Yoshinori Suzuki

Drug interactions between micafungin at high doses and cyclosporine A in febrile neutropenia patients after allogeneic hematopoietic stem cell transplantation.

OBJECTIVES The aim of this study was to assess the drug interaction between high doses of micafungin and cyclosporine A (CyA) in allo-HSCT patients. METHODS We assigned 15 patients to Groups 1, 2, or 3. We investigated the serial changes in the blood concentration/dose (C/dose) of intravenous CyA during micafungin coadministration in 5 patients during the switch from the prophylactic dose (150 mg/body) to the therapeutic dose (300 mg/body) of micafungin (Group 1), and compared each of the 5 patients in Group 1 with those who continued to receive the prophylactic doses of 150 mg or 50 mg/body of micafungin (Groups 2 and 3). We collected blood samples from patients in Group 1 receiving CyA at 0 h (C0) and (C3) 3 h on the 7th day after allo-HSCT, and on the 3rd and 10th days after escalation of the dose of micafungin to 300 mg. RESULTS In Group 1, no significant difference was observed between C0/dose (2.11 ± 0.14) and C3/dose ratios of CyA (11.1 ± 5.34, p > 0.05) under 150 mg; the C0/dose and C3/dose ratios of CyA were 2.40 ± 0.60 and 10.8 ± 4.72 on the 3rd day and 2.23 ± 0.41 and 11.8 ± 3.06 on the 10th day, respectively, after dose escalation of micafungin to 300 mg. No significant differences were observed in those ratios between Groups 1 and 2 and between Groups 1 and 3. CONCLUSION Thus, high dose of micafungin seems to be safe and does not significantly interact with CyA in allo-HSCT.

Role of serum high mobility group box 1 in hematological malignancies complicated with systemic inflammatory response syndrome and effect of recombinant thrombomodulin

Abstract High mobility group box 1 (HMGB1) mediates inflammation. We investigated the role of serum HMGB1 in 54 patients with hematological malignancies with and without systemic inflammatory response syndrome (SIRS). There was no difference between groups 1 (complete remission of hematological disease: n = 13) and 2 (no remission: n = 16) in serum HMGB1 levels. However, those of group 3 (complicated by SIRS: n = 25) were significantly higher (vs. group 1: p < 0.001 and vs. group 2: p = 0.008, respectively). Seventeen patients in group 3 also developed disseminated intravascular coagulation and received recombinant human thrombomodulin (rhTM). Thirteen of those with SIRS improved, and serum HMGB1 levels significantly decreased (p = 0.047). Seven patients in group 3 who died within 28 days of SIRS onset had significantly higher serum HMGB1 levels than the survivors (p = 0.016). The anti-HMGB1 properties of rhTM might be useful therapy if serum HMGB1 is associated with the development of SIRS in the presence of hematological malignancies.

Pharmacokinetics of cyclosporine A at a high‐peak concentration of twice‐daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation

What is known and Objective:  The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft‐versus‐host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice‐daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration–time curve (AUC0–24) higher than 10 000 ng·h/mL in 12 patients.

Pharmacokinetics of cyclosporine a conversion from twice-daily infusion to oral administration in allogeneic hematopoietic stem cell transplantation.

Twice-daily administration of cyclosporine A (CyA) has often been used for prophylaxis of acute graft versus host disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT). But there have not been any reports that calculated the conversion ratio of the switch from twice-daily intravenous infusion to oral administration of CyA in adult patients. To establish the conversion ratio and the best strategy of twice-daily administration of CyA, the authors investigated the serial changes in the blood CyA concentration during the switch from twice-daily intravenous infusion to oral administration while maintaining high-peak concentration (over 1000 ng/mL) and calculated the bioavailability of Neoral, a micro emulsion cyclosporine, in 11 patients. All the patients underwent allo-HSCT with graft versus host disease prophylaxis consisting of CyA at a high-peak concentration of twice-daily infusion with short-term methotrexate and oral administration. Neoral was started at an oral dose, 2 times daily, at twice the latest dose of intravenous dose according to the bioavailability of healthy volunteers. Micafungin, a mild inhibitor of CYP3A4, was administered for prophylaxis against fungal infection. The total area under the concentration–time curve during oral administration (AUCpo) was nearly the same as AUC during intravenous infusion (AUCiv) (mean ± SD, 7206 ± 1557 ng·h−1·mL−1 and 7783 ± 897.7 ng·h−1·mL−1, respectively). The bioavailability of Neoral, defined as F = AUCpo × DOSEiv/AUCiv × DOSEpo was 0.58 ± 0.15 (mean ± SD, range: 0.41–0.94). When patients were switched from twice-daily infusion to oral administration, the dose conversion ratio of 1:2 seemed to be appropriate. At that time, the target trough level of Neoral was nearly the same as that of the infusion.

PAX5-positive plasma cell myeloma with t(9;14;11)(p13;q32;q13), a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32)

We describe herein the case of a 64-year-old man with a diagnosis of plasma cell myeloma (PCM). A chromosome analysis based on G-banding and spectral karyotyping revealed the following complex karyotype: 46,XY,del(3)(p?), t(4;15)(q31;q24),t(9;14;11)(p13;q32;q13),add(15)(q24),add(18)(q21). Fluorescence in situ hybridization (FISH) detected one signal each for the immunoglobulin heavy chain (IGH) and cyclin D1 (CCND1) genes, and three fusion signals of IGH and CCND1. FISH analysis of metaphase spreads revealed fusion signals on the derivative chromosomes 9, 11, and 14. Immunohistochemical analysis identified abnormal expression of CCND1 and PAX5. PAX5-positive PCM is rare because the down-regulation of PAX5 is essential for the terminal differentiation of B cells into plasma cells. To the best of our knowledge, this is the first reported case of a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32).

Spontaneous remission in a patient with follicular lymphoma carrying T cell-rich neoplastic follicles and a new complex variant translocation of t(14;18): t(5;14;18)(p15;q32;q21.3)

Follicular lymphoma (FL) is a neoplasm of mature B cells that has a nodular cell growth pattern. Eighty percent of patients with FL have t(14;18)(q32;q21.3), the standard type of 18q21.3/BCL2 trans...

Cell dynamics during differentiation therapy with all- trans retinoic acid in acute promyelocytic leukemia

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

Cytogenetic Study and Analysis of Protein Expression in Plasma Cell Myeloma with t(11;14)(q13;q32): Absence of BCL6 and SOX11, and Infrequent Expression of CD20 and PAX5.

The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B-cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports.