Abstract
Although hematopoietic stem cell transplantation (HSCT) with a conditioning regimen consisting of fludarabine (F-araA) and cyclophosphamide (Cy) is associated with improved outcome in young patients with aplastic anemia (AA) and Fanconi anemia (FA), several factors limit the success of the procedure. We evaluated the population pharmacokinetics (POPPK) of F-araA and its influence on HSCT outcome in patients (n=53) with AA and FA undergoing HSCT. Patients carrying a 5′-UTR polymorphism in NT5E gene (rs2295890 G>C) exhibited significantly lower plasma F-araA clearance compared to those with wild-type genotype (7.12 vs 5.03 L/h/m2 (29%) P<0.05). F-araA clearance was significantly higher in patients with AA compared to FA (2.46 ×, P<1e−6). Of all the outcome parameters evaluated (engraftment, rejection/graft failure, GvHD, TRM, OS), high F-araA AUC (>29.4 μm*h) was the only significant factor associated with the development of aGvHD by both univariate and multivariate analysis (P=0.02). The influence of plasma F-araA levels need to be evaluated in a larger cohort of patients to propose the need for therapeutic drug monitoring.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the curative modalities of treatment in patients with bone marrow failure conditions including aplastic and Fanconi anemia (FA)
Forty patients with AA and 13 with FA were enrolled in the study
The F-araA clearance was significantly higher in the AA group compared to patients with FA (median clearance 6.47L/h/m2 in AA vs 2.22L/h/m2 in FA; P o 0.0001; Figure 1)
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the curative modalities of treatment in patients with bone marrow failure conditions including aplastic and Fanconi anemia (FA). Cyclophosphamide (Cy)/anti-thymocyte globulin (ATG) is considered the standard conditioning regimen for patients with severe aplastic anemia (SAA) undergoing HSCT from a HLAmatched sibling donor,[1] with bone marrow source and cyclosporine (CSA)/methotrexate (MTX) as GvHD prophylaxis for a longterm overall survival. Screening for polymorphisms in F-AraA metabolism and transport: Genetic variants in the NT5E gene[17] (rs2295890, rs9450278, rs9450279, rs4599602 and rs4458647) hENT126 (rs747199), hCNT316 (rs7853758) and NT5C227,28 (rs4917996) (with an allele frequency of 40.1 based on 1000 genome database) were screened in the HSCT patients using PCR followed by sequencing/RFLP analysis. -rayni;kLSeMd=ybi;yfulltÁhe=inr where θi,full are the individual PK parameter estimates using all 6 sample times and θi,LSM are the individual PK parameter estimates using the 3 or 4 timepoint LSMs. The influence of F-araA PK, PG and demographic factors on HSCT outcome parameters including engraftment, day 28 chimerism status, graft rejection, GvHD and overall survival, were evaluated. Overall the study was designed to have a power of 85% to see its effect on HSCT outcome, especially TRM and GvHD
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