Abstract
Unrelated cord blood transplantation (CBT) for Diamond–Blackfan anemia (DBA), a systemic ribosomopathy affecting the disposition of conditioning agents, has resulted in outcomes inferior to those by transplantations from matched donors. We report the experience of the pharmacokinetics-guided myeloablative unrelated CBT in a DBA patient with a germline RPL11 mutation. The conditioning consisted of individualized dosing of fludarabine (based on weight and renal function with a target area under the curve (AUC) of 17.5 mg·h/L) and busulfan (based on therapeutic drug monitoring with a target AUC of 90 mg·h/L), as well as dosing and timing of thymoglobulin (based on body weight and pre-dose lymphocyte count to target pre-CBT AUC of 30.7 AU·day/mL and post-CBT AUC of 4.3 AU·day/mL, respectively). The pharmacokinetic measures resulted in a 27.5% reduction in busulfan and a 35% increase in fludarabine, as well as an over three-fold increase in thymoglobulin dosage with the start time changed to day-9 instead of day-2 compared to regular regimens. The transplantation resulted in rapid, complete, and sustained hematopoietic engraftment. The patient is now healthy over 3 years after CBT. A pharmacokinetics-guided individualized dosing strategy for conditioning might be a feasible option to improve the outcomes of DBA patients receiving unrelated myeloablative CBT.
Highlights
Hematopoietic cell transplantation (HCT), mostly from related or unrelated human leukocyte antigen (HLA)-matched donors, is a curative option for the severe hematological changes seen in Diamond–Blackfan anemia with transfusion dependency or glucocorticoid toxicities [1]
Steroids were effective in terms of limiting transfusions, the treatment resulted in severe side effects, and it is deemed an inappropriate approach by international consensus [18]
The results from HLA-matched HCT for Diamond–Blackfan anemia (DBA) patients are satisfactory, with overall survival reaching over 90% [20,21,22]
Summary
To identify genetic variants in the patient, genomic DNA from leukocytes of the subject was subjected to WES. Low-quality bases and sequencing adapters in raw data were removed using Trimmomatic (v.0.36), and the reads were aligned to a reference genome (hg19) using the Burrows–Wheeler aligner (BWA, v.0.7.17). The results of the alignment step were recorded in .bam format, and the .bam file was processed using Picard tools (v.2.17.2), with processes like sorting and duplicate marking. Analysis of the variants in the genes associated with DBA led to the identification of RPL11 c.95_96del,p.(Arg32ThrfsTer22) mutation. 3730xl DNA analyzer, was carried out to verify the RPL11 mutation. A fragment of DNA containing the RPL11 mutation site was amplified by PCR using oligonucleotide primers. Our results confirm the RPL11 mutation in the patient and revealed the mother had wild-type RPL11 alleles
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