Individual Pharmacokinetic Targeting of Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation Is Essential for Infants with MLL Gene-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL03 Study
Authors: Takachi Takayuki , Arakawa Yuki , Nakamura Hiroyoshi , Watanabe Tomoyuki , Aoki Yuki , Ohshima Junjiro , Takahashi Yoshihiro , Hirayama Masahiro , Miyamura Takako , Sugita Kanji , Koh Katsuyoshi , Horibe Keizo , Ishii Eiichi , Tomizawa Daisuke 
Published: October 2019

Dose adjustment of busulfan (BU) based on individual pharmacokinetics (PK) has been established as an important clinical tool in conditioning of hematopoietic stem cell transplantation (HSCT). Wide interindividual variety of achievable BU concentration in infants by recommended formula is a problematic issue. Nevertheless, there is no sizable BU PK data in infants. We report here the characteristics of BU PK data in infants with MLL gene-rearranged acute lymphoblastic leukemia (MLL-r ALL) and its relevance to the outcome of HSCT.

MLL03, a nationwide study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), enrolled 62 infants with MLL-r ALL from 2004 to 2009 and tested whether an early intervention of allogeneic HSCT in first complete remission (1CR) could prevent early relapse and produce improved event-free survival (EFS) (Koh K, et al. Leukemia 2015). Protocol determined conditioning consisted of BU combined with etoposide and cyclophosphamide. Plasma BU concentration was measured by high performance liquid chromatography assay based on one-compartment model. The initial BU dose was determined according to an individual BU PK test measured one week prior to the start of HSCT conditioning, and further adjusted on the PK results.

Among the 43 infants who received HSCT in 1CR, complete BU PK data were available in 30 cases (21 cases were transplanted from unrelated cord blood donor and 9 from family donor). Oral (PO) BU was given in 18 cases and intravenous (IV) BU in 12 cases. These 30 cases were analyzed for correlation with the clinical outcome. We set the target range of steady state concentration (Css) of BU calculated from PK within 600-900 ng/ml. As a result of BU PK test, the level of estimated Css in the group receiving PO-BU and IV-BU reached the range of 405-949 ng/ml and 484-1247 ng/ml, respectively; 61% of PO-BU group and 46% of IV-BU group were within the desired range. There was a trend of IV-BU group to attain higher targeted Css level with relatively lower dose of recommended formula, while higher dose of PO BU was necessary to achieve proper Css level. Thus, higher level of Css could be easily reached in the IV-BU group compared to the PO-BU group. After adjustment of BU dose based on the PK test results, no case showed abnormally high Css and one case showed extremely low Css than the targeted range despite twice as higher recommended PO BU dose were given. Despite wide diversity of PK data observed in each individual, permissible Css levels could be attained in most of the cases.

All the cases achieved full engraftment. There was no statistical significance in the outcome including overall survival, EFS, relapse rate, and treatment-related mortality according to the level of Css nor BU formula. Sinusoidal obstruction syndrome (SOS) occurred in 6 cases (20%; two grade 3, three grade 2, and one grade 1), although Css levels of all the 6 cases did not exceed the upper limit (median 638 ng/ml, range 540-790 ng/ml). However, SOS occurred in another 5 cases out of 13 patients who did not undergo BU PK adjustment, with trend of more severe disease (38%; one grade 4, three grade 3, and one grade 2). We therefore consider that the BU dose adjustment based on PK test is useful to reduce both severity and incidence of SOS. Besides SOS, one case died of transfusion related lung injury.

In conclusion, wide interindividual variety of BU PK was observed in infants with MLL-r ALL and dose adjustment of BU based on PK test would be essential for BU containing conditioning of allogeneic HSCT for infants in terms of both safety and efficacy.

Disclosures

Off Label Use: Off-label use of CliniMACS purified CD34+ cells.