Blinatumomab Maintenance Therapy Following Bone Marrow Transplantation for Early Relapsed Pediatric B-cell Precursor Acute Lymphoblastic Leukemia and Analysis of Lymphocyte Subset Changes.

Blinatumomab, a CD19/CD3 bispecific T-cell engager, is recognized as an effective immunotherapy for relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the efficacy and safety of blinatumomab in post-hematopoietic stem cell transplantation (HSCT) maintenance therapy has not been established. A 5-year-old male patient with BCP-ALL suffered a relapse in his bone marrow during maintenance therapy. After re-induction therapy with UK-R3 regimen, 2.3% of the blasts remained. Then the blinatumomab was administered, and he achieved minimal residual disease (MRD)-negative complete remission (CR). After two cycles of blinatumomab, he underwent allogeneic bone marrow transplantation (BMT) from his human leukocyte antigen (HLA)-matched sibling, following conditioning with total body irradiation, etoposide, and cyclophosphamide. Two cycles of blinatumomab maintenance therapy were initiated to prevent relapse. There was no exacerbation of graft-versus-host disease (GVHD) or other severe adverse events. CR was maintained for >22 months after BMT. A t-distributed symmetric neighbor embedding (tSNE) analysis revealed that blinatumomab altered the CD8+ population, as with pre-HSCT use, and markedly reduced the CD8+19dim+/CD8+CD19- ratio (i.e., naïve lymphocyte predominance). Blinatumomab maintenance therapy after HSCT may be considered a safe treatment.

Successful Salvage of Very Early Relapse in Pediatric Acute Lymphoblastic Leukemia With Inotuzumab Ozogamicin and HLA-haploidentical Peripheral Blood Stem Cell Transplantation With Posttransplant Cyclophosphamide.

Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.

[Improvement in platelet count and bleeding symptom during treatment with eltrombopag in a patient with X-linked thrombocytopenia].

Herein, we describe a 13-year-old male adolescent who had chronic thrombocytopenia since infancy. In this case, X-linked thrombocytopenia (XLT) was suspected owing to a family history of chronic thrombocytopenia and small-sized platelets. Moreover, the patient was refractory to immunoglobulin therapy. The Wiskott-Aldrich syndrome protein (WASP) expression analysis revealed a decreased expression. Results showed a missense mutation [c.296A>G (p.Gln99Arg)] in exon 3 of the WASP-interacting protein region. Therefore, a diagnosis of XLT was made. To lift exercise restrictions, we initiated treatment with eltrombopag at a dose of 12.5 µg/day. The platelet count of the patient increased to approximately 50×103/µl after the treatment dose was escalated to 25 µg/day, and bleeding symptoms decreased after the patient resumed exercise. Ultrastructural platelet abnormalities and abnormal platelet aggregation were observed on transmission electron microscopy after the administration of eltrombopag. Therefore, eltrombopag treatment can increase platelet count and reduce bleeding symptoms in patients with XLT.

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

BACKGROUND: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 µmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 µmol/L min; P < 0.01). CONCLUSIONS: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.

Central venous catheter-related blood stream infection with pyomyositis due to Stenotrophomonas maltophilia after allogeneic bone marrow transplantation in a patient with aplastic anemia.

Stenotrophomonas maltophilia causes pneumonia and CVC-CRBSI in HSCT. However, there are few reports of pyomyositis due to S. maltophilia. We report a patient with CRBSI and pyomyositis due to S. maltophilia after allogeneic HSCT who was successfully treated by removing the CVC and antibiotics without surgical drainage. Removing the CVC and the combined antibiotics without preventing the neutrophil engraftment could avoid surgical drainage in pyomyositis due to S. maltophilia when detected in an early stage.

Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients.

Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-∞)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-∞) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-∞). In single-point sampling strategies, the AUC(0-∞) predicted based on C(6) (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0-∞) = 2556.5 C6 + 320.9 (r(2) = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-∞), suggesting that this time-point is acceptable for busulfan monitoring.