Title: More Intensive Fludarabine/Busulfan (Flu/Bu) Conditioning Regimens Result in Similar Outcomes Without Adding Serious Toxicity When Compared to Fludarabine/Melphalan (Flu/Mel) in Patients Undergoing Allogeneic Hematopoietic Cell Transplant (Allo-HCT)
Abstract: Background: Recent studies have shown lower incidences of non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD), and toxicity with Flu/Bu using 2 days of busulfan, whereas Flu/Mel has been associated with longer overall (OS) and relapse-free survival (RFS) [Baron et al., Cancer 2015]. We sought to compare the toxicities and outcomes among patients receiving Flu/Bu using either 3 or 4 days of busulfan (Flu/Bu3 and Flu/Bu4, respectively) and Flu/Mel. Methods: We retrospectively evaluated patients with hematologic malignancies who underwent allo-HCT between 2010 - 2015 and were conditioned with Flu/Mel or Flu/Bu. Busulfan was pharmacokinetically (PK) dosed. We collected all grade ≥ 3 non-hematologic toxicities from the start of conditioning to day +365 or relapse/death. Results: We included 167 patients: 42 received Flu/Bu and 125 received Flu/Mel. Baseline patient and HCT characteristics are shown in Figure 1. The most common GVHD prophylaxis in both arms was tacrolimus and mini-methotrexate. More Flu/Bu patients received ATG and had a diagnosis of acute leukemia/myelodysplastic syndrome. The median time to neutrophil (12 v. 13 days) and platelet engraftment (16 v. 20 days) was similar between Flu/Bu and Flu/Mel, respectively. Though there were no statistically significant differences in the incidence of toxicities by category between Flu/Bu and Flu/Mel (Figure 2), certain toxicities varied. Flu/Mel patients had a trend toward higher incidence of bacteremia (15.2% v. 4.8% at 1 year, P = .08), sepsis (8% v. 0% at 1 year, P = .06), and anorexia (16.8% v. 4.8% at 1 year, P = .05), compared to Flu/Bu. The incidence of hepatic injury was similar for Flu/Mel and Flu/Bu (32% v. 31% at 1 year, respectively, P = .82), and veno-occlusive disease was rare, occurring in 2 patients receiving Flu/Bu and 1 patient receiving Flu/Mel. Compared to Flu/Bu3, Flu/Bu4 significantly increased the incidence of mucositis (1 year 21.1% v. 56.2%, respectively, P = .02). There was a trend toward a lower incidence of aGVHD in patients receiving Flu/Bu compared to Flu/Mel (31% v. 48% at day 100, P = .06). There was no significant difference in NRM, OS, or RFS between Flu/Bu and Flu/Mel. However, OS was significantly lower for Flu/Bu3 compared to Flu/Bu4 (63.2% v. 93.8% at 1 year, P = .04). There was no difference in the incidence of aGVHD or RFS at 1 year between Flu/Bu3 and Flu/Bu4.Figure 2Incidence of grade ≥3 toxicities by day +365.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: Our results showed similar survival, incidence of aGVHD, and specific organ toxicities between more intense Flu/Bu regimens and Flu/Mel. Compared to Flu/Bu3, Flu/Bu4 improved OS without significantly increasing toxicity or aGVHD in our limited data set. These data suggest that using PK-dosed busulfan to target more intense Flu/Bu regimens can maximize disease control without increasing serious toxicities. Extending PK-dosing to melphalan may similarly achieve favorable outcomes while minimizing toxicity.