Pre-Transplant Conditioning Using Intravenous Busulfan Is a Feasible and Effective Option in Reduced-Intensity Cord Blood Transplantation.
Authors: Uchida Naoyuki , Yamamoto Hisashi , Matsuno Naofumi , Ishiwata Kazuya , Tsuji Masanori , Takagi Shinsuke , Araoka Hideki , Kato Daisuke , Yoshimi Mayumi , Seo Sachiko , Masuoka Kazuhiro , Wake Atsushi , Narita Madoka , Sagawa Kimiko , Yoneyama Akiko , Makino Shigeyoshi , Taniguchi Shuichi 
Published: October 2019

Abstract
Although cord blood (CB) transplantation with reduced-intensity conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, the optimal pre-transplant conditioning has not been established yet. Intravenous busulfan (ivBu) has been incorporated in conditioning regimens before bone marrow or peripheral blood stem cell transplantation, but the feasibility in cord blood transplantation has been controversial. In order to address this issue, we retrospectively reviewed patients who underwent RICBT including ivBu. Twenty-one patients, who were at ECOG performance status of 2 or less and received RICBT at our institute from June 2007 to April 2008 consecutively, were included in this study. Median age was 56 years (range, 21–71). Seventeen were AML, 3 were ALL, and 1 was MDS RA. All but 2 (MDS RA and ALL in CR2) were not in remission, 5 had CNS involvement, and 9 had history of prior transplantation. Seventeen had HCT-specific comorbidity index score ≥1, including 8 ≥2, and 6 ≥3. Fludarabine phosphate 125–180mg/m2 and ivBu 6.4–12.8mg/kg were used in all patients. All but 2 received additional melphalan (Mel) or total body irradiation (TBI); Mel 80–140mg/m2 for 10, 2–8Gy of TBI for 8, and Mel 40mg/m2 plus 4Gy of TBI for 1. Graft-versus-host disease prophylaxis consisted of tacrolimus plus mycophenolate mofetil in 11, tacrolimus alone in 8, and cyclosporine alone in 1. Single cord blood units, matched at 4/6 in 20 and 5/6 in 1, of 2 x 107/kg of recipient body weight at minimum were infused. Seventeen achieved neutrophil recovery ≥500/μl on day 19 post-transplant at medium (range, 12–30). Among 4 who failed to achieve neutrophil recovery, 2 experienced early disease progression, 1 showed rejection, and 1 died before engraftment due to interstitial pneumonia. All 17 patients who achieved neutrophil engraftment and 1 who died before engraftment showed complete donor-type chimerism on 13 days post-transplant at medium (range, 8–35). Median follow-up time of survivors was 398 days (range, 162–532) post-transplant. Cumulative incidence of non-relapse mortality at day 100 and day 365 post-transplant were both 19%. No VOD/SOS was observed. Disease-free survival and overall survival (OS) at 1 year post-transplant were 40±11% and 61±9%, respectively. Thus, ivBu can be safely administered, and have potential to achieve successful engraftment as well as sufficient disease control, indicating possible benefit of incorporating this drug in pre-transplant conditioning of RICBT. The optimal dosing schedule or combination with other therapeutic modalities needs further investigation in prospective clinical trials.