Intravenous Once-Daily BuCy 2 With Pharmacokinetic (PK)-Guided Dose Adjustment As Conditioning Regimen For AML Patients In First Complete Remission

Busulfan (Bu) represents a backbone as conditioning prior to hematopoietic stem cell transplantation (HSCT). The intravenous (IV) form of Busulfan allows 100% bioavaibility and a limited inter- and intra-patient (pt) variability compared to the oral form. In Europe, IV Bu (Busilvex^® fixed dose of 0.8 mg/kg x 16 doses) in combination with Cyclophosphamide (60 mg/kg/d x 2) is indicated prior to conventional HSCT in adults when the combination is the best available option. IV BuCy2 allows a precise delivery with 80% of adult pts within the defined therapeutic window [900 μmol/L x min-100 μmol/L x min] without dose-adjustments. Despite major advances in the risk-stratification and management of acute myelogenous leukaemia (AML) based on cytogenetics and molecular biology, the relapse rate remains high. Several published experiences suggested that Bu exposure may have an impact on the clinical outcomes after allogeneic HSCT.

The study was implemented to explore the use of a narrow range and high values of Bu exposure [4400 µmol/Lx min to 6000 µmol/Lx min] with a PK-guided dose adjustments and once-daily administration x 4 days.

The study was a prospective non-randomized multicentric phase II. The eligible pts were required to have AML in first complete (CR1, cytological remission) and to be eligible allogeneic HSCT following a myeloablative regimen. On the first day of the conditioning regimen IV Bu was administered as a single dose of 3.2 mg/kg; further daily dose of IV Bu were determined based on the previous Bu AUC exposure. The graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor, IV methotrexate post-transplant. The addition of antithymoglobulin (ATG) for unrelated donors was decided by each center based on their institutional guidelines. Pts could either receive related or unrelated bone marrow or peripheral blood stem cells. Nine centres with laboratory facilities for the pharmacokinetics analysis entered the study.

Thirty AML pts in CR1 (21 males, 70%) were treated between may 2010 and may 2012, 87% of pts had de novo AML. Twenty pts (67%) had matched sibling donor, the remaining pts received allograft from an unrelated donor. The median age of the cohort was 43.5 years [19.3-55.5]. The performance status score was comprised between 90 and 100. The majority of the cohort (83%) had an intermediate or unfavorable cytogenetic risk-factors. In 3 cases (10%) the karyotyping analyses could not be performed; 1 pt (3%) did not have cytogenetic test performed.

Thirty pts were treated and analyzed. The expected cumulative AUC over 4 days [17600 µmol/Lxmin -24000 µmol/Lxmin] was reached in 90% of pts. The mean dose of IV Bu administered was 3.51 mg/kg/day. The mean total cumulative dose of IV Bu over 4 days was 13.25 mg/kg [8-21.3]. All pts engrafted. For the entire cohort, the neutrophil engraftment [absolute neutrophil count (ANC) > 0.5 x 10 ⁹/L] occured at a median time of 17.5 d (11-35). Overall, 3 episodes (10%) of sinusoidal obstruction syndrome (S.O.S) occured (one mild, two severe, all resolved) in two patients. One pt developed 2 severe episodes of S.O.S and received defibrotide. Overall, 12 pts out of 30 (40%) developed acute GVHD between day 0 and day +100 after transplant (4 pts had grade III, 6 pts had grade II and 2 pts developed grade III, no patient developed grade IV). The median follow-up was 12 months [95% CI (11.9-12.2)] After day +100, 4 pts died of non-relapse causes ; one death from pulmonary fibrosis was related to the conditioning regimen. The cumulative incidence of TRM was 13.3% [95% CI (11.1%-15.6%)]. Five pts relapsed at a median time of 3.3 months [2-5.6] and 4 pts died of relapse. The cumulative incidence of one-year survival was 73.3% [95% CI (53.7%-85.7%)].

The AUC intensification with once-daily IV BuCy2 is effective and yields an acceptable one year TRM for pts with high-risk AML in CR1. However, longer follow-up is needed in order to assess the impact of AUC intensification on the relapse rate and survivals.

Suarez:Laboratoires Pierre Fabre: Travel grant Other. Off Label Use: IV Busulfan was administered in once-daily in this study. In Europe, IV Busulfan combined to cyclophosphamide is registered with a different schedule (infusion of IV Busulfan four times a day). IV Busulfan (Busilvex(r)) is an alkylating agent used as a conditioning regimen prior to hematopoietic stem cell transplantation. Socié:Laboratoires Pierre Fabre: Speakers Bureau. Michallet:Genzyme, MSD, BMS, Novartis, TEVA, Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Paci:Laboratoires Pierre Fabre: Honoraria. Blaise:Laboratoires Pierre Fabre: Speakers Bureau, travel grant Other. Marcais:Laboratoires Pierre Fabre: travel grant Other. Xhaard:Laboratoires Pierre Fabre: Honoraria. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Furst:Laboratoires Pierre Fabre: travel grant Other. Levrault:Laboratoires Pierre Fabre: Employment. Riggi:Laboratoires Pierre Fabre: Employment. Ta Thanh Minh:Laboratoires Pierre Fabre: Employment.