Evaluation of FVIII pharmacokinetic profiles in Korean hemophilia A patients assessed with myPKFiT: a retrospective chart review.

PURPOSE: This study aimed to investigate the pharmacokinetics (PK) of factor VIII (FVIII) in Korean patients, as limited information is available on the PK of FVIII in this population. METHODS: We collected the FVIII PK results from patients with moderate-to-severe hemophilia A using myPKFiT. PK variations were assessed according to age, blood type, inhibitor history, von Willebrand factor antigen (vWF:Ag) level, and body mass index. Additionally, the correlation between the PK profile and prophylaxis regimen was specifically analyzed for each product in severe cases. RESULTS: The PK data of 48 and 81 patients treated with octocog alfa and rurioctocog alfa pegol, respectively, were obtained. The median half-lives of octocog alfa and rurioctocog alfa pegol were 9.9 (range: 6.3-15.2) h and 15.3 (range: 10.4-23.9) h, respectively. The PK profiles for each product did not differ according to age group; however, blood type-O patients had shorter half-lives and time to 1% compared to non-blood type-O patients. In regression analysis, the PK of octocog alfa showed a statistically significant difference according to age, whereas the PK of rurioctocog alfa pegol correlated with vWF:Ag. Only the frequency of rurioctocog alfa pegol use showed a statistically significant difference in relation to time to 1%, although the coefficient of determination was small. CONCLUSION: This study confirmed significant interpatient variation in the PK of FVIII among Korean patients with hemophilia A. To achieve optimized prophylaxis, personalizing the regimen based on the PK profile of each individual patient is essential.

Safety and Efficacy of B-domain Deleted Third Generation Recombinant Factor VIII (GreenGene F™) in Korean Patients with Hemophilia A: Data from a Post-marketing Surveillance Study.

BACKGROUND: New B-domain deleted third generation recombinant factor VIII (FVIII; GreenGene F™, beroctocog alfa) was launched in 2010. We determined safety and efficacy of GreenGene F™ during routine clinical practice in patients with hemophilia A over a period of 12 months. METHODS: From July 2010 to July 2014, a total of 136 hemophilia A patients were enrolled in a post-marketing surveillance (PMS) study. Among them, 134 patients were assessed for drug safety and 114 patients were analyzed for drug efficacy. Patients with differing hemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. RESULTS: Among 134 patients evaluated, 85 (63.4%) had severe hemophilia. Ninety-two received a total of 1,266,077 units for prophylaxis, and 42 received 516,491 units for bleeding episodes. Three patients developed inhibitors. In 112 previously treated patients, one patient (0.9%) developed inhibitor after intensive FVIII treatment for surgery. Among 22 previously untreated patients, inhibitors were observed in 2 infants (9.1%). Overall, there were a total of 47 adverse events (other than inhibitors) of all types in 30 patients (22.4%), 11 in 10 patients (7.5%) of which were considered showing serious adverse events (SAEs); most of which were hemorrhages at different sites. None of the SAEs were judged as product related. An excellent/good efficacy rate of 91.3% for hemostasis and 89.4% for hemorrhage prevention was recorded. CONCLUSION: The results of this PMS study support the use of GreenGene F™ as safe and efficacious in hemorrhage prevention and treatment of hemophilia A. These results are consistent with the findings from previously published GreenGene F™ studies.

Analysis of stored and transplanted cord blood units from KoreaCORD: reappraisal of banking guidelines and selection strategy.

BACKGROUND: We analyzed the characteristics of stored and transplanted cord blood (CB) units from the Korean network for public CB donation (KoreaCORD) to reassess the banking guidelines and optimize CB selection based on cell dose and human leukocyte antigen (HLA) mismatching. STUDY DESIGN AND METHODS: We retrospectively reviewed data, with regard to total nucleated cell (TNC) count and HLA match in the KoreaCORD registry from August 2001 to December 2010. RESULTS: A total of 21,914 CB units have been registered, of which 904 units (4.1%) contained less than 5 × 10(8) TNCs, which did not meet the present storage criteria for public CB banking in Korea. Although the proportion of stored CBs providing TNC of 5 × 10(8) to 7.9 × 10(8) was 45.7%, only 22.0% of all transplanted CBs were derived from these stored CBs. In the single CB transplantation setting, 79% (85/108) of CB units provided 4 × 10(7) TNCs/kg or more in the transplanted one-mismatch (1-MM) CB units and 51% (19/37) of CBs provided 6 × 10(7) TNCs/kg or more in the transplanted 2-MM CB units. CONCLUSIONS: The minimal requirement of TNCs for banking of CB units for public banking should be evaluated and increased to support the selection of CB units with higher cell doses, especially for use in the 1- and 2-MM transplant settings.

Tetrasomy 21 as a sole acquired abnormality without GATA1 gene mutation in pediatric acute megakaryoblastic leukemia: a case report and review of the literature.

We report a case of pediatric acute megakaryocytic leukemia (AMKL) showing 48,XX,+21,+21 as a sole acquired cytogenetic abnormality without the mutation of GATA1 gene. A physical examination showed a phenotypically normal female. Bone marrow findings showed diffuse infiltration of leukemic blasts having scanty cytoplasm with budding blebs and prominent nucleoli, which were negative for myeloperoxide (MPO) stain, Sudan black B stain and periodic acid-Schiff stain. Immunophenotyping of leukemic cells revealed positive expression of CD34, CD13, CD33, CD117, CD41, CD61, CD7 and negative expression of TdT, anti-MPO, CD64, CD56, CD2, CD3, CD5, CD10, CD19, CD20 and CD22. A fluorescence in situ hybridization analysis showed four distinct AML1 signals in 284 of 300 interphase nuclei. The entire six exons of the GATA1 gene (7757bp) were directly sequenced. We could not find any mutations, including known polymorphisms, which are known to be involved in transient myeloproliferative disorder and acute megakaryocytic leukemia of Down syndrome. After achieving complete remission, the tetrasomy 21 disappeared.

Unusual type of TLS/FUS-ERG chimeric transcript in a pediatric acute myelocytic leukemia with 47,XX,+10,t(16;21)(p11;q22).

We report on a case of pediatric acute myelocytic leukemia showing 47,XX,+10,t(16;21)(p11;q22) that resulted in an unusual TLS/FUS-ERG chimeric transcript. The leukemic cells showed erythrophagocytosis, positive reactions for myeloperoxidase and Sudan black B stains, and negative reactions for periodic acid-Schiff and alpha-naphtyl butyrate esterase stains as well as expression of myeloid antigens. We also confirmed a very rare type of TLS/FUS-ERG chimeric transcript by fusion of the 5' part of the TLS/FUS gene in chromosome 16p11 and the 3' part of the ERG gene in chromosome 21q22 using reverse-transcriptase polymerase chain reaction and direct sequencing. After achieving a complete remission with two cycles of induction chemotherapy, the patient received an umbilical cord blood transplantation.

Immunotherapy using autologous monocyte-derived dendritic cells pulsed with leukemic cell lysates for acute myeloid leukemia relapse after autologous peripheral blood stem cell transplantation.

Although a second stem cell transplantation (SCT) can be used as salvage therapy in patients with relapsing leukemia after SCT, most of these patients have a poor outcome. We tried clinical vaccination using monocyte-derived dendritic cells (DCs) pulsed with leukemic lysates to treat relapsing acute myeloid leukemia (AML) after autologous SCT. To generate DCs, CD14+ cells isolated from peripheral blood stem cell products were cultured in AIM-V in the presence of GM-CSF and IL-4. Adding TNF-alpha on day 6 induced maturation of the DCs, which were harvested on day 8 or 9. The DCs were incubated with tumor lysate and KLH for 2 hr at 37 degrees C. After certifying the absence of microorganisms and endotoxins, the patients received four DC vaccinations at two- to three-week intervals. Two patients received four DC vaccinations with means of 7.8 x 10(6) and 9 x 10(6) DCs at two- to three-week intervals. The DC vaccinations were well tolerated with no apparent side effects. After the vaccinations, the patients showed immunological responses with positive delayed-type hypersensitivity skin reaction and increasing autologous T cells stimulatory capacity to the DCs; however, the BM blast percentage of the patients did not improve. The results suggest that DCs are a feasible cellular therapy for relapsing AML after autologous SCT.

Generation of cytotoxic donor CD8+ T cells against relapsing leukemic cells following allogeneic transplantation by stimulation with leukemic cell- or leukemic lysate pulsed donor cell-derived dendritic cells.

To treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the possibility of immunotherapy using donor CD8+ T cells that were generated by stimulating leukemic cell-derived dendritic cells (leukemic-DCs) or leukemic cell lysate pulsed donor cell-derived DCs (donor-DCs). Leukemic- and donor-DCs were generated from mononuclear cells of patients and CD14+ cells of HLA-matched donors, respectively. The expression of CD80, CD83, CD86, CD1a, and CD40 on leukemic-DCs was significantly lower than that on donor-DCs. Donor-DCs exhibited a higher capacity to stimulate allogeneic T cells compared with leukemic-DCs. Donor CD8+ T cells stimulated by leukemic- or donor-DCs were more cytotoxic than unprimed CD8+ T cells, and slightly higher cytotoxicity was observed with donor-DCs compared to leukemic-DCs. This study indicates that leukemic- or donor-DCs pulsed with leukemic cell lysates can effectively prime donor cytotoxic T cells in vitro, and that they may be used as a potential alternative tool for treating leukemic patients who relapse after allogeneic HSCT.

The role of PGE(2) in the differentiation of dendritic cells: how do dendritic cells influence T-cell polarization and chemokine receptor expression?

The role of prostaglandin E(2) (PGE(2)) in the function of dendritic cells (DCs), T-cell polarization, and expression of chemokine receptors was evaluated in human cells. Immature DCs were generated from peripheral blood CD14(+) cells using a combination of GM-CSF and interleukin-4 (IL-4) with or without PGE(2). On day 6, maturation of DCs was induced by the addition of tumor necrosis factor alpha with or without PGE(2). DCs harvested on day 6 (immature DCs) or day 9 (mature DCs) were examined using functional assays. In the presence of PGE(2), immature and mature DCs showed, phenotypically, a lower expression of CD1a and, functionally, a higher allostimulatory capacity at a high DC/T-cell ratio than control cells cultured in the absence of PGE(2). DCs cultured in the presence of PGE(2) induced the differentiation of naïve T cells toward a helper T-cell type 1 (Th1) response, which was independent of IL-12 secretion in the basal state despite a slightly lower interferon gamma secretion compared with control cells. However, the function of cytotoxicity-stimulating autologous T cells was not augmented by the addition of PGE(2). Immature DCs expressed the inflammatory chemokine receptors, CCR1 and CXCR4, but not CCR6, regardless of the presence or absence of PGE(2). Mature DCs expressed CCR7 equally, measured using a migration test and the measurement of calcium flux with macrophage inflammatory protein-3beta and reverse transcription-polymerase chain reaction assay in all of the groups. All of these findings suggest that PGE(2) affects the DC-promoted differentiation of naïve T cells to a Th1 response in the basal state, without affecting chemokine receptor expression on DCs.

Allogeneic peripheral blood stem cell rescue of late graft failure after bone marrow transplantation in patients with aplastic anemia.

We investigated the effect and outcome of allogeneic peripheral blood stem cell (PBSC) rescue for aplastic anemia (AA) patients with graft failure after allogeneic bone marrow transplantation (BMT). Seven (28%) of 25 AA patients who received BMT from HLA-identical sibling donors developed late graft failure at a median of 7 months (range, 2.0-9.3 months) after transplantation. The patients with graft failure were treated with PBSC collected from the original donor after mobilization with granulocyte-colony stimulating factor (G-CSF). The median boost dose of peripheral blood mononuclear cells was 3.1 x 10(8)/kg (range, 1.4-11.9 x 10(8)/kg). Median times to reach an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 50 x 10(9)/L were 7 days (range, 4-14 days) and 9 days (range, 3-41 days), respectively. There was sustained graft function in 6 of 7 patients, with a median follow-up duration of 3.3 yr (range, 1.0-6.2 yr). Grade-I acute graft-versus-host disease (GVHD) occurred in 2 patients, while extensive chronic GVHD developed in 3 patients. This report shows that G-CSF-mobilized allogeneic PBSC rescue is very effective in achieving complete and sustained engraftment in patients with AA after graft failure. However, more efficacious measures to prevent extensive chronic GVHD remain to be developed.