Dose of IV Busulfan in Reduced Toxicity Conditioning Regimen for Older and/or Frail Patients with AML or MDS

Introduction: Reduced intensity conditioning (RIC) based on fludarabine and busulfan (FB) is a common option to transplant patients who are unfit for a standard myeloablative conditioning (MAC) regimen. We previously reported on a prospective trial that FB RIC using a 6.4 mg/kg total dose of i.v. busulfan (over 2 days) was feasible for older patients (Blaise, Haematologica, 2015, PMID: 25425691). However, disease control after RIC remains a challenge, notably in cases of myeloid malignancy. Thus, FB regimens using higher doses of busulfan (9.6 and 12.4 mg/kg, over 3 and 4 days, respectively) were developed with promising results in patients unfit for conventional MAC. However, the optimal busulfan dose in the FB regimen is still unknown and no prospective randomized trial has been conducted so far in this setting. We here investigated the impact of busulfan dose (2 vs. 3 vs. 4 days) in a prospective randomized trial in patients unfit for MAC who underwent allogeneic transplantation for myeloid malignancies (NCT01985061).

Methods: This is a prospective, open label, multicenter randomized phase II trial. Main selection criteria were diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); presence of an HLA matched related (MRD) or 10/10 unrelated donor (MUD); ineligibility for MAC due to age from 55 to 65 years, or <55 years with a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score >2. All patients received a conditioning regimen with fludarabine (30 mg/m² from day-6 to day-2) and i.v. busulfan at 3.2 mg/kg/day during 2, 3 or 4 days, according to the randomization arm, respectively named Bx2, Bx3 and Bx4. Graft-versus-host disease (GVHD) prophylaxis was based on antithymocyte globulin (ATG) (2.5 mg/kg on day-3 and day-2) and cyclosporin A from day-3 to day+180. Graft source was peripheral blood stem cells.

Results: Of the 169 randomized patients, 152 (90%) were transplanted and analyzed according to treatment arm (61 Bx2, 56 Bx3 and 35 Bx4). The Bx4 arm was prematurely closed after 35 treated patients because of an excess of non-relapse mortality (NRM). Median age was 61 years (IQR: 55-63), 98 (64%) and 54 (36%) patients had AML and MDS, respectively, and 53 (35%) and 99 (65%) patients received an allogeneic stem cell transplant (allo-SCT) from an MRD and an MUD, respectively. There was no significant difference in baseline characteristics between the randomization arms.

Grade 2-4 acute GVHD at day+100 was 26%, 45% and 51% in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.121, Bx2 vs. Bx4 p=0.052, Bx3 vs. Bx4 p=0.501). No significant difference was observed in 2-year extensive chronic GVHD (Bx2=34%, Bx3=36%, Bx4=34%). NRM at 2 years was 7%, 17% and 34% in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.146, Bx2 vs. Bx4 p=0.001, Bx3 vs. Bx4 p=0.062), without significant difference in relapse incidence (Bx2=20%, Bx3=29%, Bx4=14%). Overall survival (OS) probability was 81%, 63%, 54% at 2 years in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.060, Bx2 vs. Bx4 p=0.008, Bx3 vs. Bx4 p=0.412, Figure 1). Multivariate analysis showed that higher total busulfan doses (Bx3 and Bx4) and the use of an MUD significantly increased the risk of grade 2-4 acute GVHD. Age >60 years and Bx4 were the only independent poor prognostic factors that significantly influenced NRM and OS.

Conclusions: In older or unfit patients, the use of 3 or 4 days of busulfan in the FB platform failed to improve outcome of patients compared to the 2-day administration, notably, no benefit in disease control was observed. In addition, the use of 4 days of busulfan is not feasible in this situation due to a high risk of NRM. Finally, fludarabine plus 2 days of i.v. busulfan resulted in better OS with a lower incidence of NRM and may be considered as a standard RIC regimen in this setting.

Forcade:Jazz: Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Other: Travel Support; MSD: Other: Travel Support; Gilead: Other: Travel Support, Speakers Bureau. Mohty:Takeda: Honoraria; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pfizer,: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Chevallier:Abbvie: Honoraria; Incyte: Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Honoraria; Takeda: Honoraria.