have compared Flu/Bu4 and Flu/Bu2 in patients with MDS. We thus retrospectively performed a nationwide study to compare the outcomes of Flu/Bu4 and Flu/Bu2 in MDS patients undergoing allo-HSCT.

Methods

Clinical data were obtained from the Japanese Data Center for Hematopoietic Cell Transplantation. Inclusion criteria were age ≥16 years, diagnosis of de novo MDS, first allo-HSCT between 2006 and 2018, and receiving Flu/Bu4 consisted of intravenous busulfan (12.8 mg/kg) and fludarabine (125-180 mg/m ²) or Flu/Bu2 consisted of intravenous busulfan (6.4 mg/kg) and the same dose of fludarabine. Administration of anti-thymocyte globulin and low-dose total body irradiation (TBI, total dose ≤4 Gy) was permitted. Propensity score (PS)-matched analysis was performed to minimize selection bias, and the PS was calculated by logistic regression using the following factors: age, sex, hematopoietic cell transplantation-comorbidity index, French-American-British classification at diagnosis, cytogenetic risk, International Prognostic Scoring System score at diagnosis, disease status at allo-HSCT, bone marrow (BM) blasts at allo-HSCT, days from diagnosis to allo-HSCT, stem cell source, graft-versus-host disease (GVHD) prophylaxis, administration of anti-thymocyte globulin and TBI, and year of allo-HSCT. PS matching was performed at a 1:1 ratio using the nearest neighbor-matching method; caliper width was fixed at 0.2. The primary endpoint was the 3-year overall survival (OS).

Results

In total, 3406 patients underwent their first allo-HSCT: 447 and 256 received Flu/Bu4 and Flu/Bu2, respectively. Among them, 202 patients were assigned to each of the Flu/Bu4 and Flu/Bu2 groups after PS matching. The PS model created comparable cohorts with balanced baseline characteristics. The median age was 61 (range, 21-75) years. At the time of allo-HSCT, BM blasts were ≥5% in 273 (67.6%) patients. Regarding stem cell source, BM, peripheral blood stem cell, and cord blood was used in 268 (66.3%), 51 (12.6%), and 85 (21.0%) patients, respectively. The median follow-up period for survivors was 1117 (range, 40-3784) days.

The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = 0.671, Figure 1A). The 3-year GVHD- and relapse-free survival rates were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%; P = 0.357, Figure 1B); the 3-year cumulative incidence of relapse, 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%; P = 0.471, Figure 1C); and the 3-year cumulative incidence of NRM, 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%; P = 0.597, Figure 1D) in the Flu/Bu4 and Flu/Bu2 groups, respectively. The 100-day cumulative incidence of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8-48.4%] vs. 29.3% [95% CI, 23.2-35.7%], P = 0.012, Figure 1E). The 100-day cumulative incidences of grade III-IV acute GVHD were 11.4% (95% CI, 7.5-16.3%) and 6.5% (95% CI, 3.6-10.5%; P = 0.064), while the 1-year cumulative incidences of extensive chronic GVHD were 19.5% (95% CI, 14.2-25.4%) and 15.1% in the Flu/Bu4 and Flu/Bu2 groups, respectively (95% CI, 10.5-20.6%; P = 0.196, Figure 1F). According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens (Figure 2).

Conclusion

The OS did not significantly differ between the Flu/Bu4 and Flu/Bu2 groups. While the Flu/Bu4 group was at an increased risk of acute GVHD, the relapse was not significantly different between the two groups. Data from more patients are needed to determine the optimal intensity of conditioning regimens in patients with MDS.

Figure 1

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Figure 1

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